Antimicrobial Resistance Benchmark 2018

First independent assessment of pharmaceutical company action on AMR Antimicrobial Resistance Benchmark 2018

Access to Medicine Foundation

ACCESS TO MEDICINE FOUNDATION

January 2018

1 Antimicrobial Resistance Benchmark 2018

ACCESS TO MEDICINE FOUNDATION The Access to Medicine Foundation is an independent non-profit organisation based in the Netherlands. It aims to advance access to medicine in low- and middle-income countries by stimulating and guiding the pharmaceutical industry to play a greater role in improving access to medicine.

For 10 years, the Foundation has been building consensus on the role for the pharmaceutical industry in improving access to medicine and vaccines. It publishes the Access to Medicine Index every two years, with the next Index due in late 2018. In 2017, the Foundation published the first Access to Vaccines Index. This is the first Antimicrobial Resistance Benchmark.

ACKNOWLEDGEMENTS The 2018 Antimicrobial Resistance Benchmark has been made possible through collaboration with experts and specialists working across the spectrum of organisations working to curb antimicrobial resistance.1 The Foundation is grateful for their time and expertise, and would like to thank them for providing valuable insights throughout the development of this research and its methodology.

Expert Review Committee Research Team Reviewers Hans Hogerzeil (Chair) Gowri Gopalakrishna Niranjan Konduri Greg Frank Adrián Alonso Ruiz Joakim Larsson Nina Grundmann Dulce Calçada Marc Mendelson Magdalena Kettis Karrar Karrar Jean-Pierre Paccaud Joakim Larsson Josefien Knoeff Marie Petit Marc Mendelson Marijn Verhoef Andrew Singer Katarina Nedog Evelina Tacconelli Editorial Team Evelyn Wesangula Anna Massey Deirdre Cogan Rachel Jones Emma Ross FUNDERS The Antimicrobial Resistance Benchmark research programme is made possible with financial support from UK AID and the Dutch Ministry of Health, Welfare and Sport.

Address Contact Naritaweg 227 A For questions about this report, please contact NL-1043 CB Amsterdam Jayasree K. Iyer, Executive Director 1 This acknowledgement is not intended to imply that the individuals and institutions referred to above endorse The Netherlands [email protected] the Antimicrobial Resistance Benchmark methodology, +31 (0) 20 215 35 35 analyses or results. Decisions regarding the final analysis were ultimately made by the Access to Medicine www.amrbenchmark.org Foundation.

2 Access to Medicine Foundation The superbugs can be stopped – if we put good ideas into action

At the Access to Medicine Foundation, we have been analys- ing how pharmaceutical companies tackle access to medicine for more than a decade. This first Antimicrobial Resistance Benchmark is the first independent, detailed evaluation of how pharmaceutical companies are halting the rise of drug resistance. new antimicrobials. Nevertheless, a core group of companies remain committed to providing these critical medicines, Drug resistance – also called antimicrobial resistance or AMR with some continuing to develop innovative new products to – is on the increase and it can spread fast. But if action is replace the ones that don’t work anymore. Without antibi- taken now, it can be contained. Global AMR strategies focus otics, common infections will become harder to treat. Many on improving how we all use antimicrobials, so that bacteria other areas of modern medicine will become riskier, such as and other pathogens have less chance to develop resistance. cancer therapy, surgery and even childbirth. These strategies must also ensure people can still get hold of these lifesaving medicines when they need them: many mil- In this first AMR Benchmark, we found that almost all compa- lions of people around the world lack reliable access to anti- nies we looked at are taking some action to limit AMR. There microbials or to good information on how to use them. are good practices in most areas we examined, although there is also much more to be done. The ‘superbug’ threat cannot be removed by one single person, organisation or sector working alone. Coordination, com- I invite you to use this first Benchmark as you review AMR mitment and collaboration are key, from political leaders and strategies – use it as a book showing the good ideas now policymakers to doctors, farmers and pharmaceutical execu- being implemented, and as a map of the opportunities to tives. In recent years, the international community and the pri- amplify current efforts to contain AMR. The power of busi- vate sector have swung their collective weight behind efforts ness, the public sector and individuals to radically transform to contain AMR – these commitments now need to lead to society is immense. real action, with progress toward set targets being publicly monitored. New ideas and new opportunities are also needed to limit AMR, including new ways of incentivising further action. Importantly, good practices must be shared, so that companies and other stakeholders can seize more opportunities to make change.

As a global community, we look to pharmaceutical companies to bring us safe and effective antimicrobials. It is Jayasree K. Iyer widely acknowledged to be a challenging and commer- Executive Director cially unattractive market, with little incentive to develop Access to Medicine Foundation

3 Antimicrobial Resistance Benchmark 2018 Table of contents

6 EXECUTIVE SUMMARY 83 COMPANY REPORT CARDS 84 Achaogen, Inc. 10 INTRODUCTION 86 Aspen Pharmacare Holdings Limited 88 Aurobindo Pharma Limited 16 BENCHMARK PERFORMANCE 90 Cempra, Inc. 16 AMR: what are the priorities and where are pharmaceuti- 92 Cipla Limited cal companies focussing? 96 Dr. Reddy’s Laboratories Ltd. 18 The Antimicrobial Resistance Benchmark – 98 Entasis Therapeutics Inc. which companies lead? 100 Fresenius Kabi AG 102 GlaxoSmithKline plc 24 KEY FINDINGS 106 Johnson & Johnson 24 Out of 28 antibiotics in late stages of clinical develop- 110 Lupin Limited ment, only two have both access and stewardship 112 Macleods Pharmaceuticals Ltd. provisions in place 115 Melinta Therapeutics, Inc. 25 Nearly half of companies with products on the market 117 Merck & Co., Inc. are involved in AMR surveillance 120 MGB Biopharma 26 Eight companies are setting limits on antibiotic 122 Motif Bio plc wastewater discharge 124 Mylan NV 27 Four companies move to decouple antibiotic sales vol- 127 Nabriva Therapeutics plc umes from sales agents’ bonuses 129 Novartis AG 132 Pfizer Inc. 28 PORTFOLIO ANALYSIS 135 Polyphor Ltd. 28 Antimicrobial portfolios: what medicines are 137 Roche Holding AG on the market? 140 Sanofi 30 Case studies: how three companies are addressing 143 Shionogi & Co., Ltd. access and stewardship in tandem 146 Summit Therapeutics plc 34 Vaccines in the push to limit antimicrobial resistance 148 Sun Pharmaceutical Industries Ltd. 150 Tetraphase Pharmaceuticals, Inc. 39 RESEARCH AREAS 152 Teva Pharmaceutical Industries Ltd. 40 Research & Development: What is in companies’ antimi- 154 The Medicines Company* crobial pipelines? 156 Wockhardt Limited 58 Manufacturing & Production: How pharmaceutical companies ensure the production of antibiotics does 159 APPENDICES s not contribute to resistance 160 I - Methodology scopes 66 Access & Stewardship: How pharmaceutical companies 163 II - Priority pathogens for R&D approach access and stewardship for antibiotics 164 III - Products for access 169 IV - Countries for access 170 V - Analysis, scoring and review 173 VI - Limitations 174 VII - Scoring guidelines 179 VIII - Guide to report cards 180 IX - List of figures 181 X - Definitions 183 XI - Acronyms

4 Access to Medicine Foundation About this report

The Antimicrobial Resistance Bench- Framework of analysis gathered from public sources was veri- mark provides the first independent The analytical framework is structured fied, cross-checked and supplemented assessment of how pharmamaceutical across three Research Areas: Research by the Foundation’s research team using companies are responding to AMR. The & Development; Manufacturing & public databases, sources and support- 30 companies in scope include those Production; and Appropriate Access & ing documentation. with the largest R&D divisions, the Stewardship. The Benchmark assesses largest market presence, and specific company behaviour regarding infec- The first baseline for companies expertise in developing critically needed tious diseases and product types and AMR is increasingly recognised as medicines and vaccines. The goal of the in a specific geographic scope, depend- a growing public health problem. Antimicrobial Resistance Benchmark is ing on the Research Area in question. Governments, policy-makers, farmers, to guide and incentivise such compa- Its metrics correspond to areas where doctors and pharmaceutical executives nies to adopt and implement effective experts and stakeholders agree that have a role to play. The Antimicrobial actions for tackling AMR. It highlights pharmaceutical companies can and Resistance Benchmark provides an ini- where good ideas for limiting AMR are should be taking action to limit AMR. tial baseline measure of how pharma- being implemented and where action ceutical companies are limiting AMR. is still required. The AMR Benchmark What the Benchmark analyses Companies and stakeholders can use is independently funded by UK AID and The Benchmark evaluated data gath- this analysis to inform priorities and the Dutch Ministry of Health, Welfare ered via a detailed survey of company strategies, and learn where new incen- and Sport. behaviour regarding AMR and from pub- tives or stronger strategies would spur lic sources. It included ongoing/active companies towards greater engage- projects up until 8 September 2017. ment in tackling AMR. Data submitted by the companies or

SECTIONS IN THIS REPORT

Benchmark performance Portfolio analysis and case Three Research Areas 30 Company Report Cards and Key Findings studies In-depth analyses of com- Each company report card A comparative analysis of A breakdown of the anti- pany performances in three provides a detailed over- how pharmaceutical com- microbials marketed by the Research Areas: Research & view of how the company is panies performed, with Key companies evaluated and an Development; Manufacturing addressing AMR, as evalu- Findings in R&D for prior- analysis of how they corre- & Production; Appropriate ated by the metrics used by ity pathogens, AMR surveil- spond to medicines on the Access & Stewardship. the Benchmark. Each report lance, environmental risk WHO Model List of Essential card includes overviews of management, and promotion Medicines, with case stud- the company’s portfolio and practices. ies of companies balancing pipeline. access and stewardship.

5 Antimicrobial Resistance Benchmark 2018 Executive Summary

Antimicrobial resistance (AMR) is increasingly recognised as biopharmaceutical companies. The antimicrobial market is a growing global health problem. Without effective antibi- increasingly consolidated, with companies facing commercial, otics, infections become more difficult to treat, and medical scientific and regulatory challenges. Nevertheless, the recent and surgical procedures can become high-risk interventions. prioritisation of AMR appears to have encouraged a few com- Antimicrobials are losing their effectiveness at an increasing panies to return to this space. The Benchmark methodol- rate, accelerated by their misuse in humans and in the agri- ogy was developed through consultation with a wide range of cultural sector. To slow the rise of resistance, antimicrobials stakeholders and experts working in AMR. must be used only when needed. Global stewardship strate- This report sets out the results of this first Benchmark, gies are being developed that address how antimicrobials are assessing and comparing companies’ activities to address used in humans and animals, as well as the antimicrobial load internationally agreed AMR priorities. It outlines the key find- in the environment. AMR strategies also focus on developing ings and presents detailed analysis of companies’ perfor- new antimicrobial medicines to replace those that are becom- mances in three areas of corporate activity: R&D for new anti- ing less effective. Pharmaceutical companies, including 24 microbials, policies for ensuring responsible antibiotic man- of the companies in scope, have signed up to industry-wide ufacturing, and approaches to ensuring antimicrobials are commitments to tackling AMR. accessible and being used wisely. The business models, sizes Strategies to improve the rational use of antimicrobials and portfolios of the different groups give them different must also address access issues. Millions of people currently roles and responsibilities regarding AMR. Thus, companies live without reliable access to antimicrobials or to good infor- are evaluated only in metrics relevant to their businesses. The mation on how to use them. This lack is particularly acute report concludes with detailed company report cards, includ- in low- and middle-income countries, where weaknesses in ing portfolio and pipeline analyses. These cards explain each healthcare delivery systems can limit access to antimicrobials company’s performance in the Benchmark and any indus- while also promoting their inappropriate use. For many path- try-leading practices, and present company-specific opportu- ogens, resistance rates are generally higher in low- and mid- nities to further support efforts to control AMR. dle-income countries than in wealthier countries. Bringing AMR under control requires consolidated, con- The 2018 AMR Benchmark – which companies lead? certed action by multiple stakeholders. Governments have a The AMR Benchmark identified 10 areas where align- central role to play, as do policy-makers, public health author- ment exists on AMR priorities for pharmaceutical compa- ities, academic institutions and agricultural and pharmaceu- nies between the final report of the UK Review on AMR, the tical companies. Pharmaceutical companies can determine Interagency Coordination Group (IACG) on Antimicrobial to a large extent where their products are available and how Resistance and the Declaration by the Pharmaceutical, they are priced and promoted. They have significant influ- Biotechnology and Diagnostics Industries on Combating ence on manufacturing chains and have extensive expertise in Antimicrobial Resistance. There is evidence of action by mul- researching, developing and commercialising new medicines. tiple companies in each area, with most companies active in antimicrobial R&D. Some companies, such as GSK, are First independent report active in all areas. Other companies are active in only a few The Antimicrobial Resistance Benchmark is the first inde- areas, while low disclosure prevents a full analysis of a few pendent report to systematically evaluate how a cross-sec- companies. tion of the pharmaceutical industry is responding to the AMR The eight large research-based pharmaceutical compa- threat. It compares 30 companies selected on their mar- nies are led by two companies: GSK, which has the largest ket presence, expertise in developing critically needed anti- antimicrobial pipeline for priority pathogens, and Johnson microbials and their public commitments to tackling AMR. & Johnson, which has a focus on tuberculosis. They are fol- They include eight large research-based pharmaceuti- lowed by Novartis, Pfizer and Sanofi together. Compared cal companies, ten generic medicine manufacturers and 12 to the other two groups of companies analysed, the large

6 Access to Medicine Foundation

Figure 1. Antimicrobial Resistance Benchmark – Company Research-basedPerformances pharmaceutical companies met correcties 20/12 The radials compare how close companies are to achieving 100% of their maximum potential score. 13 companies achieve over 50%.

Eight large research-based pharmaceutical companies

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active against AMR: six out of eight achieved more than 50% n c of the points available. . Mylan, Cipla and Fresenius Kabi lead the 10 generic medicine manufacturers in scope. All three are active in steward- R is o rt c a ship. Mylan and Cipla are the only two companies in thisGeneric group medicine manufacturersh v e o to report equitable pricing approaches. Disclosure among N generic medicine manufacturers is generally lower than P zer among the other two groups of companies. Of the 12 biopharmaceutical companies included, the Ten generic medicine manufacturers strongest performance comes from Entasis, particularly when Aspen A it comes to planning ahead for access and stewardship of clin- ur a ob ev i T nd ical-stage candidates. Entasis is followed by Polyphor, Summit o and Tetraphase in joint second place, when comparing companies by points earned. However, when comparing compa- a m r C a i p h nies by how close they are to achieving 100% of their maxi- l P a

u mum potential score, MGB Biopharma comes second in this S of max. group. possible score.

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i b ported by plans to ensure the successful candidate canBiopharmaceutical companiesM a ac K le us o ni be made accessible and used wisely once it reaches the ds se Fre market. Lupin • Nearly half of companies evaluated are involved in efforts to track patterns in antibiotic drug resistance, with AMR sur- Twelve biopharmaceutical companies veillance programmes running in 147 countries. Pneumonia Achaogen dt C ar em is the most widely-tracked infection. kh p oc ra W • Eight companies are setting limits on the levels of s e in antibiotics that can be released into the environment in ic y E d n n e a t p a M s m i wastewaters at their antibiotic manufacturing facilities. Yet s e o h C no company publishes what is released in practice. T of max. possible score. • Four companies are taking steps to separate sales agents’ e M s

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● Research & Development ● Manufacturing & Production ● Appropriate Access & Stewardship ● Remaining potential score 7 Antimicrobial Resistance Benchmark 2018

FINDINGS PER RESEARCH AREA

Portfolio analysis and case studies Research & Development The companies in scope have at least 741 antimicrobial med- 20 companies analysed icines on the market – more than half target bacterial infec- 1 GSK is the leader among large research-based pharma- tions and a further quarter are antivirals. The antibacterials ceutical companies, followed by Johnson & Johnson and include 189 beta-lactam antibiotics, which remain important Sanofi. Among biopharmaceutical companies, Entasis antibiotics for their broad-spectrum effectiveness. Ensuring leads. Four generic medicine manufacturers are active in access to these is a public health priority. antimicrobial R&D: Aurobindo, Cipla, Macleods and Mylan. Out of 741 marketed products, 268 correspond to anti- 2 The majority of R&D projects target pathogens deemed biotics on Section 6 of the WHO Model List of Essential priority AMR threats by the WHO and/or the US Centers Medicines (EML). In 2017, the WHO EML grouped antibiotics for Disease Control and Prevention (referred to in this into ‘Access’, ‘Watch’ and ‘Reserve’ groups. The Benchmark report as priority pathogens). found that companies have far more antibiotics in the Access 3 Around half of R&D projects targeting priority pathogens group than in the Reserve group. Access antibiotics should are being conducted through partnerships. be widely available, affordable and quality-assured. Reserve 4 Companies have varied plans for ensuring successful can- group antibiotics should only be used for the most severe didates are accessible and appropriately used. Licensing cases when all alternative treatments have failed. plans, equitable pricing and AMR surveillance are the most The Benchmark describes three examples of how phar- common components of such plans. maceutical companies are balancing access to treatment 5 Only two antibiotics in late-stage development for prior- and stewardship for specific products. Johnson & Johnson’s ity bacteria are supported by plans addressing both access breakthrough medicine for multidrug-resistant tuberculo- and appropriate use of a successful candidate. sis (bedaquiline, Sirturo®) is being tightly controlled through national TB programmes and donations. GSK combines broad Manufacturing & Production registration and pricing strategies with measures to pro- 18 companies analysed mote the appropriate use of an off-patent first-line antibi- 1 Six companies pull ahead in this area: GSK, followed by otic (amoxicillin/clavulanic acid, AugmentinTM). Cipla is the Johnson & Johnson, Novartis, Pfizer, Roche and Sanofi. only generic medicine manufacturer of those evaluated in 2 Most companies have environmental risk-management the Benchmark that runs educational activities for healthcare strategies in place; the depth and breadth of strategies professionals on antibiotic stewardship. vary. 3 Eight companies set discharge limits for antibiotics, but none disclose actual discharge levels. 4 Only one company discloses names of third-party manufacturers, seen as important for bringing accountabil- ity into environmental risk management for antibiotic production.

8 Access to Medicine Foundation

CONCLUSION

Appropriate Access & Stewardship The actions by pharmaceutical companies to address AMR 18 companies analysed priorities evaluated here represent only a start. Overall there 1 Four companies stand out in this area: GSK, Johnson & is more that all companies in scope can do. It is likely that this Johnson, Pfizer and Novartis. All four demonstrate a range is true for other pharmaceutical companies active in antimi- of activities across the indicators measured. crobials but not analysed by the Benchmark. 2 Looking at companies’ most recently introduced There are important products being developed. Yet, there antibiotics, only four have been filed in more than half of are too few to replace the antimicrobials now losing effective- the countries where access to medicine is likely limited. ness. The pipeline needs to be further strengthened. Once 3 Companies report using a range of mechanisms to miti- candidates reach late stages of clinical development, they gate conflict of interest in AMR educational programmes must be supported by concrete plans to ensure they will be targeting healthcare professionals. accessible yet used responsibly when they reach the market. 4 Two of 10 generic medicine manufacturers evaluated For products already on the market, the Benchmark finds report having an equitable pricing strategy that covers some examples of companies addressing both access and countries with poorer populations. stewardship. All companies should look at how they can 5 Nine companies are active in AMR surveillance pro- expand these practices, particularly for antibiotics that fall grammes. Between them, the programmes are running in into the WHO’s ‘Access’, ‘Watch’ and ‘Reserve’ groups. Such 147 countries. products must take priority as companies review their strate- 6 The line between marketing and educational activities gies for improving access and for stewardship. about AMR for healthcare professionals appears blurred. Governments and other funders must act to ensure the 7 Four companies are taking steps to adjust incentives for antimicrobial market can offer sufficient commercial incen- sales teams to decouple them from antibiotic sales vol- tive to keep pharmaceutical companies active in this space: ume: GSK, Shionogi, Pfizer and Novartis. One other com- for example by acting on commitments to develop addi- pany (Johnson & Johnson) is carrying out no direct pro- tional and robust market-shaping mechanisms that support motion of a specific product (bedaquiline, Sirturo®). access objectives, stewardship, global supply and quality. Governments and NGOs can forge partnerships with pharmaceutical companies to ensure antimicrobial supplies are sufficient to meet demand, with reliable supply chains, and support pharmaceutical companies in managing the access and stewardship of antimicrobials.

9 Antimicrobial Resistance Benchmark 2018

INTRODUCTION The rise of AMR and the role of the pharmaceutical industry

Antimicrobial resistance (AMR) is a The true extent of the burden of AMR is in low- and middle-income coun- widely recognised and growing global even less well characterised for low and tries. Yet change is occurring as mul- public health problem. Though there middle-income countries. Using popula- tiple initiatives have arisen in previ- are no exact figures that capture the tion attributable fraction (PAF), which is ous years that address this challenge. true global burden of AMR, let alone an estimate of the proportion of cases The Global Antimicrobial Resistance in low- and middle-income countries of a disease that could be averted by Surveillance System (GLASS), sup- (LMICs), latest estimates show that modifying or removing an exposure to ported by WHO, supports a standard- AMR causes over 700,000 deaths annu- a risk factor (resistance), the number ised approach to the collection, analysis ally worldwide.¹,² At the same time, mil- of resistance attributable neonatal sep- and sharing of data at a global level. In lions of people lack access to much sis deaths is estimated to be 214,500 October 2017, the Bill & Melinda Gates needed antimicrobial medicines for cur- globally.³ Foundation, the UK government and the able infections, which is evident by the Exacerbating the situation is a wide- Wellcome Trust launched a global pro- 445,000 community-acquired pneu- spread absence of local disease sur- ject, Global Burden of Disease AMR, to monia deaths that occur in children veillance systems, which are criti- help track and document diseases asso- under five.³ The issue of AMR and lack cal for monitoring and preventing the ciated with AMR in 195 countries. Low- of access must be addressed in tandem. rise and spread of diseases. The abil- and middle-income countries (such as Steps to increase access must include ity of different stakeholders to under- Zimbabwe)⁶ are creating national plans measures to prevent resistance, and stand and respond to the challenges to curb AMR through the help of WHO, steps to curb resistance must include raised by AMR is affected by significant with surveillance being an integral part measures to enable appropriate access. data limitations. For instance, informa- of these plans. These data collection ini- Addressing both requires a coordinated tion about antibiotic use, resistance lev- tiatives are critical in the fight to under- effort from various stakeholders, not els and transmission patterns is still stand and curb the true burden of AMR least in government, but also across scarce in many countries, particularly globally. the healthcare and farming industries, and the development and global health communities. Figure 2. Antibiotic resistance and increased risk of death The figure compares death rates (mortality) in patients with resistant and sensitive strains of selected AMR threatens all countries bacteria. Some pathogens are shown more than once, representing available data sets. AMR affects human health when appropriate antimicrobial medicines cease to E. coli work, exist, are unavailable, are of poor A. baumannii quality, or come at a prohibitively high A. baumannii* cost to individuals and society. AMR is K. pneumoniae widespread, irrespective of countries’ K. pneumoniae level of income. In Europe, it has been K. pneumoniae estimated that 25,000 people die every S. aureus year from antibiotic-resistant bacte- S. aureus ria (see figure 2).⁴ A recent report by the US Centers for Disease Control and Prevention (CDC) estimated that ● Resistant strain ● Sensitive strain *Not fully sensitive at least 2 million illnesses and 23,000 deaths a year in the USA could be Source: Adapted from ReAct: Action on Antibiotic Resistance, attributed to antibiotic resistance.⁵ www.reactgroup.org, May 2012

10 Access to Medicine Foundation

PATHOGENS AND RESISTANCE

Four main groups of pathogenic microorganisms are relevant to current efforts to curb AMR: bacteria (such as those causing pneumonia and menin- LIBRARY PHOTO NIBSC/SCIENCE gitis), viruses (such as HIV), fungi (such as Candida spp.) and parasites (such as Plasmodium falciparum, which causes malaria). There is large variation among LIBRARY PHOTO MICROSCOPY/SCIENCE DENNIS KUNKEL these groups in how resistance emerges and is transferred. Most infections with methicillin-resistant The HIV virus (above) has been identified by Certain pathogens are already resist- Staphylococcus aureus (MRSA, above) occur in WHO as a priority for strategies to address AMR. ant to most antimicrobials on the mar- a hospital setting. ket. Resistance emerges due to a variety of reasons such as the inappropriate use of medicines, low-quality medicines, incorrect prescriptions and issues with infection prevention and control.

New and adapted medicines targeting different pathogens must take into account their modes of resistance. KATERYNA KON/SCIENCE PHOTO LIBRARY PHOTO KON/SCIENCE KATERYNA EYE OF SCIENCE/SCIENCE PHOTO LIBRARY PHOTO OF SCIENCE/SCIENCE EYE Resistance mechanisms can comprise, for example, structural changes in or around a medicine’s target molecule; reduced permeability of the cell membrane to the medicine; and the production of enzymes that inactivate the Some strains of the Candida auris fungus There is a limited number of drugs available to medicine. (above) are resistant to all three major classes of treat or prevent malaria caused by certain strains antifungal drugs. of the protozoan parasite Plasmodium falciparum (above).

Balancing access and stewardship closely interlinked, attempts to increase challenging settings such as hospital The exact impact of AMR on individ- access can lead to overuse, which intensive care units. The resistant path- uals and communities depends on an leads in turn to greater resistance. This ogens that have emerged here are not interplay of factors, including the dis- then increases the need for second- as common as the underlying conditions tribution of pathogens, the prevalence and third-line products that are more and invasive procedures that set the of resistance to each, and the availabil- expensive, and thus harder to access. stage for their presence. Yet, the con- ity of economic and healthcare deliv- The need for new strategies and pro- sequences of such infections for those ery resources. Weaknesses in health- grammes to appropriately increase with otherwise treatable conditions care delivery systems can limit appro- access to antimicrobial medicines are life-threatening. Unless addressed priate access to existing antimicro- remains particularly acute in low- and early, the chance exists for a dramatic bial medicines while also promoting middle-income countries.³ increase in high-risk infections. their overuse. There is also a risk that In the hospital setting, particularly in lack of access could not only lead pre- high-income countries, the main pub- Growing demand scribers to resort to multiple thera- lic health focus is shifting to the increas- Infectious disease products may broadly peutic courses using first-line drugs, ing burden of chronic diseases, includ- be broken down into three categories: but also drive use of falsified and sub- ing cancers, relative to infectious dis- vaccines, diagnostics and antimicro- standard drugs, both of which could eases. Where this shift has taken bial medicines. The global market for result in the increase of AMR - at an place, the infections that persist now such products reached USD 108.4 bil- even greater scale.⁷ These issues are tend to occur in sicker patients and in lion in 2015, and is forecast to reach

11 Antimicrobial Resistance Benchmark 2018

USD 183.2 billion in 2021.⁸ The antibiotic and stakeholders (including govern- These fragile market incentives market is expected to grow from USD ments and healthcare profession- increase the risk that pharmaceutical 27.1 billion in 2015 to USD 35.6 billion in als). Pharmaceutical companies also companies, including those controlling 2022, in step with growing demand for play a fundamental role, given their key antimicrobials, will leave the anti- generic antibiotics from emerging mar- unique expertise in translating scientific microbial market and thereby weaken kets.⁹ Between 2002 and 2010, global advancements into promising candi- multi-stakeholder efforts to limit AMR. consumption of antibiotics increased by dates and deploying marketed products There are signs that the level of consol- 36%, and three quarters of this increase to millions of patients. As a result, it is idation is already increasing. In August was accounted for by Brazil, Russia, key to maintain pharmaceutical compa- 2016, AstraZeneca announced the India, China and South Africa (BRICS).³ nies engaged in the efforts to limit AMR. divestment of its late-stage small mol- Growing demand coupled with poor Unfortunately, market incentives to ecule antibiotics business, explain- surveillance and stewardship is likely develop and deploy antimicrobials (and, ing its decision by stating an objective to drive the emergence of resist- in particular, antibiotics) are weak.¹¹ The to reinforce its strategic focus in three ant strains, particularly in high-burden main reason why the market is failing other main therapy areas: Oncology, areas. is simple: new antibiotics are urgently Cardiovascular & Metabolic Diseases The majority of antibiotics are needed, yet will be tightly controlled and Respiratory.¹⁷ In January 2018, generic; only a small number remains once they reach the market to limit the The Medicines Company sold its infec- on patent.¹⁰ In general, new antibiot- risk of resistance emerging. Moreover, tious disease business unit to Melinta ics, antimicrobial medicines and vac- in comparison with medicines for other Therapeutics, explaining its decision by cines are developed by either large conditions, antibiotics are cheaper stating an objective to focus on cardio- research-based pharmaceutical compa- and taken for a shorter time period.¹² vascular care.¹⁸ nies or smaller biopharmaceutical com- These factors, together with signifi- The level of consolidation in the panies. However, some large research- cant scientific and regulatory hurdles, market also poses challenges to small- based pharmaceutical companies have make high-volume and/or high-margin to medium-sized biopharmaceutical generic medicine divisions (such as pharmaceutical markets less likely to companies (SMEs) that are active today Novartis, Pfizer and Sanofi), while some develop.¹³ in AMR.¹¹ They generally have few rev- generic medicine manufacturers also The consequence is that there is enue-generating streams to support invest in R&D (such as Aurobindo, Cipla, little money to be made today from their investments in antimicrobial R&D, Macleods and Mylan). deploying old antibiotics and there is lit- and there is a shrinking group of large tle money to be made tomorrow from pharmaceutical companies stepping developing new antibiotics. Regarding in early to support development. As a A FUNDAMENTAL ROLE BUT A the deployment of old antibiotics, a result, SMEs can struggle to finance FRAGILE MARKET 2015 study showed that 25 out of 36 clinical trials and commercialisation of old but potentially useful antibiotics promising candidates. This all being Finding the right balance between were marketed in a little over half of the said, the recent prioritisation of AMR access and stewardship requires a countries in Europe, USA, Canada, and has encouraged a few companies, such concerted effort by multiple sectors Australia (in 20 out of 39 countries). as Roche, to reconsider this space. (including farming and agriculture) Economic factors were the major reasons for not marketing these antibiot- The imperative of maintaining compa- ics, including high registration costs, nies engaged Figure 3: Change in the Number of limited volume sales and low prices.¹⁴ In January 2016, more than 100 phar- New Antibacterial Drug Approvals in Regarding the development of new maceutical companies and associa- USA 1980-2014. antibiotics, pharmaceutical companies tions signed the Declaration by the Source: Ventola, C (2015)¹⁶ assess the business case for R&D pro- Pharmaceutical, Biotechnology and jects by looking at the risk-adjusted Diagnostics Industries on Combating Number of net present value (rNPV): the expected Antimicrobial Resistance (referred to as approvals return adjusted for investments, oppor- the ‘Davos Declaration’). This document tunity costs and risks. In comparison outlines a set of principles for global with other therapeutic categories, the action on AMR.¹⁹ In September 2016, 13 rNPV of antibiotics is low: −$50 million pharmaceutical companies, all signato- against +$720 million for a neurologi- ries to the Davos Declaration, published cal drug and +$1.15 billion for a muscu- the Industry Roadmap for Progress on loskeletal drug.¹⁵ This is one of the rea- Combating Antimicrobial Resistance sons why, since 2000, the number of (referred to as the ‘Industry Roadmap’), new antibiotic market approvals has which laid out a more detailed set fallen significantly (see figure 3).¹⁶ of commitments for pharmaceutical

12 Access to Medicine Foundation companies.²⁰ These documents are clear Center for Health Policy,²² the German A BENCHMARK TO GUIDE signs that a group within the pharmaceu- Global Union for Antibiotics Research DEEPER PHARMACEUTICAL tical industry is willing to address AMR. and Development (GUARD) Initiative ²³ INDUSTRY ENGAGEMENT IN Recognising the efforts that these and and the UK Review on AMR,²⁴ have pro- AMR other pharmaceutical companies make, duced policy recommendations on how and maintaining their engagement in to best structure new pull incentives. The Antimicrobial Resistance Bench- addressing AMR is essential. Indeed, Efforts should be made to make mark has been developed to give phar- several organisations have developed better use of old antibiotics as well. maceutical companies, governments, financial and non-financial incentives Governments have been called to facil- investors, NGOs and others an inde- that offset the weakness of current itate their registration, encourage the pendent and public tool for deepen- market incentives for antimicrobials. transference of technology to new ing industry engagement in efforts to manufacturers and to develop appro- curb AMR. It maps the responses of a Financial incentives priate economic incentives to improve cross-section of the pharmaceutical In a bid to reinforce antimicrobial R&D the commercial availability of these industry to AMR against the consensus pipelines and encourage pharmaceu- medicines.²⁵ view on where they can and should be tical companies to invest in antimi- taking action. crobial R&D, several ‘push’ incentives Non-financial incentives, such as the To develop the Benchmark’s meth- have been established to reduce the AMR Benchmark odology, the Foundation has applied its costs of necessary inputs for develop- As supported by the example of the proven process for building consensus ers. For instance, the US government’s Access to Medicine Index, public rec- on the role of pharmaceutical compa- Biomedical Advanced Research and ognition of pharmaceutical companies’ nies in tackling global health priorities. Development Authority (BARDA) and contribution to global health targets The Foundation’s research team sought the Wellcome Trust provide funding is a powerful supplement to strength- input and gathered feedback from a to the Combating Antibiotic Resistant ened market dynamics.²⁶ If society gives wide range of stakeholders, such as Bacteria Biopharmaceutical Accelerator credit to those companies that have governments, non-governmental organ- (CARB-X), which finances compa- remained committed to developing and isations, pharmaceutical companies and nies working on promising early-stage deploying life-saving antimicrobials, it industry associations, investors, aca- antibiotics and rapid diagnostics to increases the likelihood that compa- demia, public-private partnerships and treat drug-resistant bacterial infec- nies will continue and reinforce relevant relevant international organisations. tions. The World Health Organization activities. Such public reporting also The aim of this process was two-fold: (WHO) and the Drugs for Neglected gives other pharmaceutical companies to build consensus on the pharmaceu- Diseases initiative (DNDi) have cre- the opportunity to learn from the lead- tical industry’s role in limiting AMR; and ated the Global Antibiotic Research and ers, and gives investors the ability to to ensure the Antimicrobial Resistance Development Partnership (GARDP), a factor AMR risks and opportunities into Benchmark is a useful tool for pharma- product development partnership that decision-making processes. ceutical companies and others seek- aims to develop and deliver new treat- The Access to Medicine Foundation, ing to curb AMR. The methodology was ments for bacterial infections where with funding from the UK govern- developed in consultation with experts drug resistance is present or emerg- ment’s Department for International on AMR and reviewed by an independ- ing, or for which inadequate treatment Development and the Dutch Ministry ent Expert Committee that included exists. GARDP is supported by sev- of Health, has responded to this need, representation from top-level academic eral European governments, the gov- drawing on its expertise in develop- centres, donor governments, local government of South Africa and the NGO ing industry metrics related to pub- ernments in low- and middle-income Médecins Sans Frontières (MSF). lic health. The Foundation has pro- countries, investors and pharmaceutical ‘Pull’ incentives are also being devel- duced the Antimicrobial Resistance industry bodies. oped, but at a slower pace. Pull incen- Benchmark, the first independent and The Benchmark analysis highlights tives involve the promise of a reward public tool that compares how pharma- where there is good practice and where for the development of new antimicro- ceutical companies are responding to progress can be expanded. It exam- bials that target pathogens that repre- AMR. ines company actions in R&D, access sent a high AMR risk. For instance, the and stewardship, and in manufacturing United States’ Generating Antibiotic and production. This first Benchmark Incentives Now (GAIN) Act grants an focusses on those areas where compa- additional five years of market exclusiv- nies have a core responsibility to act. ity for companies developing antibiotics Future iterations of the Benchmark will that target a selected group of qualify- both deepen and expand this analysis. ing pathogens. Several initiatives, such as the DRIVE-AB,²¹ the Duke-Margolis

13 Antimicrobial Resistance Benchmark 2018

REFERENCES

1. Woolhouse, M., et al. (2016). Global 9. Research and Markets. (January, 16. Ventola, C. L. (2015). The antibiotic 23. Breaking through the Wall - A Call for disease burden due to antibiotic resist- 2017). Global Antibacterial Drugs Market resistance crisis: part 1: causes and threats. Concerted Action on Antibiotics Research ance–state of the evidence. Journal of to 2022 - Vaccines Retain Market Pharmacy and Therapeutics, 40(4), 277. and Development. (2017, February). global health, 6(1). Prominence While Pipeline Offers Retrieved from https://www.bundes- Innovative Approaches to Tackling 17. AstraZeneca to sell small mole- gesundheitsministerium.de/fileadmin/ 2. O’Neill, J. (December, 2014). Antimicrobial Resistance. Retrieved from cule antibiotics business to Pfizer. (2016, Dateien/5_Publikationen/Gesundheit/ Antimicrobial resistance: tackling a crisis https://www.researchandmarkets.com// August 24). Retrieved from https:// Berichte/GUARD_Follow_Up_Report_ for the health and wealth of nations. The research/pbw973/global www.astrazeneca.com/media-centre/ Full_Report_final.pdf Review on Antimicrobial Resistance. press-releases/2016/AstraZeneca-to-sell- 10. Grand View Research. (October, small-molecule-antibiotics-business-to- 24. Tackling Drug-Resistant 3. Laxminarayan, R. et al. (2015). Access 2016). Antibiotics Market Analysis By Pfizer-24082016.html Infections Globally: Final Report and to effective antimicrobials: a world- Drug Class (Cephalosporins, Penicillins, Recommendations. (2016, May). Retrieved wide challenge. The Lancet, 387(10014), Fluoroquinolones, Macrolides, 18. The Medicines Company Announces from https://amr-review.org/sites/ 168-175. Carbapenems, Aminoglycosides, Definitive Agreement to Sell its Infectious default/files/160525_Final%20paper_ Sulfonamides), By Mechanism Of Action Disease Business Unit to Melinta with%20cover.pdf 4. ECDC & EMEA. (September, 2009). (Cell Wall Synthesis Inhibitors, Protein Therapeutics. (2017, November 29). Technical Report. The bacterial chal- Synthesis Inhibitors, DNA Synthesis Retrieved from http://www.themed- 25. Pulcini, C., et al. (2017). Ensuring uni- lenge: time to react. DOI:10.2900/2518. Inhibitors, RNA Synthesis Inhibitors, icinescompany.com/investors/news/ versal access to old antibiotics: a crit- Retrieved from http://www.ecdc.europa. Mycolic Acid Inhibitors, Folic Acid medicines-company-announces-defin- ical but neglected priority. Clinical eu/en/publications/Publications/0909_ Synthesis Inhibitors), And Segment itive-agreement-sell-its-infectious-dis- Microbiology and Infection, 23(9), TER_The_Bacterial_ Challenge_Time_to_ Forecasts To 2024. Retrieved from ease-business 590-592. React.pdf http://www.grandviewresearch.com/ industry-analysis/antibiotic-market 19. Declaration by the Pharmaceutical, 26. How the Access to Medicine Index 5. U.S. Centers for Disease Control and Biotechnology and Diagnostics Industries inspires stronger action by pharma com- Prevention (CDC). (April, 2013). Antibiotic 11. Thayer, A. M. (2016). Antibiotics: will on Combating Antimicrobial Resistance. panies. (2016, March 9). Retrieved from resistance threats in the United States, the bugs always win?. Chem Eng News, Signatories as at January, 2017. Retrieved https://accesstomedicinefoundation.org/ 2013. Retrieved from http://www.cdc.gov/ 94, 36-43. from https://www.ifpma.org/wp-con- news/how-the-access-to-medicine-index- drugresistance/threat-report-2013/pdf/ tent/uploads/2016/01/briefing-declara- inspires-stronger-action-by-pharma-com- ar-threats-2013-508.pdf 12. Luepke, K. H., et al. (2017). Past, pres- tion-a4-2017_SCF.pdf panies/ ent, and future of antibacterial econom- 6. Zimbabwe One Health Antimicrobial ics: increasing bacterial resistance, lim- 20. Industry Roadmap for Progress on Resistance National Action Plan 2017- ited antibiotic pipeline, and societal impli- Combating Antimicrobial Resistance 2021. (September, 2017). Retrieved from cations. Pharmacotherapy: The Journal of – September 2016. Retrieved from https://www.ed.ac.uk/files/atoms/files/ Human Pharmacology and Drug Therapy, https://www.ifpma.org/wp-content/ zimbabwe_nap_2_1.pdf 37(1), 71-84. uploads/2016/09/Roadmap-for-Progress- on-AMR-FINAL.pdf 7. Commitments to Responsible Use 13. Christoffersen, R. E. (2006). of Antimicrobials in Humans. Meeting Antibiotics—an investment worth making?. 21. Okhravi, C., et al. (2017, April). Oslo, Norway, 13-14 November 2014 – Nature biotechnology, 24(12), 1512-1514. Simulating market-oriented policy Background document. Retrieved from interventions for stimulating antibiot- https://www.fhi.no/globalassets/doku- 14. Pulcini, C., et al. (2017). Forgotten ics development. In Proceedings of the menterfiler/moba/pdf/supporting-docu- antibiotics: a follow-up inventory study in 50th Annual Simulation Symposium (p. ments---background-pdf.pdf Europe, the USA, Canada and Australia. 2). Society for Computer Simulation International journal of antimicrobial International. 8. BCC Research. (January, 2016). agents, 49(1), 98-101. Global Markets for Infectious Disease 22. Value-based strategies for encour- Treatments. Retrieved from https://www. 15. Sharma, P., & Towse, A. (2010). New aging new development of antimicrobial bccresearch.com/market-research/phar- drugs to tackle antimicrobial resistance: drugs. (2017, August 3). Retrieved from maceuticals/infectious-disease-treat- analysis of EU policy options. https://healthpolicy.duke.edu/PAVE ments-markets-report-phm061c.html

14 Access to Medicine Foundation Antimicrobial Resistance Benchmark 2018

This first section of the report includes the top-level comparative analyses of how the 30 companies in scope are addressing antimicrobial resistance, comparing their performances in the three Research Areas analysed by the Benchmark. It looks ahead to where companies and other stakeholders can do more.

In this section:

Benchmark Performance Analysis and discussion of how the 30 companies in scope are addressing antimicrobial resistance. Companies are compared with their peers in three groups: large research-based pharmaceutical companies, generic medicine manufacturers and biopharmaceutical companies.

Key Findings Covering R&D for priority pathogens, AMR surveillance, environmental risk management, and promotion practices.

Portfolio analysis and case studies Breakdown of the antimicrobials on the market from companies in scope and analysis of how they correspond to medicines on Section 6 of the WHO Model List of Essential Medicines.

Vaccines and AMR Looking at the importance of vaccines for AMR and companies’ activities regarding vaccines R&D, manufacturing and access.

15 Antimicrobial Resistance Benchmark 2018

BENCHMARK PERFORMANCE AMR: what are the priorities and where are pharmaceutical companies focussing?

The AMR Benchmark has evaluated have acknowledged their role in lim- The AMR Benchmark has identified ten how a cross-section of the pharmaceu- iting AMR, by signing the Davos areas where alignment exists regarding tical industry is responding to the threat Declaration by the Pharmaceutical, AMR priorities for pharmaceutical com- of antimicrobial resistance (AMR). The Biotechnology and Diagnostics panies. It looked at priorities defined 30 companies in scope include those Industries on Combating AMR (Davos by the Benchmark, the UK Review on with the largest R&D divisions, the Declaration),³ or its counterpart the AMR, the AMR Framework for Action largest market presence, and specific Industry Roadmap for Progress on by the IACG and industry-led initia- expertise in developing critically needed Combating Antimicrobial Resistance tives. The ten aligned priorities include medicines and vaccines. These compa- (Industry Roadmap).⁵ By signing up to six of the ten ‘fronts’ identified by the nies have chosen to remain in a market these initiatives and engaging with the UK Review on AMR and ten of the 14 that is increasingly challenging. The sci- Benchmark, companies recognise the areas identified by the IACG’s frame- entific and regulatory hurdles involved need to develop new and more effec- work. They also align with the com- in developing new antimicrobial prod- tive antimicrobials, the need to ensure mitments in the Davos Declaration and ucts are large, and the market is not affordable access to antimicrobials and Industry Roadmap. There are other pri- commercially attractive. To tackle AMR, the need to actively conserve the effec- orities that may require participation by companies must also limit their misuse tiveness of antimicrobials. pharmaceutical companies but are not (stewardship) while ensuring they are central to their role, and were thus not available to people when needed. AMR priorities for pharma companies evaluated in the first iteration of the Nevertheless, as developers and pro- Several initiatives have set priorities Benchmark. These include areas such as ducers of antimicrobials, pharmaceuti- for limiting AMR for different stake- sanitation and hygiene, food safety and cal companies must join efforts to con- holders. Some, such as the UK govern- animal infection prevention and control. trol AMR. Companies have different ment’s Review on AMR¹ and the AMR roles to play depending on their busi- Framework for Action developed by Which priorities get most attention? ness models, sizes and portfolios. Most the Interagency Coordination Group on Figure 4 shows how many of the 30 companies evaluated in the Benchmark Antimicrobial Resistance (IACG),² have companies evaluated in the Benchmark focussed on broad multi-sector objec- disclose activities that address each BACKGROUND tives. Others have focussed specifically of the ten priority areas where align- on the role of the pharmaceutical indus- ment exists. It also includes two fur- • The Benchmark aligns with AMR try, including the Davos Declaration ther priority areas not in the scope of priorities defined by the UK Review and Industry Roadmap. The AMR the Benchmark: diagnostics and agricul- on AMR, IACG and industry-led ini- Benchmark also focusses exclusively on ture/animal health. Companies’ activi- tiatives, among others. the role for pharmaceutical companies.⁴ ties are reported by the Benchmark but There is general agreement between not evaluated further (scored). • It compares 30 companies against the sets of AMR priorities defined More companies are addressing 16 metrics that cover R&D, by these initiatives. For example, the R&D priorities, particularly the develop- Manufacturing & Production and Review on AMR identifies ten ‘fronts’ ment of new antimicrobial medicines, Appropriate Access & Stewardship. where action is needed to curb AMR, than are active in priorities related to which cover almost all areas measured either manufacturing and production • The Benchmark methodology was by the Benchmark. These include anti- or access and stewardship. GSK is tak- independently developed through microbial R&D, the release of antibi- ing steps to address all of the priorities consultation with a wide range of otics into the environment, AMR sur- mapped in figure 4: for example, it has AMR experts. veillance and education for healthcare the largest antimicrobial pipeline eval- professionals. uated, a strategy to limit the impact of

16 Access to Medicine Foundation

antibiotic manufacturing on the envi- access and limit misuse. This includes In stewardship, nine companies are ronment and the most widely registered 18 companies with significant volumes involved in efforts to track resist- antibiotic assessed. Several other com- of antimicrobials on the market, 11 of ance as it emerges. They are run- panies, such as Johnson & Johnson, which are taking action to address pri- ning or supporting 19 AMR surveil- Merck & Co., Inc., Novartis, Pfizer and orities linked to access. lance programmes across 147 coun- Sanofi, are taking comparable steps for For six companies, there is no evi- tries. Surveillance data must be shared many priorities. Others, such as Cipla, dence they are addressing access, openly, and progammes must be Macleods, Mylan and Wockhardt, are whether by registering products where expanded and integrated, particularly active on a few key fronts. needed, addressing affordability or for pathogens that can be markers for strengthening supply chains. Together, resistance to multiple antibiotics, such R&D gains most attention these six companies have at least 127 as S. aureus and E. coli. There are 24 companies in the scope of medicines on the WHO Model List of Some pharmaceutical compa- the Benchmark developing antimicro- Essential Medicines (Section 6),⁶ mean- nies have shown that they can develop bial medicines, including five that are ing they are thought essential to the structured access approaches for prod- also working on vaccines. Pipelines are functioning of a basic healthcare sys- ucts in therapeutic areas such as diabe- still small, particularly considering the tem. Considering how many people tes and HIV/AIDS.⁷ Companies with anti- attrition rates of projects in R&D, and die because they cannot access antimicrobials on the market can transfer the high number of new treatments microbial medicines in low- and mid- this knowledge and experience to pro- needed to combat resistance. Out of 67 dle-income countries, access cannot be grammes for limiting AMR. antimicrobial medicines in clinical devel- ignored by the pharmaceutical industry. opment, only 17 (including nine antibiotics) are novel candidates with new modes of action. New modes of action Figure 4. Pharmaceutical companies are active in ten AMR priority areas. offer the best chance that a new antibi- The AMR Benchmark identified ten areas where alignment exists between the UK Review on AMR, UN otic will remain effective longer. Only 16 IACG and the Industry Roadmap on AMR priorities for pharmaceutical companies. There is evidence of of the companies active in antimicrobial action by multiple companies in each area, with most companies active in antimicrobial R&D. R&D are putting plans in place to make successful candidates either acces- R&D medicines sible or to limit their misuse (stew- R&D vaccines ardship). Yet, many of the plans that Access and/or Stewardship plans in R&D are being put in place are not yet fully Environmental risk management developed. New push and pull incen- Manufacturing quality tives are needed to stimulate further Access through registration and/or pricing R&D; many organisations are already Education of HCPs (human capital development) working on this issue. These incentives AMR surveillance should require recipient companies to Brochure and packaging (according to needs) take specific and measurable actions to Appropriate promotion address access and stewardship. Diagnostics Agriculture/Animal health Access and stewardship In total, 21 companies have antimicro- Number of companies active bial medicines on the market, which ● Research & Development ● Manufacturing & Production means they have the power to improve ● Appropriate Access & Stewardship ● Priority areas not in scope

17 Antimicrobial Resistance Benchmark 2018

BENCHMARK PERFORMANCE The Antimicrobial Resistance Benchmark – which companies lead?

THE LEADERS The Benchmark compares companies They generally market few or no prod- The large research-based pharmaceu- in three groups. The business mod- ucts and their main potential lies in fill- tical companies are led by two compa- els, sizes and portfolios of the differing the pipelines further with novel anti- nies: GSK, which has the largest anti- ent groups give them different roles and microbials, supported by plans to facil- microbial pipeline for priority patho- responsibilities regarding AMR. itate access and stewardship should gens, and Johnson & Johnson, which There are eight large research- they reach the market. has a focus on tuberculosis. The large based pharmaceutical companies in The companies are evaluated only in research-based companies are the most scope. They have a prominent role to metrics that are relevant to their main active against AMR: six out of eight play in the R&D of new antimicrobi- business focus. For example, companies achieved more than 50% of the points als. With many products on the market, with products on the market are eval- available. Mylan, Cipla and Fresenius they also have the power to help ensure uated in metrics related to improving Kabi lead the generic medicine man- the appropriate use of antimicrobials, access, preventing misuse and ensuring ufacturers in scope. Both Mylan and while leveraging their geographic reach responsible manufacturing practices. Cipla are active in stewardship and in supply and manufacturing chains. There are two ways of looking at they are the only two companies in this Generic medicine manufactures have a how companies are performing. The group to report having equitable pricing similar role, due to their business model radial graphs compare how close the approaches. Disclosure among generic based on delivering off-patent medi- companies are to achieving 100% of medicine manufacturers is generally cines at volume. There are 10 generic their maximum potential score. The lower than among the other two groups medicine manufacturers in scope, the bar charts compare actual scores and of companies. Of the 12 clinical-stage largest players by volume in the antibi- the number of points on offer to each biopharmaceutical companies included, otics market. The 12 biopharmaceutical company. the strongest performance comes from companies in scope are all developing at Entasis, particularly when it comes to least one promising clinical-stage R&D planning ahead for access and steward- candidate. ship of clinical-stage candidates.

Figure 5. 30 companies in scope

Large research-based pharmaceutical companies Generic medicine manufacturers Biopharmaceutical companies Revenue Revenue Revenue Country (bn USD) Country (bn USD) Country (mn USD) GSK GBR 34.4 Aspen ZAF 2.4 Achaogen USA 41.8 Johnson & Johnson USA 71.9 Aurobindo IND 2.3 Cempra USA 18.0 Merck & Co., Inc. USA 39.8 Cipla IND 2.3 Entasis USA – Novartis CHE 47.6 Dr. Reddy’s IND 2.2 Melinta USA – Pfizer USA 52.8 Fresenius Kabi DEU 6.3 MGB Biopharma GBR – Roche CHE 49.6 Lupin IND 2.6 Motif Bio GBR 0.0 Sanofi FRA 35.6 Macleods IND – Nabriva IRL 6.5 Shionogi JPN 3.0 Mylan USA 11.0 Polyphor CHE – Sun Pharma IND 4.7 Summit GBR 3.0 Teva ISR 21.9 Tetraphase USA 5.1 Due to the variation between companies in scope, The Medicines Company USA 167.8 not all indicators are applicable to every company. Wockhardt IND 619.0 See Appendix for full overview.

– Data unavailable

18 Access to Medicine Foundation

BENCHMARK PERFORMANCE The Benchmark evaluates companies only in the metrics that are relevant to their businesses. The radial graphs compare Which companies lead the how close the companies are to achieving 100% of their Research-based pharmaceutical companies met correcties 20/12 maximum potential score. The bar charts compare actual Benchmark? scores – and the number of points on offer to each company.

LARGE RESEARCH-BASED PHARMACEUTICAL COMPANIES GSK J oh ns gi o o n GSK n & io J This is the most h o S h Johnson & Johnson . n s active group of o Merck & Co., Inc. n companies against of max. Novartis . M possible score.

AMR: six out of e

r Pzer c k

eight achieved &

Roche n a

more than 50% of o

Sano n

c the points available. . Shionogi GSK and Johnson Points & Johnson lead. Generic medicine manufacturers R is o rt c a h v e o ● Research & Development ● Manufacturing & Production N ● Appropriate Access & Stewardship ● Remaining potential score P zer

GENERIC MEDICINE MANUFACTURERS Aspen A ur a ob ev i T nd Aspen . o Mylan, Cipla and Fresenius Kabi Aurobindo lead this group. All three are active a Cipla . m in stewardship. Mylan and Cipla are r C a i p h Dr. Reddy's l P a

the only two in this group to report n

Fresenius Kabi S having equitable pricing approaches. of max. Lupin possible score. Disclosure among generic medicine Macleods s ' M manufacturers is generally lower y

y d Mylan l d a e than among the other two groups n R

. Sun Pharma r of companies. D Teva Biopharmaceutical companies i b M a Points ac K le us o ni ds se ● Research & Development ● Manufacturing & Production Fre Lupin ● Appropriate Access & Stewardship ● Remaining potential score

BIOPHARMACEUTICAL COMPANIES Achaogen dt C ar em kh p oc ra W Achaogen s The biopharmaceutical compa- e in ic y E Cempra d n n e a t nies in scope are all developing p a M s m i Entasis s e o important antimicrobial candidates. h C Melinta T Entasis leads. It has a novel antibi- of max. possible score. e

MGB Biopharma M s

otic candidate with a new mode of e

l i

Motif Bio n

t r

action in its pipeline, for which it has a

e Nabriva T a licensing agreement in place with Polyphor GARDP. It is followed by Polyphor, S a Summit u m B m Summit and Tetraphase in joint r m G a i M h Tetraphase t p second place. io The Medicines Company B Po o ly Bi Wockhardt ph if or ot M Nabriva Points ● Research & Development ● Remaining potential score

19 Antimicrobial Resistance Benchmark 2018

BENCHMARK PERFORMANCE Large research-based pharmaceutical companies

Research-based pharmaceutical companies met correcties 20/12 Figure 6. Comparing scores: large research- Figure 7. Comparing potential: large research- based pharmaceutical companies. based pharmaceutical companies.

GSK J GSK oh ns gi o o n Johnson & Johnson . n & io J h o S h Merck & Co., Inc. n s o Novartis . n of max. Pzer M possible score.

r Roche c k

Sano n

Shionogi n c

. Points

These companies were analysed in all ● Research & Development R is o rt c a three Research Areas. h v e o ● Manufacturing & Production N ● Appropriate Access & Stewardship P zer ● Remaining potential score

GSK and Johnson & Johnson lead, fol- target priority pathogens and four are AMR-related educational activities for lowed closely by Novartis, Pfizer and vaccine projects. It is involved in a num- healthcare professionals. Roche has a Sanofi. GSK leads all research areas, ber of educational and surveillance pro- low performance in this group. It has with the largest antimicrobial pipe- grammes, sharing data. Sanofi performs been historically active in antimicrobials, line (55 projects). It has 55 R&D pro- strongly in R&D, developing 32 projects, concentrating in only a few markets. It jects, including 13 vaccines, and access with 18 targeting pathogens prioritised is now taking steps to re-enter the field or stewardship provisions for more pro- by WHO and/or the US CDC for AMR, of AMR. jects than other companies. It also dis- including six vaccine candidates. It is closes the most comprehensive envi- engaged in a number of educational and Looking ahead ronmental risk-management strat- long-term surveillance programmes. All three Research Areas are being ad- egy. For marketed products, it under- Novartis also performs well, especially dressed by all eight companies. GSK takes a range of access and stewardship in Manufacturing & Production and came closest to achieving 100% of its activities, including a comparatively Appropriate Access & Stewardship. It maximum potential score in this first broad equitable pricing approach. It has has a pipeline of 32 projects (16 target Benchmark, with most other companies uncoupled the remuneration of sales a priority pathogen, including two novel surpassing the 50% mark. Companies staff from sales volume. antimalarials). in this group have the potential to im- Johnson & Johnson also deliv- Shionogi and Merck & Co., Inc. fol- prove across all areas measured, includ- ers a strong performance, with a focus low. Shionogi currently only has opera- ing explicitly linking access and stew- on tuberculosis. For example, in stew- tions in Japan, Taiwan and the USA and ardship strategies to more products. ardship, Johnson & Johnson engages does not yet have a worldwide response Antimicrobials marketed by some com- in several tuberculosis-related educa- to AMR. However, it is transparent on panies do not yet appear to be widely tional programmes for healthcare pro- its activities in combating AMR, and available in many markets (based on fessionals, taking action to mitigate has uncoupled the remuneration of its how widely newer products are being conflict of interest. It also supports sur- sales staff from the volume of antibi- filed for registration). All companies are veillance programmes for tuberculosis, otic sales. According to publicly availa- encouraged to look at whether their sharing data with public health author- ble information, Merck & Co., Inc. has 16 products are in the WHO’s ‘Access’, ities. Pfizer, Novartis and Sanofi are antimicrobial R&D projects in its pipe- ‘Watch’ and ‘Reserve’ groups, as they close behind the leaders. Pfizer has a line, including nine that target prior- review strategies for registering prod- pipeline of seven projects, six of which ity pathogens. It is involved in multiple ucts and for stewardship.

20 Access to Medicine Foundation

BENCHMARK PERFORMANCE Generic medicine manufacturers

Generic medicine manufacturers

Figure 8. Comparing scores: generic medicine Figure 9. Comparing potential: generic medicine manufacturers. manufacturers.

Aspen A Aspen . ur a ob ev i T nd Aurobindo o Cipla .

a Dr. Reddy's m r C a i p h Fresenius Kabi l P a

Lupin S of max. Macleods possible score. Mylan s ' M y

y d Sun Pharma l d a e n R

. Teva r D

Points i b M a These companies were analysed in ● Manufacturing & Production ac K le us o ni the Manufacturing & Production and ds e ● Appropriate Access & Stewardship res Appropriate Access & Stewardship F Lupin Research Areas only. ● Remaining potential score

In evaluating these companies, the risk management, but did not per- generic medicine divisions. Generic Benchmark faced a low level of disclo- form as well in access and affordability. medicine manufacturers are also more sure; their low scores must be inter- Aurobindo and Teva performed equally involved in global health challenges and preted with this in mind. Mylan, Cipla well in Manufacturing & Production. the international collectives addressing and Fresenius Kabi take the lead. They Macleods has filed two of its new- them. For example, Cipla, Fresenius Kabi, perform well for two reasons: their est antibiotics for registration in sev- Lupin, Mylan and Teva have signed the response to AMR is more defined and eral low- and middle-income coun- Davos Declaration, and Cipla has signed broader than other generic medicine tries, yet does not report an equitable the Industry Roadmap on AMR (as has manufacturers, and they report publicly pricing strategy. Lupin and Aspen per- Wockhardt, evaluated in this Benchmark about their plans, giving greater cred- formed moderately in Manufacturing & as a biopharmaceutical company). ibility to their actions. They delivered Production. Neither Aspen, Aurobindo, Regarding disclosure, many of varying performances across the two Lupin, Macleods nor Teva reports any these companies do not report con- research areas. information regarding stewardship, sistently about non-financial activities. Overall, Mylan performed best. It dis- despite producing antimicrobials for the Nevertheless, there is little evidence of closes its environmental risk-manage- market. Dr. Reddy’s and Sun Pharma leadership in stewardship, despite this ment strategy, which it also applies to disclose limited information about their being critical for combating AMR, and API and drug-product suppliers. It also AMR responses, despite having at least only a few companies are taking some commits to GMP at its suppliers’ sites. 22 and 69 antimicrobials on the market, action identified by the Benchmark to Mylan reports an intra-country equita- respectively. support access. This is concerning, con- ble pricing approach for antimicrobi- sidering that the core business of such als, and takes several steps to improve Looking ahead companies is to make off-patent med- supply chain efficiency. Cipla delivered For decades, generic medicine manu- icines available and affordable at vol- a strong performance in Appropriate facturers have brought off-patent med- ume. There is tremendous potential to Access & Stewardship, yet its perfor- icines to billions worldwide. The dis- limit AMR, through strengthening envi- mance in Manufacturing & Production tinction between these and large re- ronmental risk management, ensuring is lower. It reported having an environ- search-based companies is blurring, as efficient supply and ensuring steward- mental risk-management strategy in some generic medicine manufactur- ship, should these and other companies development. Fresenius Kabi performed ers invest in incremental R&D units, and continue to develop and expand their on par with Mylan for environmental as research-based companies establish actions on this front.

21 Antimicrobial Resistance Benchmark 2018

BENCHMARK PERFORMANCE Biopharmaceutical companies

Biopharmaceutical companies

Figure 10. Comparing scores: biopharmaceutical Figure 11. Comparing potential: companies. biopharmaceutical companies.

Achaogen dt C ar em Achaogen kh p oc ra W Cempra s e in ic y E Entasis d n n e a t p a M s m i Melinta s e o h C MGB Biopharma T of max. possible score. e

Motif Bio M s

l i

Nabriva n

e Polyphor T These companies were analysed in the Summit Research & Development Research Area

S only. a Tetraphase u m B m r m G a i M h The Medicines Company t p io Wockhardt B ● Research & Development P o io ly B ph tif Points ● Remaining potential score or Mo Nabriva

These 12 biopharmaceutical compa- access and/or stewardship commit- A few notable companies are also nies were selected, as they had at least ment or plan for products in their clini- addressing access and stewardship for one investigational antibiotic in their cal pipeline. their products on the market. For clinical pipeline that targeted a prior- examples, Wockhardt runs a surveil- ity pathogen, as identified by the WHO Looking ahead lance programme in India. and the CDC. The strongest and most With few or no products on the mar- To fulfil their potential in addressing comprehensive response to AMR comes ket, these companies must continually AMR, these companies are encouraged from Entasis, followed by Polyphor, compete for sufficient resources to fur- to think systematically about access Summit and Tetraphase and then MGB ther develop their R&D pipelines. This is and stewardship already during clinical Biopharma, Nabriva, and The Medicines why the role of push funding provided development. Funders can work with Company. by organisations such as GARDP and the biopharmaceutical companies they All 12 of these companies are devel- CARB-X is key. Venture capital fund- support to ensure such provisions are oping important antimicrobials, including into antibiotics development has put into practice. Such steps will go a ing several that have novel mecha- decreased by 33% between 2008 and long way in ensuring that the promising nisms of action. Entasis, Nabriva and 2013.⁸ These companies are gener- candidates from these companies have Wockhardt have the largest pipelines ally also small- to medium sized, with- the maximum useful lifespan. targeting bacteria prioritised by WHO out the resources, operations or exper- and/or CDC. Entasis engages actively in tise that a larger company can call on public-private partnerships for antimi- to introduce a product while prioritis- crobial R&D, such as GARDP. Together ing access and stewardship. Success with Tetraphase, Entasis also stands out in combating AMR is only possible for for ensuring access or stewardship ini- companies that attract more fund- tiatives are in place for antibiotic candi- ing, and can forge collaborations that dates in late-stage clinical development. help plan access and stewardship However, only Tetraphase has devel- programmes. oped a concrete access and steward- Despite these challenges, the ship provision for one of its late-stage Benchmark recognises the commenda- products. Only five out of the 12 com- ble efforts these companies are making panies assessed explicitly include an to replace redundant antimicrobials.

22 Access to Medicine Foundation

REFERENCES

1. O’Neill, J. (May, 2016). Tackling 3. Declaration by the Pharmaceutical, 5. Industry Roadmap for Progress on 7. Access to Medicine Foundation. drug-resistant infections globally: final Biotechnology and Diagnostics Industries Combating Antimicrobial Resistance (2016). Access to Medicine Index. report and recommendations. The Review on Combating Antimicrobial Resistance. – September 2016. Retrieved from Retrieved from https://accesstomedicine- on Antimicrobial Resistance. Signatories as at January, 2017. Retrieved https://www.ifpma.org/wp-content/ index.org/ from https://www.ifpma.org/wp-con- uploads/2016/09/Roadmap-for-Progress- 2. Interagency Coordination Group on tent/uploads/2016/01/briefing-declara- on-AMR-FINAL.pdf 8. Thomas, D., & Wessel, C. (2015). Antimicrobial Resistance. (August, 2017). tion-a4-2017_SCF.pdf Venture funding of therapeutic innovation. AMR Framework for Action Supported 6. WHO. (2017). WHO Model List of Biotechnology Industry Organization. by the IACG. Retrieved 11 December 4. Access to Medicine Foundation. Essential Medicines 20th List (Amended 2017 from http://www.who.int/antimi- (2017). Antimicrobial Resistance August 2017). Retrieved 11 December crobial-resistance/interagency-coordina- Benchmark 2018: Methodology 2017. 2017 from http://www.who.int/medi- tion-group/20170818_AMR_FfA_v01.pdf Retrieved from https://accesstomedi- cines/publications/essentialmedicines/ cinefoundation.org/publications/meth- en/ odology-for-2018-antimicrobial-resistance-benchmark/

23 Antimicrobial Resistance Benchmark 2018

KEY FINDING 1 Out of 28 antibiotics in late stages of clinical development, only two have both access and stewardship plans in place

As more microbes develop drug resist- alongside efforts to ensure appropri- drug, which is important to ensure its ance, a robust pipeline of new antimi- ate access to antimicrobials. More peo- appropriate use. crobial medicines is critical for replacing ple die from lack of access to antimicro- Bedaquiline (Sirturo®), condition- less effective medicines. bials than from drug-resistant microbes. ally approved for the treatment of mul- The pipelines captured in the Bench- Companies must put access and stew- tidrug-resistant tuberculosis (MDR-TB) mark have 175 antimicrobial medicines ardship plans in place at the same in adults, is now being developed by targeting pathogens seen by WHO and time to ensure they are most effective, Johnson & Johnson for the treatment CDC as the biggest AMR threats. Of and before a new product enters the of MDR-TB in children. The company those, 40 – one quarter – are drug can- market. will use the same access and steward- didates in late stages of clinical develop- Of the 28 antibiotics in late- ship provisions that are in place for the ment, including 28 antibiotics. Several stages of clinical development, only adult formulation. These include a man- are novel, with new modes of action, two (eravacycline, Phase III; bedaqui- aged access programme through the including new classes of antibiotics to line for paediatrics, Phase II) have both Global Drug Facility (GDF) and with its treat multidrug-resistant S. aureus. In access and stewardship provisions in own subsidiaries. To limit resistance to much of the world, more than half of place. Eravacycline is being developed bedaquiline, the company’s stewardship S. aureus infections are reported to be by Tetraphase to treat complicated provisions include educational activities resistant to standard treatment with intra-abdominal and urinary tract infec- for paediatric healthcare profession- methicillin (known as methicillin-resist- tions caused by a range of pathogens, als that aim to improve knowledge and ant S. aureus, or MRSA).1 including A. baumannii, S. aureus, and C. awareness on the appropriate use of Once a new antibiotic has market difficile. To plan for access, Tetraphase the antibiotic. approval, AMR response strategies call is seeking licensing partners to increase Two other antibiotics in the late- for it to be used prudently, to slow the access in several regions of the world. stage clinical pipeline have steward- emergence of resistance and maxim- For stewardship, it provides hospitals ship provisions, but no access plan: ise the antibiotic’s useful lifespan. Such with testing strips that check whether a GSK’s gepotidacin (Phase II) for gon- stewardship measures must be pursued patient’s infection is susceptible to the orrhoea; and Pfizer’s avibactam/aztreonam (Phase II) for multidrug-resistant gram-negative bacterial infections. Figure 12. Few late-stage antibiotics with access and stewardship plans. Three have an access plan in place, but The Benchmark identified 28 antibiotics in clinical development that target pathogens posing significant no stewardship provisions: a second threats due to AMR (according to WHO and CDC). Only two have plans in place to ensure they will be gonorrhoea medicine, an antibiotic for accessible, yet used prudently: eravacycline from Tetraphase and paediatric bedaquiline from Johnson acute skin infections, and a gel for treat- & Johnson. ing umbilical stump infections (being developed by Entasis, Melinta and GSK respectively).

antibiotics Besides antibiotics, there are 12 21 have no plans reported 3 have access plans other medicines in late-stage clinical 2 have both access and development targeting priority path- stewardship plans products 2 have stewardship plans ogens, including five with both access 12 and stewardship provisions. All are anti- 40 other virals for HIV/AIDS being developed by in clinical antimicrobials development GSK, either alone (three) or in partnership with Johnson & Johnson (two).

24 Access to Medicine Foundation

KEY FINDING 2 Nearly half of companies with products on the market are involved in AMR surveillance

Curbing AMR depends on knowing AMR surveillance. Wockhardt collects data from a repre- which pathogens are developing resist- The Benchmark found that nine of sentative sample of the entire health- ance and where. Yet there are major the 19 companies reporting such efforts care infrastructure in India; and Pfizer’s gaps in global AMR surveillance, with are running or supporting 19 AMR sur- ATLAS project tracks susceptibility countries having differing levels of surveillance programmes across 147 coun- and resistance patterns for a variety of veillance capacity and a lack of data har- tries. These are seven of the eight large pathogens and medicines across more monisation, making it more difficult to research-based companies in scope, than 60 countries. use the data that are shared. one of the 10 generic medicine manu- Pneumonia gets the most atten- The pharmaceutical industry can facturers, and one of the 12 biopharma- tion, followed by other respiratory make an important contribution in ceutical companies. infections, including tuberculosis. this area. Companies that signed the The activities are diverse in terms of Resistance is also being tracked in a 2016 Industry Roadmap for Progress scale, focus and duration. For instance, variety of pathogens considered a pri- in Combating Antimicrobial Resistance GSK periodically monitors interna- ority for monitoring, including S. aureus, (including 10 the Benchmark measures) tional resistance trends in commu- E. coli and H. influenzae. Some pro- agreed to support efforts to increase nity-acquired respiratory infections; grammes track a single pathogen (e.g., Johnson & Johnson’s DREAM pro- Figure 13a. Nine out of 19 companies support AMR surveillance. gramme, focussed on M. tuberculosis), The Benchmark found that nine of the 19 companies evaluated in this area are running or supporting while others monitor several patho- 19 AMR surveillance programmes, spanning 147 countries. gens and medicines in the same project (e.g., GSK’s SOAR and Merck & Co., Inc.’s Surveillance contributors: SMART programmes). Cipla, GSK, Johnson & Johnson, Sharing the surveillance data with Companies Companies Merck & Co., Inc., Pfizer, Sanofi, not involved Companies involved third-party initiatives that track AMR Shionogi, Roche, Wockhardt trends is a fundamental next step. At least eight companies reported their data are presented at public conferences or published in journals, while two Figure 13b. AMR surveillance programmes are being conducted in 147 countries – Merck & Co., Inc. and Pfizer – publish worldwide. their surveillance data on the Internet. Nine companies assessed by the Benchmark in this area are engaged in surveillance programmes, GSK reported plans to publish all its sur- active in 75% of countries in the world. veillance data on the Internet and to collaborate with other organisations aiming to publish an online database conglom- erating pharmaceutical industry AMR surveillance data. Key challenges for ensuring that industry AMR surveillance efforts have maximum impact include increasing involvement, harmonising data, convert- ing prevalence studies into long-term monitoring programmes and increasing collaboration with public health bodies ● No surveillance programmes ● 1-2 surveillance programmes ● ≥3 surveillance programmes coordinating surveillance.

1 2 3 4 5 6 Antimicrobial Resistance Benchmark 2018

KEY FINDING 3 Eight companies are setting limits on antibiotic wastewater discharge

Antibiotics released into the envi- rely on untreated groundwater for their factory discharges, to developing a ronment in factory wastewaters are household water supplies.3 Significantly mechanism to demonstrate their supply increasingly thought to be contribut- curtailing the release of antibiotics into chains meet the standards set, and to ing to AMR. The exposure of bacteria in the environment is seen as an important agreeing, by 2020, on targets for antibi- soil and water to discharged antibiotic measure for slowing AMR. Consensus otic levels released in waste discharge. ingredients can trigger the emergence around safe limits for antibiotic dis- They also committed to reviewing their of resistance genes.2 Large volumes of charge has yet to emerge. actions to identify good practice. Seven antibiotics are manufactured in some On this issue, the Benchmark ques- of the eight companies that reported countries where local populations often tioned the 18 companies in scope with setting limits were signatories of this significant manufacturing presence.* Of Roadmap. these, 15 reported having some form Figure 14. Eight companies set of an environmental risk-management discharge limits. No company strategy in place, with eight also report- publishes discharge levels. ing that they have set factory discharge Eight of 18 companies evaluated in this research limits for antibiotics. In a further step, area reported that they have set discharge four said they also require their suppli- limits for antibiotics. Four of these companies ers of antibiotic active ingredients and also require upstream suppliers of antibiotic drug products to adhere to the same APIs and drug products to adhere to the same limits. All eight also disclosed that they limits. Yet no company publishes its discharge audit the implementation of their envi- levels. All eight companies reported that they ronmental risk-management strate- audit the implementation of their environmental gies. However, no company publishes its risk-management strategies at their own environmental audit results, or its dis- manufacturing sites. charge levels. For the remaining ten companies, four reported they do not set limits and four did not respond to the question. The Benchmark was unable to find independent information on the performance in this area for the four companies who declined to answer the question. The two remaining companies, Aurobindo and Dr. Reddy’s, report that they do not set limits as they do not

Signed Industry Roadmap Signed limits Sets discharge levels discharge Publishes sites suppliers’ Applies limits to implementation strategy Audits release wastewater. Instead they vapor- GSK ● ● ○ ● ● ise the waste and dispose of the resid- Johnson & Johnson ● ● ○ ● ● ual solids by other means. Novartis ● ● ○ ○ ● Ten of the companies included in Pfizer ● ● ○ ● ● this Benchmark have signed the 2016 Roche ● ● ○ ● ● Industry Roadmap for Combatting Sanofi ● ● ○ ○ ● Antimicrobial Resistance, thereby com- *In its analysis of Manufacturing & Production practices, Shionogi ● ● ○ ○ ● mitting to establishing a common the Benchmark uses global antibiotic sales volumes to Teva ○ ● ○ ○ ● framework for managing antibiotic inform its selection of companies to analyse.

26 Access to Medicine Foundation

KEY FINDING 4 Four companies move to decouple antibiotic sales volumes from sales agents’ bonuses

The more that antibiotics are used, the of overuse.5 The Benchmark has found GSK has led in this area, having since faster they become ineffective.4 One of that four companies are changing the 2013 separated pay from antibiot- the strategic pillars of the global effort way they remunerate sales staff in ics sales volume for all its sales staff in to address antimicrobial resistance is ways that should remove the incentive every country in which it sells antibiot- therefore to ensure that antibiotics are to oversell antibiotics: GSK, Shionogi, ics. Shionogi also reports that it does used appropriately, only when needed, Pfizer and Novartis report that bonuses not remunerate its sales teams based to prolong their effectiveness. are fully decoupled or that the com- on antibiotic sales volume. Pfizer and The more antibiotics that are sold, pany has taken steps towards adjusting Novartis are now following. In 2018, the more that are available, and this is incentives for its sales teams’ bonuses Pfizer will start working on pilots that thought to contribute to the problem from the volume of antibiotics they sell. aim to decouple the remuneration of its sales teams from sales volume. Novartis is starting to increase the weight of Figure 15. Decoupling sales volumes from sales agents’ bonuses: four fixed pay in overall compensation for companies are taking action sales staff, while reducing the variable GSK, Novartis, Pfizer and Shionogi report that bonuses are fully decoupled from the volume of antibiotics component. they sell or that the company has taken steps towards adjusting incentives for its sales teams’ bonuses. At least one other company is taking a different approach at the product GSK Shionogi level. Johnson & Johnson’s new anti-tuberculosis drug, bedaquiline (Sirturo®), • Full decoupling • Full decoupling is provided solely through national • All bonuses decoupled from sales • Bonuses decoupled from antibiotic tuberculosis programmes and there- volume sales volume for all sales staff fore does not require any marketing • Applies to all sales staff globally materials. The company reports that it • Changes made in 2013 does not deploy any sales organisations for the sale of Sirturo® in countries in scope. Pfizer Novartis

• Pilot • Adjusting incentives • All bonuses decoupled from sales • Lowering % of bonuses linked to volume sales volume • Applies to sales staff in selected geographies • Starts in 2018

REFERENCES TO THE KEY FINDINGS

1. WHO. (2014). WHO’s first global 2. Larsson, D. G. J. (2014). Pollution 3. Luo, Y., et al. (2013). Proliferation of 5. Clift, C., et al. (October, 2015). report on antibiotic resistance reveals from drug manufacturing: review and per- Multidrug-Resistant New Delhi Metallo-ß- Towards a new global business model for serious, worldwide threat to pub- spectives. Philosophical Transactions lactamase Genes in Municipal Wastewater antibiotics: delinking revenues from sales. lic health. Derived 12 December from: of the Royal Society B, 369(1656). doi: Treatment Plants in Northern China. Chatham House. Retrieved from https:// http://www.who.int/mediacentre/news/ 10.1098/rstb.2013.0571. Environmental Science & Technology www.chathamhouse.org/publication/ releases/2014/amr-report/en/ Letters, 1(1), 26-30. towards-new-global-business-model-antibiotics-delinking-revenues-sales 4. Laxminarayan, R., & Chaudhury, R. R. (2016). Antibiotic resistance in India: drivers and opportunities for action. PLoS medicine, 13(3), e1001974. 27 Antimicrobial Resistance Benchmark 2018

PORTFOLIO ANALYSIS Antimicrobial portfolios: what medicines are on the market?

Antimicrobials must be used conserva- many bacterial infections.¹ Per product, of antimicrobials on the market, while tively to preserve their useful lifespan. it is critical that pharmaceutical com- also increasing people’s ability to access However, many people live without panies, governments, donors and other antimicrobials when they need them. access to the antimicrobials they need, stakeholders integrate and expand including for malaria, tuberculosis and plans for conserving the effectiveness

88 Antiprotozoals Figure 16. Which antimicrobial 13 Anthelminthics medicines are available on the 24 Antiamoebic and antigiardiasis medicines market? 7 Intestinal anthelminthics 6 Antileishmaniasis medicines The companies in scope have at least 741 0 Antifilarials 45 Antimalarial medicines antimicrobial medicines on the market – 2 Antischistosomals and other 9 Antipneumocystosis and more than half of which (454) target bacterial antitrematode medicines antitoxoplasmosis medicines infections. Resistance to different products 4 Multiple categories 0 Antitrypanosomal medicines emerges at different rates, with some products 4 Multiple categories already being less effective. 1.5 billion people are infected with helminths, Out of 88 antiprotozoals, 45 target malaria, such as threadworms.³ A sharp increase in including some older products that are redun- anthelminthic resistance in livestock has raised dant due to AMR. Most countries now rely on concerns over the development of resistance artemisinin-based antimalarials. Stewardship in human helminths. Some countries have now of these medicines and R&D into replace- restricted anthelminthics to prescription use * ments is critical.² Other antiprotozoals target only. In the last 30 years, only one new anthel- products NTDs, such as leishmaniasis for which treat- minthic has been introduced. ⁴ ment is available but not widely accessible.

177 Antivirals 454 Antibacterials

24 Antiherpes medicines 189 Beta-lactam antibacterials 114 Antiretrovirals 180 Other antibacterials 6 Other antivirals 1 Antileprosy medicines 21 Antihepatitis medicines 50 Antifungal medicines 55 Antituberculosis medicines 12 Multiple categories 29 Multiple categories Fungal infections now cause more deaths than Out of 177 antivirals, most are antiretroviral malaria or tuberculosis. Resistance to antifun- More than half the products in the portfolio therapies (ART) for HIV/AIDS. In 2010, almost 7% gals has been described for almost all fungal are antibacterials, including 189 beta-lactams. of people receiving ART had drug-resistant HIV. pathogens including Candida.⁶ However, fewer These remain important antibiotics for their Increased use of ART will likely increase resist- than 10 national surveillance programmes have broad-spectrum effectiveness. Ensuring ance.⁸ This analysis includes 61 fixed-dose ART been developed to monitor the resistance access to these is a public health priority. A combinations, which reduce the pill burden for trends of fungal infections.⁷ further 55 antibacterials target tuberculosis patients, improving patient adherence and lim- (TB). There has only been one new TB med- iting resistance.⁹ New Direct Acting Antivirals icine introduced in 40 years. Stewardship of for hepatitis C have shorter treatment regimens this medicine is being managed in national TB which also improve patient adherence.¹⁰ programmes.⁵

*41 medicines are effective against pathogens in more than one of the five categories and were counted in all relevant categories. 28 Access to Medicine Foundation

PORTFOLIO ANALYSIS Access is a leading priority for half of antibiotics on WHO EML

The Benchmark has compared compa- WHO EML. In 2017, the WHO EML cate- antibiotics should be widely available, nies’ portfolios against Section 6 of the gorised antibiotics into three groups – affordable and quality assured. Reserve WHO Model List of Essential Medicines Access, Watch and Reserve. Companies group antibiotics should only be used (EML). Out of 741 marketed products, have far more Access group antibiotics for the most severe cases when all 268 correspond to antibiotics on the than ones in the Reserve group. Access alternative treatments have failed.11

Figure 17. Companies in scope have at least 268 antibiotics on the WHO EML (Section 6).

Access: always on the shelf Reserve: the last resort Access antibiotics are first- and second-line Watch: the balancing act Antibiotics in the Reserve group are essential treatments that should be widely availa- To manage antibiotics in this group, companies treatments against the most resistant patho- ble. Broad strategies are needed to improve must take a nuanced and weighted approach, gens. It is vital that companies engage in stew- access to them in countries where health sys- developing suitable access plans that are inte- ardship activities that promote the appro- tems are weak. Key elements include plans for grated with stewardship practices that limit priate use of these antibiotics, while rigor- widely registering antibiotics, affordability and misuse and overuse and predict emerging ously monitoring the growing threat of their strengthening supply chains. resistance trends. resistance.

Pzer Novartis Sun Pharma Mylan Teva Fresenius Kabi Wockhardt Aurobindo Macleods Lupin

Sano Proportion of companies’ Aspen marketed antibiotics listed in Cipla the WHO EML antibiotic groups GSK Dr. Reddy's Roche Shionogi antibiotics ● Access group only The Medicines Company ● Access & Watch groups Merck & Co., Inc. ● Watch group only ● Reserve group Johnson & Johnson ● Not grouped

Risk of resistance Changing supply and demand Most antibiotics in companies’ portfolios are The WHO EML antibiotic groups will likely influence demand from in the WHO EML’s Access group. This includes national governments. This will impact antibiotic supply chains, particu- many that are also in the Watch group, mean- larly for Reserve group medicines. Companies, governments and multi- ing risk of resistance is higher. lateral agencies must investigate how supply and demand are aligned as well as mechanisms for securing supply. Companies with many Watch and Reserve antibiotics must put strong governance and stewardship activities in place but governments and payers should maintain sufficient

References for this section see p.33 incentives to keep these medicines on the market.

29 Antimicrobial Resistance Benchmark 2018

PORTFOLIO ANALYSIS Case studies: how three companies are addressing access and stewardship in tandem

Over the past 30 years, there has been treatment and stewardship. Bedaquiline stewardship and innovation cannot suc- a marked reduction in the global inci- (Sirturo®) from Johnson & Johnson is ceed without explicitly addressing the dence of infectious diseases. This has a new, on-patent medicine. Because it needs of the underserved. been achieved in part due to increased is being produced by only one company, The examples put forward are only a access to antibiotics and is linked to the the access programmes, coupled with small snapshot of the different situa- development of emerging economies tight stewardship controls, have a good tions companies face to tackle this sit- and their health systems. Yet, infec- chance of preventing drug-resistance. uation. All companies, independent of tious diseases are still among the most Amoxicillin/clavulanic acid, in this case their business models, have a collec- deadly, and access to lifesaving antibi- sold by GSK as Augmentin™, is a much tive responsibility to preserve antibiotics in low- and middle-income coun- older, off-patent widely-used antibiotic. otic effectiveness and promote univer- tries remains limited.¹ At the same time It must continue to be widely available sal access. human behaviour is stimulating the – indeed access needs to increase – yet emergence of antimicrobial resistance with multiple competitors in the mar- among pathogens. ket, stewardship is particularly complex. CASE STUDY 1 Cipla manufactures a wide range of Bedaquiline (Sirturo®), Johnson & Today, the need to curb antimicrobial antibiotics, such as the low-cost azith- Johnson resistance is at the top of the global romycin and amoxicillin, which are both public health agenda. Achieving this aim widely used for a variety of infections. CASE STUDY 2 depends on three inter-related issues: The common thread running through Amoxicillin/clavulanic acid 1 the urgent need to develop new these case studies is the balancing act (Augmentin™), GSK antibiotics and to conserve their of access and stewardship. The appro- effectiveness as they enter the priate approach depends on two things: CASE STUDY 3 market; the application of each product as a Broad Generic Antimicrobial Portfolio, 2 the equally pressing need to increase first-, second- or third-line treatment Cipla access to antimicrobials; and and the nature of both the product and 3 the need to ensure existing anti- the market. Companies, governments biotics are used appropriately, in and others must take these aspects into ways that delay the emergence of account as they seek to prevent or limit resistance. resistance. Pharmaceutical companies have a role to play in addressing all three In a situation where more incentives of these issues. On a per-product are needed to engage innovators to basis, companies are expected to develop new antibiotics, there is also take steps that support efforts to the need to ensure universal access to ensure access without promoting existing and newly introduced therapies, resistance. while avoiding the inappropriate use of these medicines. This is a challenging The AMR Benchmark has examined situation that affects not only compa- the approaches pharmaceutical com- nies, but also governments, health sys- panies are taking to ensure access and tems, patients, donors, etc. The lack of also to address AMR. Here it presents rigorous efforts to assure coverage of three case studies of how pharmaceu- antibiotics increases the likelihood of tical companies are balancing access to resistance, but global efforts aimed at

30 Access to Medicine Foundation

CASE 1: BEDAQUILINE (SIRTURO®), JOHNSON & JOHNSON Access to new MDR-TB medicine is tightly controlled through national TB programmes and donations.

NEW MILESTONE MDR-TB TREATMENT CONTROLLED ACCESS STEWARDSHIP • First MDR-TB treatment to reach market in • Restrictive access conditions require pharma- • Supports education for healthcare profession- 40 years covigilance infrastructure, clinical monitoring als on AMR, including on pharmacovigilance • New mechanism of action (ATP Synthase • Access provided through national pro- and TB-specific workshops Inhibitor) grammes and donations via the USAID • No sales teams deployed • Only available for pulmonary MDR-TB with Bedaquiline Donation Programme. • Surveillance programme running (DREAM) long-course regimens and shorter regimens • Equity-based inter-country tiered pricing approach in place • Registered in 23 countries where access to medicine is likely limited

Tuberculosis (TB) poses a critical threat bedaquiline is not registered, access Stewardship measures from AMR. In 2012, the U.S. Food & is possible with a WHO import waiver. Johnson & Johnson supports activities Drug Administration (FDA) gave fast- Across the various access channels, to raise awareness of TB and MDR-TB track accelerated approval, based on 35,000 cumulative treatments have among healthcare professionals (HCPs) Phase II clinical studies, to the first inno- been delivered, mostly to India, Russia and achieve optimal clinical outcomes vative treatment for pulmonary multi- and South Africa. The donation pro- with bedaquiline. These include award- drug resistant tuberculosis (MDR-TB) gramme was developed in 2015 with ing unrestricted educational grants and extensively drug-resistant tubercu- USAID to increase access in over 100 through the International Union Against losis (XDR-TB) in 40 years: Johnson & low- and middle-income countries. TB for the design and delivery of Johnson’s bedaquiline (Sirturo®). The company committed to donat- MDR-TB HCP educational programmes Due to its accelerated approval, the ing 30,000 treatment courses in four in Ghana, Lesotho, Peru, South Africa, medicine was not tested for long-term years. According to Johnson & Johnson, the Democratic Republic of Congo, effectiveness and safety in larger pop- 103 countries now have access, includ- and Rwanda. With USAID, Johnson & ulations. To further test the medicine ing 29 of the 30 countries with high Johnson runs workshops on national and also to prevent acquired resistance MDR-TB burdens. The programme also pharmacovigilance programmes for from emerging, WHO issued a strict includes specialist education on the use staff of national TB programmes and interim guideline on its use, monitor- of bedaquiline and on activities to min- national regulators in several low- and ing and pharmacovigilance.² Countries imise risk, as well as technical support middle-income countries. with weaker health systems may be less for establishing active pharmacovigi- The company only provides bedaqui- likely to meet some of these criteria. lance. These capacity building activities line under restricted access conditions When filing bedaquiline for regis- are supported by USAID, national and – with no promotional activities or sales tration, Johnson & Johnson prioritised local partners. agents for the medicine, removing per- countries with high TB burdens. Russia verse incentives to oversell. Johnson & was second to receive market approval, Addressing the cost barrier Johnson also supports efforts to track following the USA. Approval was To address affordability of bedaquiline, and predict the emergence of resist- granted in South Africa, the Philippines Johnson & Johnson has an equitable ance to bedaquiline. Its DREAM sur- and Peru in 2014, the same year as in pricing strategy that sets prices accord- veillance programme (Drug Resistance the European Union. These are coun- ing to a country’s ability to pay. Its pric- Emergence Assessment in MDR-TB) tries with some of the highest MDR-TB ing tiers are based on criteria such as runs in collaboration with National burdens. World Bank income classifications, Tuberculosis Programmes and WHO’s Today, bedaquiline is available via GDP/GNI per capita and MDR-TB bur- Supranational Reference Laboratories. five routes: traditional reimbursement den. Countries that do not meet the cri- The Benchmark has assessed access by national authorities, purchasing via teria or WHO’s Guidelines, may receive and stewardship practices for 18 com- the Global Drug Facility (GDF), equitable additional technical support via other panies in relation to their antibiotics. tiered pricing, institutional purchasing stakeholders, including the WHO and The measures put in place by Johnson by international NGOs, and through a USAID. & Johnson for bedaquiline represent tightly controlled donation programme the most comprehensive of those spe- managed by USAID. In countries where cifically linked to a single product.

31 Antimicrobial Resistance Benchmark 2018

CASE 2: AMOXICILLIN/CLAVULANIC ACID (AUGMENTIN™), GSK Strategy aims to balance access and stewardship for off-patent widely-used antibiotic.

OFF-PATENT ANTIBIOTIC INCREASING ACCESS STEWARDSHIP • Multiple companies produce versions of amox- • Broad registration, now in 71 low- and mid- • Continuing medical education programmes icillin/clavulanic acid dle-income countries • Marketing materials include information on • Resistance has been noted in a range of path- • Equitable pricing strategy, with different pric- AMR trends ogens including Klebsiella spp. ing tiers in-country • Decoupling of sales staff incentives from sales • Placed in WHO EML’s Access group of anti- • Pricing strategy based on (e.g.,) GNI, burden of volume biotics disease, health system financing • Antibiotic surveillance activities

Amoxicillin/clavulanic acid (Augmentin™) Registration: the 1st step to by patients. Looking across the data is a broad-spectrum antibiotic used to availability from the other 13 companies in scope treat mild-to-moderate bacterial infec- GSK has filed to register amoxicillin/ that market amoxicillin/clavulanic acid, tions, including sinusitis, cellulitis, acute clavulanic acid in 71 of 106 low- and GSK performs well in balancing access otitis media and community-acquired middle-income countries where access and stewardship for this product. To pneumonia. It was first introduced by to medicine is likely limited. This makes maximise the effectiveness of GSK’s GSK in 1981, following UK approval. It it the most widely registered prod- actions, and extend the lifespan of this came off patent in 2002, triggering the uct in this group of countries analysed important antibiotic, other producers arrival of many generic versions on the by the Benchmark. GSK has also devel- must meet or exceed the standard GSK market. Of the 21 companies with mar- oped an equitable pricing approach for sets. keted products in the Benchmark’s setting prices at the national level, as Amoxicillin/clavulanic acid is a widely scope, 13 report marketing at least one well as for populations within coun- marketed off-patent product produced formulation of amoxicillin/clavulanic tries. When setting prices for this medi- by multiple companies, which makes acid. Where there are more versions of cine, GSK reports that it considers mul- the challenge of expanding access while a product available, the ability to control tiple socio-economic factors, includ- also protecting the product from resist- resistance decreases. ing: a country’s ability to pay, its burden ance-promoting behaviour particularly This broad-spectrum antibiotic is a of infectious diseases, how healthcare complex. On the one hand, affordabil- widely-used treatment for a wide range is financed, and its level of socio-eco- ity and availability are easier to achieve of infectious diseases. As a result, it has nomic inequality. There are many due to competition from multiple been classified as an Access antibiotic generic versions of amoxicillin/clavu- generic medicine manufacturers. On by the WHO in its 2017 WHO Model List lanic acid that are lower in cost than the other hand, a wider number of pro- of Essential Medicines – meaning that GSK’s version (Augmentin™). ducers means more actors that must it should be widely available, afforda- adopt best practices for stewardship. It ble and quality assured as a first- and Appropriate promotion is vital that all producers of amoxicillin/ second-line treatment for many infec- In parallel to its measures addressing clavulanic acid consider and implement tious diseases.³ However, as it is among affordability, GSK also runs stewardship stringent stewardship policies across all the most commonly prescribed anti- activities for amoxicillin/clavulanic acid. healthcare settings. biotics worldwide, a wide range of dif- These include the provision of medical ferent pathogens have developed high education programmes regarding the resistance rates to this medicine, includ- appropriate use of the medicine. It also ing Klebsiella spp. (61% of isolates are undertakes several practices for ensur- resistant in Egypt, 33% in Brazil), and ing the product’s appropriate promo- Streptococcus pneumoniae (17% resist- tion: it includes AMR-related informa- ant isolates in Vietnam).⁴ While access tion and trends in its marketing mate- remains a priority, the stewardship of rials, and has completely separated the this important medicine is also critical remuneration of its sales staff from the to ensure it can continue to be effective. sales volume of antibiotics, including amoxicillin/clavulanic acid. GSK has also adapted some of its brochures to facilitate the appropriate use of the product

32 Access to Medicine Foundation

CASE 3: BROAD GENERIC ANTIMICROBIAL PORTFOLIO, CIPLA Generic medicine manufacturer stands out for stewardship practices.

GENERIC ANTIMICROBIALS INCREASING ACCESS STEWARDSHIP • Has more than 1500 products on the market • One of only two generic medicine manufactur- • Educational activities to educate HCPs on • Markets at least 25 antimicrobials, including 23 ers with an equitable pricing approach antibiotic stewardship on Section 6 of the WHO EML • Takes account of country’s GNI when setting • Illustrates AMR trends in some marketing prices materials • Adapts packaging to support rational use • Engages in AMR surveillance

As a generic medicine manufacturer, Cipla has a presence in more than 80 Stewardship activities Cipla uses a low-cost, high-volume countries, with 43 manufacturing facil- Cipla is the only generic medicine man- model that allows it to specialise in ities worldwide and markets more than ufacture in the scope of the Benchmark developing generic versions or formu- 1,500 products across various therapeu- that engages in multiple activities lations of products such as amoxicil- tic areas. This includes at least 25 anti- to educate healthcare professionals lin and azithromycin after patent expiry. microbial medicines, 23 of which are (HCPs) on antibiotic stewardship. The Across the industry, this business model listed on Section 6 of the WHO Model company also implements brochure has proven highly successful at expand- List of Essential Medicines (EML). It is and packaging adaptations to facili- ing access to medicines in recent dec- one of only two generic medicine manu- tate appropriate use of antibiotics by ades, particularly through price reduc- facturers in the scope of the Benchmark patients. For example, it includes infor- tion. Yet it is seemingly at odds with that reported an equitable pricing strat- mation about treatment duration on the the need to reduce the overuse of anti- egy that covers antimicrobials as well as strip of the box of the antibiotic azith- biotics. Looking ahead, generic medi- multiple stewardship activities, particu- romycin to help improve patient adher- cine manufacturers have a clear respon- larly surveillance. Its inter-country equi- ence to the treatment. It has conducted sibility to market their antibiotics table pricing strategy is based on coun- several AMR-related prevalence studies, appropriately. tries’ levels of income (gross national delivering the results via conferences income (GNI) per capita). and peer-reviewed journals.

REFERENCES REFERENCES FOR PORTFOLIO SECTION (P 28-29)

1. Laxminarayan, R., et al. (2016). 3. WHO. (2017). WHO Model List of 1. Laxminarayan, R., et al. (2016). Access 7. Stop neglecting fungi. (2017). Antimicrobials: access and sustaina- Essential Medicines 20th List (Amended to effective antimicrobials: a world- Nature Microbiology, 2. doi:10.1038/ ble eff ectiveness 1 Access to eff ective August 2017). Retrieved 24 November wide challenge. The Lancet, 387(10014), nmicrobiol.2017.120 antimicrobials: a worldwide challenge. 2017 from http://www.who.int/medi- 168-175. The Lancet, 387, 168-175. doi:10.1016/ cines/publications/essentialmedicines/ 8. WHO. (2017). Global Action Plan On S0140-6736(15)00474-2. en/ 2. WHO. (2017). World Malaria Report HIV Drug Resistance 2017-2021. Retrieved 2017. Retrieved 20 December 2017 from 14 December 2017 from: http://apps.who. 4. Antimicrobial Testing Leadership http://apps.who.int/iris/bitstream/10665/ int/iris/bitstream/10665/255883/1/9789 2. WHO. (2013). The Use of and Surveillance (ATLAS). Retrieved 24 259492/1/9789241565523-eng.pdf?ua=1 241512848-eng.pdf?ua=1 Bedaquiline in the Treatment of November from: https://atlas-surveillance. Multidrug-Resistant Tuberculosis com/. Assessed January 2018. 3. WHO. (2017). Soil-transmitted hel- 9. WHO. (2017). HIV drug resistance Interim Policy Guidance. Retrieved minth infections. Retrieved 14 December report 2017. Retrieved 18 December 2017 from http://apps.who.int/iris/bitstr 2017 from http://www.who.int/ from http://apps.who.int/iris/bitstream/ eam/10665/84879/1/9789241505482_ mediacentre/factsheets/fs366/en/. 10665/255896/1/9789241512831-eng. eng.pdf pdf?ua=1 4. Vercruysse, J., et al. (2011). Is anthelmintic resistance a concern for the con- 10. WHO. (2017). Global Hepatitis Report trol of human soil-transmitted helminths? 2017. Retrieved 20 December 2017 from International Journal for Parasitology: http://apps.who.int/iris/bitstream/10665/ Drugs and Drug Resistance, 1(1), 14-27. 255016/1/9789241565455-eng.pdf?ua=1

5. WHO. (2017). Global tuberculosis 11. WHO. (2017). WHO Model List of report 2017. Retrieved 20 December 2017 Essential Medicines 20th List (Amended from http://apps.who.int/iris/bitstream/ August 2017). Retrieved 11 December 10665/259366/1/9789241565516-eng. 2017 from http://www.who.int/medi- pdf?ua=1 cines/publications/essentialmedicines/ en/ 6. Sanglard, D. (2016) Emerging Threats in Antifungal-Resistant Fungal Pathogens. Frontiers in Medicines, 3:11.

33 Antimicrobial Resistance Benchmark 2018

CROSS-CUTTING STORY Vaccines in the push to limit antimicrobial resistance

It is more than 30 years since research- and economic benefits they can offer in PREVENTING INFECTION AND ers first discovered that bacteria pro- this area. In this article, the Benchmark AVOIDING ANTIMICROBIAL ducing extended-spectrum beta-lacta- reports how companies are marketing MEDICINE MISUSE AND mase (ESBL) enzymes were resistant to and developing vaccines against path- EXPOSURE many penicillin and cephalosporin anti- ogens with a critical level of resistance. biotics, and to other types of antibiotics. This overview shows the pathogens There is overwhelming evidence that Today, antimicrobial resistance (AMR) is and diseases for which the focus should immunisation programmes can have recognised as a growing threat, emerg- be on improving immunisation cover- a profound impact on public health in ing at a global level. It poses complex age, on sustaining R&D efforts and/or general, and AMR more specifically. A challenges to the treatment of infec- on embarking on R&D in the very first recent notable example is the USA’s tious diseases, particularly in low- and place. introduction of the 13-valent pneumo- middle-income countries1 and in infec- coccal vaccine in 2010, which has led tions acquired in hospital settings. to a significant reduction in disease in Vaccines have the potential to play a both vaccinated (direct protection) and significant role in helping to alleviate the unvaccinated (herd protection) chil- problem of drug resistance. This role dren.9 Between 1998 and 2008, use of has been promoted by several organisa- pneumococcal vaccines in the USA has tions, such as Chatham House and the Sabin Vaccine Institute.2,3,4 The potential has also been acknowledged in the FigureVaccines 18. g Global3 coverage of older vaccines exceeds 80% - for newer vaccines final report of the UK-based Review on coverage remains relatively low Antimicrobial Resistance5, the 2016 UN In the period 2014 to 2016, global coverage of older vaccines remains stable at above 80%. For newer declaration on antimicrobial resistance6, vaccines, global coverage is increasing but remains low.¹⁵ (Source: WHO Immunization Coverage 2016) the UN IACG Framework for Action7 and the Davos Declaration.8 While it is vital DTP (3 doses) to develop new antibiotics to treat peo- Polio (3 doses) ple who have a bacterial infection, it is equally vital to develop vaccines to pre- Measles (1 dose) vent the incidence of infection. Vaccines Hepatitis B virus (3 doses) can guard against major diseases such as tuberculosis and malaria, and can Maternal and neonatal tetanus prevent viral infections (for which anti- Hib (3 doses) biotics are often wrongly prescribed). Vaccines do not just avert morbidity Measles (2 doses) and mortality; they also reduce the need Rubella to use antibiotics. By limiting the use of antimicrobial medicines, they can, in Hepatitis B (birth dose) turn, slow or curtail the emergence of Pneumococcal resistance. To combat AMR, vaccines consti- Rotavirus tute a clear and key line of defence. Yet, there is still much work to be done to Coverage % explore and assess the range of health ● Coverage during 2014 (%) ● Coverage during 2016 (%)

34 Access to Medicine Foundation been shown to reduce antibiotic-resist- 2016 was just 42% (figure 18). In gen- systematic approach to equitable pric- ant infections in children by 64%, and eral, the factors that deter or pre- ing, particularly for countries that in elderly patients by 45%.10 Further, in vent vaccination include weaknesses in receive no Gavi support and cannot par- geographic regions where vaccines for health systems and supply chains, insuf- ticipate in pooled-procurement sys- S. pneumoniae (pneumococcus) and ficiencies in the supply of vaccines, tems. They need to form clear strat- N. meningitidis (meningococcus) have challenges in financing and difficulties egies on pricing for all low- and mid- been introduced and widely deployed, within communities in accepting vacci- dle-income countries, and share this resistant strains have been eliminated.11 nation. For newer vaccines, affordability global pricing information. This will help Similarly, use of the H. influenzae type and production capacity are among the to facilitate negotiations and, by pro- b (Hib) conjugate vaccine, used to pre- key issues. The situation remains com- moting a more competitive environ- vent Hib from causing meningitis and plex, but the impact of missed opportu- ment, help to ensure prices are fair. non-central nervous system infections nities for immunisation is profound. More broadly, in some countries, com- has, in certain areas, almost eliminated panies can improve the way they prior- ampicillin-resistant Hib.11 Introduction of Providing greater access to vaccines itise registration of vaccines according rotavirus vaccination in the USA in 2007 The spread of disease in a commu- to public health needs. has led to more than an 80% decline nity can be halted when enough people In low- and middle-income coun- in community-acquired rotavirus hos- receive a vaccine, leaving too few sus- tries, governments and other vaccine pital admissions and more than a 60% ceptible individuals to infect. While it is procurers need to invest further in reg- decrease in hospital-acquired infec- often desirable to administer vaccines ulatory systems and immunisation pro- tions.12 After introduction of a 7-valent across large proportions of populations, grammes. This investment is especially pneumococcal vaccine in South Africa these vaccines must first be purchased important for vaccines used to prevent in 2009, rates of invasive pneumococcal in considerable volumes. As immuni- infections caused by priority pathogens disease dropped more than 50% in chil- sation programmes often aim to reach (see figure 19). Access to and wider use dren younger than two years of age and whole demographic groups, even small of these vaccines has the potential to more than 30% in adults 25 to 44 years decreases in unit price can make large curtail antibiotic resistance, and to avert of age, between 2005 and 2012.13 differences in the cost of each round of 2.6 million deaths per year from infec- Nevertheless, vaccines continue immunisation. tious diseases, most of them (2.4 mil- to have a huge untapped potential for Affordability – particularly of lion) from tuberculosis and pneumonia improving public health. Millions of chil- newer vaccines – remains an issue. worldwide.† dren around the world die from vac- Affordability issues can become acute Global vaccine coverage against cine-preventable diseases before they when a country’s level of national pneumococcal disease was estimated reach the age of five. Overall, some income rises, and it moves from low-in- to potentially avert up to 11.4 mil- two million of these deaths each year come up to lower-middle income sta- lion days of antibiotics for pneumo- may be prevented if children receive tus (as defined by the World Bank). nia caused by S. pneumoniae per year the right vaccine. While immunisa- Typically, it then loses access to in children younger than five years of tion coverage is increasing globally, pooled-procurement systems, putting age.19 in 2015 nearly one in five children did pressure on the country’s resources, Supply, availability and affordabil- not receive the basic life-saving vac- especially for procuring more expensive ity are closely interlinked. Multiple fac- cines recommended by WHO for rou- vaccines (e.g., for human papillomavi- tors affect whether a population is able tine immunisation. The number of those rus (HPV), rotavirus and pneumococcal to obtain sufficient vaccine coverage, not immunised with newer vaccines, infections).18 but an essential first step is to make such as those to prevent pneumococcal UNICEF* and the Pan American high-quality, effective vaccines availa- disease and rotavirus infection, is even Health Organization (PAHO)** run ble and affordable, allowing procurers higher (see figure 18).14,15,16 WHO esti- pooled-procurement systems, as does to purchase the quantities of vaccines mates that among children under five Gavi, the Vaccine Alliance***, a pub- necessary to immunise adequately the years old, there are 14.5 million episodes lic-private global health partnership populations they target. As they work of serious pneumococcal infections aiming to increase access to immunisa- to create and guarantee a stable and each year worldwide, with more than tion. These systems, which enable low- affordable supply, all parties involved 800,000 deaths17 arising from pneumo- and middle-income countries to club must recognise and reward effort, and nia, meningitis, ear and sinus infections, together to buy vaccines in bulk, have pool resources wherever possible. and bloodstream infections. been successful in helping countries to Although pneumococcal vaccines negotiate lower prices for vaccines. are marketed and available, the world- Companies that make and market vac- wide immunisation rate of infants in cines need to develop and embed a

* UNICEF is the world’s largest supplier of vaccines *** Gavi brings together many key organizations in a sin- † Data from Global Health Data Exchange, based on 2016 to children and works with many stakeholders to gle decision-making body regarding access to vaccines, calculations for H. influenzae type b (48,000 deaths), increase demand for vaccines, including through pooled and works to accelerate the introduction of new and pneumonia (1.2 million), tuberculosis (1.2 million) and procurement. underused vaccines in over 70 of the poorest countries. typhoid fever (128,000). ** PAHO is a UN public-sector procurement agency that 35 has established a fund that enables member states to access lower vaccine prices. Antimicrobial Resistance Benchmark 2018

OVERVIEW OF COMPANIES IN them to take action in this area.20 This The remaining four companies dis- SCOPE analysis discusses the practices of cussed here are all generic medicine nine pharmaceutical companies. These manufacturers: Aurobindo, Mylan, Sun The 2017 Access to Vaccines Index include five of the large research- Pharma and Wockhardt. Other major examined the actions taken by the based companies that were also in producers of vaccines, such as Serum world’s largest manufacturers of vac- the scope of the Access to Vaccines Institute of India, are not currently in cines to improve access to vaccines. It Index: GSK, Johnson & Johnson, the Benchmark’s scope. The five large also assessed the factors that prompt Merck & Co., Inc., Pfizer and Sanofi. research-based pharmaceutical companies are all marketing and developing vaccines. They are each con- Figure 19. More research and development needed on vaccines against priority ducting vaccines R&D through one or pathogens. more public-private partnerships. Of Five Benchmark companies (GSK, Johnson & Johnson, Merck & Co., Inc., Pfizer and Sanofi) market these, GSK is involved in three Product vaccines against four of 19 priority pathogens. To date, the companies are developing vaccines against Development Partnerships (PDPs), 12 priority pathogens, with projects at various stages. None of the companies has vaccines either while Johnson & Johnson and Sanofi marketed or in development against seven remaining priority pathogens. are involved in one and two PDPs respectively. Mylan and Wockhardt have Vaccines in preclini -

Marketed vaccines vaccines on the market. Aurobindo and Priority pathogens Vaccines in clinical cal development Sun Pharma are developing vaccines. development

Are vaccines available for priority pathogens? Of a total of 19 priority pathogens, com- Bacteria panies in scope of the Benchmark have Multidrug-resisant Enterobacteriaceae (incl. CRE and 1 1 so far targeted 12 with vaccines that are ESBL-producing) either marketed already, or in develop- Multidrug-resistant Acinetobacter spp. (incl. A. ment (see figure 19). The priority patho- baumannii) gens were identified based on the WHO Multidrug-resistant Pseudomonas aeruginosa priority pathogens list as of 25 February Neisseria gonorrhoeae 1* 2017 and ‘CDC’s US Biggest Threats as Drug-resistant Campylobacter spp. of April 2013’. For those pathogens, new Vancomycin-resistant Enterococcus (VRE) innovative medicines and vaccines are Drug-resistant Salmonella spp. 4** 2 highly needed. Drug-resistant Staphylococcus aureus 2 1 The five large research-based phar- Clarithromycin-resistant Helicobacter pylori maceutical companies in scope (GSK, Drug-resistant Shigella spp. 1 2 Johnson & Johnson, Merck & Co., Inc., Drug-resistant Streptococcus pneumoniae 4‡ 1 4 Pfizer and Sanofi) market 23 vaccines Ampicillin-resistant Haemophilus influenzae (Hib) 14*** 3† that have the potential to prevent or Drug-resistant Mycobacterium tuberculosis 1II 1 2 reduce antibiotic-resistant infections Clostridium difficile 1 2§ caused by four priority pathogens: H. Erythromycin-resistant group A Streptococcus influenzae (Hib), M. tuberculosis, S. Clindamycin-resistant group B Streptococcus 1 1 pneumoniae and Salmonella enterica ser. Typhimurium. In 2016, global immu- Viruses nisation coverage data showed 70% of Human immunodeficiency virus (HIV) 3 infants were vaccinated against Hib and 42% against pneumonia. Rates of immu- Protozoa nisation for TB and salmonella are not Multidrug-resistant Plasmodium falciparum 2 known.11

Fungi Unaddressed priority gaps Fluconazole-resistant Candida spp. Of the 19 priority pathogens overall, seven remain untargeted by com- * Includes one adaptation † Includes two adaptations ** Targeting S. enterica ser. Typhimurium: GSK’s Typherix ‡ GSK’s Synflorix; Merck & Co., Inc.’s Pneumovax 23; panies in scope (see figure 19): mul- and Hepatyrix; Sanofi’s Typhym VI and Viatim Pfizer’s Prevenar 13; Sanofi’s Pneumo 23 tidrug-resistant Acinetobacter spp. *** GSK’s Hiberix / Vaxem Hib, Menitorix, MenHibrex, § Includes one candidate that was terminated after the Infanrix Hexa, Infanrix Hib, Quinvaxem and Infanrix IPV period of analysis (including A. baumannii), drug-re- II Hib; Johnson & Johnson’s Quinvaxem; Merck & Co., Inc.’s Merck & Co., Inc.’s BCG vaccine USP sistant Campylobacter spp., PedVax Hib and Vaxelis; Sanofi’s ActHib, Hexaxim, Shan5 and Pentacel / Pentavac / Pentaxim

36 Access to Medicine Foundation

vancomycin-resistant Enterococcus analyse and share data on infec- creating immunity and reducing infec- (VRE), multidrug-resistant P. aerugi- tion rates and associated mortality tion, vaccines can eliminate the need nosa, erythromycin-resistant group A rates. On top of 19 surveillance pro- for antimicrobial medicines. This helps Streptococcus, clarithromycin-resist- grammes on antibiotics assessed by the to prevent the use of these medicines, ant H. pylori and fluconazole-resistant Benchmark, another programme mon- averting the need for further interven- Candida spp. No company in scope has itors the effects of one or more vac- tions to conserve their utility. Several yet marketed a vaccine for these, or has cines. Pfizer’s programme is notable, organisations – including the Bill & an R&D project under development. as it monitors the effects of vaccina- Melinda Gates Foundation25, Gavi, the Companies in scope have yet to bring tion as part of the wider effort to com- Vaccine Alliance26 and the Wellcome to market any vaccines to guard against bat antimicrobial resistance. It is part- Trust27 – are now advocating for vaccine 15 of the 19 identified priority patho- nering with academic research groups development and higher rates of vacci- gens (see figure 19). However, in addi- around the world to look at epidemio- nation globally, not only to prevent dis- tion to developing new vaccines for logical changes in disease caused by S. ease but also as an essential interven- Hib, M. tuberculosis, S. pneumoniae and pneumoniae. tion in tackling AMR. Salmonella enterica ser. Typhimurium, Using studies that focus on inva- Companies play an integral part the five companies above are develop- sive pneumococcal disease, pneumo- in this intervention, as they have the ing vaccines against an additional eight nia, otitis media and nasopharyngeal means and responsibilities to make priority pathogens. carriage, Pfizer is examining how the this a reality by: (1) responding to R&D Attrition rates for R&D projects are introduction of pneumococcal conju- gaps as identified by WHO and CDC to high, and other organisations may be gate vaccination in children and adults develop new vaccines; and (2) ensuring developing vaccines against these prior- may change patterns of antimicrobial the accessibility, affordability and sup- ity pathogens. Even so, it is important to non-susceptibility. Through reports, ply of these vaccines that make it to the incentivise large players – such as those conference presentations and peer-re- market. The incentives put forward by in the scope of the Benchmark, which viewed publications, Pfizer shares its major funders and other stakeholders have the resources to develop and roll results with regulatory agencies (as part involved must be aligned with these two out vaccines effectively – to engage of its regulatory commitments), pub- responsibilities. Major funders can sup- in developing vaccines that can pre- lic health authorities and the scientific port companies’ efforts in vaccine R&D vent infection from these drug-resistant community. and assist in the pooled procurement pathogens. of vaccines to improve accessibility and affordability. Surveillance of vaccines THE WAY FORWARD: ENSURE So far, five large research-based It is important to monitor the impact of VACCINES ARE ACCESSIBLE pharmaceutival companies in scope vaccines on the emergence of resist- (GSK, Johnson & Johnson, Merck & Co., ance, so that efforts to curb AMR can The use and effectiveness of vaccines Inc., Pfizer and Sanofi) have vaccines on be evaluated. To this end, pharmaceuti- to address AMR remains understated the market against four priority path- cal companies can support national and and under-reported. Among options ogens – with the potential to avert at international efforts to run AMR sur- proposed to tackle the problem of AMR, least four million deaths per year glob- veillance programmes, which collect, vaccines comprise an important tool. By ally.* These same companies are now involved in R&D for the development of additional vaccines against twelve prior- Figure 20. Five companies market and develop vaccines for priority pathogens. ity pathogens (including the four path- A core group of five large research-based pharmaceutical companies, included in the Benchmark, ogens already targeted - see figure 20). Vaccines g 3 targets priority pathogens for AMR with vaccines on the market or in development. The same GSK, Johnson & Johnson and Sanofi companies have R&D projects for vaccines against 12 priority pathogens: these include 8 projects at are developing some of these vaccines preclinical stage and 21 projects at clinical stage. Projects provided on the basis of confidentiality were through PDPs. For candidate vaccines not included. in the pipeline it is vital that companies work with stakeholders to ensure that GSK affordable access and adequate sup-

Sano ply are prioritised when these vaccines reach the market. Merck & Co., Inc.

Pzer * Data from Global Health Data Exchange (http://ghdx. healthdata.org/gbd-results-tool), based on 2016 calcula- Johnson & Johnson tions for H influenzae type B (48 thousand deaths), pneumonia (1.2 million), tuberculosis (1.2 million), typhoid fever (128 thousand), shigellosis (212 thousand), malaria (700 ● Vaccines in pipelineNumber ● Marketed of products vaccines thousand) and HIV (1.0 million).

37 Antimicrobial Resistance Benchmark 2018

REFERENCES

1. ReAct - Action on Antibiotic 7. IACG on Antimicrobial Resistance. 13. Von Gottberg, A., et al. (2014). Effects 21. Mylan. (2017). The online resource Resistance. (October, 2017). Antibiotic (August, 2017). AMR Framework for of Vaccination on Invasive Pneumococcal for Mylan influenza vaccines in the UK. resistance strikes hardest at the poor. Action Supported by the IACG. Retrieved 1 Disease in South Africa. New England Retrieved 26 October 2017 from http:// Retrieved 26 October 2017 from https:// November 2017 from http://www.who.int/ Journal of Medicine, 371, 1889-1899. www.influvac.co.uk/ www.reactgroup.org/news-and-views/ antimicrobial-resistance/interagency-co- news-and-opinions/year-2017/antibiot- ordination-group/20170818_AMR_FfA_ 14. UNICEF. (2016). Immunization: 22. Wockhardt. Biopharmaceuticals. ic-resistance-strikes-hardest-at-the-poor v01.pdf Introduction. Retrieved 25 October 2017 Retrieved 14 November 2017 from http:// from https://www.unicef.org/immuniza- www.wockhardt.com/how-we-touch- 2. Heyman, D. & Omaar A. (September, 8. Declaration by the Pharmaceutical, tion/index_2819.html lives/biopharmaceuticals.aspx 2016). Chatham House: New vaccines are Biotechnology and Diagnostics Industries essential to fighting antimicrobial resist- on Combatting Antimicrobial Resistance. 15. WHO. (July, 2017). Immunization 23. Sun Pharma. (October, 2016). Press ance. Retrieved 1 November 2017 from (January 2016). Retrieved 3 January 2018 coverage. Retrieved 24 October 2017 release: Sun Pharma ICGEB announce col- https://www.chathamhouse.org/expert/ from https://www.amrindustryalliance. from http://www.who.int/mediacentre/ laboration to develop novel dengue vac- comment/new-vaccines-are-essen- org/wp-content/uploads/2017/12/AMR- factsheets/fs378/en/ cine. Retrieved 26 October 2017 at http:// tial-fighting-antimicrobial-resistance Industry-Declaration.pdf www.sunpharma.com 16. WHO. (October, 2017). Children: 3. Clift, C. & Salisbury D.M. (2017). 9. Tomczyk, S., et al. (2016). Prevention reducing mortality. Retrieved 25 24. Aurobindo. Annual Report Enhancing the role of vaccines in com- of Antibiotic-Nonsusceptible Invasive November 2017 from http://www.who.int/ 2016-2017. batting antimicrobial resistance. Vaccine, Pneumococcal Disease with the 13-Valent mediacentre/factsheets/fs178/en/ 4(35):6591-93. Pneumococcal Conjugate Vaccine. Clinical 25. Abbott, A. (July, 2017). Vaccines pro- Infectious Diseases, 62(9), 1119-25. 17. O’Brien, K., et al. (2009). Burden of moted as key to stamping out drug-resist- 4. Gellin, B. (August, 2017). Vaccines disease caused by Streptococcus pneu- ant microbes. Nature. Retrieved 3 January are part of the solution to the emerg- 10. Hampton, L., et al. (2012). moniae in children younger than 5 years: 2018 from https://www.nature.com/ ing crisis of antibiotic resistance. STAT. Prevention of antibiotic-non suscepti- global estimates. Lancet, 374, 893–902. articles/d41586-017-01711-6. Retrieved 1 November 2017 from https:// ble Streptococcus pneumoniae with con- www.statnews.com/2017/08/01/ jugate vaccines. Journal of Infectious 18. UNICEF. Vaccine Price Data. 26. Gavi. (September, 2016). Seth antibiotic-resistance-vaccines/ Diseases, 205(3), 401–11. Retrieved 18 December 2017 from Berkley highlights role of vaccines in pre- https://www.unicef.org/supply/ venting AMR. Retrieved 1 November 2017 5. O’Neill, J. (May, 2016). Tackling 11. Lipsitch, M., et al. (2016, June). index_57476.html from http://www.gavi.org/library/news/ drug-resistant infections globally: final How Can Vaccines Contribute to Solving gavi-features/2016/seth-berkley-high- report and recommendations. The Review the Antimicrobial Resistance Problem? 19. Laxminarayan, R., et al. (2016). lights-role-of-vaccines-in-preventing-amr/ on Antimicrobial Resistance. MBio, 7(3), e00428-16. doi: 10.1128/ Access to effective antimicrobials: a mBio.00428-16. worldwide challenge. Lancet, 387, 168–75. 27. Wellcome Trust. Drug-resistant 6. United Nations. (September, 2016). infections: leading the global response. Draft political declaration of the high- 12. Anderson, E., et al. (2011) Impact 20. Access to Medicine Foundation. Retrieved 3 January 2018 from https:// level meeting of the General Assembly of Rotavirus Vaccination on Hospital- (2017). Access to Vaccines Index. wellcome.ac.uk/what-we-do/our-work/ on antimicrobial resistance. Retrieved Acquired Rotavirus Gastroenteritis in Retrieved from https://accesstovaccine- drug-resistant-infections 26 October 2017 from https://www. Children. Pediatrics, 127(2), e264–e270. sindex.org/media/atvi/2017-Access-to- un.org/pga/71/wp-content/uploads/ doi:10.1542/peds.2010- 1830. Vaccines-Index.pdf sites/40/2016/09/DGACM_GAEAD_ ESCAB-AMR-Draft-Political-Declaration- 1616108E.pdf

38 Access to Medicine Foundation Analyses of industry activity

This section includes three analyses of industry performance, exploring how the 30 companies are addressing key AMR challenges. They are based on the Benchmark analysis of data submitted by the companies, contextualised against real- world constraints and stakeholder expectations where possible and appropriate.

Research Area Analyses Research & Development - R&D investments - R&D projects in the pipeline - Partnerships - Facilitating access and stewardship

Manufacturing & Production - Environmental risk-management strategies - Disclosure regarding environmental risk management Appropriate Access & Stewardship - Ensuring access - Supporting stewardship through HCP education - Appropriate promotion - Brochure and packaging - Surveillance

MAIN FINDINGS

Research & Development: Leaders in R&D address global needs and plan ahead to ensure successful candidates are both accessible in low- and middle-income countries and used conservatively.

Manufacturing & Production: Most companies have environmental risk-management strategies in place that aim to minimise the impact of antibiotics discharged from manufacturing processes. However, the depth and breadth of these strategies differ widely regarding the different aspects evaluated by the Benchmark.

Appropriate Access & Stewardship: Leaders in this Research Area have access strategies in place regarding antimicrobial medicines in low- and middle-income countries, alongside their global stewardship of antibiotics.

39 Antimicrobial Resistance Benchmark 2018

RESEARCH AREA: RESEARCH & DEVELOPMENT What is in companies’ antimicrobial pipelines?

Figure 21. Company performance: research & development THE LEADERS

In Research & Development, GSK is the Large research-based pharmaceutical companies leader amongst large research-based pharmaceutical companies, followed by GSK Johnson & Johnson and Sanofi. GSK Johnson & Johnson is the largest investor in the space of Merck & Co., Inc. antimicrobial R&D and has a promis- Novartis ing pipeline in terms of size as well as Pzer the number of vaccines and novel anti- Roche microbial candidates. Among biophar- Sano maceutical companies, Entasis leads. Shionogi It has a novel antibiotic candidate in its pipeline, for which it has an access pro- Biopharmaceutical companies vision in place through its agreement Achaogen with GARDP. All leaders in this Research Cempra Area have novel antimicrobial candi- Entasis dates in their pipelines. Melinta MGB Biopharma Motif Bio Nabriva Polyphor Summit Tetraphase ● Research & Development The Medicines Company ● Remaining potential score Wockhardt Points

CONTEXT WHAT THE BENCHMARK As AMR increases, there is a pressing have both identified pathogens that are MEASURES need for novel products to be developed priorities for R&D into new medicines, The Benchmark captures the antimicro- to replace ineffective treatment options. vaccines and diagnostics. bial pipelines of 20 companies active in this Major scientific hurdles, alongwith tech- Once a new antimicrobial medicine is area of pharmaceutical R&D. It matches nical and regulatory complexities, form approved, the challenge is to introduce their pipelines with the WHO and CDC lists significant disincentives to investing in it in a way that (a) ensures its rapid and of priority pathogens, and reports on com- such R&D. Nevertherless, investment is appropriate accessibility for patients in panies’ plans to ensure access and stew- needed, including from those pharma- need while (b) conserving its use to slow ardship of successful candidates. It also ceutical companies that have resolved to the inevitable emergence of resistance. evaluates the scale of companies’ invest- remain in this sector. Certain pathogens Pharmaceutical companies are encour- ments in antimicrobial R&D. pose a greater threat of resistance than aged to engage with others to plan others; the WHO and the US Centers for ahead, during the development process, Disease Control and Prevention (CDC) to achieve these twin aims.

40 Access to Medicine Foundation

IN SUMMARY

Majority of R&D projects for infectious diseases target priority pathogens Of the 30 companies in scope,* the Benchmark has identified 24 companies carrying out a total of 276 R&D projects that target infectious diseases. Of these, the majority (175) target pathogens identified as priorities for further R&D by the WHO and/or the CDC (referred to by the Benchmark as priority pathogens). Of the 175 R&D projects, 88 are in preclinical development, and 87 in clinical stage. Almost one third (54 out of 175) targets gram-negative bacteria, a critical target for AMR: over half of these are in the preclinical stages of development. GSK has the fullest pipeline, with a large proportion of projects focussing on priority pathogens. It also has the highest number of vaccines in development that target priority pathogens. The pipelines of biopharmaceutical companies are comparatively smaller, as would be expected for companies of this type. These companies focus on R&D for priority areas.

Over half of R&D projects targeting priority pathogens are conducted through partnerships More than 50% of the 130 new R&D projects (excluding adaptations) are now being conducted in partnership. In 58 partnership-based projects, companies are working with public- or non-profit-sector partners only. In eight projects, companies’ partners include both public- or non-profit- and private-sector entities. In the remaining seven projects, companies are working with other private-sector partners only. Open collaborations, including PDPs, comprise a third of the overall number of project partnerships analysed by the Benchmark. Only one PDP (GARDP) is involved with the discovery and development of antibiotics against gram-negative (GNB) and/or gram-postivie bacteria (GPB). Sanofi is developing half of the 16 new candidates targeting priority pathogens in its pipeline through open collaborations, which is comparatively high versus other companies assessed in this Research Area.

Out of 28 antibiotics in late stages of clinical development, only two have both access and stewardship provisions in place The Benchmark identified 56 R&D projects in late stages of clinical development targeting priority pathogens (out of 175 projects), including 28 antibiotics and 14 vaccines for bacterial infections (the other 14 candidates focus on HIV/AIDS and malaria). Of these 28 antibiotics, only two meet the standard of having plans in place to ensure both rapid access where needed and stewardship of the success- ● Research & Development ful candidate: eravacycline, being developed by Tetraphase, targets a group of pri- ● Remaining potential score ority pathogens that cause complicated intra-abdominal and urinary tract infections; and paediatric bedaquiline for the treatment of tuberculosis, in development by Johnson & Johnson. Two other antibiotics – being developed by GSK for gonorrhoea and Pfizer for multidrug-resistant gram-negative bacterial infections – have stewardship provisions but no access plan, while three other antibiotics in the clinical pipeline (being developed by GSK, Entasis and Melinta) have an access plan in place but no stewardship provisions.

Access provisions for late-stage candidates are varied The most common access provisions for medicines and vaccines in late stages of development are: plans to register these products in countries where there is a high need (upon approval), plans for equitable and/or tiered pricing, and commitments to license IP to partners who work in geographic areas where access to medicine is likely limited. GSK, Johnson & Johnson, Pfizer and Sanofi have the most access provisions in place. The most predominant stewardship provision is the development of a surveillance programme for monitoring resistance.

*This chapter reports on all R&D projects identified by the Benchmark for the 30 companies in scope. Please note, however, that generic medicine manufacturers were not scored in this research area to preserve comparability within that group of companies. 41 Antimicrobial Resistance Benchmark 2018 – Research & Development

RESEARCH & DEVELOPMENT METHODOLOGY: WHAT THIS RESEARCH AREA MEASURES

In this Research Area, the Benchmark all 12 biopharmaceutical companies in Diagnostics Industries on Combating assesses pharmaceutical compa- scope. These companies have valiantly Antimicrobial Resistance; ten have nies engaged in antimicrobial R&D remained innovating in antimicrobials signed the Industry Roadmap for (i.e., in new antimicrobial drug devel- despite scientific, regulatory and com- Progress on Combating Antimicrobial opment and/or the adapting of exist- mercial challenges. A key selection cri- Resistance. In signing up to these indus- ing antimicrobial medicines and vac- terion for biopharmaceutical compa- try-wide initiatives, companies reaffirm cines, including those in preclinical and nies was that they are already develop- their commitment to investing in anti- clinical development, e.g., to develop ing at least one R&D project that tar- microbial R&D. new formulations or label extensions). gets a priority pathogen, as identified in The Benchmark analyses data col- It looks at the size of companies’ pipe- WHO’s report ‘Antibacterial Agents in lected through survey and from public lines, whether they are targeting prior- Clinical Development’.¹ The Benchmark sources. As far as possible, this data is ity pathogens identified by WHO and/or does not assess the R&D activities of clarified, cross-referenced and verified CDC, their R&D investments, R&D part- the 10 generic medicine manufactur- by the research team. How data is col- nerships and how they plan ahead to ers in scope so as to preserve the com- lected in the first instance depends on ensure successful candidates are both parability of this group. However, the a company’s level of engagement with accessible in low- and middle-income Benchmark highlights the product the Benchmark research. All compa- countries and used conservatively. development activities of these companies were surveyed, and data from pub- Of the 30 companies in the scope of nies where the information is available. lic sources were analysed for all compa- the Benchmark, this research area Most companies in scope (24) nies. Not all companies participated in analyses 20: all eight large research- have signed the Declaration by the the survey. based pharmaceutical companies and Pharmaceutical, Biotechnology and

INDICATORS ABOUT THIS CHAPTER A.1 R&D Investments Figure 22. Companies in scope In this chapter, the Benchmark reports A.2 R&D Projects its findings in four sections, each relat- A.2.1 Pipeline size Applicable indicators ing to a separate indicator (the section A.2.2 Novelty of pipeline A on A.2 covers all sub indicators). A.2.3 Vaccines in pipeline 1 2.1 2.2 2.3 3 4 p43 A.1 A.3 R&D Collaborations Large research-based pharmaceutical p44 A.2.1–A2.3 A.4 Facilitating access and companies p49 A.3

stewardship GSK ● ● ● ● ● ● p53 A.4 Johnson & Johnson ● ● ● ● ● ● Merck & Co., Inc. ● ● ● ● ● ● For a full listing of indicators and scor- Novartis ● ● ● ● ● ing eligibility see Appendix V. Pfizer ● ● ● ● ● ● Roche ● ● ● ● Sanofi ● ● ● ● ● ● Shionogi ● ● ● ● ●

Biopharmaceutical companies Achaogen ● ● ● ● Cempra ● ● ● ● Entasis ● ● ● ● Melinta ● ● ● ● MGB Biopharma ● ● ● Motif Bio ● ● ● ● Nabriva ● ● ● ● Polyphor ● ● ● ● Summit ● ● ● ● Tetraphase ● ● ● ● Aurobindo, Cipla, Macleods and Mylan were not eligible for this Research Area. However, the companies are active The Med. Company ● ● ● ● in antimicrobial R&D and are mentioned in this Research Wockhardt ● ● ● ● Area where relevant.

42 Access to Medicine Foundation

INVESTMENT INDICATOR What approaches do companies take to invest A.1 R&D Investments in antimicrobial R&D?

As antimicrobial resistance increases, for maintaining profitability and a com- from USD 5 million to USD 80 million. there is a pressing need for novel petitive edge in the market. The highest investments come from products to be developed to treat The Benchmark reports on the finan- Cempra, Achaogen and Tetraphase, life-threatening infections. Yet there is cial resources that companies’ report- which all invest over USD 60 million. little incentive for pharmaceutical com- edly dedicated to antimicrobial R&D in Four out of 10 generic medicine panies to invest in antimicrobial R&D, the fiscal year 2016, including in-kind manufacturers in scope (Aurobindo, not least because of the major scien- resources and contributions to collabo- Cipla, Macleods and Mylan) reported tific challenges involved in discover- rations. For both large research-based investments in R&D, directed toward ing and developing new antimicrobial pharmaceutical companies and biophar- adapting existing antimicrobial classes, but also the regulatory hurdles maceutical companies in scope, abso- medicines. of complex and divergent requirements lute amounts of investments are cap- to obtain market approval. The business tured, however only large research- model is also problematic, requiring based pharmaceutical companies were considerable investment in R&D but low scored in this area. Generic medicine returns compared to alternative R&D manufacturers are not evaluated in this areas, particularly as novel antibiotics Research Area. must be used conservatively to limit the risk of resistance emerging. This makes high-volume, high-return markets less LARGE DIFFERENCES IN likely to develop, as well as undesirable WHAT COMPANIES INVEST IN from the perspective of AMR control. ANTIMICROBIAL R&D Nevertheless, the pharmaceutical industry has a keen interest in the Five out of eight of the large research- development of new antibiotics, as based pharmaceutical companies evalu- they are the basis of modern medicine. ated reported their annual investments Even non-infectious diseases, such as in antimicrobial R&D. Of all companies many cancers, cannot be treated with- evaluated, GSK is the largest investor in out the availability of effective antibiot- antimicrobial R&D, followed by Johnson ics. Therefore, debate on the need for & Johnson. While these companies are sustained push funding and pull incen- the largest investors in absolute terms, tives is critical, as it is important that Shionogi is the largest investor when sufficient investment is made into the comparing R&D investments with reve- development of new antimicrobials and nue. Large research-based pharmaceu- vaccines. tical companies show large differences In order to stimulate antimicro- in what they earn from antimicrobials bial R&D, companies need to make and in what goes back into antimicro- and attract predictable and sustained bial R&D. Various companies state that investments, and follow clear plans to specific revenue and R&D expenditure develop key products. Companies may information cannot be reported in the be able to make use of existing push area of antimicrobials. incentives (which reduce the costs of Smaller biopharmaceutical compa- financial inputs for developers) and pull nies are fully reliant on external funders incentives (such as fast-track regulatory as their only source of income. Their reviews and extended market exclusiv- pipelines tend to be small and focussed ity). Companies can also be involved in on antibiotic drug discovery, on aver- the debate and implementation of new age including two clinical-stage anti- industry incentives to spur antimicrobial biotic candidates. Across this group, R&D in the future.² These are essential investments in antimicrobial R&D vary

43 Antimicrobial Resistance Benchmark 2018 – Research & Development

PIPELINE INDICATORS How many projects target priority pathogens? A.2 R&D Projects A.2.1 Pipeline size A.2.2 Novelty of pipeline A.2.3 Vaccines in pipeline

As resistance to current antimicrobi- R&D project that targets priority bacte- preclinical pipeline there is a major als grows, the need for new and novel ria, as identified in a 2017 WHO report.¹ focus on gram-negative bacteria includ- treatment options will become increas- The Benchmark examines: the size of ing the four bacteria classified as ‘criti- ingly acute. New antibiotics that tar- each company’s R&D pipeline target- cal’ by WHO. get resistant pathogens are particu- ing priority pathogens; how many of its larly sought after, as are new vaccines. candidates are novel; and whether the Priority R&D: a breakdown By preventing disease, vaccines remove company is engaged in vaccine R&D. Of the 175 R&D projects targeting pri- the need for treatment, which in turn The Benchmark does not assess the ority pathogens, 88 are in preclinical helps to preserve its effectiveness. R&D activities of the 10 generic medi- development and 87 in clinical stage. New diagnostics are also needed, to cine manufacturers in its scope. Despite Almost one third (54 out of 175) targets ensure antibiotics are only used when nine having R&D units, only four are gram-negative bacteria, a critical target they will actually work. New and exist- observed to be active in the area of for AMR: over half of these are in the ing products must be tied together in AMR.* preclinical stages of development. One Health approaches: strategies that In antibacterial R&D, gram-negative encapsulate all aspects of protection, bacteria are an important target as they treatment, infection control and relapse ALMOST TWO THIRDS OF R&D pose significant scientific challenges. prevention. PROJECTS TARGET PRIORITY Where gram-positive bacteria have a Existing antimicrobials and vaccines PATHOGENS single cell membrane (enabling many can also be improved through adapta- types of antibiotic to enter the cell), tions, for example, to qualify for addi- Of the 30 companies in scope* the gram-negative bacteria have a more tional indications or new fixed-drug Benchmark has identified 24 companies complex cell wall as well as other mech- combinations (FDCs). Such R&D can carrying out a total of 276 R&D projects anisms to expel toxic compounds. be useful in helping patients adhere to that target infectious diseases. Overall, Preclinical development involves pro- treatment guidelines and reduce any there are 97 projects that focus on viral jects that are in discovery and preclini- unnecessary exposure, e.g., by lowering infections and 147 projects that target cal phases. Preclinical indicates a phase the dosage or lessening the time-length bacteria. Other classes of pathogens of research before a medicine is tested of a treatment.³,⁴ As adaptive R&D receive less attention, including fungi in humans, when researchers collect builds upon previous efforts, the ther- and helminths. The majority of projects important data about feasibility, testing apies it yields may be ready for clinical identified (175 out of 276) target path- and drug safety. Projects in clinical devel- trials more quickly and, if approved, be ogens identified as priorities for fur- opment have reached at least Phase I, integrated more rapidly into healthcare. ther R&D by the WHO and/or the CDC the first testing in human subjects. In To encourage and shape the direc- (referred to by the Benchmark as pri- its analysis of clinical stage projects, the tion of antimicrobial R&D, it is impor- ority pathogens): including 54 targeting Benchmark has also included five prod- tant to know what is already being gram-negative bacteria (GNB), 27 tar- ucts that have been approved by reg- developed. The Benchmark maps the geting gram-positive bacteria (GPB), 20 ulatory agencies since 2016. Out of 87 pipelines of these companies against targeting both GNB & GPB, 29 targeting clinical-stage projects targeting prior- the priority pathogen lists published by M. tuberculosis, 28 targeting HIV, 14 tar- ity pathogens, 38 are new medicines, WHO and the CDC, as well as HIV and geting P. falciparum and three targeting 17 new vaccines and 32 adaptations to P. falciparum (malaria) since these are Candida spp. existing medicines or vaccines. Looking AMR priority areas identified by WHO.¹,⁵ The WHO and CDC prioritisation only at the 38 new medicines, 29 target In its pipeline analysis, the reports appear to be effective in direct- priority bacteria, with 26 being identified Benchmark evaluates 20 companies on ing company R&D activity toward spe- in WHO’s 2017 report on ‘Antibacterial the size and character of their pipelines. cific pathogens. In the past, WHO and agents in clinical development’.⁶ These include all eight large research- significant funders have focussed on based pharmaceutical companies and HIV/AIDS, malaria and tuberculosis. The largest pipelines 12 biopharmaceutical companies in They have helped to steer pharmaceu- GSK has the largest overall antimicro- scope. A key selection criterion for bio- tical companies to prioritise R&D in bial R&D pipeline (55 projects), and pharmaceutical companies was that these areas and have provided incen- within this the largest number of pro- they are already developing at least one tives for engagement. Especially in the jects targeting priority pathogens (40,

* This chapter reports on all R&D projects identified by the Benchmark for the 30 compa- 44 nies in scope. Please note, however, that generic medicine manufacturers were not scored in this Research Area to preserve comparability within that group of companies. Access to Medicine Foundation

Figure 23. Antimicrobial pipelines contain 276 R&D projects. Figure 24. Criteria for WHO and CDC The companies in scope are developing 276 antimicrobial R&D projects. Of these, 136 are in clinical prioritisation of pathogens. Number of products stages of development. Gram-negative bacteria (GNB) receive the most attention. Projects shown in Priority pathogens identified by the Benchmark this figure include adaptations. are drug-resistant pathogens as defined by the PATHOGENS WHO R&D Priority List and by the CDC Biggest Drug-sensitive bacteria Threat List - priority lists to guide research and GNB & GPB bacteria Mycobacteria development. Viruses Arenavirus WHO CDC Denguevirus Ebolavirus Filoviruses Flavivirus Mortality ● ● Hepatitis B virus Preventability ● ● Hepatitis C virus Herpesvirus Transmissibility ● ● Human papillomavirus (HPV) Treatability ● ● Inuenzavirus Norovirus 10-year projection of resistance ● Poliovirus Community burden ● Polyomavirus Rabiesvirus Healthcare burden ● Respiratory syncytial virus (RSV) Existing R&D pipeline ● Rhinovirus Rotavirus Prevalence of resistance ● Zikavirus 10-year projection of incidence ● Trypanosomes Leishmania Economic burden ● T. brucei Incidence ● T. cruzi Fungi Helminths P. vivax

PRIORITY PATHOGENS Bacteria (GNB) Bacteria (GPB) There are 175 projects targeting Bacteria (GNB & GPB) priority pathogens, including 87 M. tuberculosis HIV clinical-stage candidates. P. falciparum (malaria) Candida spp. ● Preclinical stage ● Clinical stage

Figure 25. Breakdown of the clinical pipeline for priority pathogens. CompaniesR&D are p45focussing erratum antimicrobial R&D efforts on high-priority pathogens§ as identified by WHO and/or the CDC. Most attention is given to Enterobacteriaceae (CRE† and ESBL‡-producing), S. aureus and S. pneumoniae. Several pathogens receive little or no attention such as Candida spp., Campylobacter spp. and H. pylori. Projects shown in this figure exclude adaptations. At publication, this figure incorrectly grouped the pathogen VRE (vancomycin-resistant enterococcus) with gram-negative bacteria. This has been updated.

ThreatPathogen level PATHOGEN WHO* CDC** Medicines Vaccines Bacteria (GNB & GPB) Gram-negative bacteriaGram-negative (GNB)*** bacteria (GNB)*** CRE† ● CRE†● ESBL-producing Enterobacteriaceae‡ESBL‡producing Enterobacteriaceae● ● A. baumannii A.● baumannii● P. aeruginosa P.● aegurinosa● N. gonorrhoea N. ●gonorrhoea● Campylobacter spp. Campylobacter● ● Salmonella spp. Salmonella● ●spp. H. pylori ● H. pylori● Shigella spp. Shigella● ●spp. H. influenzae ●H. inuenza● Gram-positive bacteria Gram-positive(GPB)*** bacteria (GPB)*** S. aureus ● S. aureus● VRE ● ●VRE S. pneumoniae S. pneumoniae● ● C. difficile C. dicile● Gr. A Streptococcus Gr. A Streptococcus● Gr. B Streptococcus Gr. B Streptococcus● M. tuberculosis M. tuberculosis● HIV WHO AMR priority area HIV P. falciparum (malaria) P. falciparum (malaria) Candida spp. Candida spp.●

WHO CDC Medicines Vaccines Critical ● Urgent ● Phase I ● Phase II ● Phase III ● Approval ● Phase I ● Phase II ● Phase III High ● Serious Medium ● Concerning * WHO Priority Pathogens List ** CDC Biggest Threats list 45 *** Projects that target both GNB and GPB are included for each relevant pathogen † CRE: carbapenem-resistant Enterobacteriaceae ‡ ESBL: Extended Spectrum ß-Lactamase § One of these projects has been terminated after the period of analysis Antimicrobial Resistance Benchmark 2018 – Research & Development constituting 70% of all its projects).* of antimicrobials, while also ensuring treatment regimen, which can occur Johnson & Johnson and Sanofi have that the pathogen will be eliminated.⁷ more easily with oral regimens. the second and third largest antimicro- Eighteen companies in scope are adapt- GSK, Merck & Co., Inc., Pfizer and Sanofi bial pipelines, albeit with smaller pro- ing existing antimicrobials through are examples of other large research- portions of projects that target prior- R&D, including four generic medicine based pharmaceutical companies ity pathogens. Of Johnson & Johnson’s manufacturers. involved in adapting existing agents. 48 projects, 15 target these patho- Johnson & Johnson is the large Notably, GSK is developing its meningo- gens.** Of Sanofi’s 32 projects, 18 tar- research-based pharmaceutical com- coccal B vaccine (Baxsero®) for the pre- get them.*** While Pfizer’s antimicrobial pany with the most adaptations in its vention of gonorrhoea. pipeline is smaller than these compa- pipeline (six), including a paediatric for- Four generic medicine manufac- nies, it focusses mainly on priority path- mulation for bedaquiline and long-act- turers in scope are active in adap- ogens. It has seven projects in developing parenteral formulations for rilpivir- tive R&D for antimicrobials, account- ment in infectious diseases, six of these ine (for stand-alone use and in combina- ing for 18 projects. For example, Cipla target priority pathogens, four of which tion with cabotegravir, being developed is developing a taste-masked four-in- are vaccine candidates. in partnership with GSK). The long-act- one tablet formulation (abacavir/lam- The 12 biopharmaceutical compa- ing formulation maintains viral sup- ivudine/lopinavir/ritonavir) for the nies in scope have smaller pipelines, pression over a long period, and avoids treatment of HIV/AIDS in children. but almost all of their antimicrobial the risk of patients not adhering to a Aurobindo, Macleods and Mylan are R&D projects (40 out of 41) target priority pathogens. Among them, Entasis, Nabriva and Wockhardt have theR&D largest g 3.2 a Figure 26. GSK is developing the most projects that target priority pathogens. pipelines targeting priority pathogens. GSK directs approximately 70% of its antimicrobial R&D projects towards priority pathogens. The eight Wockhardt has the most R&D projects large research-based pharmaceutical companies that were analysed for this pipeline are developing 122 in clinical-stage development (four new products targeting priority pathogens in total. clinical-stage R&D projects and one GSK adaptation). Johnson & Johnson Sano Five companies active in vaccine R&D Novartis The companies with the largest pipe- Shionogi lines are also developing vaccines. Five Merck & Co., Inc. companies are developing vaccines Roche overall: GSK, Johnson & Johnson, Merck Pzer & Co. Inc., Pfizer and Sanofi are developing new vaccines (30 in total), for Number of projects example, for the development for HIV and S. pneumoniae. The use of vaccines ● Projects targeting priority pathogens ● Projects targeting other pathogens to prevent infectious diseases is valuable because it limits subsequent inap- Figure 27. Projects targeting priority pathogens by biopharmaceutical propriate use of antimicrobial medi- R&Dcompanies. g 3.2 b cines; which, in turn, can limit the emer- The antimicrobial R&D pipelines of biopharmaceutical companies are smaller compared to large gence of resistance. research-based pharmaceutical companies, but their R&D efforts are focussed almost exclusively on priority pathogens.

Entasis GENERIC MEDICINE Nabriva MANUFACTURERS ACTIVE IN Wockhardt ADAPTIVE R&D Achaogen Melinta The R&D project pipeline that the MGB Biopharma Benchmark assesses includes 45 Cempra adapted medicines and vaccines. Polyphor Adapting medicines and using them for ● Projects targeting Tetraphase a new purpose can help to curb antimi- priority pathogens Motif Bio crobial resistance. For example, reduc- ● Projects targeting other The Medicines Company ing the dosage or treatment dura- pathogens Summit tion can be useful to decrease exposure to unnecessarily high amounts Number of projects * One project (GSK3342830) was terminated after the period of analysis ** One project (Rilpivirine long-acting nanosuspension) was terminated after the period of analysis 46 *** One project (C. difficile vaccine) was terminated after the period of analysis Access to Medicine Foundation adapting antimicrobials that target HIV little R&D attention from the companies ©Novartis through new fixed drug combinations. in scope: that includes Campylobacter Macleods is also investigating the effec- spp., Salmonella spp., Shigella spp. and tiveness and tolerability of lower dos- H. pylori. While Novartis has one med- ages or new formulations of anti-tuber- icine in clinical development (LYS228) culosis products for the use in children. that may be efficacious against The company is, for example, examin- Salmonella spp. and Shigellae spp., it is ing the effectiveness of a 150 mg dis- not developing the candidate for indi- persible tablet of linezolid, compared to cations caused by these pathogens. the current recommended dose of 400 Instead, this candidate is being devel- Inspecting bacterial growth at Novartis Institute mg to 600 mg (as per the WHO Model oped for the treatment of complicated for Biomedical Research. List of Essential Medicines). Access intra-abdominal infections and compli- to novel treatments will take time to cated urinary tract infections caused by companies: Entasis, GSK, Nabriva, MGB establish. In the meantime, patients suf- drug-resistant gram-negative bacteria. Biopharma, Polyphor, Roche, Summit fering from tuberculosis have much GSK has two clinical-stage vaccines and The Medicines Company (see fig- to gain from incremental R&D to regi- for Shigella sonnei and Shigella flexneri, ure 28). mens, e.g., reduction of treatment side in addition to its preclinical develop- Four of these companies have a effects.⁸,⁹ This type of adaptive R&D is ment of two vaccines that cover non-ty- product in development that meets all therefore encouraged. As generic med- phoidal Salmonella and S. enterica ser. four of the WHO’s criteria: Polyphor icine manufacturers, Aurobindo, Cipla, Typhimurium. Overall, however, com- has murepavidin, a new antibiotic can- Macleods and Mylan are not scored in panies in scope are giving no attention didate that targets the cell membrane this Research Area. at clinical stage to some gram-negative of drug-resistant P. aeruginosa; MGB bacteria, such as H. pylori and drug-re- Biopharma and Summit are developing Multidrug-resistant sistant Campylobacter spp. compounds that target C. difficile (MGB Enterobacteriaceae and S. aureus Merck & Co., Inc., MGB Biopharma Biopharma with MGB-BP-3, a DNA receive most attention and Shionogi are the only compa- minor groove binder; and Summit with There are 87 projects in clinical devel- nies evaluated by the Benchmark to ridinilazole, a bisbenzimidazole)⁶; and opment targeting priority patho- be investing in antifungal drug candi- Roche is developing a biological agent gens: the largest proportion antibi- dates that target fluconazole-resistant against S. aureus consisting of a mon- otics targeting Enterobacteriaceae Candida; all in preclinical stage. oclonal antibody that binds to the sur- (including carbapenem-resistant There are twice as many new drug face of the bacterium and releases rifa- Enterobacteriaceae (CRE) and extend- candidates in clinical development mycin to kill it. ed-spectrum ẞ-lactamase (ESBL)- (38) as there are new vaccine candi- Of the remaining four companies, producing Enterobacteriaceae) and dates (17). The likelihood of regula- The Medicines Company has devel- S. aureus. Others focus on S. pneu- tory approval for vaccines is higher than oped the ẞ-lactamase inhibitor mer- moniae, H. influenzae type b (Hib) and for medicines: 16% of the vaccines in openem/vaborbactam (Vabomere™); Acinetobacter spp. While these path- Phase I clinical development will receive Nabriva is developing lefamulin, which ogens are indeed priorities for R&D, approval initially, as compared with just belongs to a drug class that has been there is also a great need for new anti- 6% for a Phase I medicine.¹⁰ used in animals and in a topical formula- biotics with a broad-spectrum activity tion for humans, and for which levels of against pathogens identified as ‘Critical’ How novel are new antimicrobials in cross-resistance are yet unknown; GSK by the WHO.¹ the pipeline? is developing gepotidacin; and Entasis Thirteen companies are involved in Of the 38 medicines in clinical devel- is developing zoliflodacin. Gepotidacin 17 clinical-stage candidates that target opment, the Benchmark identifies 17 and zoliflodacin both have novel chem- ‘Critical’ pathogens, mainly gram-neg- that can be considered novel. To qualify ical structures targeting existing func- ative bacteria, identified by WHO.¹ as novel, a candidate must fulfil one or tional targets, and to which cross-resist- These include projects (16 antibi- more of the criteria defined by WHO⁶: it ance has not emerged. otic candidates and one vaccine) tar- represents a new chemical class; aims at GSK is the only company develop- geting Enterobacteriaceae (CRE and a new target; has a new mode of action; ing novel medicines that treat tubercu- ESBL-producing), and multidrug-re- and/or has an absence of cross-resist- losis and HIV/AIDS. Its clinical pipeline sistant Acinetobacter spp., including ance from existing antimicrobials. This includes a novel anti-tuberculosis drug A. baumannii. The second most com- includes nine novel antibiotics that tar- canditate and four novel agents that mon target are gram-positive bacte- get priority bacteria, including M. tuber- target HIV. ria (S. aureus, S. pneumoniae and C. culosis (also identified in the WHO Novartis, Sanofi and Johnson & difficile) followed by HIV. Other prior- report)⁶. These nine antibiotic candi- Johnson are developing novel anti- ity gram-negative bacteria receive very dates are being developed by eight malaria medicines to target the

47 Antimicrobial Resistance Benchmark 2018 – Research & Development

Figure 28. What makes an antibiotic novel? Absence of CR**

There are nine novel drug candidates in companies’ clinical pipelines, five fulfilling all four criteria New drug class

defined by the WHO.⁶ A majority (six) of these are developed by biopharmaceutical companies. New target New MoA*

Company Antibiotic Clinical phase Pathogen MGB Biopharma MGB-BP-3 Phase I C. difficile ● ● ● ● Polyphor Murepavadin (POL7080 iv) Phase II P. aeruginosa ● ● ● ● Roche Anti-S. aureus TAC (RG7861)*** Phase I S. aureus ● ● ● ● Summit Ridinilazole Phase II C. difficile ● ● ● ● GSK GSK3036656 Phase I M. tuberculosis ● ● ● ● Entasis Zoliflodacin (ETX0914) § Phase II N. gonorrhoeae ● ○ ● ● GSK Gepotidacin § Phase III N. gonorrhoeae ● ○ ● ● Nabriva Lefamulin § Phase III S. aureus, H. influenzae ●† ○ ● ‡ The Medicines Company Meropenem/vaborbactam (Vabomere™) Approved CRE ● ○ ○ ‡

* Mode of action † First systemic formulation of this class for human use (currently ** Cross-resistance used topically in humans and systemically in animals) *** New Biological Entity ‡ Data is inconclusive or agreement with the WHO advisory group § Broad-spectrum antibiotic candidate by nature was lacking. drug-resistant P. falciparum. Working Of the 29 new antibiotic candidates in as complicated urinary tract infections with Medicines for Malaria Venture clinical development, ten are known to (cUTI), community-acquired bacterial (MMV), Novartis is developing two novel the Benchmark to be broad-spectrum, pneumonia (CABP) and hospital-ac- medicines, while Sanofi and Johnson & meaning that they act against both quired bacterial pneumonia (HABP), and Johnson have one each. gram-positive and gram-negative bac- acute bacterial skin and skin structure While not considered novel accord- teria. Seven companies are currently infections (ABSSSI) – caused by a wide ing to WHO criteria, a further 21 anti- developing these broad-spectrum anti- set of pathogens. biotic candidates at the clinical stage biotics with a focus on a single indica- Among broad- and narrow-spectrum involve new agents within an exist- tion, albeit where public need for treat- antibiotics the range of bacteria against ing chemical drug class, such as the ment is high. These companies could which they are active varies from very ß-lactam antibiotic class. These classes opt to develop these medicines for a broad spectrum to very narrow spec- have been in use for some time (in most wide selection of indications. Entasis, trum and everything in the middle. cases for decades) and resistance has for example, decided to develop its Narrow-spectrum antibiotics are active emerged. As a result, the bacteria they broad-spectrum candidate zoliflodacin against a selected group of bacterial target are more likely to have cross-re- solely to treat gonorrhoea. types, for example gram-positive bac- sistance to new generations, and may Other companies, such as Cempra teria, or more specifically one species adapt faster. and Melinta (merged in November of gram-positive bacteria. These antibi- 2017), are doing the opposite. They are otics have the benefit that they do not TEN REPORTED BROAD- broadening the reach of their antibiotic affect most other bacteria present in SPECTRUM ANTIBIOTICS IN THE candidates to enlarge the number of the body, which can prevent the emer- PIPELINE patients these can treat, and are includ- gence of resistance in other bacteria. ing multiple different indications – such For curbing AMR, they are best used in tandem with diagnostics tools that can Figure 29. Few novel clinical-stage projects targeting priority bacteria. quickly identify that the indicated bac- There are 130 projects targeting bacteria prioritised by WHO and/or CDC as AMR risks. Looking at the teria are indeed causing the infection. projects in clinical development, only nine are considered novel, e.g., they have a new mode of action or Such point-of-care diagnostics are still new target, meaning they have a lower risk that bacteria already show resistance. lacking, which means it can take more than 16 hours to identify bacteria and Novel drug candidates their susceptibility profile to the antibi-

New vaccine candidates otic in question.¹¹ Broad-spectrum antibiotics are often empirically used to projects for Preclinical stage bridge the time period between diag- priority projects Adaptations bacteria nostic testing and the arrival of susceptibility results. However, this means Clinical stage New drug candidates exposing all bacteria in the body, increasing the chance of resistance

48 Access to Medicine Foundation emerging. Knowing this, researchers medicines.¹² Access may be restricted pathogenic heterogeneity of infec- may choose to develop broad-spectrum when biologicals reach the market due tions and therefore the need for costly antibiotics for use against only one indi- to affordability issues and the capacity – and often non-existent – diagnostics.¹⁴ cation with the intention of limiting its to use and monitor treatments appro- These complexities lead to the require- usage and decreasing the likelihood of priately. One hurdle for the development of more patients, which in turn resistance emerging. ment of narrow-spectrum antibiotics increases the time and cost of clinical is the challenge associated with tradi- trials. For example, a post hoc analysis The market for narrow-spectrum anti- tional regulatory evaluation.¹³,¹⁴ Clinical of the effectivity of linezolid over van- biotics is financially less attractive com- trials are designed to demonstrate non- comycin in HABP/VABP took five years pared to broad-spectrum, as the target inferiority, meaning a candidate medi- to complete.¹⁵ Polyphor is an example of population is smaller. All antibody-based cine is at least as safe and effective as a company developing a single-patho- biologicals are narrow-spectrum: each the current standard treatment. gen antibiotic (murepavadin); it started targets a specific pathogen species. However, demonstrating this non-in- a timely process with EMA and FDA Biologicals are in turn also more costly feriority for narrow-spectrum antibi- to develop a customised clinical trial to manufacture compared to synthetic otics can be more difficult, due to the design for murepavadin.

PARTNERSHIPS

Around half of R&D projects are being INDICATOR A.3 R&D Collaborations conducted in partnership

When pharmaceutical companies col- Venture (MMV), which has multiple area are working with in antimicrobial laborate in R&D, they can reduce dupli- partnerships with several companies. drug development. cation, share risk, pool expertise, and Much PDP funding comes from major stimulate innovation that leads to suc- global health donor organisations like Over half of R&D projects target- cessful development. This can be the Bill & Melinda Gates Foundation and ing priority pathogens are conducted achieved through various forms of part- the Wellcome Trust.¹⁴ through partnerships nership. Public-private partnerships can As an alternative to the PDP model, More than 50% of the 130 new R&D take various forms including: product governments, private foundations and projects (excluding adaptations) are development partnerships (PDPs) or NGOs can also directly invest in com- now being conducted in partnership. partnerships with governments, NGOs panies’ drug development. Such push In 58 partnership-based projects, com- or public institutes such as universities. incentives are used by governments panies are working with public- or Public-private collaboration encour- and NGOs to stimulate need-based non-profit-sector partners only. In eight ages open and collaborative sharing of R&D. Examples of such partners include projects, companies’ partners include intellectual property (IP), facilitates the the Bill & Melinda Gates Foundation, both public- or non-profit and pri- rapid deployment of resources, and pro- Biomedical Advanced Research and vate-sector entities. In the remaining motes the development of products.¹⁶ Development Authority (BARDA), the seven projects, companies are working Consequently, public-private partner- European Commission (through the with other private-sector partners only. ships are useful for targeting diseases Innovative Medicines Initiative (IMI)) and (see figure 30). that have a disproportionate effect on the Wellcome Trust. In comparison, the 2016 Access to people living in low- and middle-income The Benchmark looks at the lev- Medicine Index analysed the R&D pro- countries, for whom there is less com- els at which pharmaceutical companies jects being carried out by 20 of the mercial incentive to develop solutions. engage in public-private R&D collabora- world’s largest research-based com- For the last two decades, PDPs have tions to discover and develop new med- panies targeting a defined set of 51 proven particularly effective in this icines and vaccines that target priority high-burden diseases (including com- regard. PDPs take the form of central- pathogens. It looks for partnerships in municable and non-communicable dis- ised non-profit organisations that ena- three categories: (1) PDPs or open col- eases, neglected tropical diseases and ble the public, private, academic, and laborations; (2) direct partnerships with maternal and neonatal health condi- philanthropic sectors to aggregate governments and/or NGOs; (3) direct tions): it found that a lower propor- funding for (and pool the risk of) devel- partnerships with public institutes such tion, one third, of the 420 R&D pro- oping medicines, vaccines and other as universities. The Benchmark also pre- jects identified were being carried out health tools. An example of such a part- sents an overview of the partners that in partnership. nership is the Medicines for Malaria the companies assessed in this research

49 Antimicrobial Resistance Benchmark 2018 – Research & Development

began to be prioritised internationally. Figure 30. Half of new R&D projects involve partnerships with public or non- A large proportion of the projects in profit partners. the priority pathogen pipeline (exclud- 66 out of 130 R&D projects involving new medicines or vaccines targeting priority pathogens ing adaptations) that are for the treat- are carried out in partnerships with public or non-profit partners. These involve 27 PDPs or open ment of HIV/AIDS, malaria and tubercu- collaborations, of which only two focus on new antibiotics for GNB and/or GPB – these are managed by losis (19 out of 45) are in development GARDP and IMI. The remaining PDP projects are focussed on HIV/AIDS, malaria and tuberculosis. with a PDP. Two out of 82 R&D projects that target priority GNB and/or GPB are collaborative efforts involving a PDP or open collaboration. The Innovative In-house R&D projects Public partners only projects Medicines Initiative’s New Drugs 4 Bad Bugs (ND4BB, launched in 2013) is a large multi-stakeholder research con- Private partners only Public & private partners sortium focussed on the scientific, regulatory, and business challenges of AMR, and covers two R&D projects involving GSK, Pfizer and Sanofi.¹⁷ The only PDP The Benchmark finds that PDPs and from different organisations. One exam- focussing on antibiotics againts GNB open collaborations comprise a third ple is the collaboration between Sanofi and/or GPB is the Global Antibiotic of the overall number of project part- and MMV to formulate a new arte- Research and Development Partnership nerships. These include 14 in preclini- fenomel/ferroquine antimalarial treat- (GARDP), launched in 2016 as a joint ini- cal-stage and 13 in clinical-stage devel- ment for children. The majority of PDP tiative between WHO and the Drugs for opment, as well as others that aim to projects focus on HIV/AIDS, malaria and Neglected Diseases Initiative (DNDi). develop novel fixed drug combinations tuberculosis and have been running PDPs in the field of antibiotic resistance (FDCs) using investigational agents since around 2000 when these diseases are thus still in their infancy.

Figure 31. Half of the partnering bodies are focussed on antibacterial R&D. This figure provides an overview of public partners (PDPs and funders) active in the space of AMR. Six organisations (Wellcome Trust, MMV, Bill & Melinda Gates Foundation, US NIH, BARDA and TB Alliance) are involved in most of the projects that target priority pathogens carried out in public-private partnerships.* P. falciparum (malaria) Bacteria (GNB & GPB) Number of projects M. tuberculosis Candida spp. HIV Partner Companies involved** Wellcome Trust 11 ● ● ● GSK, Merck & Co., Inc., Novartis, Polyphor, Summit, Tetraphase MMV 10 ● Cipla, GSK, Johnson & Johnson, Novartis, Sanofi Bill & Melinda Gates Foundation 8 ● ● ● ● Achaogen, GSK, Johnson & Johnson, Sanofi, Pfizer US National Insitutes of Health (NIH) 8 ● ● Achaogen, Entasis, GSK, Johnson & Johnson, Sanofi, Tetraphase BARDA 7 ● Achaogen, Cempra, GSK, Pfizer, Roche, Tetraphase, The Medicines Company TB Alliance 7 ● Macleods, Sanofi, Shionogi US Ministry of Defence 5 ● ● GSK, Johnson & Johnson, Sanofi Innovative Medicines Initiative (IMI) 3 ● GSK, Pfizer, Sanofi, Polyphor*** CARB-X 3 ● Achaogen, Entasis, Tetraphase Aeras 2 ● GSK, Sanofi PATH 2 ● ● GSK, Johnson & Johnson HIV Vaccine Trials Network 2 ● Johnson & Johnson GARDP 1 ● Entasis DNDi 1 ● Cipla * The public-private partnerships shown in this figure IAVI 1 ● Johnson & Johnson exclude partnerships with public research institutes. Pox-Protein Public & Private Partnership (P5) 1 ● GSK, Sanofi ** The list of companies involved is not exhaustive as some details were provided on the basis of confidentiality. Swiss Innovation Agency 1 ● Polyphor ***After the Benchmark’s period of analysis, Polyphor European Vaccines Initiative 1 ● GSK entered into collaboration with IMI.

50 Access to Medicine Foundation

Two PDPs focus on tuberculosis: TB ©GSK active against a broader range of patho- Alliance for the development of new gens including M. tuberculosis. medicines and Aeras for the development of new vaccines. Which company does the most R&D in The Benchmark finds that in addi- partnership? tion to PDPs and open collaborations, Sanofi is comparatively more engaged 27 (20%) other R&D pipeline projects in R&D partnerships: it is developing (excluding adaptations) assessed in half of the 16 projects in its pipeline in this research area are funded by pub- scope through collaborative PDPs. GSK, lic organisations, including govern- Research on HIV taking place in GSK’s HIV Centre. Johnson & Johnson and Novartis are ments and NGOs. The most prom- also active, with GSK engaging in nine inent funders, directly or indirectly This gives GARDP the right to manufac- PDPs out of 35 R&D projects eligible for (e.g., through initiatives such as the ture the drug worldwide and to sell or this indicator (new candidates targeting Combating Antibiotic Resistance distribute it in 168 countries and territo- priority pathogens). Bacteria Biopharmaceutical Accelerator, ries outside the developed world. Cipla and Macleods are the only or ‘CARB-X’), are the US Biomedical As companies and partnerships two generic medicine manufacturers Advanced Research and Development develop antimicrobials, they need to link involved in collaborative public-private Authority (BARDA), the US National provisions for access with safeguards R&D. In collaboration with the Drugs for Institutes of Health and the Wellcome for stewardship. CARB-X is one public Neglected Diseases Initiative (DNDi), Trust. partner that requests stewardship plans Cipla is developing an innovative new from all biopharmaceutical companies treatment for infants and children living Public partners advocate in its portfolio. As yet, discussions are with HIV/AIDS, to be delivered through global access ongoing concerning how these plans taste-masked granules combining There are 18 public partners (see fig- should be designed. four antiretroviral ingredients (lopina- ure 31) involved in drug develop- vir, ritonavir, abacavir and lamivudine). ment focussed at priority patho- Innovative models: open-source drug Macleods collaborates with TB Alliance gens with companies analysed. Eight discovery and UNITAID on the development of of these require companies to make In partnership with the MMV, GSK and paediatric formulations of tuberculosis commitments regarding access provi- Novartis have developed an innova- medicines. sions (plans and strategies for ensur- tive open-source drug discovery pro- Most of the biopharmaceutical coming access to the approved product). gramme. This is accelerating progress panies (9 out of 12) in scope have no The Benchmark finds that public part- in discovery by publishing raw data products on the market yet. As such, ners can influence these provisions in and results in the public domain, and they do not gain revenue from sales two ways. encouraging scientists to make incre- and are fully dependent on external One way is to insert a clause into the mental contributions. Such a model funding, such as private venture capi- funding agreement that requires a com- helps keep down costs, and removes tal and research grants, to cover their pany to ensure access to the product in the ability to patent results, allowing R&D expenditures. Half of biopharma- countries where need is high. If, follow- others to build upon these discoveries. ceutical companies assessed in this ing market approval, the company can- In antimicrobial resistance, MMV research area receive public or NGO not prove within a specified amount of applied the open-source drug discovery funds. Entasis is the only one involved time that it is providing this access, the model in an initiative called the Malaria in a PDP (with GARDP, established in public or non-profit partner reserves Box which was launched in 2011. Each 2016). The R&D projects in these pipe- the right to share its intellectual prop- Malaria Box assembled 400 diverse lines are funded by BARDA, CARB-X, erty (IP) with other partners who can molecules active against P. falciparum, the Wellcome Trust and the National provide access in specified countries. derived from an extensive screening of Institute of Allergy and Infectious The Wellcome Trust is one such partner libraries held by GSK, Novartis, and the Diseases (NIAID) among others. to use this measure. US-based St Jude Children’s Research The remaining companies finance their Another way that public organ- Hospital. Using an open data-sharing R&D activities through private financing isations ensure companies provide platform, MMV despatched more than rounds or a stock exchange listing. Even access through a PDP is to divide the 160 of these boxes, free of charge, to so, it is encouraging that some private IP rights for a product in development researchers in 27 countries, to help cat- investors remain willing to invest in anti- among countries where need is high. alyse drug discovery and research. In biotic development. An example of this is seen in the agree- December 2015, MMV launched a sim- ment between GARDP and Entasis, to ilar initiative: The Pathogen Box, filled develop a potential new treatment, zoli- with 400 diverse, drug-like molecules flodacin, for drug-resistant gonorrhoea.

51 Antimicrobial Resistance Benchmark 2018 – Research & Development

PDPS IN ACTION: EXAMPLES OF LATE-STAGE CANDIDATES DEVELOPED THROUGH PARTNERSHIP

Case study 1 Case study 2 Toward a new combination treatment for malaria Potential new treatment for drug-resistant gonorrhoea

Partners: Sanofi & Medicines for Malaria Venture (MMV) Partners: Entasis and GARDP Candidate: artefenomel/ferroquine Candidate: zoliflodacin Start date: 2011 Start date: 2017

Ferroquine is a compound originated from and patented by GARDP aims to develop treatments for bacterial infec- University Lille 1. Sanofi, which has developed it for ten years, tions where drug resistance is present or emerging. Its first began to collaborate with MMV in 2011 to develop a combina- announced project, with Entasis, is to develop zoliflodacin to tion of ferroquine and MMV’s investigational compound arte- treat gonorrhoea. The partnership agreement makes GARDP fenomel (OZ439). Five years previously, WHO guidelines rec- responsible for pharmaceutical activities and clinical trials: ommended new treatments should combine two medicines this will include financing, managing, and coordinating Phase with different mechanisms of action. Ferroquine is a novel fer- III trials to demonstrate the safety and efficacy of zolifloda- rocene 4-aminoquinoline, while artefenomel exerts antimalar- cin in patients infected with gonorrhoea, comprising clini- ial activity via its peroxide bond (owing to its differing struc- cal safety, pharmacovigilance, and drug registration in coun- ture, it is likely to remain effective against artemisinin-resist- tries where it has licensing rights. Entasis Therapeutics holds ant strains). Sanofi and MMV are developing this combina- the patent for the active pharmaceutical ingredient (API) tion as a single-dose formulation, which may be preferable for zoliflodacin, and is working with GARDP on a clinical trial to the current 3-day ACT regimens. For the partnership, the development strategy to ensure successful registration. It is main scientific challenges involve ensuring firstly that the for- responsible for sharing information to develop the drug can- mulation contains a sufficient amount of medicine and sec- didate into Phase III, and for registering the drug candidate ondly that it can be absorbed optimally. MMV is contributing in its countries and territories; also for post-marketing phar- its extensive malaria research expertise, while Sanofi is spon- macovigilance in these, and maintaining a worldwide patient- soring clinical trials, regulatory leadership, scientific engage- safety database. Entasis has developed clinical plans and will ment and manufacturing. work with GARDP to help implement these, and advise on execution. As there is a geographical limitation to the license, Entasis has given GARDP an exclusive and royalty-free license for the medicine’s use in the treatment of gonorrhoea. This licence includes sub-licensing rights for manufacturing worldwide and for the sale and/or distribution in 168 countries or territories outside the developed world. In relation to any new IP rights generated during the development process, Entasis and GARDP agree to grant certain royalty-free exclusive licensing rights to each other, and the right to sub-license to enable registration and manufacturing.

52 Access to Medicine Foundation

ACCESS & STEWARDSHIP INDICATOR A.4 Facilitating access and Priority pathogens: few companies are stewardship planning ahead for access and/or stewardship of new antibiotics

Antimicrobial resistance is doubt- some account of populations’ varying The Benchmark assesses the access lessly on the rise. Unchecked, it threat- ability to pay), gaining WHO prequalifi- and stewardship provisions put in place ens many aspects of modern medicine. cation and following a regulatory pro- during development by the 20 compa- Nevertheless, more people die today cedure known as Article 58 (European nies evaluated in this Research Area – through lack of access to existing anti- Medicines Agency; see inset), which looking only at projects targeting path- microbials than die due to drug-resist- helps companies to increase access to ogens prioritised by WHO and/or CDC ant infections. It is vital that new med- medicines and vaccines in low- and mid- for R&D due to the threat of AMR. In icines are introduced in a way that (a) dle-income countries and improve pub- scope are all eight large research-based ensures its rapid and appropriate acces- lic health. By developing access provi- pharmaceutical and 12 biopharmaceu- sibility for patients in need while (b) sions during R&D, companies can sub- tical companies. It is expected that all conserving its use more broadly to slow stantially accelerate the speed at which large research-based pharmaceutical the inevitable emergence of resistance. they make new products available at companies can use their often consider- Pharmaceutical companies are encour- an affordable price, and in sufficient able logistical experience and capacity aged to plan ahead, during the devel- volume. to facilitate access and stewardship for opment process, to achieve these twin For antimicrobial medicines, stew- new products. aims. ardship measures can include surveil- This analysis applies to (a) access There are various mechanisms, lance of antimicrobial resistance (AMR), provisions relating to new and adap- such as licensing and affordability com- activities to educate people and health- tive antimicrobial candidates (medicines mitments, that can enhance access to care professionals about AMR, and the and vaccines) in late-stage development newer medicines and vaccines in low- introduction of more appropriate mar- (clinical Phase II onwards) that target and middle-income countries where keting practices (e.g., developing per- priority pathogens and are applied in access to medicine is likely limited. For formance incentives for sales staff that any of the 106 low- and middle-income antimicrobial medicines, such mecha- are not linked to sales volumes). countries (countries where access to nisms must be rolled out in tandem with The Benchmark looks at how com- medicine is likely limited; see Appendix complementary plans to ensure new panies plan to apply relevant steward- IV); and (b) stewardship provisions for products are used appropriately, only ship strategies globally. As with access the same medicines, excluding vaccines, when needed. provisions, companies can develop with a global scope. Examples of access provisions plans for stewardship during product include filing for registration, creating development. equitable pricing strategies (that take

What is WHO prequalification? What is EMA’s article 58? WHO prequalification entails the evaluation of quality, safety Article 58 was introduced by the European Medicines and efficacy of pharmaceutical products, based on informa- Agency (EMA) in 2004 to help increase access to medicines tion submitted by the manufacturers, and the inspection of and vaccines in LMICs, while simultaneously strengthen- the corresponding manufacturing and clinical sites. It is an ing the drug assessment capabilities of national regulatory important mechanism as many LMICs have weak or non-ex- agencies of these countries. It involves a pathway that com- istent national regulatory authorities. The information is bines EMA’s scientific, clinical, and manufacturing review used by the UN and other procurement agencies to help expertise with the local epidemiology and disease expertise make purchasing decisions. For example, UNICEF only pro- of the WHO and LMIC national regulators to provide a sci- cures prequalified vaccines to ensure acceptability, quality, entific opinion for the corresponding LMICs. Seeking arti- safety and efficacy in target populations. cle 58 is useful for accelerating the introduction of a new medicinal product in low- and middle-income countries.

53 Antimicrobial Resistance Benchmark 2018 – Research & Development

TWO LATE-STAGE ANTIBIOTICS clinical Phases II and III, or approved currently in place for the adult formu- HAVE BOTH ACCESS AND after 2016: 23 medicines and 16 vac- lation of bedaquiline (Sirturo®). This STEWARDSHIP PROVISIONS IN cines. GSK accounts for the major- includes a managed access programme PLACE ity of late-stage candidates (15), and through the Global Drug Facility (GDF) is followed by Johnson & Johnson and its own subsidiaries. The Benchmark finds that of the 56 (eight), Sanofi (six), Merck & Co., Inc. Sanofi plans to file for WHO pre- late-stage antimicrobial candidates that (five), Novartis (four), Pfizer (three) and qualification and/or for the EMA arti- target priority pathogens, 14 are cov- Shionogi (one). Of these 39 projects, cle 58 appraisal for three of its vaccines ered by an access provision. Out of the 13 have an access provision (7 drug and in late-stage development. Pfizer has 40 medicines in late-stage develop- 6 vaccine candidates), the majority of two vaccines in Phase II and III clinical ment targeting priority pathogens, ten which is indicated for HIV/AIDS. development, for which it will apply an are covered by a stewardship provision. Large research-based pharmaceu- equitable pricing policy that is based on Only seven are covered by both access tical companies report applying access countries’ ability to pay, while covering and stewardship strategies. Two are provisions sporadically, including man- research and development costs. antibiotic candidates, and the other five aged access programmes (i.e., managed Three large research-based phar- are antivirals targeting HIV being devel- with an NGO or a government), com- maceutical companies, GSK, Johnson oped by GSK, either alone (three) or in mercialisation via third parties in low- & Johnson and Pfizer, have developed partnership with Johnson & Johnson and middle-income countries, and non- stewardship strategies for a total of (two). profit business models (see figure 32). nine late-stage antimicrobial medicines Of the 28 antibiotics in late-stage GSK, Johnson & Johnson, Pfizer (six antiretroviral medicines and three development for priority pathogens, and Sanofi are the most mature in plan- antibiotics). only two (eravacycline, Phase III; pae- ning access. GSK has seven late-stage GSK has a stewardship plan in place diatric bedaquiline, Phase II) meet the HIV candidates, including a vaccine. For for six antiretroviral candidates and its standard of having provisions in place to all these, it has a tiered-pricing model antibiotic candidate – gepotidacin. This ensure both rapid access where needed and a needs-driven registration pol- plan entails educating healthcare pro- and stewardship of the successful can- icy for countries with greater need of fessionals and other stakeholders about didate. Eravacycline, being developed access. For most candidates, GSK com- antimicrobial resistance and antibiotic by Tetraphase, targets a group of pri- mits to licensing, if the candidate is suc- stewardship, and decoupling sales force ority pathogens that cause compli- cessful, which would allow generic med- incentives from sales volumes. Johnson cated intra-abdominal and urinary tract icine manufacturers to produce the pat- & Johnson reports to provide medi- infections caused by a range of patho- ented medicine. In addition, GSK com- cal education for the use of bedaquiline gens. Bedaquiline (Sirturo®), condition- mits to making its vaccines available in (Sirturo®), and will expand this to pae- ally approved for the treatment of mul- 54 of the world’s least-developed coun- diatric healthcare professionals for the tidrug-resistant tuberculosis (MDR-TB) tries and reports having (but does not paediatric formulation. in adults, is now being developed by disclose) a tiered pricing strategy for For the avibactam/aztreonam com- Johnson & Johnson for the treatment vaccines. bination, Pfizer plans to continue its of MDR-TB in children. GSK is, amongst other large AMR surveillance programmes, as well Two other antibiotics, being devel- research-based pharmaceutical com- as launch educational initiatives regard- oped by GSK for gonorrhoea and Pfizer panies, an advocate of a market entry ing the risks of AMR and how vaccines for multidrug-resistant gram-nega- reward for antibiotics (a potential pull could play a role in addressing this pub- tive bacterial infections have steward- incentive to stimulate antibiotic R&D), lic health threat. ship provisions but no access plan, while and is willing to participate in a pilot Overall, but especially for antibiot- three other antibiotics in the clinical to facilitate this initiative. Questions ics, there is a lack of stewardship strat- pipeline have an access plan in place but remain over whether it will register its egies. Moreover, while large research- no stewardship provisions, being devel- novel antibiotic (gepotidacin) in low- based pharmaceutical companies are oped by GSK, Entasis and Melinta. and middle-income countries. familiar with the need to provide access Johnson & Johnson reports an strategies for non-antibiotic antimicro- Few provisions for access and stew- access provision for its HIV vaccine in bials, especially targeting HIV, they do ardship in place for late-stage anti- late-stage development, and the two not appear to be developing such plans biotic candidates FCDs (cabotegravir/rilpivirine; dolute- for antibiotics. All but one large research-based phar- gravir/rilpivirine (Juluca®)) for HIV/ maceutical companies in scope (all AIDS that are being developed with ViiV except Roche) have clinical candidates Healthcare. For the paediatric formula- targeting priority pathogens and thus tion of bedaquiline, Johnson & Johnson relevant to this analysis. In total, they reports that it will use the same access are developing 39* such products in and stewardship activities that are

*Three projects are being developed in collaboration 54 between multiple companies in scope. Access to Medicine Foundation

Figure 32. Almost half of the companies have at least one access and/or stewardship provision in place for a late-stage clinical candidate. Common access provisions include voluntary licensing, needs-based registration and equitable pricing. Stewardship Large research-based pharma- Biopharmaceutical provisions are focussed on surveillance programmes for ceutical companies companies monitoring resistance. Tetraphase Johnson & Shionogi Johnson Novartis Summit Melinta Entasis Sanofi Pfizer Total GSK

Access Availability Voluntary licensing ● ○ ○ ○ ○ ○ ● ● ○ ● 4 Needs-based registration ● ● ○ ● ○ ○ ○ ○ ○ ○ 3 EMA Article 58 ● ○ ○ ○ ● ○ ○ ○ ○ ○ 2 Affiliates in low- and middle income countries ○ ● ○ ○ ○ ● ○ ○ ○ ○ 2 Managed Access programme with NGO and government(s) ● ● ○ ○ ○ ○ ○ ○ ○ ○ 2 Commitment to NGO, with permission to exploit ○ ○ ○ ○ ○ ○ ○ ○ ● ○ 1 WHO prequalification ○ ○ ○ ○ ● ○ ○ ○ ○ ○ 1

Affordability Equitable tiered pricing ● ● ● ● ○ ○ ○ ○ ○ ○ 4 Non-profit business model ● ○ ○ ○ ○ ○ ○ ○ ○ ○ 1

Stewardship Resistance surveillance ● ● ○ ● ○ ○ ○ ○ ○ ● 4 Educating healthcare professionals ● ● ○ ● ○ ○ ○ ○ ○ ○ 3 Decouple sales force incentives from volume sales ● ○ ○ ○ ○ ○ ○ ○ ○ ○ 1

GSK has access and stewardship plans International Cohort Consortium of have an access provision. Entasis has in place for HIV candidates Infectious Disease). It is also supporting agreed that its development partner, GSK has reported it will market its HIV regional and local investigators, includ- GARDP, will obtains the rights of the candidates through ViiV Healthcare (a ing the Botswana Epidemiological ART product developed within its partner- joint venture between GSK, Pfizer and Treatment (BEAT) Cohort Study. ships in low- and middle-income coun- Shionogi), which has in place its own tries. Melinta’s Baxdela™, an antibiotic access-to-medicine policy. This includes Fewer access and stewardship plans used to treat acute skin and skin struc- several aspects, such as the priori- from biopharmaceutical companies ture conditions, was approved in June ties of needs-driven R&D and registra- Biopharmaceutical companies have 2017. From 2015 onward, the company tion strategy, and a commitment to vol- fewer candidates with an access provi- has been planning to contract partners untary licensing to enable the generic sion. Typically, as these companies aim to commercialise this product in Latin manufacture and supply of medicines in to be acquired by larger pharmaceutical America, Asia-Pacific and various undis- low- and middle-income countries. ViiV companies or rely on partnerships, they closed countries in the Middle East and Healthcare has a flexible pricing policy do not establish business processes to Africa. that it applies in middle-income coun- commercialise their pharmaceuticals. In countries that do not have tries. In addition, to improve affordabil- Often, they seek third parties (such as well-organised healthcare systems, ity, it takes account of the gross domes- regional pharmaceutical companies) to stewardship can be hard to control. tic product (GDP) of each country and commercialise their products in other As weaknesses in healthcare systems uses inter-country equitable pricing. It countries, and this may create a differ- increase the risk of resistance emerg- also considers the extent to which the ent attitude toward developing access ing, pharmaceutical companies can be HIV/AIDS epidemic has affected each strategies. reluctant to market their newest antimi- country. The biopharmaceutical companies crobials – especially antibiotics – in low- Regarding stewardship at a evaluated have 17 antibiotics in late- and middle-income countries. In gen- global level, ViiV Healthcare is sup- stage development, all targeting priority eral, the Benchmark finds that biophar- porting studies of HIV-1 drug resist- pathogens. Only three, being developed maceutical companies do not engage in ance surveillance with RESPOND (the by Entasis, Melinta and Tetraphase, planning stewardship; some state that

55 Antimicrobial Resistance Benchmark 2018 – Research & Development they see it as the responsibility of gov- Its Antimicrobial Voluntary Evaluation Some governments or NGOs that fund ernments and hospitals. Programme, or AVEP, provides strips companies’ R&D projects put an access Tetraphase is the exception. It leads and disks that enable hospitals to test commitment into their funding agree- in this area, being the only clinical-stage susceptibilities of pathogens against ments. The Wellcome Trust, for exam- biopharmaceutical company to have the antibiotic. As eravacycline is now in ple, obtains the intellectual property both an access and stewardship provi- clinical Phase III, it is not yet clear how rights to make arrangements for par- sion in place for its most advanced can- Tetraphase will apply this susceptibil- ticular countries where specific public didate, eravacycline, used to treat com- ity test after it gains market approval. health needs are not met within a spe- plicated urinary tract infections (cUTI) In addition, through a third-party sup- cific time frame. This has been the case caused by a range of pathogens: ESBL- plier, Tetraphase runs a global surveil- for Summit’s ridinilazole, an antibiotic producing Enterobacteriaceae, CRE, A. lance programme to monitor the sus- for treating C. difficile infections. baumannii, S. aureus, VRE, C. difficile. ceptibility of hospitalised patients with The company actively seeks partners to bacterial infections for eravacycline on develop and commercialise eravacycline an annual basis. Substantial investments in regions including Asia-Pacific, Eastern for both programmes have been made Europe, India, the Middle East and North (more than USD 1 million to date). Africa, and South America.

56 Access to Medicine Foundation

REFERENCES

1. WHO. (2017). Global priority list 6. WHO. (2017). Antibacterial agents 11. Clinical and Laboratory Standards 17. New Drugs 4 Bad Bugs. Retrieved 14 of antibiotic-resistant bacteria to guide in clinical development: an analy- Institute. M100-S27: performance stand- November 2017 from http://www.nd4bb. research, discovery, and development of sis of the antibacterial clinical devel- ards for antimicrobial susceptibility test- eu/ new antibiotics. Retrieved from http:// opment pipeline, including tuberculo- ing; 27th informational supplement. CLSI www.who.int/medicines/publications/ sis. Retrieved from http://www.who.int/ document M100-S27. Wayne, PA: CLSI, 18. Årdal, C., & Røttingen, J.A. (2012). WHO-PPL-Short_Summary_25Feb-ET_ medicines/areas/rational_use/antibac- 2017. Open Source Drug Discovery in Practice: NM_WHO.pdf terial_agents_clinical_development/ A Case Study. PLoS Neglected Tropical en/ 12. Culyer, A. J. (2014). Encyclopedia of Diseases, 6(9), e1827. http://doi. 2. Theuretzbacher, U., et al. (2017). health economics. Elsevier. org/10.1371/journal.pntd.0001827 Linking Sustainable Use Policies to 7. Bergman, M., et al. Effect of mac- Novel Economic Incentives to Stimulate rolide consumption on erythromycin 13. Rex, J. H., et al. (2013). A comprehen- 19. Medicines for Malaria Venture. Antibiotic Research and Development. resistance in Streptococcus pyogenes in sive regulatory framework to address the Open access Malaria Box. Retrieved Infectious Disease Reports, 9(1), 6836. Finland in 1997–2001. Clinical Infectious unmet need for new antibacterial treat- 20 October 2017 from https:// DOI:10.4081/idr.2017.6836 Diseases, 38(9), 1251-1256. ments. The Lancet Infectious Diseases, www.mmv.org/research-devel- 13(3), 269-275. opment/open-source-research/ 3. Singh, N., et al. (2000). Short-course 8. Tekle, B., et al. (2002). Defaulting open-access-malaria-box empiric antibiotic therapy for patients from DOTS and its determinants in three 14. Timsit, J. F., et al. (2017). Appropriate with pulmonary infiltrates in the intensive districts of Arsi Zone in Ethiopia. The endpoints for evaluation of new anti- 20. Medicines for Malaria Venture. About care unit: a proposed solution for indis- International Journal of Tuberculosis and biotic therapies for severe infections: a the Pathogen Box. Retrieved 20 October criminate antibiotic prescription. American Lung Disease, 6(7), 573-579. perspective from COMBACTE’s STAT- 2017 from https://www.pathogenbox.org/ journal of respiratory and critical care Net. Intensive Care Medicine, 43(7), medicine, 162(2), 505-511. 9. Awofeso, N. (2008). Anti-tuberculosis 1002–1012. http://doi.org/10.1007/ 21. Laxminarayan, R., et al. (2015). Access medication side-effects constitute major s00134-017-4802-4 to effective antimicrobials: a world- 4. Costelloe, C., et al. (2010). Effect factor for poor adherence to tuberculo- wide challenge. The Lancet, 387(10014), of antibiotic prescribing in primary care sis treatment. Bulletin of the World Health 15. Wunderink, R. G., et al. (2012). 168-175. on antimicrobial resistance in individ- Organization, 86(3), B–D. http://doi. Linezolid in methicillin-resistant ual patients: systematic review and org/10.2471/BLT.07.043802 Staphylococcus aureus nosocomial meta-analysis. BMJ, 340, c2096. pneumonia: a randomized, controlled 10. Thomas, D. W., et al. (2016). Clinical study. Clinical Infectious Diseases, 54(5), 5. U.S. Centers for Disease Control and development success rates 2006-2015. 621-629. Prevention (CDC). (April, 2013). Antibiotic San Diego: Biomedtracker/Washington, resistance threats in the United States, DC: BIO/Bend: Amplion. 16. Cole CB, Iyer JK. (2016). Ensuring 2013. Retrieved from http://www.cdc.gov/ sustained incentives for pharma to drugresistance/threat-report-2013/pdf/ develop medicine for the poor. Access to ar-threats-2013-508.pdf Medicine Foundation.

57 Antimicrobial Resistance Benchmark 2018

RESEARCH AREA: MANUFACTURING & PRODUCTION How pharmaceutical companies ensure the production of antibiotics does not contribute to resistance

Figure 33. Company performance: Manufacturing & Production THE LEADERS

In Manufacturing & Production, the Large research-based pharmaceutical companies scores near the top are closely packed. Nevertheless, six companies pull ahead GSK of other large research-based phar- Johnson & Johnson maceutical companies and the generic Merck & Co., Inc. medicine manufacturers: GSK, fol- Novartis lowed by Johnson & Johnson, Novartis, Pzer Pfizer, Roche and Sanofi. GSK under- Roche takes every environmental risk-manage- Sano ment activity that the AMR Benchmark Shionogi examines, with the other five companies undertaking the majority of them. Generic medicine manufacturers All leaders make a commitment to man- Aspen . ufacturing all antibiotic drug prod- Aurobindo ucts in a manner consistent with Good Cipla . Manufacturing Practices (GMP). Dr. Reddy's Fresenius Kabi Lupin Macleods Mylan Sun Pharma ● Manufacturing & Production Teva ● Remaining potential score Points

CONTEXT WHAT THE BENCHMARK MEASURES The process for manufacturing and pro- The Benchmark assesses specific poli- The Benchmark also looks at the mech- ducing antibiotics by pharmaceutical cies and actions companies can take to anisms companies use to maintain companies can contribute to antimicro- uphold manufacturing practices in both high-quality standards in the production bial resistance (AMR) in two main ways: areas. It evaluates how thorough their of antibiotics. when companies release waste into the environmental risk-management strate- As this research area concerns manu- environment that includes antibiotics or gies are, if companies take into account facturing and production, the Benchmark antibiotic resistant bacteria1; and when antibiotic discharge; how they apply evaluates only those companies with they manufacture substandard antibi- these strategies to third-party suppliers; important sales volumes of antibiotic otics with sub-therapeutic levels of the and their transparency regarding strate- products. active antibiotic ingredient.2 Both routes gies, audit results, discharge levels, and can expose bacteria to levels of antibi- the identities of third-party suppliers of otics that promote the emergence of active pharmaceutical ingredients (APIs) resistance. and drug products.

58 Access to Medicine Foundation

IN SUMMARY

Most companies have environmental risk-management strategies in place; depth and breadth of strategies vary The majority of companies analysed (15 of 18) show evidence of having some form of an environmental risk-management strategy that aims to minimise impact of antibiotics discharged from manufacturing processes. The depth and breadth of these strategies differ widely regarding the different aspects evaluated by the Benchmark. Six large research-based pharmaceutical companies (GSK, Johnson & Johnson, Novartis, Pfizer, Roche and Sanofi) lead the field, applying their environmental risk-management strategies most broadly, both to their own manufacturing sites and to those operated by third-party manufacturers of APIs and drug products. The performance of generic medicine manufacturers varies, with only the leaders focussing beyond their own manufacturing sites. Fifteen companies have strategies for their own manufacturing sites, which most (14) also support with regular audits. Nearly half of those analysed (eight) report that they also apply their strategies to sites managed by third-party manufacturers of APIs and drug products. Six companies reported that they apply their strategies to external waste-treatment plants. Looking at auditing and the setting of discharge limits, 14 companies reported that they audit their own manufacturing sites, seven audit sites managed by third parties, and three audit external waste- treatment plants. Regarding discharge limits, eight companies set these for their own manufacturing sites, four for sites managed by third-party suppliers of APIs and drug products, and two for external waste-treatment sites.

Eight companies set discharge limits for antibiotics, but none discloses actual discharge levels Eight companies report that they have set limits on antibiotic discharge in wastewaters, but none discloses publicly its levels of actual discharges. This information is valuable and vital. Disclosing it could enhance the ability of governments, researchers and other stakeholders to understand the relationship between the discharge of active antibiotic ingredients into the environment and the development of antibiotic resistance. Four companies have set discharge limits for their own sites as well as those of third-party manufacturers of APIs and drug products, reporting that they also audit the implementation of their environmental risk-management strategies. One company (GSK) extends its discharge limits to both third-party manufacturers and external waste-treatment plants. GSK is also the only company that discloses predicted no-effect concentrations (PNEC) for resistance selection. It discloses these to the Benchmark, also giving reference to external sources for these PNECs. It does this for a subset of the antibiotics in its portfolio. The company publicly discloses safety data sheets for antibiotics, but doesn’t publicly disclose PNECs.3

Only one company discloses names of third-party manufacturers The Medicines Company is the only company identified by the Benchmark that discloses the identities of its third-party manufacturers, making it an example of best practice in this area. In its 2016 annual report, it disclosed the identity of all third- party API and drug-product suppliers for its marketed branded antibiotics minocycline (Minocin® IV), oritavancin (Orbactiv®), and meropenem/vaborbactam (Vabomere™). It also disclosed suppliers for its generic medicines, azithromycin and clindamycin. Disclosing the identities of third-party suppliers enables governments, researchers and others to assess the impact of individual manufacturing chains on antibiotic resistance. Please note: The Medicines Company was not scored in this research area. As a biopharmaceutical company in scope, it is in scope for the R&D Research Area only.

59 Antimicrobial Resistance Benchmark 2018 – Manufacturing & Production

MANUFACTURING & PRODUCTION METHODOLOGY: WHAT THIS RESEARCH AREA MEASURES

In Manufacturing & Production, the reasonable influence on upstream sup- Merck & Co., Inc., Novartis, Pfizer, Roche, Benchmark uses global antibiotic sales pliers. Consequently, their policies and Sanofi, Shionogi and Teva) are also work- volumes to inform its selection of com- practices may affect antimicrobial resist- ing together on environmental risk man- panies to analyse. It focusses on anti- ance more significantly than those of agement in the Pharmaceutical Supply biotics (rather than all antimicrobial other companies. Chain Initiative (PSCI).8 medicines). This is because antibiotic Most companies in scope (24) The Benchmark analyses data col- manufacturing and its potential impact have signed the Declaration by the lected through surveys and from pub- on resistance is better described and Pharmaceutical, Biotechnology and lic sources. As far as possible, this data understood than other areas of antimi- Diagnostics Industries on Combating is clarified, cross-referenced and verified crobial manufacturing. As such, it was Antimicrobial Resistance; ten have by the research team. How data is col- possible to identify and develop metrics signed the Industry Roadmap for lected in the first instance depends on a for this first iteration of the Benchmark. Progress on Combating Antimicrobial company’s level of engagement with the Of the 30 companies in scope, the Resistance.⁶ In signing up to these indus- Benchmark research. All companies were Benchmark analyses 18 companies that try-wide initiatives, companies commit to surveyed, and data from public sources were included based on the importance support measures to reduce the impact were analysed for all companies. Not all of their antibiotics sales volumes.4,5 The on the environment from the production companies contributed in the survey. scale of these companies’ sales volumes of antibiotics, and have installed a work- suggests they are the prominent play- ing group responsible for this topic.7 Nine ers in multiple manufacturing chains with companies (GSK, Johnson & Johnson,

INDICATORS Figure 34. Companies in scope ABOUT THIS CHAPTER

B.1 Environmental risk-management Applicable In this chapter, the Benchmark reports strategy indicators its findings in two sections. The first B.2 Disclosure on environmental risk B1 B2 B3 relates to indicator B.1. The second

management Large research-based relates to indicators B.2 and B.3. B.3 Manufacturing high-quality pharmaceutical companies p61 B.1 antibiotics GSK ● ● ● p63 B.2 & B.3 Johnson & Johnson ● ● ● Merck & Co., Inc. ● ● ● For a full listing of indicators and scoring Novartis ● ● ● eligibility see Appendix V. Pfizer ● ● ● Roche ● ● ● Sanofi ● ● ● Shionogi ● ● ●

Generic Medicine Manufacturers Aspen ● ● ● Aurobindo ● ● ● Cipla ● ● ● Dr. Reddy's ● ● ● Fresenius Kabi ● ● ● Lupin ● ● ● Macleods ● ● ● Mylan ● ● ● Sun Pharma ● ● ● Teva ● ● ●

The Medicines Company did not meet the criteria used to select the two other company groups in scope, and was therefore not eligible for this Research Area. However, the company has notable activities in this area, which are mentioned in this Research Area where relevant.

60 Access to Medicine Foundation

RISK-MANAGEMENT STRATEGIES INDICATOR How do companies manage environmental B.1 Environmental risk- management strategy AMR risk during antibiotic manufacturing?

During antibiotic manufacturing, the these areas is referred to as the ‘depth’ of the questionnaires or ranking of the release of wastewater can at times of strategies. companies this time. lead to the discharge of active antibi- To manufacture antibiotics, most otic ingredients into the environment. pharmaceutical companies rely at Recent studies have shown that some least partly on third parties to supply DEPTH AND BREADTH OF environments around drug manufactur- them with API and drug products. As STRATEGIES VARY; SOME ing sites contain high concentrations API manufacturing units and formula- COMPANIES MEET MOST of antibiotics.1,9 Once in the wider envi- tion manufacturing sites are process- REQUIREMENTS ronment, active antibiotic ingredients ing the active ingredients in antibiotics, can accelerate the development of anti- there is a risk that these sites can dis- In this area, the Benchmark evaluated biotic resistance in bacteria. This can charge these active ingredients into the the 18 companies in its scope that make happen when antibiotic levels are suffi- environment. and market an important volume of ciently high to enable natural selection Some manufacturing sites have antibiotics. Fifteen showed evidence of for resistant strains of bacteria. on-site wastewater-treatment plants, having an environmental risk-manage- As research is being conducted to while others use external plants. Both ment strategy that aims to minimise understand the impact of industrial dis- on-site and off-site plants play a role in risks for possible antibiotic discharges charges on antibiotic resistance, those preventing the discharge of antibiotics from manufacturing processes. working to understand the potential into the environment. The depth and breadth of strate- impact need greater insight about how Commonly, pharmaceutical compa- gies differ widely (see figure 35). Most often and under what circumstances nies that market antibiotics sit at the of these companies have strategies for such discharges are high, what levels end of the manufacturing chain. As their own manufacturing sites, sup- of antibiotics impose an unacceptable well as being able to control standards ported by regular audits, and nearly half risk, and how risks should best be man- at their own sites, they may be able to of those analysed (eight) could show aged. What is understood is that some- exert considerable influence over the they apply their strategies to sites man- times discharged levels of antibiotics environmental risk management of their aged by third-party manufacturers of are unacceptable, and pharmaceutical suppliers. To prevent antibiotics being APIs and drug products. Six gave evi- companies do have the technical abil- discharged from manufacturing sites dence of how they apply their strate- ity to reduce such discharges, although into the environment, those involved gies to external waste-treatment plants. awareness and sufficient incentives may in the manufacturing chain must work Auditing follows a similar trend. not always be there. together. Fourteen companies reported that they As there is as yet a general pau- The Benchmark looks at whether audit their own manufacturing sites and city of specific regulations on antibiot- companies are applying environmen- seven companies audit sites managed by ics discharges, companies would need tal risk-management strategies: to their third parties, but just three audit exter- to set their own discharge limits below own manufacturing sites; to third-party nal waste-treatment plants. Regarding predicted no-effect concentrations manufacturers of APIs and/or drug discharge limits, eight companies set (PNEC) for resistance selection.10 It is products; and to external waste-treat- these for their own manufacturing sites important for combatting AMR that dis- ment plants. Performance in these and four companies do so for sites man- charge limits are based on PNECs for areas is referred to as the ‘breadth’ of aged by third-party suppliers of APIs and resistance selection and not for, e.g., strategies. drug products, but only two set limits for aquatic toxicity. There are also risks associated with external waste-treatment sites. The AMR Benchmark examines discharges of antibiotic-resistant bac- which companies are setting such strat- teria that may be the result of highly Leaders expand focus beyond their egies, assessing three distinct areas: antibiotic-contaminated wastewaters own sites whether a company has a clear envi- with microbes. Disinfection of such Six companies lead in this area: GSK, ronmental risk-management strategy; wastewaters are important to prevent Johnson & Johnson, Novartis, Pfizer, whether it audits this strategy regularly; releases of generated antibiotic-resist- Roche and Sanofi. and whether its strategy includes limits ant bacteria; however, this was not part All six have a clear strategy, and apply on antibiotic discharge. Performance in this both to their own manufacturing

61 Antimicrobial Resistance Benchmark 2018 – Manufacturing & Production sites and to the sites operated by third- party manufacturers of API and drug Figure 35. Depth and breadth of environmental risk-management strategies products. All strategies include audit vary widely. plans for the companies’ own sites and The AMR Benchmark looks at where companies are applying environmental risk-management those of suppliers. In addition, all six strategies (breadth), and whether these strategies include audits and limits on antibiotic discharge companies set discharge limits for cer- (depth). Six large research-based pharmaceutical companies are leading in this area by including the tain antibiotics (when manufactured at most elements in their strategy. Generic medicine manufacturers mainly focus their strategies on their their own sites), though they have not own manufacturing sites. yet developed limits for other antibiotics that are manufactured at their own Breadth Third party man- sites or at third-party manufacturing ufacturing sites Own manufac- of API and Drug External waste- sites. turing sites Products treatment plants

Among these leaders, GSK stands Depth Strategy Strategy Strategy Audits Audits Audits Limits Limits Limits out. It undertakes every environmental risk-management activity that the AMR Benchmark examines (see figure Large research-based pharmaceutical companies 35). The company applies its strategy, GSK ● ● ● ● ● ● ● ● ● including audits, to its own manufactur- Johnson & Johnson ● ● ● ● ● ● ● ing sites, to the sites of third-party API Merck & Co., Inc. ● ● ● ● and drug-product manufacturers, and to Novartis ● ● ● ● ● ● ● external waste-treatment plants. GSK Pfizer ● ● ● ● ● ● sets limits on antibiotic discharges and Roche ● ● ● ● ● ● ● applies these not only to its own man- Sanofi ● ● ● ● ● ● ● ufacturing sites, but also to the sites Shionogi ● ● ● of third-party manufacturers and to Generic medicine manufacturers waste-treatment plants. Taking respon- Aspen ● ● sibility for its manufacturing chain, GSK Aurobindo ● ● ● ● sets limits for all those directly involved Cipla in manufacture and discharge, including Dr. Reddy’s ● its direct suppliers. Fresenius Kabi ● ● Johnson & Johnson applies its envi- Lupin ronmental risk-management strategy to Macleods ● ● its own manufacturing sites, to the sites Mylan ● ● of third-party manufacturers, and to Sun Pharma waste-treatment plants. At its own sites Teva ● ● ● ● and those of third-party manufacturers, it performs audits and has set limits on drug products. It extends its strategy to on discharge of antibiotics, and regular antibiotic discharges. cover external waste-treatment plants, audits. As Pfizer’s third-party manufac- Novartis has a risk-management but does not audit these or monitor dis- turers do not yet have a full set of antibi- strategy to minimise the environmen- charge limits. otic discharge limits, Pfizer engages with tal impact of antibiotic discharge from Sanofi has a risk-management them to help set limits on discharge for manufacturing. It applies this to its own strategy to minimise the environmen- antibiotics below PNEC for resistance. facilities, to those of third-party man- tal impact of antibiotic discharge from Pfizer’s manufacturing sites include pri- ufacturers of API and drug products, manufacturing. It applies this, with mary waste treatment plants. Secondary and to external waste-treatment plants. audits, to its own facilities, to those waste treatment occurs on and off site. Novartis performs audits at its own of third-party manufacturers, and to Pfizer’s environmental risk-manage- manufacturing sites and those of third- waste-treatment plants. Sanofi sets dis- ment strategy does not apply to off-site party manufacturers. It sets discharge charge limits for its own manufactur- waste-treatment plants. limits for its own manufacturing sites ing sites, but it does not set limits for Although not evaluated by the and for external wastewater-treatment third-party manufacturers and external Benchmark, Pfizer has a public policy plants. waste-treatment plants. that includes a requirement for improve- Roche has developed an environ- Pfizer has an environmen- ment plans or supplier exit if suppliers mental risk-management strategy that tal risk-management strategy that it are unable to meet expectations. it applies – with audits and discharge applies to its own sites and those of limits – to its own sites and to those of third-party API and drug-product man- third-party manufacturers of APIs and ufacturers. Its strategy includes limits

62 Access to Medicine Foundation

DISCHARGE LIMITS: NOT antibiotics in its portfolio. The company No statement on environmental risk WIDELY REPORTED publicly discloses safety data sheets for management antibiotics, but does not include PNECs Three companies – Cipla, Lupin and Sun Eight companies out of 18 report that in the safety data sheets.3 Roche com- Pharma – have reported no evidence they have set discharge limits. For half mits to disclosing PNECs publicly by of a risk-management strategy to mini- of these companies (four), these limits the end of 2017. By sharing their PNEC mise the impact of their antibiotic man- apply to both their own sites and those information publicly, companies give ufacturing discharge on the environ- of third-party manufacturers. Two com- governments, researchers, generic ment. Cipla has, however, committed panies (GSK and Novartis) extend them medicine manufacturers and others to develop an environmental risk-man- to external waste-treatment plants. the opportunity to use this data in their agement strategy in 2018 in line with its GSK is the only company that work to minimise the impact of manu- commitments to the Industry Roadmap reported PNECs for resistance selection facturing discharge of antibiotics. as a signatory. Lupin and Sun Pharma to the Benchmark, also giving reference have not reported their intentions in to external sources for these PNECs.10,11 this area to the Benchmark, nor have It does this for a subset of the they done so publicly.

MANUFACTURING HIGH-QUALITY ANTIBIOTICS INDICATORS B.2 Disclosure on environmen- What do companies disclose about tal risk management B.3 Manufacturing high-quality environmental risk-management? antibiotics

By disclosing their environmental Another step companies can take to (available on company websites) that risk-management practices – that is, the reduce antimicrobial resistance is to describe their strategies to prevent the publication of strategies to minimise maintain high manufacturing stand- discharge of antibiotics into the envi- the discharge of antibiotics; details of ards. They can do this by comply- ronment. Making such disclosures is an manufacturing responsibilities and the ing with GMP, which will help them to important first step. It provides a meas- management of active ingredients; and prevent substandard antibiotics from ure of transparency, showing the will- indications of strategy implementation reaching patients, meaning the bacte- ingness of pharmaceutical companies to – companies make it easier to share ria are exposed to a non-effective con- adjust their manufacturing practices in knowledge about good practice and centration, which can not only harm order to minimise antibiotic resistance. ways to effectively manage discharge of the patients taking these medicines to The remaining three companies with antibiotics. For example, transparency cure infections, but also accelerate the an environmental risk-management about discharge levels can facilitate dis- development of antibiotic resistance strategy are Shionogi, Dr. Reddy’s and cussions about the scientific ration- in bacteria by the selection of resistant Macleods. ale behind the limits. Disclosure also strains.12 In this section, the Benchmark Shionogi engineer at its own manufacturing plant. enables independent organisations to captures the mechanisms companies ©Shionogi review the practices of third-party man- report using to maintain high manufac- ufacturers and waste-treatment plants, turing standards. which may otherwise remain less transparent. By disclosing, companies enable others to hold them accountable for MAJORITY OF COMPANIES WITH their policies and practices. A STRATEGY DISCLOSES THEIR In this Research Area, the STRATEGY Benchmark assesses companies for transparency in five areas. These are: Out of 18 companies assessed in this environmental risk-management strat- area, 15 have put in place an environ- egy; audit results from their own man- mental risk-management strategy. ufacturing sites; audit results from the Of these, 12 disclose their strategies manufacturing sites of their third par- publicly. They are Aspen, Aurobindo, ties; antibiotic discharge levels; and the Fresenius Kabi, GSK, Johnson & identities of third parties who supply Johnson, Merck & Co., Inc., Mylan, antibiotic drug products, antibiotic APIs, Novartis, Pfizer, Roche, Sanofi and Teva. and who treat waste. All 12 disclose one or more documents

63 Antimicrobial Resistance Benchmark 2018 – Manufacturing & Production

Figure 36. More than half of companies publicly disclose GMP commitments. By publicly disclosing commitments to produce high-quality antibiotics, in compliance with GMP, companies demonstrate their efforts in preventing substandard antibiotics from reaching patients. These efforts can be strengthened by extending them to third-party manufacturing sites.

GMP commitment not disclosed Public GMP commitment at own manufacturing sites

GMP commitment Companies Companies disclosed to the Benchmark Public GMP commitment at own and third-party GMP commitment manufacturing sites publicly dislcosed

These three do not disclose their strat- public insight into how these chains are commit themselves to establishing sci- egies publicly. However, Shionogi com- structured enables governments, NGOs ence-driven targets for antibiotic dis- mits to disclosing its strategy in its 2017 and other stakeholders to analyse the charge concentrations, and to standard- environment, health and safety report. environmental impact of specific/other ising these. companies along the supply chain. Eight companies in scope for this Only one company discloses the iden- No other company in scope has been research area report that they have set tities of third-party manufacturers transparent in this area. None has dis- limits for antibiotic discharge. As yet, no Only one company – The Medicines closed the identities of the third par- company discloses publicly its levels of Company* – discloses the identities ties that manufacture their APIs and antibiotic discharge. This information is of third-party manufacturers, making drug products, or of their third-party valuable. Disclosing it could enhance the it an example of best practice in this waste-treatment plants. Some compa- ability of governments, researchers and area. By disclosing this information, The nies comment that they consider this to other stakeholders to investigate and Medicines Company acknowledges its be confidential business information. eventually better understand the rela- share of responsibility for policies, prac- Shionogi commits to disclosing its tionship between industrial discharges tices and possible discharges at those third parties in its 2017 environment, of active antibiotic ingredients into the sites. health and safety report. environment, and the development of In its 2016 annual report, this com- antibiotic resistance. By disclosing their pany disclosed the names of all third- No public disclosures of discharge levels of discharged antibiotics, com- party API and drug-product suppli- levels panies also enable others to hold them ers for its marketed branded products Manufacturing discharges are hav- accountable for their discharges. minocycline (Minocin® IV), oritavancin ing an impact on antibiotic resistance. (Orbactiv®), and meropenem/vaborbac- Researchers are currently studying the tam (Vabomere™). It also disclosed sup- extent and nature of this impact.13 BROAD COMMITMENT TO GOOD pliers for its generic medicines, azithro- Ten companies in the Benchmark’s MANUFACTURING PRACTICE mycin and clindamycin. scope signed the Industry Roadmap By disclosing the identities of (see Appendix I). Through this, they Pharmaceutical companies are third-party suppliers, The Medicines expected to produce all their antibi- Company enables governments, Pfizer assessors at supplier locations in India. otics using the highest quality stand- researchers and others to assess the (imaged used with permission) ards, such as those of GMP. Using GMP impact of its manufacturing chains on ©Pfizer standards helps companies avoid expos- antibiotic resistance. The companies in ing patients to sub-therapeutic levels of scope are generally dominant players antibiotics, and avoid aiding the spread in their manufacturing chains — those of resistance. The Benchmark urges with the most power to negotiate terms companies to make a public endorse- and influence standards and practices. ment of GMP for all their manufacturing This includes influence over the man- processes. It also encourages compa- ufacturing and risk-management prac- nies to share their insights and experi- tices of third-party suppliers. Greater ences of how, along their manufacturing *Please note: The Medicines Company was not scored in this research area. As a biopharmaceutical company in scope, it is in scope for the R&D research area only. 64 Access to Medicine Foundation chains, they are upholding GMP stand- maintaining a high quality of antibiotic In 2017, three companies, Lupin, Mylan ards (see figure 36). production, consistent with GMP, only and Pfizer, received a warning letter by The Benchmark asked companies at their own manufacturing sites. They the FDA regarding significant violations what mechanisms they have in place to do not disclose a commitment to apply- of current good manufacturing practice ensure that their own and third-party ing GMP at their third-party antibiotic regulations for finished pharmaceuti- production facilities manufacturing anti- drug-product manufacturers. cals. In 2017 EMA issued a statement of biotics maintain high-quality production Three remaining companies (Dr. Reddy’s, non-compliance with GMP for one com- standards. Macleods and Sun Pharma) do not pro- pany, Dr. Reddy’s. Of the 18 companies the Benchmark vide any evidence of having mecha- assessed in this area, 13 commit to man- nisms in place in this area — Dr. Reddy’s ufacturing all antibiotics and antibi- and Sun Pharma do not publicly disclose otic drug products in a manner con- this information while Macleods did not sistent with GMP. These companies provide evidence to the Benchmark. are Aurobindo, Fresenius Kabi, GSK, They do not make any disclosure of Johnson & Johnson, Lupin, Merck & commitments to maintain a high quality Co., Inc., Mylan, Novartis, Pfizer, Roche, of antibiotic production consistent with Sanofi, Shionogi and Teva. Two further Good Manufacturing Practice. companies, Aspen and Cipla, commit to

REFERENCES

1. Larsson, D. G. (2014). Pollution from 5. Mordor Intelligence. (2016). Top 9. Bielen, A., et al. (2017). Negative envi- 12. ReAct. Problems related to drug manufacturing: review and perspec- 10 Generic Antibiotic Manufacturers by ronmental impacts of antibiotic-contam- quality of antibiotics. Retrieved 3 tives. Philosophical Transactions of the Volume – Custom Study. Bangalore, India. inated effluents from pharmaceutical November 2017 from https://www. Royal Society B, 369(1656). doi: 10.1098/ industries. Water research, 126, 79-87. reactgroup.org/toolbox/under- rstb.2013.0571. 6. Industry Roadmap for Progress on stand/how-did-we-end-up-here/ Combating Antimicrobial Resistance 10. Bengtsson-Palme, J., & Larsson, D. problems-related-to-quality-of-antibiotics/ 2. Kelesidis, T., & Falagas, M. E. (2015). – September 2016. Retrieved from J. (2016). Concentrations of antibiot- Substandard/counterfeit antimicro- https://www.ifpma.org/wp-content/ ics predicted to select for resistant bac- 13. Bengtsson-Palme, J., et al. (2017). bial drugs. Clinical microbiology reviews, uploads/2016/09/Roadmap-for-Progress- teria: Proposed limits for environmental Environmental factors influencing the 28(2), 443-464. on-AMR-FINAL.pdf regulation. Environment International, 86, development and spread of antibiotic 140-149. resistance. FEMS microbiology reviews. 3. GSK. (2017). Material Safety 7. IFPMA. Antimicrobial Resistance. doi: 10.1093/femsre/fux053. Data Sheets & Environmental Risk Retrieved 6 December 2017 from 11. BSAC. (May, 2013). BSAC Methods Assessments. Retrieved 26 September https://www.ifpma.org/subtopics/ for Antimicrobial Susceptibility 2017 from http://www.msds-gsk.com/ antimicrobial-resistance/ Testing. Retrieved 3 November 2017 SDSList.aspx from http://bsac.org.uk/wp-content/ 8. PSCI. The Principles. Retrieved 6 uploads/2012/02/Version-12-Apr-2013_ 4. Mordor Intelligence. (2016). Global December 2017 from https://pscinitiative. final.pdf Antibiotics Market Leaders – Top 10 org/principles by value, volume and company profiles. Bangalore, India.

65 Antimicrobial Resistance Benchmark 2018

RESEARCH AREA: APPROPRIATE ACCESS & STEWARDSHIP How pharmaceutical companies approach

GSK Sun Cipla Teva Lupin access and stewardshipPzer Roche Sano forAspen antibioticsMylan Novartis Shionogi Macleods Aurobindo Dr. Reddy's

Fresenius Kabi Merck & Co., Inc.

Johnson & Johnson

Figure 37. Company performance: Access & Stewardship THE LEADERS

Across this research area, four compa- Large research-based pharmaceutical companies nies stand out: GSK, Pfizer, Novartis and Johnson & Johnson. All four demon- GSK strate a range of activities across the Johnson & Johnson . indicators measured. Across access indi- Merck & Co., Inc. cators, GSK leads, followed by Johnson Novartis . & Johnson, Pfizer, Novartis and then Pzer Sanofi. All five companies have filed Roche their newest antibiotics for registra- Sano tion in some countries in scope, and Shionogi have considered the pricing and sustainable delivery of these medicines. In Generic medicine manufacturers stewardship, GSK also leads, followed Aspen by Johnson & Johnson, Pfizer, and Aurobindo Novartis. Each of these companies pro- Cipla vided evidence of stewardship in most Dr. Reddy's areas, although Novartis lacks a surveil- Fresenius Kabi lance programme. Lupin Macleods Mylan Sun Pharma ● Appropriate Access & Stewardship Teva ● Remaining potential score Points

CONTEXT WHAT THE BENCHMARK MEASURES Rising antimicrobial resistance (AMR) The challenges of ensuring access to on the market, the Benchmark does not poses twin challenges: ensure their ap- safe, effective, quality and affordable evaluate the biopharmaceutical com- propriate use (stewardship) while ad- essential medicines and vaccines are sig- panies in its scope. Most of these com- dressing the lack of access for millions nificantly higher in poorer countries4; the panies have no products on the market. globally.1,2 Pharmaceutical companies Benchmark assesses companies’ strate- However, the Benchmark highlights the can influence these two issues.3 To en- gies to address access to antimicrobials relevant activities of these companies sure access, they can put in place strate- in 106 low- and middle-income countries where possible. gies, relating to product registration, af- where access to medicine is likely limited fordability and improving supply chains. (see Appendix III). It considers steward- Regarding stewardship, the role for phar- ship activities that specifically relate to maceutical companies spans a range of antibiotics, with a global scope, looking areas such as education of healthcare at a range of areas such as education of professionals (HCPs), surveillance, and HCPs, surveillance, and appropriate pro- ensuring marketing practices take ac- motion practices. As this Research Area count of the risks of overuse and misuse. concerns activities relating to products

66 Access to Medicine Foundation

IN SUMMARY

For the majority of newer antibiotics, registrations appear Range of mechanisms reported for mitigating conflict of to be lower than for older ones interest in HCP education The Benchmark finds that newer antibiotics are currently Companies report several different mechanisms and pro- registered in fewer countries than older products. To illus- cesses to mitigate COI in their educational activities directed trate: 12 products in the analysis were introduced after 2011. at HCPs. Out of 29 programmes, 21 give information about These were (on average) filed for registration in fewer than actions to mitigate COI; for most of these (18), content is five countries; the 24 products introduced before this point developed independently; almost a third (13) run without were (on average) filed for registration in almost 30 coun- branded materials; 11 do not require attendance payments tries. Several products stand out, most notably Johnson & for participants; and six have no commercial team involved in Johnson’s bedaquiline – a long-awaited new medicine for their development. In general, companies can develop clearer tuberculosis. This is the only product introduced in the past policies and protocols for mitigating COI. One very effec- five years, assessed by the Benchmark, that has been filed tive mechanism is to partner with a public organisation in the for registration in more than ten countries in scope – indeed, development and running of educational programmes. Both it has been filed in 23 countries. Products were included in Johnson & Johnson and Pfizer are running educational pro- this analysis where the year of their first global regulatory grammes with public health organisations such as USAID, approval could be verified. National TB programmes, hospitals and other health facilities.

Two of ten generic medicine manufacturers report an Nine companies are active in AMR surveillance equitable pricing strategy programmes All large research-based pharmaceutical companies disclose Out of 19 companies (including Wockhardt), nine are active an equitable pricing strategy that covers countries where in AMR surveillance programmes, with a combined total of 19 access to medicine is likely limited. Equitable pricing strate- active programmes. Ten of these have a national focus, while gies take some measures to ensure affordability. The qual- the remaining nine are international. Eleven programmes aim ity of the strategies identified by the Benchmark varies; some to measure long-term trends in antibiotic resistance. Almost are general strategies, whereas others are linked to specific half of programmes (eight) have run for fewer than three products; some set prices at the national level, whereas oth- years, while six have run for more than ten years. Companies ers set prices for populations within countries. Out of ten are running surveillance programmes across 147 countries, generic medicine manufacturers analysed, Cipla and Mylan including 94 out of 106 countries where access to medicine is stand out for reporting an equitable pricing strategy. Generic likely limited. Only three companies are conducting more than medicine manufacturers generally price their medicines one surveillance programme (Cipla, Pfizer and Shionogi). lower than those of their large research-based competitors. However, this practice on its own offers no guarantee that Four companies take steps to adjust incentives for sales medicines will be affordable. teams Out of the 18 companies in scope, only four are taking steps The line between marketing and educational activities to adjust sales teams’ incentives. GSK demonstrates best appears blurred practice in this area, decoupling all sales incentives for sales The Benchmark finds that the line between marketing and agents from volumes of sales. Shionogi does not remunerate educational activities appears blurred. Companies generally its sales teams based on antibiotic sales volume. Two other lack clear educational targets, use similar content and goals companies are also working towards this. Novartis is taking for both marketing and educational purposes, and some pro- steps to adjust incentives for its sales agents, reducing the grammes are reported as having both marketing and educa- variable portion in the overall compensation, while Pfizer will tional purposes. The Benchmark excluded some HCP educa- begin a pilot to fully decouple its agents’ antimicrobial incen- tion strategies from analysis for too closely resembling mar- tives from sales volumes. keting tools, and offering little or no educational content. At least one other company is taking a different approach Several companies, conversely, stand out for their good prac- at the product level. Johnson & Johnson’s new anti-tubercu- tices in this area. GSK, Novartis and Pfizer show evidence of losis drug, bedaquiline (Sirturo®), is provided solely through having content independently developed and using mecha- national tuberculosis programmes and therefore does not nisms to mitigate conflicts of interest (COI), including policies require any marketing materials. The company reports that of not paying attendees or speakers in some cases and/or in it does not deploy any sales organisations for the sale of some programmes. Companies generally use congresses and/ Sirturo® in countries in scope. or courses to deliver educational material.

67 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship

APPROPRIATE ACCESS AND STEWARDSHIP METHODOLOGY: WHAT THIS RESEARCH AREA MEASURES

In Appropriate Access & Stewardship, The 18 companies are evaluated on their data with public health bodies and the Benchmark uses global antibiotic their access strategies and global stew- healthcare professionals, to working to sales volumes to inform its selection of ardship interventions. Access strategies improve understanding of resistance companies to analyse: the Benchmark are evaluated where they relate to anti- trends, and to helping increase surveil- assesses 18 companies in this research microbials in 106 low- and middle-in- lance capabilities around the world.7 area.5,6 These comprise all eight large come countries (where access to med- The Benchmark analyses data col- research-based pharmaceutical compa- icine is likely limited; see Appendix III). lected through survey and from public nies in scope and all ten generic medi- It considers stewardship activities that sources. As far as possible, this data is cine manufacturers. The scale of these specifically relate to antibiotics, with a clarified, cross-referenced and verified companies’ sales volumes suggests that global scope. by the research team. How data is col- their policies and practices can likely Most companies in scope (24) lected in the first instance depends on have a significant impact on antimicro- have signed the Declaration by the a company’s level of engagement with bial resistance. The Benchmark does Pharmaceutical, Biotechnology and the Benchmark research. All compa- not assess the activities of the 12 bio- Diagnostics Industries on Combating nies were surveyed, and data from pub- pharmaceutical companies in scope so Antimicrobial Resistance; ten have lic sources were analysed for all compa- as to preserve the comparability of this signed the Industry Roadmap for nies. Not all companies participated in group. Most of these companies have Progress on Combating Antimicrobial the survey. no products on the market. However, Resistance. In signing up to these indus- the Benchmark highlights the relevant try-wide initiatives, companies agreed activities of these companies where to support efforts to increase AMR sur- possible. veillance. Signatories commit to sharing

INDICATORS Figure 38. Companies in scope ABOUT THIS CHAPTER

C.1 Registration of antibiotics Applicable indicators In this chapter, the Benchmark reports C.2 Pricing of antimicrobials C1 C2 C3 C4 C5 C6 C7 its findings in six sections, each relating

C.3 Ensuring efficient supply Large research-based to separate indicators or a set of indi- C.4 Supporting educational steward- pharmaceutical companies cators. The indicators relating to access ship activities GSK ● ● ● ● ● ● ● are covered together in the first section. C.5 Appropriate promotion prac- Johnson & Johnson ● ● ● ● ● ● ● p69 C.1–C.3 tices Merck & Co., Inc. ● ● ● ● ● ● ● p73 C.4 C.6 Brochure and packaging Novartis ● ● ● ● ● ● ● p77 C.5 C.7 AMR surveillance Pfizer ● ● ● ● ● ● ● p78 C.6 C.8 Reducing uncontrolled use Roche ● ● ● ● ● ● ● p78 C.7 Sanofi ● ● ● ● ● ● ● p81 C.8 Shionogi ● ● ● ● ● For a full listing of indicators and scor- Generic Medicine Manufacturers ing eligibility see Appendix V.

Aspen ● ● ● ● ● ● ● Aurobindo ● ● ● ● ● ● ● Cipla ● ● ● ● ● ● ● Dr. Reddy's ● ● ● ● ● ● ● Fresenius Kabi ● ● ● ● ● ● Lupin ● ● ● ● ● ● ● Macleods ● ● ● ● ● ● ● Mylan ● ● ● ● ● ● ● Sun Pharma ● ● ● ● ● ● ● Teva ● ● ● ● ● ● ●

Wockhardt is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market, and notable practices relevant to this area are mentioned.

68 Access to Medicine Foundation

ACCESS INDICATORS How do companies address the affordability C.1 Registration of antibiotics of antibiotics? C.2 Pricing of antimicrobials C.3 Ensuring efficient supply

Although AMR is a natural phenomenon, apply (‘file’) to register its medicine with pricing policy for such innovations. This its development is being accelerated a country’s regulatory authority. Once must take account of affordability in by human actions – including the mis- approved, it can then be offered for low- and middle-income countries. use and overuse of antimicrobial med- sale. The Benchmark assesses compa- Supply: Companies share responsi- icines.8,9 Yet, millions of people do not nies on their efforts to register their five bility for maintaining and improving the have access to antimicrobials, despite most recently introduced antibiotics on efficiency of antimicrobial supply chains. having potentially curable infections.10 the WHO EML (Section 6) in countries This includes having measures in place Low- and middle-income countries have in scope (see Appendices III and IV). to avoid stock-outs, and to improve how a particular need for new strategies and Affordability: This concerns both they forecast demand for their anti- programmes to increase access to anti- those needing to buy medicines on microbial medicines. The Benchmark microbial medicines. Weak healthcare behalf of others (such as government assesses the mechanisms companies systems may limit access to antimicro- agencies and other organisations) and have put in place to align supply and bial medicines while also causing inap- individuals who need to buy medi- demand and to respond promptly to propriate use.11,12 cines for personal or family use out of stock-outs. Many of the global initiatives to pocket. One of the main approaches address AMR aim to balance the need that pharmaceutical companies can use to enhance access where neces- to address affordability is ‘equitable’ FIVE COMPANIES TAKE ACTION sary with that of ensuring optimal and pricing, which proactively considers the ACROSS REGISTRATION, appropriate use of antimicrobial medi- ability of a patient or healthcare system AFFORDABILITY AND SUPPLY cines through stewardship.8,13 By stew- to afford specific prices for medicines. ardship, the Benchmark means a sys- The Benchmark considers two types of The 18 companies the Benchmark tematic and comprehensive process equitable pricing strategies: inter-coun- assesses have a combined total of at that aims to ensure that all aspects of try, through which companies set prices least 710 antimicrobial medicines in prescription (e.g., drug, dose, duration), per country at a national level (based their portfolios. Of these products, 437 dispensing, and use of antibiotics follow on GDP, for example); and intra-country, correspond to medicines on the WHO’s the evidence available in order to mini- through which companies set prices for most recent model list of essential med- mise the emergence of resistance. different population segments within a icines, specifically in the section that This section explores the strate- country, taking into account the ability profiles infectious diseases (Section gies companies use to improve access of those populations to pay. Both types 6, 2017 WHO Model List of Essential to antimicrobial medicines in countries of strategies aim to ensure affordability Medicines, or EML). Products on this list where access is likely limited. It exam- for the poorest population segments in are considered, by WHO, as among the ines access approaches from 18 compa- both lower- income countries and coun- minimum medicine needs for a basic nies: eight large research-based phar- tries with income inequality. For this healthcare system to function. maceutical companies and ten generic measure, the Benchmark assesses com- The best performances come from a medicine manufacturers. panies’ pricing practices for their high- group of five companies: GSK, Johnson The Benchmark has identified 106 est-volume antimicrobial medicines & Johnson, Novartis, Pfizer and Sanofi. low- and middle-income countries (measured on global sales volume). These companies have filed their new- whose populations are expected to This analysis, by including highest-vol- est (i.e., most recently introduced) anti- have inadequate access to antimicrobial ume antimicrobial medicines, does not biotics for registration in at least some medicines. It evaluates access strategies include innovative antibiotics that have countries in scope, and have developed across these countries and in relation been approved in the last five years. equitable pricing strategies for their to companies’ newest* and highest-vol- These will probably not be sold in large highest-volume antimicrobial medicines. ume antimicrobial medicines. It meas- volumes in the future, as public health They also have supply-chain strategies ures access approaches in three areas: systems should aim to keep new anti- to prevent or respond to stock-outs. A registration, affordability and supply. biotics in reserve in order to limit the further six companies analysed in this Registration: To make a new antimi- emergence of resistance. Companies area (Cipla, Fresenius Kabi, Macleods, crobial medicine available to the peo- need to work closely with governments, Merck & Co., Inc., Mylan and Roche) ple that need it, a company must first NGOs and companies to develop a demonstrate activities in at least one

*Newest in this context refers to those medicines most recently introduced. 69 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship

of these areas, but not in all three. One company, Shionogi, has not filed to reg- Figure 39. Almost 65% of antibiotics are registered in countries where access is ister any antimicrobial medicines (nor less likely. markets any) in the countries in scope. Eleven companies provided registration information about 43 antibiotics. GSK, Pfizer, Roche and Sanofi The remaining six companies have the highest number of registration filings in countries in scope. (Aspen, Aurobindo, Dr. Reddy’s, Lupin, Sun Pharma and Teva) do not disclose any information about their efforts to provide access to antimicrobial medi- ● > 30 countries cines in the 106 countries where access ● 11-30 countries antibiotics to medicine is likely limited. Together, ● 1-10 countries these six companies have at least 216 ● not registered antimicrobial medicines on the market, with 127 of them on the WHO EML (Section 6). taken from the year of its first global Older antibiotics have been filed ▶ REGISTRATION regulatory approval. for registration in more countries than Steady increase over time in geo- Overall, the companies provided reg- ones more recently introduced, with a graphic range of registrations per istration information about 43 antibi- steady increase in the number of filings product otic products. Fifteen have not been of progressively older products (see fig- The Benchmark assesses the registra- filed for registration in any country in ure 40). Products introduced in the past tion filings of 18 companies (eight large scope, while 10 have been filed in up six years were, on average, filed for reg- research-based pharmaceutical compa- to 10 countries, and 18 have been filed istration in fewer than five countries, nies and ten generic medicine manufac- in more than 10 countries (see figure whereas products introduced before this turers). It looks at whether they have 39). Of the 43 antibiotics for which reg- point were, on average, filed for registra- filed their five newest antibiotics for istration details have been disclosed, tion in more than 25 countries. Products registration in 106 low- and middle-in- the following have been filed for reg- were included in this analysis only where come countries. In evaluating compa- istration in the majority of countries the year of their first global regulatory nies in this metric, the Benchmark cal- in scope: amoxicillin/clavulanic acid approval could be verified. One company, culates the average number per com- (Augmentin™, GSK, 71 countries), azith- Novartis, introduced its five newest anti- pany of countries in which it has filed romycin (Zithromax®, Zmax®, Pfizer, 63 biotics in 2011 or after (see figure 41). to register its newest antibiotics. The countries), cefuroxime axetil (Ceftin®, ‘newness’ of a product refers to when Zinnat®, GSK, 63 countries) and mupiro- it was first introduced to the market, cin (Bactroban®, GSK, 55 countries).

Figure 40. Four antibiotics have been filed in more than half of the countries in scope. Products introduced* since 2011 have been, on average, filed for registration in fewer than five countries, whereas older products have been filed in more than 25 countries. Four older antibiotics have been filed most widely, including the commonly used antibiotic amoxicillin/clavulanic acid (Augmentin™) by GSK. AA&SJohnson g 2 & Johnson’s bedaquiline (Sirturo®) is the only new antibiotic (past five years) that has been filed for registration in more than 10 countries in scope.

Number of countries where company led to register

half the countries in scope

Years since registration

* Introduction refers to the year of approval by the US FDA, EMA or Japan’s PMDA or the year a product was introduced as reported by the company. Products were included in this analysis only where the year of their first global regulatory approval was reported.

70 Access to Medicine Foundation

Figure 41. Only three companies have registered new antibiotics in low- and middle- income countries this decade. Johnson & Johnson, Novartis and Teva are the only companies who have filed new antibiotics for registration this decade. Three companies (Shionogi, Cipla, Teva) who have disclosed their five newest antibiotics to the Benchmark have not registered any products in countries in scope. Products with the highest number of filings (bold) include some of the most commonly used antibiotics worldwide. GSK’s Augmentin™ has the highest registration filings as it was first Number of introduced in 1984 and is one of Year of first countries Company Most recently introduced products registration where filed the most commonly used broad- GSK amoxicillin/clavulanic acid (Augmentin™) 1981 ‡ 71 spectrum antibiotics today. ceftazidime (Fortum®) 1990* 31 cefuroxime axetil (Ceftin®, Zinnat®) 1987* 63 GSK has filed to register three mupirocin (Bactroban®) 1987* 55 of its newest products in the retapamulin (Altargo®) 2007** 9 majority of countries in scope. Johnson & Johnson bedaquiline (Sirturo®) 2012* 23 levofloxacin (Levaquin®) 1996* 10 ofloxacin (Floxin®) 1990* 7 Novartis amoxicillin/clavulanic acid 2017 ‡ Not disclosed linezolid 2015* Not disclosed meropenem 2011* Not disclosed moxifloxacin 2015 ‡ Not disclosed tobramycin inhaler 2013* Not disclosed

Large research-based pharmaceutical companies pharmaceutical research-based Large Pfizer azithromycin (Zithromax™, Zmax™) 1991* 63 Pfizer has filed to register one of its linezolid (Zyvox®) 2000* 30 newest products in the majority of piperacillin/tazobactam (Tazosyn®, Zosyn®) 1993* 46 countries in scope. dalfopristin/quinupristin (Synercid®) 1999* 0 tigecycline (Tygacil®) 2005* 37 Roche ceftriaxone (Rocephin®) 1984* 49 sulfamethoxazole/trimethoprim (Bactrim®) 1969‡ 34 Sanofi cefixime (Oroken®) 1989* 20 cefpodoxime (Orelox®) 1992* 21 levofloxacin (Tavanic®) 1997** 45 Sanofi has filed to register all of roxithromycin (Rulid®) 1992 † 29 its newest products in at least teicoplanin (Targocid®) 1990** 29 20 countries in scope. Shionogi cefcapene (Flomox®) 1997*** 0 doripenem (Finibax®) 2005*** 0 flomoxef (Flumarin®) 1988*** 0 latamoxef (Shiomarin™) 1982*** 0 vancomycin Not provided 0 Cipla clarithromycin Not provided 0 fosfomycin Not provided 0 minocycline Not provided 0 polymyxin Not provided 0 Macleods isoniazid/pyrazinamide/rifampicin Not provided 30 isoniazid/rifampicin Not provided 30 manufacturers Generic medicine Teva daptomycin 2016* 0 linezolid 2012* 0

* Year of approval by the US FDA ** Year of approval by the EMA (or the Netherlands MEB) *** Year of approval by Japan’s PMDA † Year of approval by Australia’s TGA ‡ Year when the company reported the product was introduced

71 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship

Johnson & Johnson’s bedaquiline than large research-based pharmaceu- model that prices medicines lower than (Sirturo®) is the only product intro- tical companies. Generally, as a result, do large research-based pharmaceu- duced in the past five years that has a generic medicine manufacturer’s five tical companies, this does not guaran- been filed for registration in more than newest antibiotics are likely to have tee affordability. As they set prices, it is 10 countries in scope. Indeed, it has been introduced much more recently important these manufacturers show been filed in 23 such countries. It is also than a large research-based pharma- how pricing strategies take account of worth noting that through the Global ceutical company’s five newest antibiot- socio-economic factors, and the abili- Drug Facility, more than 70 countries ics. This difference in chronology means ties of patients or healthcare systems have approved importation of bedaqui- that the newest antibiotics from generic to afford medicines. line prior to regulatory approval. medicine manufacturers are often registered less widely than the newest prod- Leaders apply inter- and intra-country Leaders file for registration in >25 ucts from large research-based pharma- equitable pricing countries ceutical companies (see figure 41). GSK, Novartis and Johnson & Johnson Of the large research-based pharma- Generic medicine manufacturers lead in the area of equitable pricing for ceutical companies in scope, the best Fresenius Kabi and Macleods disclosed antimicrobial medicines. All are large performers in this area have filed to registration details of their antibiot- research-based pharmaceutical com- register their five newest products ics. Macleods has filed to register two panies, and all apply inter-country equi- in more than 25 countries on aver- of its newest products in 30 countries. table pricing strategies to the antibi- age. These companies are GSK, Pfizer Other generic medicine manufacturers otics and antimicrobial medicines in and Sanofi. GSK has filed to regis- did not disclose details of their efforts their portfolios that have the largest ter three of the antibiotics it has intro- to register their newest antibiotics in global sales volumes. They also have duced most recently in the majority those countries in greatest need of product-specific intra-country equita- of countries in scope. Its most widely access, and this information is not pub- ble pricing strategies for at least some filed antibiotic, amoxicillin/clavulanic licly available. products. GSK is the leading company. acid (Augmentin™), is also the most It commits to applying a product-spe- widely filed antibiotic of all products ▶ AFFORDABILITY cific equitable pricing strategy, among analysed; it has been filed for registra- Two of ten generic medicine manu- and within countries, to the majority of tion in 71 of the 106 countries in scope. facturers report an equitable pricing its highest-volume antimicrobial medi- GSK has filed to register the two other strategy cines in more than half of the countries of its newest antibiotics in up to half of The Benchmark assesses companies in scope. These products are amoxicil- the countries concerned. Its five newest on the equitable pricing strategies they lin/clavulanic acid (Augmentin™), amox- antibiotics were introduced between have developed for the five antibiot- icillin (Amoxil®), albendazole (Zentel™), 1981 and 2007. ics and antimicrobial medicines with dolutegravir (Tivicay®)*, abacavir/lam- Pfizer has filed to register its the highest volumes of sales (it does ivudine (Epzicom®, Kivexa®)*, abacavir five newest antibiotics, introduced not consider specific price points). The (Ziagen®)* and lamivudine/zidovudine between 1991 and 2005, in 35 coun- Benchmark also evaluates whether (Combivir®)*. tries on average. Of these, azithromycin companies address the needs of differ- Novartis commits to applying an (Zithromax®) was filed for registration ent population segments by taking into equitable pricing strategy among coun- in 63 countries, but dalfopristin/quin- account affordability among and within tries to all its highest-volume antibi- upristin (Synercid®) has not been filed countries in scope. otics and non-antibiotic antimicro- in any country in scope. Pfizer did not All the large research-based phar- bial medicines. As part of its partner- report filing information about newer maceutical companies in scope dis- ship established with the WHO in 2001, antibiotics acquired recently (i.e., from close – publicly or to the Benchmark – in which Novartis committed to making AstraZeneca in 2016 and from Basilea in an equitable pricing strategy for the 106 artemether/lumefantrine (Coartem®) 2017), as these products are still being countries where access to antimicro- available without profit to the public integrated into Pfizer’s portfolio (i.e., bial medicines is likely limited. The qual- sector of malaria-endemic countries, it ongoing MAA transfer processes in sev- ity of these strategies varies accord- applies equitable pricing models within eral markets). ing to whether they are general or prod- countries, for more than half of the 106 Sanofi has filed to register five of its uct-specific, and whether they relate to countries in scope. Originally a ten-year newest antibiotics, introduced between pricing within a country, among coun- agreement, the company continues this 1989 and 1997, in 29 countries (on aver- tries or both. Two of the ten generic commitment. age). All of its newest antibiotics were medicine manufacturers in scope – Johnson & Johnson commits to filed in at least 20 countries in scope. Cipla and Mylan – reported to the applying a product-specific equita- Generic medicine manufacturers, Benchmark an equitable pricing strat- ble pricing strategy among countries because of the nature of their busi- egy (details below). While generic med- to bedaquiline (Sirturo®), darunavir ness, launch more medicines per year icine manufacturers may use a business (Prezista®) and simeprevir (Olysio®).

* This product is marketed via ViiV Healthcare 72 Access to Medicine Foundation

It also commits to applying prod- the antimicrobial medicines they sell in their antimicrobial medicines, and this uct-specific equitable pricing within the highest volumes publicly, nor to the helps to prevent or minimise stock-outs. countries to bedaquiline (Sirturo®), Benchmark. The three companies have mechanisms mebendazole (Vermox®) and simeprevir (such as internal workflows, safety (Olysio®), three of its highest-volume ▶ SUPPLY stocks and supply chain management antimicrobial medicines. Leaders engage with others to systems) that enable them to respond Shionogi has no antimicrobial med- align supply and demand, prevent efficiently to stock-outs in countries in icines registered in countries in scope, stock-outs scope. Mylan is engaging in global seri- so does not disclose a pricing strategy. The Benchmark has examined compa- alisation efforts to improve traceability Roche reports that it has no strategy in nies’ mechanisms for preventing stock- of products along the supply chain. GSK place. outs and improving demand forecasting and Johnson & Johnson hold a por- Cipla commits to improving afforda- for their highest-volume antimicrobials. tion of safety stock in their warehouses bility by applying a general equita- Only eight companies disclosed supply across the globe to balance out changes ble pricing strategy among countries and demand information for their high- in demand and variation. using income, whereas Mylan commits est-volume antibiotics and antimicro- No other companies demonstrate to improving affordability by applying a bial medicines. Six of the eight strate- engagement with relevant stakeholders general equitable pricing strategy within gies were eligible for scoring in this indi- to improve the efficiency of their sup- countries, to the antimicrobial medi- cator, because information was spe- ply chains. A lack of engagement may cines they sell in the highest volumes. cific to antimicrobial medicines. GSK, lessen their ability to prevent stock- Other generic medicine manufac- Johnson & Johnson and Mylan lead in outs and continue to deliver sustainably turers in scope (Aspen, Aurobindo, this area. They engage with stakehold- to those 106 countries where access to Dr. Reddy’s, Fresenius Kabi, Lupin, ers such as government health minis- medicine is likely limited. Macleods, Sun Pharma and Teva) do not tries, The Global Fund and WHO to align disclose equitable pricing strategies for forecasting of supply and demand for

EDUCATION INDICATOR C.4 Supporting educational Do companies educate healthcare stewardship activities professionals about AMR and stewardship?

The consumption of antibiotics, includ- At the same time, companies need to that arise from their programmes. The ing the misuse and overuse of antibi- be held accountable for their influ- Benchmark also examines how phar- otics for human and animal purposes, ence over HCPs and healthcare deliv- maceutical companies develop the con- is driving the emergence of AMR.9 To ery. Transferring gifts, meals, travel tent of their educational programmes, change this behaviour, one of the first offers, payments and other forms of specifically to assess whether and how steps is to raise awareness of AMR influence has been documented across commercial teams or external experts while also building knowledge about the industry as companies seek to build are involved in that process. how to prevent resistance from emerg- relationships with HCPs. These prac- ing.3,8 Pharmaceutical companies have tices are often legal, but are acknowl- a rich depth of knowledge and exper- edged to represent conflicts of interest LINE BETWEEN MARKETING tise about antimicrobial resistance for the companies and HCPs involved. AND EDUCATION IS BLURRED (AMR) and can play an important role in At stake are the prescribing behaviours changing prescribing behaviours among that should ensure patients receive only The Benchmark finds that, in this area, healthcare professionals (HCPs). The the medicines they need. As compa- the line between marketing and edu- scale and geographic reach of many nies create and implement HCP educa- cation activities is blurred. Companies’ companies’ operations gives them a tional programmes, they must take care programmes regarding AMR generally major opportunity to educate a large to mitigate these and other conflicts of appear to lack clear educational tar- number of HCPs. Such programmes can interest (COIs).14 gets and use similar content and goals focus on how and why antimicrobials The Benchmark looks at the educa- for both marketing and educational pur- must be used appropriately, namely by tional programmes reported by compa- poses. Some programmes are reported prescribing the right drug, at the right nies aimed at healthcare professionals as having both marketing and educa- time, at the right dose and for the right relating to AMR. It looks at how com- tional purposes. The blurring of this duration. panies mitigate conflicts of interest line means that even when a company

73 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship

has the ability to reach a large num- resistance, and programmes aimed at educational programmes about multi- ber of healthcare professionals, market- conserving the efficacy of antimicrobi- drug-resistant tuberculosis, including ing-based approaches can compromise als). Examples include Pfizer’s collabo- the MDR-TB New Drug Introduction and the value of educational programmes to rations with the University of Dundee Protection (NDIP) programme in China, curb AMR. As a result, the Benchmark and the British Society for Antimicrobial which provides conferences and train- took the step of excluding from its anal- Chemotherapy (BSAC), and Merck ing courses on clinical management and ysis some HCP education strategies & Co., Inc.’s collaboration with the infection control, in combination with that too closely resemble marketing National Quality Forum to develop a donation programme for bedaquiline tools, offering little or no educational guidelines for implementing steward- (Sirturo®). content. ship programmes in hospital settings GSK, Novartis and Pfizer perform (National Quality Partners Playbook: best when it comes to providing edu- Antibiotic Stewardship in Acute Care). COMPANIES SHOW A cational content that is independently Other companies use data from surveil- PREFERENCE FOR ACTIVE developed and supports steward- lance programmes to build expertise: LEARNING ship activities. These companies report examples include GSK’s Surveillance five, three and seven educational pro- of Antibiotic Resistance (SOAR) pro- The Benchmark evaluated 29 educa- grammes respectively that support gramme of webcasts and meetings, tional programmes run by 18 companies stewardship activities. They show evi- where the company shares and dissem- (see figure 42). dence of independently developing inates up-to-date information about Twenty-two of the programmes content and using mechanisms to mit- the treatment of community-acquired deliver content through active learn- igate conflicts of interest, for exam- respiratory tract infections, to spread ing channels such as courses, trainings, ple, not paying speakers or attendees. awareness on AMR. meetings and congresses; and twelve They generally use congresses and/or use passive learning (usually text- courses to deliver educational material. Rational use of antibiotics based) methods such as books, leaflets WHO defines rational use as ‘patients and webpages. Methods such as web- receiving medications appropriate to casts are in between, with both active EDUCATIONAL PROGRAMMES their clinical needs, in doses that meet and passive examples. Active learning FOCUS ON THREE TOPICS their own individual requirements, for methods are generally defined as those an adequate period of time, and at the where attendees receive direct feed- AMR stewardship lowest cost to them and their commu- back from an instructor, as an integral Of all programmes submitted to the nity.’¹⁵ In company programmes, top- part of the lesson; passive learning is Benchmark for analysis, almost 90% ics within this theme include appro- typified by the traditional lecture, where have content that deals with issues priate diagnosis and prescription, the student does not interact with the of AMR awareness and stewardship, improved adherence to treatment instructor.16 and offers ways to increase aware- guidelines, and appropriate use of anti- Of the 29 programmes assessed, ness of AMR among healthcare pro- biotics to avoid unnecessary consump- more than half (17) include meet- fessionals. Companies such as Merck & tion. Linked to the paragraph before, ings and congresses as a way of deliv- Co., Inc. and Pfizer focus on the imple- GSK’s SOAR programme consists of ering educational content (see fig- mentation of surveillance and stew- meetings to educate HCPs on appropri- ure 43). Other frequently used meth- ardship programmes (i.e., programmes ate prescribing and updated guidelines ods are courses and trainings (in 11 pro- that monitor the rise and spread of to improve appropriate use by patients; grammes), as well as more passive tools or Novartis’ work with the Interregional such as leaflets, books and webpages Figure 42. Companies prefer active Association for Clinical Microbiology (12). Webcasts are the least recurrent learning techniques to educate HCPs. and Antimicrobial Chemotherapy in option, with only six activities delivered Active learning techniques include courses, Russia, sponsoring congresses cover- through this channel. trainings, meetings and congresses. ing topics such as appropriate diagno- In reality, most companies combine AA&S g 4 sis and treatment of multidrug resistant both modes of learning and various microorganisms. types of delivery channel. Johnson & Does not use Johnson and Novartis, for example, use active learning Disease-specific education training sessions and meetings in half of

Content and activities in this theme their programmes, while other compa- programmes include the sharing and updating of new nies prefer delivering contents through Uses active treatment guidelines, and outlines of leaflets or webpages combined with learning clinical cases that focus on a specific courses (Shionogi & Co., Merck & Co.,

disease or groups of diseases. Johnson Inc.). Pfizer, on the other hand, chooses & Johnson, for example, has developed

74 Access to Medicine Foundation courses and trainings in most of the the Benchmark to conclude that the organisation in the development and programmes submitted. remaining programmes are in fact linked running of educational programmes. More active methods of learning to such practices, only that there is no Both Johnson & Johnson and Pfizer are may be the most successful in changing evidence that they are not. running educational programmes with the behaviour of target audiences, and In general, companies can develop public organisations. may prompt participants to seek further clearer policies and protocols for mit- GSK is a leader in the Benchmark’s education through, for example, training igating COI. One very effective mech- measure of COI mitigation, which eval- courses, massive open online courses anism is to partner with a public uates approaches, not outcomes. Of all (MOOCs), and continuing medical education (CME).17 Figure 43. Companies deliver AMR-related content through a mix of activities. Most programmes do not have a Pharmaceutical companies support the education of HCPs on AMR stewardship via different activities, clear target audience; ‘healthcare pro- with a preference for congresses and meetings to involve students more directly in the discussion. fessionals’ is the most commonly stated audience (for 20 programmes), a term that can cover highly specialised profes- GSK sionals to healthcare technicians oper- Pzer ating in rural areas. ‘Doctors’ are tar- Johnson & Johnson geted by 15 programmes (with some Shionogi directing their contents to different spe- Sano cialists, including paediatricians, gynae- Novartis ● Congresses and Meetings cologists and infectious disease special- Cipla ● Books, Leaflets and Webpages ists). Three programmes target phar- Merck & Co., Inc. ● Courses and Trainings macists, and one is for dentists. Pfizer Roche ● Webcasts is the only company to focus on policy makers, with the content in many of its Number of activities educational AMR programmes covering the implementation of stewardship initiatives. Figure 44. Only five of the 29 programmes run educational webcasts. Of the 29 programmes assessed, 16 include congresses and meetings as a way of delivering contents. Other active learning methods (courses and trainings) are less popular, with 11 of the programmes MANAGING CONFLICTS OF using them to deliver content. Other options are books, leaflets and webpages. Only five of the 29 INTEREST programmes run educational webcasts - a cost-effective and easy to use, universal medium.

The Benchmark evaluates all compa- Congresses and Meetings 16 nies on their approaches to mitigating Books, Leaets and Webpages 12 conflicts of interest (COI) within and Courses and Trainings 11 arising from AMR educational activi- Webcasts 5 ties. It considers the approaches and evaluates what companies are using to Number of programmes reduce the impact of such conflicts, and whether these are general, or particular to an individual programme. Companies Figure 45. Non-branded educational materials are the most common conflict of report several different mechanisms interest (COI) mitigation techniques. and processes to mitigate COI in their Abstaining from branded materials and product-specific contents in educational materials are the two educational activities directed at health- most common measures used by companies to mitigate COIs in AMR-related educational programmes. care professionals. Out of 29 pro- Not paying programme participants is also a relatively common measure, whereas not paying external grammes, 21 give information about speakers is relatively rare. actions to mitigate conflicts of inter- COI mitigation strategy est; most of these (18) report that con- No branded materials tent is developed independently; almost No product-specic content a third (13) run without branded mate- Not paying attendees rials; 11 do not include attendance pay- No commercial teams involved ments for participants; and six have No COI mitigations reported no commercial team involved in their Not paying external speakers development (see figure 45). It should be noted that the data do not allow Number of programmes

75 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship the companies evaluated, GSK makes it has created the website Antibio- offer attendees economic and material the strongest commitment to reduc- Responsable, giving information about incentives, for example. ing COI in its educational programmes, the responsible use of antibiotics, and Johnson & Johnson is running an and provides evidence of a clear pol- providing data about susceptibility and educational programme in South Africa icy to address COI, applicable to all resistance. in conjunction with The International units. Under this policy, it no longer Roche provides information solely Union Against Tuberculosis and Lung pays healthcare professionals to speak for Roche China. The company reported Disease and the country’s National to other prescribers about prescription that its China Headquarters provides Tuberculosis Program. Johnson & medicines and vaccines, and now uses on-demand educational materials on Johnson contributes unrestricted edu- an external body to select healthcare rational use of antibiotics for self-learn- cational grants, enabling the Union to professionals for sponsorship to attend ing purposes, but stated that due to develop and deliver medical educational congresses. Most educational pro- limited resources, it does not initi- programmes about multidrug-resistant grammes are not product-specific, and ate educational programmes inde- tuberculosis (MDR-TB) and the appro- GSK’s commercial teams are, in some pendently. Roche develops its own con- priate use of anti-tuberculosis drugs. Its cases, not involved in developing mate- tent but does not give clear details of ‘train the trainers’ approach enables a rials. It also commits to disclosing pay- strategies to mitigate COI and ensure cascade of knowledge, heightening the ments to organisations and healthcare independence. programme’s reach. The mechanism of professionals. Cipla is the only generic medi- funding the programme through unre- Novartis and Pfizer perform strongly, cine manufacturer that reports differ- stricted grants helps to ensure that con- too. Novartis develops and provides ent approaches to educate HCPs on tent is developed independently, and to programmes without the involvement AMR. Cipla’s main focus is mostly on mitigate conflict of interest. of commercial teams. Its compliance, round tables, congresses and aware- Another example is Pfizer’s collab- medical and legal teams review pro- ness campaigns to the general public. oration with the University of Dundee grammes to help address and avoid However, the company does not pro- and the British Society for Antimicrobial conflicts of interest, and activities are vide any information for mitigating con- Chemotherapy (BSAC). Together, the non-promotional. Pfizer’s programmes flict of interest (COI), or information three organisations run a Massive Open have a similar internal review process on the content development. While not Online Course (MOOC) on the sub- to ensure compliance. In addition, both assessed in this Research Area, notably, ject of antimicrobial stewardship. The companies reduce the risk of conflicts Wockhardt’s approach to AMR-related course’s content, available in six lan- of interest by partnering with universi- education is to improve patient knowl- guages, is developed by the University ties and scientific societies to run sev- edge through mobile clinics that pro- of Dundee and the BSAC, and spans eral of their programmes. vide free primary healthcare to rural a general view of the global impact of Johnson & Johnson operates most populations in India (operated by the antimicrobial resistance through to spe- of its programmes in partnership with Wockhardt Foundation). cifics about how to implement stew- stakeholders who collaborate in devel- ardship programmes. It does not use oping content. Merck & Co., Inc., has Mechanisms to mitigate COI branded materials. created, through a subsidiary, a medi- Companies use several different mech- By collaborating in this way, Pfizer cal reference website called Univadis, anisms and processes to ensure they reduces the risk of COI. In providing a which provides direct links to high-qual- mitigate conflicts of interest. One very relevant programme with independently ity information and educational effective mechanism is to partner with a developed content, it can make a pos- resources on AMR, ensuring independ- public organisation. Through this, com- itive impact to influence and change ence. Where Merck & Co., Inc. partici- panies can mitigate conflicts of inter- the behaviour of healthcare profes- pates as a partner in other educational est by, for example, enabling public sionals. The three-way partnership also programmes, it uses no company logos health authorities to educate healthcare plans to publish an interactive book or branded products. professionals. about antimicrobial stewardship, focus- Shionogi delivers educational pro- Johnson & Johnson and Pfizer are sing on how to implement and evaluate grammes without branding or prod- taking fresh, constructive approaches. programmes. uct-specific contents. More typically, pharmaceutical compa- Sanofi runs educational activities nies continue to run educational pro- in France, China, Vietnam and India, grammes that comprise congresses, using round tables and conferences and meetings and symposia in which focussing on infectious disease man- experts present and discuss a variety agement and appropriate use of anti- of topics. These programmes risk (and biotics. While it does not provide evi- may be criticised for) conflicts of inter- dence of a clear COI mitigation strategy est in multiple areas: how they develop and independent content development, content, use branded products, and

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STEWARDSHIP INDICATOR What steps are companies taking to ensure C.5 Appropriate promotion practices antimicrobials are promoted appropriately?

One of the main factors that contrib- All large research-based pharmaceutical take steps to adjust incentives for sales utes to the emergence of antibiotic companies in scope have made a com- teams. resistance is the misuse and overuse mitment to review their promotional GSK demonstrates best practice in of these medicines.8,10 Examples of this activities in order to strengthen anti- this area. Since 2013, the company has include a healthcare professional decid- microbial stewardship and promoting decoupled all sale incentives for sales ing to prescribe antibiotics to treat a the appropriate use of antibiotics. Cipla agents from volumes of sales. The com- viral infection, or the sharing of antibi- is the only generic medicine manufac- pany now remunerates its sales force otics among friends and family mem- turer in scope that commits to appro- based on their technical knowledge, bers without recommended medi- priate promotion practices, while Cipla and the quality of service they deliver cal advice. Companies whose business and Fresenius Kabi are the only generic through in-clinic evaluation and moni- models rely on making a high volume of medicine manufacturers that include toring. Shionogi has also fully decoupled sales can sometimes promote the mis- resistance trends in marketing materials its sales force’s performance incentives use and overuse of antibiotics through (see figure 46). from antibiotic sales volume. It does not their marketing practices. For example, The most frequently identified mar- remunerate its sales teams based on rewarding sales staff for achieving high keting practice is a process known antibiotic sales volume. sales volumes works against conserva- as decoupling — separating volume Two other companies are also tak- tion efforts designed to ensure antibiot- of sales-based incentives from sales- ing steps towards adjusting sales incen- ics are used only when appropriate.18,19 force remuneration. Four companies tives. Novartis is adjusting incentives This can contribute to the emergence of antibiotic resistance. Similarly, materials used to market antimicrobials pres- Figure 46. Nine companies commit to reviewing promotional ent an opportunity to raise awareness activities. of the risks of AMR. Four companies are taking steps to decouple performance incentives for sales teams from The industry is therefore encour- antibiotic sales volume. GSK and Shionogi have fully decoupled these incentives. aged to establish new business models with stakeholders to ensure access to Commits in Fully decou- the Industry ples sales new antibiotics, while supporting appro- Roadmap to Reflects Takes steps to force’s incen- priate use, as recognised in the Industry reviewing AMR trends adjust incentives from promotional in marketing tives for sales antibiotic sales Roadmap on AMR. Company activities materials teams volume The Benchmark evaluates the pro- Large research-based pharmaceutical companies motional practices that companies GSK ● ● ● ● develop to advance the appropriate use Johnson & Johnson ● ● ○ ○ of antibiotics and to incentivise their Merck & Co., Inc. ● ○ ○ ○ sales representatives to market antibi- Novartis ● ● ● ○ otics in an appropriate way. Pfizer ● ● ● ○ Roche ● ○ ○ ○ Sanofi ● ● ○ ○ EIGHT COMPANIES ARE Shionogi ● ● ● ○ ● ○ CHANGING MARKETING Generic medicine manufacturers PRACTICES IN FAVOUR OF Aspen ○ ○ ○ ○ STEWARDSHIP Aurobindo ○ ○ ○ ○ Cipla ● ● ○ ○ Of the 18 companies assessed, nine Dr. Reddy’s ○ ○ ○ ○ commit to strengthening their promo- Fresenius Kabi ○ ● ○ ○ tion practices in relation to the stew- Lupin ○ ○ ○ ○ ardship of antimicrobials. Eight out of Macleods ○ ○ ○ ○ the 18 companies already use their mar- Mylan ○ ○ ○ ○ keting materials to highlight the risks of Sun Pharma ○ ○ ○ ○ increasing resistance. Teva ○ ○ ○ ○

77 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship for its sales teams around the world they are aligned with antibiotic stew- not require any marketing materials. The increasing the weight of fixed pay in ardship principles. company reports that it does not deploy overall compensation to reduce the var- At least one other company is tak- any sales organisations for the sale of iable component. Pfizer will begin a ing a different approach at the product Sirturo® in countries in scope. pilot to fully decouple its agents’ antimi- level. Johnson & Johnson’s new anti-tu- All the other companies the crobial incentives from sales volumes. berculosis drug, bedaquiline (Sirturo®), Benchmark measures in this area show Its materials and sales force training are is provided solely through national tuber- no evidence of developing or adopting reviewed by medical experts to ensure culosis programmes and therefore does appropriate promotion practices.

BROCHURE AND PACKAGING

Are companies adapting brochures and INDICATOR C.6 Brochure and packaging packaging to facilitate stewardship?

Brochure and packaging materials can these, six received some credit for their The other is from Novartis, which has be designed to improve both access adaptations. created a dosing tool to indicate the (if understood as the combination of Most reported adaptations address- correct dose of antibiotics in children. accessibility, availability, acceptability ing stewardship comprise additional No company reports adapting bro- and quality) and stewardship: to sup- information brochures on, e.g., AMR and chures or packaging materials for lan- port access, companies can address lan- appropriate use. Two reported adap- guage requirements, including into guage and literacy rates, and ensure tations that aim to improve access for languages of specific regions within materials take account of cultural con- illiterate populations – neither has yet countries. text and sensitivities; to support stew- been implemented. Another example Cipla adapts its packaging to facil- ardship, companies can include infor- of a packaging adaptation is a blister itate appropriate use of antibiotics by mation about using the medicine only pack for bedaquiline (Sirturo®) devel- patients, by providing information on when prescribed and for the entire oped by Johnson & Johnson, which treatment duration. This can help to treatment course, for example. aims to ensure the quality of the prod- improve patient adherence to treat- From the 18 companies assessed, uct as well as improve adherence. Other ment. Mylan adapts its packaging with eight companies provided informa- adaptation for bedaquiline (Sirturo®) is symbols and pictograms illustrating the tion of possible brochure and pack- a six-month presentation that can help necessary dosage schedule for patients. aging adaptations for evaluation. Of improve adherence in places where This adaptation can also improve adher- DOTs strategies are taking place. ence for illiterate populations.

SURVEILLANCE

How are companies supporting the INDICATOR C.7 AMR surveillance surveillance of drug resistance?

Antimicrobial resistance (AMR) is a Using a comprehensive approach, amount of effort. National and inter- global issue. Dealing with it effectively national governments, international national surveillance systems are now requires information about where it is public health organisations (WHO), beginning to collect, analyse and share emerging and spreading. In turn, this non-governmental organisations, indus- AMR data at all levels: patient, clinic and means taking a collaborative approach try and those in academia should work hospital. The World Health Organisation to making assessments, gaining the together to generate knowledge about (WHO) is using its Global Antimicrobial right information to take good deci- AMR. Translating this knowledge into Resistance Surveillance System sions, and providing evidence for tak- practice should help to promote the (GLASS) to support its global action ing particular courses of action. In addi- development of a global AMR surveil- plan on AMR3,20, and to standardise pro- tion, all parties need to use harmonised lance network to closely observe and cedures and foster collaboration. standards to collect, analyse and share research antimicrobial resistance in Many pharmaceutical companies data about resistance. every field of human medicine. signed the 2016 Industry Roadmap for Building such a network requires a large Progress in Combating Antimicrobial

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Figure 47. AMR surveillance: Number, geographical scope and length of surveillance programmes. The Benchmark found that nine of the 19 companies mentioned on surveillance activities (seven large research-based pharmaceutical companies, Cipla and Wockhardt) are running or supporting 19 AMR surveillance programmes across 147 countries.

Unknown over 10 years Companies Companies National International not involved Companies involved programmes programmes 3 years or shorter between Surveillance contributors: 3 and 10 years Cipla, GSK, Johnson & Johnson, Merck & Co., Inc., Pfizer, Sanofi, Shionogi, Roche, Wockhardt

Resistance, including 10 companies in trends of how resistance spreads and The Benchmark assesses companies the scope of the Benchmark. In doing provides data on new targets for new on their efforts to build a collabora- so, they agreed to support efforts medicines, and data on new mecha- tive international AMR surveillance net- to increase the surveillance of AMR. nisms of resistance. It can also help to work. As part of this, it evaluates how Signatories commit to sharing their identify unmet needs for new antibi- they are working with academic insti- data with public health bodies and otics or diagnostics. From a marketing tutions and public health authorities to healthcare professionals, to working to perspective, it allows to model future enable the sharing of data and increase improve understanding of resistance resistance trends, and conduct pre- and transparency. Eighteen companies have trends, and to helping increase surveil- post-launch surveillance programmes been analysed in this area as they have lance capabilities around the world.7 and establish products’ lifecycles. This marketed antibiotics. Although not eligi- As antibiotic manufacturers, phar- data can help fill in the gaps for many ble for this area, Wockhardt is also men- maceutical companies have the mate- countries where health systems do not tioned due to its activity in surveillance rial and economic means, as well as have the technical expertise. programmes. the technical expertise and experience, to undertake surveillance activities. Surveillance data is also useful for companies in different aspects. From an R&D perspective, surveillance shows

Figure 48. AMR surveillance programmes are being conducted in 147 countries worldwide. Nine companies assessed by the Benchmark are engaged in surveillance programmes, active in 75% of countries in the world.

● No surveillance programmes ● 1-2 surveillance programmes ● ≥3 surveillance programmes

1 2 3 4 5 6 Antimicrobial Resistance Benchmark 2018 – Appropriate Access and Stewardship

OF THE 19 COMPANIES articles in peer-reviewed journals and as the Linezolid Efficacy and Accurate MENTIONED, ONLY NINE ARE presentations at congresses. Determination or Resistance (LEADER), ACTIVE IN AMR SURVEILLANCE GSK, Johnson & Johnson, Pfizer and and the European Surgical Site PROGRAMMES Merck & Co., Inc. have international pro- Infections Epidemiology Study (EUPJI grammes for AMR surveillance. Seven Network). One of its programmes, These companies – Cipla, GSK, Johnson of the programmes, both national and based in Latin America, reports looking & Johnson, Merck & Co., Inc., Pfizer, international, run in hospitals that offer at trends in antibiotic resistance and at Sanofi, Shionogi, Roche and Wockhardt secondary and tertiary care, and in the burden of disease due to S. aureus. – contribute to 19 programmes. GSK, operating rooms. As this region has a high need for sur- Johnson & Johnson, Wockhardt, Roche Only one programme (the SENTRY veillance systems, Pfizer’s programme and Sanofi are running one programme Programme, managed by JMI Labs and fills a gap, helping public health author- each. The other four companies (Cipla, partnered with Pfizer) reports on AMR ities to develop measures to prevent Pfizer, Merck & Co., Inc., and Shionogi) surveillance activities carried out at the resistance. are running more than one surveillance community level. This means countries Johnson & Johnson, through activity. with less specialised health networks its Drug Resistance Emergence Companies run surveillance activities have less representative data, at least Assessment in MDR-TB (DREAM) pro- in 147 countries, including 94 out of 106 from the companies in scope, which gramme, focusses on resistance to countries identified by the Benchmark constitutes a big gap. It will be impor- anti-tuberculosis drugs, such as its own as those with the greatest need of tant to help build surveillance networks product Sirturo (bedaquiline). It col- access (see figure 48). Of the 94 coun- in countries whose health systems can- laborates with WHO Supranational tries, most have 1–2 programmes run- not do this alone. Reference Laboratories and national TB ning (69), and India has the most with GSK demonstrates best practice with reference laboratories in 11 countries, five programmes. Of all countries glob- The Survey of Antibiotic Resistance, or providing funding through individual ally, Japan has the highest number of SOAR, an international programme that clinical study agreements. Johnson & programmes in progress, with six sur- focusses on observing AMR in respira- Johnson shares its surveillance results veillance activities in total. tory tract infections. SOAR shares its in peer-reviewed journals, and with Ten programmes have a national results through peer-reviewed journals national TB programmes. scope (Sanofi’s programme in France, and congresses, and collaborates with Sanofi partners with public health Shionogi’s four surveillance pro- public health authorities to develop and institutions to monitor AMR trends in grammes in Japan, Roche’s research update therapeutic guidelines. Sanofi, France, for example. The company does grants in China, Pfizer’s LEADER and Johnson & Johnson, Pfizer and Merck not own the data, and depends on its CHINET programmes in the US and & Co., Inc. are doing similar things; how- partners to publish results in journals or China, respectively, and Cipla and ever, GSK, together with the Wellcome at congresses. Wockhardt’s programmes in India), Trust and the Open Data Institute, is While the generic manufacturing while the remaining nine are interna- working to develop an industry-spon- industry has a global market presence, tional in scope. Eleven programmes aim sored surveillance database with open- Cipla is the only generic manufactur- to measure long-term trends in antimi- source anonymised data sets. This ing company to run an AMR surveillance crobial resistance, but almost half of the would harmonise and open AMR surveil- programme. Similarly, Wockhardt is the programmes (8) are fewer than three lance data from companies to different only company in the biopharmaceuti- years old, while six have run for more stakeholders. cal arena reporting a surveillance pro- than ten years. Sanofi, Johnson & Johnson, Pfizer gramme. Both operate programmes in Only two companies publish the and Merck & Co., Inc. have programmes India, where Cipla is involved in surveys results of their surveillance pro- to monitor resistance trends, shar- and prevalence studies. Wockhardt runs grammes in full: Pfizer with its ATLAS ing the results with public health agen- a surveillance programme there, which (Antimicrobial Testing Leadership and cies. Merck & Co., Inc. runs the SMART works with hospitals and laboratories to Surveillance) programme, and Merck programme, while Pfizer runs ATLAS. monitor resistance trends. & Co., Inc. with its SMART (Study for These programmes have many simi- Roche China takes a different approach. Monitoring Antimicrobial Resistance larities. Both have run for more than a The company awards grants to Trends). A further five of the 19 pro- decade, and both have a global scope researcher-led projects, without impos- grammes share their data with pub- in monitoring patterns of resistance. ing conditions on how the research is lic health authorities, engaging in fur- Results from both programmes are carried out. These grants are focussed ther AMR-related actions (such as the available publicly on webpages. on antibiotic susceptibility in China. implementation of antimicrobial stew- Both SMART and ATLAS report play- Both Roche and Wockhardt pub- ardship plans, or increasing the scope of ing a supportive role for public health lish results from their programmes in the surveillance system, etc.). Most pro- authorities. Pfizer reports engag- peer-reviewed journals. grammes (14) share their data through ing in many other programmes, such

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SALES CONTROL INDICATOR Are companies taking steps to reduce C.8 Reducing uncontrolled use (Indicator not scored, due to non-presciption (over-the-counter) sales? data quality and availability)

While it is often considered the role Roadmap on AMR that some compa- GSK’s main approach to avoid OTC sales of the government to track and con- nies in scope have signed, where they is educating pharmacists to reduce trol non-prescription or over-the-coun- committed to ‘Collaborate with govern- non-prescription sales, and other com- ter (OTC) sales, ten companies that ments, their agencies and other stake- panies include AMR-related topics in have signed the Industry Roadmap, holders to reduce uncontrolled anti- the sales agents’ educational contents, have committed to collaborate with biotic purchase, such as via over-the- so they can sensitise pharmacists and governments and other stakeholders counter and non-prescription internet retailers to reduce OTC. to reduce uncontrolled antibiotic pur- sales.’ In practice, very little has been chases, including OTC sales. Some of done, and most companies don’t know these companies are putting practices where to start. While some companies in place to facilitate the appropriate use are developing tools to track and trace of antibiotics. products, it will not necessarily reduce OTC sales unless they share the data Pfizer reported its commitment to sup- with authorities, collaborating to mon- porting government initiatives to reduce itor OTC and non-prescription sales in uncontrolled consumption of antibi- pharmacies. otics. This is aligned with the Industry

REFERENCES

1. Mendelson, M., et al. (2016). 7. AMR Industry Alliance. (September, 13. Interagency Coordination Group on 18. Clift, C., et al. (October, 2015). Maximising access to achieve appropriate 2016). Industry Roadmap for Progress Antimicrobial Resistance. (August, 2017). Towards a new global business model for human antimicrobial use in low-income on Combating Antimicrobial Resistance. AMR Framework for Action Supported antibiotics: delinking revenues from sales. and middle-income countries. The Lancet, Retrieved from https://www.amrindus- by the IACG. Retrieved 11 December Chatham House. Retrieved from https:// 387(10014), 188-198. tryalliance.org/industry-roadmap-for-pro- 2017 from http://www.who.int/antimi- www.chathamhouse.org/publication/ gress-on-combating-antimicrobial-resist- crobial-resistance/interagency-coordina- towards-new-global-business-model-anti- 2. Cox, J. A., et al. (2017). Antibiotic ance/ tion-group/20170818_AMR_FfA_v01.pdf biotics-delinking-revenues-sales stewardship in low-and middle-income countries: the same but different? 8. O’Neill, J. (May, 2016). Tackling 14. Field, M. J., & Lo, B. (2009). Conflict 19. Outterson, K. (2014). New business Clinical Microbiology and Infection, 23(11), drug-resistant infections globally: final of interest in medical research, education, models for sustainable antibiotics. Centre 812-818. report and recommendations. The Review and practice. National Academies Press. on Global health Security Working Group on Antimicrobial Resistance. Retrieved 6 October 2017 from https:// Papers, Chatham House (The Royal 3. WHO. (2015). Global Action Plan on www.ncbi.nlm.nih.gov/books/NBK22945/ Institute of International Affairs), Working Antimicrobial Resistance. Retrieved from 9. Holmes, A. H., et al. (2016). Groups on Antimicrobial Resistance. www.wpro.who.int/entity/drug_resist- Understanding the mechanisms and 15. WHO. (2002). Promoting rational use ance/resources/global_action_plan_eng. drivers of antimicrobial resistance. The of medicines: core components. Retrieved 20. WHO. (2015). Global Antimicrobial pdf Lancet, 387(10014), 176-187. 10 December 2017 at http://apps.who.int/ Resistance Surveillance System: Manual medicinedocs/pdf/h3011e/h3011e.pdf. for Early Implementation. Retrieved 10 4. United Nations. (2015). Transforming 10. Laxminarayan, R., et al. (2016). Access December 2017 at http://www.who.int/ our world: The 2030 agenda for sustaina- to effective antimicrobials: a world- 16. Haidet, P., et al. (2004). A controlled antimicrobial-resistance/publications/ ble development. A/RES/70/1. Retrieved wide challenge. The Lancet, 387(10014), trial of active versus passive learning strat- surveillance-system-manual/en/ 17 March 2017 from https://sustaina- 168-175. egies in a large group setting. Advances in bledevelopment.un.org/content/docu- Health Sciences Education, 9(1), 15-27. ments/21252030 Agenda for Sustainable 11. Mills, A. (2014). Health care systems Development web.pdf in low-and middle-income countries. New 17. Mansouri, M., & Lockyer, J. (2007). England Journal of Medicine, 370(6), A meta-analysis of continuing medi- 5. Mordor Intelligence. (2016). Global 552-557. cal education effectiveness. Journal Antibiotics Market Leaders – Top 10 of Continuing Education in the Health by value, volume and company profiles. 12. Tomson, G., & Vlad, I. (2014). The Professions, 27(1), 6-15. Bangalore, India. need to look at antibiotic resistance from a health systems perspective. Upsala jour- 6. Mordor Intelligence. (2016). Top nal of medical sciences, 119(2), 117-124. 10 Generic Antibiotic Manufacturers by Volume – Custom Study. Bangalore, India.

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82 Access to Medicine Foundation Company Report Cards

The 2018 Antimicrobial Resistance Benchmark includes 30 company report cards, which each provide a contextualised analysis of one company’s performance in the 2018 Benchmark. This includes a summary of its performance (both overall and per Research Area). Each report card includes overviews of the company’s portfolio and pipeline, and identifies tailored opportunities for it to increase access to antimicrobial medicines, while ensuring their appropriate use. The report cards are divided into five areas:

Performance This section explains the relevance of the company for the Antimicrobial Resistance Benchmark and its overall performance. It covers: • Drivers behind its scores • Main areas where the company scores well or poorly compared to peers

Sales and Operations This section provides a general description of the company’s global operations, including recent changes in its business (e.g., acquisitions or divestments), focussing on its antimicrobial business.

For biopharmaceutical companies with no products on the market, this section is called 'Operations'.

Antimicrobial Portfolio This provides a description of the number and type of antimicrobial medicines the company markets as of September 2017 and the proportion included on the WHO EML (Section 6).

Opportunities This section outlines opportunities for the company to do more to ensure access to antimicrobials and ensure their appropriate use. The opportunities take into account company-specific characteristics as far as possible.

Performance by Research Area These three sections summarise company performance for each of the Research Areas, by indicator. The paragraphs describe the company’s performance and highlight (where available) relevant examples of its activities.

83 Antimicrobial Resistance Benchmark 2018 Achaogen, Inc.

Stock exchange: XNAS • Ticker: AKAO • HQ: South San Francisco, CA, USA • Employees: 106 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Achaogen was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ○ ○ ○ ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ○ ○ ○ ○ ○ ○ ○ overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Achaogen is a biopharmaceutical company, selected for four projects in its antimicrobial R&D pipeline, all targeting having a pipeline that targets priority pathogens. It was evalu- priority pathogens. The company engages in numerous pub- ated in the area of Research & Development only. lic-private partnerships and agreements with various organi- The company’s R&D investment in antibiotic drug devel- sations to develop its antibiotic candidates. Achaogen has one opment in 2016 amounts to USD 74 million, which is high R&D project in late-stage clinical development. It reported compared to other biopharmaceutical companies in the no information about whether this project is supported by Benchmark. Achaogen is a mid-performing company com- access or stewardship provisions. pared to the biopharmaceutical companies in scope. It has

OPERATIONS

Achaogen, founded in 2002, is a biopharma- acute pyelonephritis. The company has a col- and the Bill & Melinda Gates Foundation. It was ceutical company focussing on the develop- laboration with Thermo Fisher Scientific, Inc. to listed on the NASDAQ stock exchange in 2014, ment of antibiotics to treat multidrug-resistant develop and commercialise an assay to measure having raised approximately USD 72 million from gram-negative bacterial infections. The compa- plazomicin levels in the blood, in order to ensure shareholders such as Domain Partners, Venrock, ny’s most advanced drug candidate, plazomicin, safe and effective dosing during treatment. Wellcome Trust and ARCH Venture Partners, is currently awaiting FDA approval following the Achaogen has no products on the market. To among others. In 2016, it raised USD 25 million completion of two successful Phase III trials: one date, it has received financial support from vari- from a private placement (led by New Enterprise in bloodstream infections caused by carbapen- ous funders for the development of its pipeline, Associates). em-resistant Enterobacteriaceae (CRE) and the including BARDA, the US National Institute of other in complicated urinary tract infection and Allergy and Infectious Diseases (NIAID), CARB-X

ANTIMICROBIAL PORTFOLIO

Achaogen does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Achaogen is developing one antibiotic candidate (plazomicin) in late-stage clinical development. Achaogen can ensure access and stewardship provisions are in place for plazomicin (e.g., through partnerships).

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 4 projects scored on ○ ● ● ○ ● ● pipeline 4 target priority pathogens

A.2.1-2.2 Four R&D projects that target A.3 Three R&D projects being developed A.4 No information on access or stewardship priority pathogens. with public partners. provisions. Biopharmaceutical companies in scope were Achaogen is developing two R&D projects in its Achaogen reports no information on access or selected based on their pipelines that target pri- priority pathogen pipeline through public-private stewardship provisions for its antibiotic candi- ority bacteria. Achaogen invested USD 74 mil- partnership. It has funding agreements with four date in late-stage development. It has signed lion in antibiotic drug development in 2016. public partners for the development of three the Davos Declaration, which includes a gen- The company is developing four projects that R&D projects in its priority pathogen pipeline. It eral commitment to ensuring access to antimi- target gram-negative bacteria. Three of these has received financial support from BARDA for crobial medicines and vaccines, and to support projects involve the development of new drug the development of plazomicin (≤USD 123.8 mil- the appropriate and responsible use of these candidates, while the remaining R&D pro- lion). The company also has a contract for ≤USD products. ject is an adaptation. Plazomicin, currently 5 million with the NIAID and recently received a awaiting FDA approval, is Achaogen’s most CARB-X award to support its LpxC inhibitor pro- advanced candidate. Plazomicin is an amino- gramme for the treatment of bacterial infec- glycoside with activity against carbapenem-re- tions, currently in preclinical stage. Furthermore, sistant Enterobacteriaceae, but is vulnerable to in May 2017, the company announced it would cross-resistance with other aminoglycosides receive ≤USD 10.5 million in grant funding (along such as gentamicin and amikacin. The two other with a USD 10 million equity investment) from R&D projects are candidates in preclinical stage the Bill & Melinda Gates Foundation to further and both target multidrug-resistant gram-neg- its preclinical R&D research on antibody candi- ative bacteria: one investigates LpxC inhibitor dates against gram-negative bacteria, including compounds and the other monoclonal antibod- those that cause neonatal sepsis. Achaogen has ies. The company is also developing C-Scape, also received BARDA funding for the develop- a combination of a ß-lactam and ß-lacta- ment of C-Scape (≤USD 18 million). mase inhibitor, both already on the market and off-patent.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• LpxC inhibitor • C-Scape – ESBL • Plazomicin – compounds – – Adaptation CRE, ESBL – GNB (new FDC of aminoglyco- • Monoclonal an approved side – Awaiting antibody pro- ß-lactam and approval FDC = Fixed dose combination GNB = Gram-negative bacteria gramme – GNB ß-lactamase inhibitor)

MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Achaogen was not eligible for this Research Area.

APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Achaogen was not eligible for this Research Area.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Achaogen is developing a diagnostic assay for Benchmark. This information is provided given therapeutic drug management of plazomicin in a the importance of animal health and diagnostics partnership with Thermo Fisher Scientific. This on the topic of AMR. diagnostic platform monitors the levels of plazomicin in the blood in order to ensure safe and effective dosing during treatment.

85 Antimicrobial Resistance Benchmark 2018 Aspen Pharmacare Holdings Limited

Stock exchange: XJSE • Ticker: APN • HQ: Durban, South Africa • Employees: 10,204 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Aspen was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P . M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Aspen is a prominent producer of antibiotics globally by sales no evidence, however, that these principles are applied to its volume. As a generic medicine manufacturer, Aspen was third-party suppliers of antibiotic APIs and drug products. evaluated in Manufacturing & Production and Appropriate It reports mechanisms for maintaining high quality of anti- Access & Stewardship only. It reported no information to biotic production at its own manufacturing sites. The com- the Benchmark, and publicly available information is limited. pany reports no information regarding an equitable pricing Although the company’s performance in the Benchmark is approach, or where it files products for registration. Aspen lower compared to most other generic medicine manufactur- does not report any involvement in stewardship activities that ers in scope, it reports a set of environmental risk-manage- promote appropriate antibiotic use. ment principles that include an auditing process. There was

SALES AND OPERATIONS RevenuesAspen by product§ RevenuesMade: by region§ Final: no

Aspen is a global supplier and manufacturer In 2016, Aspen acquired GSK’s portfolio of of generic pharmaceutical products and active anaesthetic products (five medicines), as well as . . pharmaceutical ingredients, as well as infant exclusive rights to commercialise AstraZeneca’s . . nutritionals and consumer health products. The anaesthetics portfolio (seven medicines) in 100 bn ZAR bn ZAR company has a substantial presence in low- and countries worldwide (including, e.g., China, but . middle-income countries in regions such as Latin excluding, e.g., the USA). In 2009, Aspen and

America, Russia, Eastern Europe, sub-Saharan GSK formed the "GSK Aspen Healthcare for ● Total revenue ● Developed Europe Africa (SSA) and South Asia, with 25 manufac- Africa" collaboration in SSA, which came to an ● Asia Pacic turing facilities worldwide. Throughout SSA, it end in January 2017, with GSK paying Aspen ● Sub-Saharan Africa ● Rest of World is a market leader in the antibiotics, respiratory, GBP 45 million. pain, cough and cold segments. Its primary therapeutic focus areas are thrombosis, anaesthetics, cytotoxics, and infant nutritionals.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Aspen mar- and ciprofloxacin, in both the Access and Watch kets at least 16 antimicrobial medicines, ten of groups. The remainder (five) of the company’s which are listed on the WHO EML (Section 6). portfolio includes antifungals, antiprotozoals and Eleven of the company’s antimicrobials are anti- the anthelminthic albendazole. The company biotics, with seven on the WHO EML (Section 6), also markets an antiseptic face wash contain- including ceftazidime, in the EML’s Watch group, ing triclosan.

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. † EML Section 6: Anti-Infective Medicines § Net revenue; FYE 30 June 2017

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OPPORTUNITIES

Engage in antimicrobial stewardship. Aspen can egy to the sites of third parties that manufacture existing antimicrobials, and ensure that they are engage in stewardship activities, e.g., through antibiotic APIs and drug products on its behalf, priced affordably. Currently, the company does surveillance activities, educational activities for as well as to external waste-treatment sites. not disclose such information. healthcare professionals on AMR (while mitigat- Aspen currently discloses a general environmen- ing conflicts of interest), and engage in appropri- tal risk-management strategy that it applies to ate promotion practices. its own manufacturing sites.

Expand environmental risk-management strat- Ensure affordability and registration plans for egy. Aspen can ensure its antibiotic discharge new and existing antimicrobials. Aspen can limits are applied to its environmental risk-man- seek to improve access in low- and middle-in- agement strategy. It can also extend this strat- come countries through registration of new and

PERFORMANCE BY RESEARCH AREA

RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Aspen’s main focus is the manufacturing of generic products and as such was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management princi- B.2 Limited transparency regarding environ- B.3 Commits to following GMP. ples for own sites. mental risk management. Aspen reports that it has mechanisms for main- Aspen has set environmental risk-management Aspen publishes its environmental risk-manage- taining a high quality of antibiotic production — principles to minimise the impact of antibiotic ment principles in its annual report. It does not namely following GMP standards. This commit- manufacturing discharge. These apply to its own disclose audit results, or the discharge levels of ment applies to its own manufacturing sites, but manufacturing sites and include auditing. There antibiotics. The company also does not share the the company does not report any commitment is no evidence that they are applicable to third- identities of its third-party suppliers of antibiotic relating to how GMP standards apply to its third- party manufacturers of antibiotic APIs and drug APIs and drug products or external waste-treat- party suppliers of antibiotic drug products. products or to external waste-treatment plants. ment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Aspen reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Aspen does not disclose how it works with Aspen does not report any involvement in stew- countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to ardship activities (from education to surveillance erwise publicly available. align supply and demand for antimicrobial med- to appropriate promotion practices) that pro- icines, specifically to prevent or minimise stock- mote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Aspen does not disclose an equitable pricing place to respond to stock-outs in countries in approach for its highest-volume antibiotics and/ scope.* or antimicrobial medicines.

87 Antimicrobial Resistance Benchmark 2018 Aurobindo Pharma Limited

Stock exchange: XNSE • Ticker: AUROPHARMA • HQ: Hyderabad, India • Employees: 13,982 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No**

Performance by Research Area How Aurobindo was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Aurobindo is a prominent producer of antibiotics glob- Stewardship. Aurobindo discloses a comprehensive environ- ally by sales volume. As a generic medicine manufacturer, mental risk-management strategy, which is applied to exter- Aurobindo was evaluated in Manufacturing & Production and nal waste-treatment plants. The company reports that it has Appropriate Access & Stewardship only. The company per- mechanisms in place for maintaining high quality of antibi- forms well when compared with the other generic medicine otic production. Aurobindo does not report any involvement manufacturers in scope. It performs well in Manufacturing in stewardship activities that promote appropriate antibiotic & Production, but falls behind in Appropriate Access & use. RevenuesAurobindo by product§ RevenuesMade: by region§ Final: no SALES AND OPERATIONS . Aurobindo is a manufacturer of active pharma- it sold 1.45 billion units (DDDs) of antimicro- . . ceutical ingredients (APIs) and oral and inject- bial medicines. Within its antimicrobial business, . . able generic formulations. Its portfolio covers the company is currently focussing on devel- bn INR bn INR seven major therapeutic areas, including antibi- oping its manufacturing capacity of penems . . otics, antiretrovirals (ARVs) and cardiovascular — broad-spectrum antibiotics used for multi- and central nervous systems. It has nine manu- drug-resistant infections. In 2017, Aurobindo ● Antimicrobials ● India facturing units for APIs and intermediate prod- entered a multilateral agreement to provide a ● Other revenue ● USA ucts and seven for formulations, as well as R&D new class of ARVs (developed within a licens- ● Europe ● Rest of World centres in India and the USA. Aurobindo markets ing agreement with Gilead Sciences Inc. and ViiV its products in more than 150 countries world- Healthcare) to low- and middle-income coun- wide, with a focus on the USA and Europe. It tries. In return for guaranteed minimum sales Antimicrobial portfolio breakdown sells antimicrobial medicines in at least 92 coun- volumes, Aurobindo will supply a generic FDC tries, at least 50 of which are low- and mid- of dolutegravir/lamivudine/tenofovir for a maxi- dle-income countries.* In the fiscal year 2016, mum price of about USD 75 per patient per year. ANTIMICROBIAL PORTFOLIO Aurobindo markets at least 40 antimicrobial ing five on the EML’s Watch group. The remain- medicines, 28 of which are listed on the WHO der (22) of the company’s portfolio comprises EML (Section 6). Eighteen of the company’s 20 antivirals (16 of which target HIV) and two antimicrobial medicines are antibiotics, with antifungals. ● Antibiotics on WHO EML† WHO EML Categories 12 listed on the WHO EML (Section 6), includ- ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped

Engage in antimicrobial stewardship. Aurobindo does not disclose such information. Expand environmental risk-management strat- can engage in stewardship activities, e.g., egy. Aurobindo can set and apply discharge through surveillance activities, educational activ- Ensure transparency regarding environmental limits for antibiotic manufacturing. It currently ities for healthcare professionals on AMR (while risk management. Aurobindo can share more has an environmental risk-management strategy mitigating conflict of interest), and engage in information on how it manages environmental that applies to its own manufacturing sites and appropriate promotion practices. risk (e.g., the company can publish the results of external waste-treatment sites. audits carried out on its environmental risk-man- Ensure affordability and registration plans for agement strategy and the identities of exter- Increase engagement in R&D innovation. new and existing antimicrobials. Aurobindo can nal waste-treatment plants). After the period Aurobindo is currently engaged in developing seek to improve access in low- and middle-in- of analysis, the company disclosed the identi- a new fixed dose combination of antiretrovi- come countries through the registration of new ties of external waste-treatment plants to the ral medicines. It can continue to engage in incre- and existing antimicrobials, and ensure that they Benchmark. mental R&D, and ensure access and stewardship are priced affordably. Currently, the company provisions are in place for these projects. * Countries in scope are 106 low- and middle-income 88 countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017 ** Company states it has applied to be a signatory Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Aurobindo One fixed dose combination for HIV/AIDS. the treatment of HIV/AIDS. In 2017, Aurobindo was not eligible for this Research Area. However, On reviewing publicly available information, the received FDA tentative approval for this FDC, the company is active in antimicrobial R&D. Benchmark found that Aurobindo has one pro- as it consists of patented antiretrovirals from ject in its antimicrobial R&D pipeline that tar- Gilead Sciences Inc., Bristol-Myers Squibb Co. gets HIV. This involves dolutegravir/lamivudine/ and ViiV Healthcare. tenofovir disoproxil fumarate, a new FDC for

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Dolutegravir/ lamivudine/ tenofovir disoproxil fumarate – HIV – Adapta- tion (new FDC) – FDA tentative approval 2017

FDC = Fixed dose combination

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management strat- mation about setting discharge limits. Aurobindo After the period of analysis the company dis- egy for own and external sites. states that it does not use third-party suppli- closed the identities of external waste-treat- Aurobindo has an environmental risk-manage- ers for the manufacturing of antibiotic drug ment plants to the Benchmark. ment strategy to minimise the impact of anti- products. biotic manufacturing discharge. The strategy B.3 Commits to following GMP. includes auditing and applies to its own sites and B.2 Limited transparency regarding environ- Aurobindo reports that it has mechanisms for external waste-treatment plants. For a subset of mental risk management. maintaining a high quality of antibiotic produc- sites, Aurobindo follows a Zero-Liquid Discharge Aurobindo publishes its environmental risk-man- tion — namely following GMP standards. process (ZLD, a water treatment process in agement strategy in its annual report. It does which all wastewater is cleaned and reused); for not disclose audit results, or the discharge levels others it deactivates antibiotics prior to external of antibiotics. The company does not share the waste treatment. The company reports no infor- identities of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Aurobindo reports no information on where it chain efficiency. ship activities. has filed its newest antibiotics for registration in Aurobindo does not disclose how it works with Aurobindo does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to surveil- erwise publicly available. align supply and demand for antimicrobial med- lance to appropriate promotion practices) that icines, specifically to prevent or minimise stock- promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Aurobindo does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiot- scope.* ics and/or antimicrobial medicines. The company states that its approach to affordability is through tenders.

89 Antimicrobial Resistance Benchmark 2018

Cempra, Inc. Merged with Melinta Therapeutics, Inc. in 2017

Stock exchange: XNAS • Ticker: CEMP • HQ: Chapel Hill, NC, USA • Number of employees: 45 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Cempra was evaluated: applicable indicators

Cempra is a biopharmaceutical company that has recently ical-stage development. The company engages in public-pri- merged with Melinta, selected for having a pipeline that tar- vate partnerships and agreements with various organisa- gets priority pathogens. It was evaluated in the area of tions to develop its antibiotic candidates. Cempra reported no Research & Development only. Its R&D investment in anti- information on having any access or stewardship provisions in biotic drug development in 2016 amounted to USD 82 mil- place for its late-stage clinical R&D projects. lion. It is a mid-performing company compared to the biopharmaceutical companies in scope. Cempra’s pipeline consists of one novel drug candidate and one adaptation, both in clin-

OPERATIONS

Cempra, founded in 2006, was a biopharma- otic to enter clinical use. This led to solithromy- cystic fibrosis patients. The company was also ceutical company focussing on the develop- cin, currently in clinical stage of development, investigating compounds from its macrolide ment of differentiated anti-infectives for acute in both intravenous and oral formulations, for platform, which have the potential to treat bac- and community care settings. In 2017, the com- the treatment of community-acquired bacterial teria typically responsible for human skin and pany announced it would merge with Melinta pneumonia and gonorrhoea. lung infections, as well as respiratory disease in Therapeutics, Inc., a biopharmaceutical company Prior to merging with Melinta, Cempra had no animal health. also in scope of the Benchmark. The merger was products on the market. In 2013, it received five- Cempra was listed on the NASDAQ stock completed in November 2017. year funding from the Biomedical Advanced exchange in 2012, raising approximately Research and Development Authority (BARDA) USD 47.7 million. Prior to this, between Cempra was formed by in-licensing Optimer for approximately USD 60 million to develop 2006 and 2009, company investors included Pharmaceuticals’ macrolide programme, with solithromycin. The company was considering Intersouth Partners, Aisling Capital, Optimer the aim of developing a superior macrolide, with additional indications for this compound, for Pharmaceuticals and Quaker Bioventures, less toxic properties than the recently intro- example, for the treatment of malaria, tubercu- among others. duced telithromycin—the first ketolide antibi- losis, H. pylori gastritis and various infections in

ANTIMICROBIAL PORTFOLIO

Cempra does not have any products on the market.

90 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 One new medicine and two The compound is in development exclusively for A.4 No information on access or stewardship adaptations in the pipeline. the US market and is currently in Phase III clini- provisions. Biopharmaceutical companies in scope were cal trials for acute bacterial skin and skin struc- Cempra reports no information on access or selected based on their pipelines that target pri- ture infections (ABSSSI) and prosthetic joint stewardship provisions for its two antibiotic can- ority bacteria. Cempra invested USD 82 million in infections. didates in late-stage development. It has signed antibiotic drug development in 2016. The com- the Davos Declaration, which includes a gen- pany has three projects in its antimicrobial R&D A.3 One R&D project being developed with eral commitment to ensuring access to antimi- pipeline, all targeting priority bacteria. Its anti- public partners. crobial medicines and vaccines, and to support biotic candidate, solithromycin, is a macrolide Cempra is developing one R&D project in its pri- the appropriate and responsible use of these developed for community-acquired bacterial ority pathogen pipeline through public-private products. pneumonia (CABP). The medicine was submit- partnership. It has received financial support ted to the FDA in 2016 for market approval, but from BARDA for the development of solithromy- was rejected due to inadequate characteristics cin. This began in 2013 and will last for five years. of liver toxicity, and detected deficiencies in the The BARDA grant provides Cempra with funding manufacturing facilities of the company’s man- for the clinical development of the compound ufacturing contractors (Wockhardt Limited and for the treatment of bacterial infections in pae- Hospira, Inc.). A similar EMA application has sub- diatric populations. The most recent funding sequently been withdrawn. Additionally, solithro- instalment (March 2016 to mid-2018) amounted mycin is in Phase III clinical development for the to USD 25.5 million, for the conclusion of Phase treatment of gonorrhoea. Cempra is also devel- II/III studies on intravenous, oral capsule and oral oping a new and proprietary regimen of fusidic suspension formulations for paediatric patients acid (Taksta™), an existing antibiotic with activity with community-acquired bacterial pneumonia against methicillin-resistant S. aureus (MRSA). (CABP).

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Fusidic acid – S. • Solithromy- aureus – Adap- cin – S. aureus, tation (new dos- S. pneumoniae, ing regimen and Hib – CABP geographic tar- – Awaiting get area (USA)) approval – ABSSSI, bone and joint infections • Solithromy- cin – N. gonorrhoeae – Adap- tation (additional indica- ABSSSI = Acute bacterial skin and skin structure infections tion) – Uncom- CABP = Community-acquired bacterial pneumonia plicated gono- coccal infections

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Cempra was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Cempra was not eligible for this Research Area.

91 Antimicrobial Resistance Benchmark 2018 Cipla Limited

Stock exchange: XNSE • Ticker: CIPLA • HQ: Mumbai, India • Number of employees: 23,043 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Cipla was evaluated: applicable indicators

Cipla is a prominent producer of antibiotics globally by sales nisms in place for maintaining a high quality of antibiotic pro- volume. As a generic medicine manufacturer, Cipla was eval- duction at its own manufacturing sites. The company reports uated in Manufacturing & Production and Appropriate Access that it has not filed its five newest antibiotics for registration & Stewardship only. The company is among the top perform- in countries in scope.* It reports equitable pricing strategies ing generic medicine manufacturers. It performs strongly for its five highest-volume antimicrobial medicines. Cipla’s in Appropriate Access & Stewardship but falls behind in performance in stewardship is driven by its engagement in a Manufacturing & Production. Cipla has no environmental number of stewardship activities including AMR surveillance risk-management strategy; however, it reports having mecha- programmes.

SALES AND OPERATIONS RevenuesCipla by product§ RevenuesMade: by region§ Final: no

Cipla is an Indian-based generic medicine man- sis, hepatitis C and reproductive health. In 2016, ufacturer founded in 1935. Its pharmaceuti- Cipla completed the acquisition of US-based . . cals segment develops, manufactures and mar- Exelan Pharma and InvaGen Pharmaceuticals, . . . kets generic medicines, as well as active phar- which expanded the company’s portfolio in the mn INR mn INR maceutical ingredients (APIs). Cipla (including USA, along with its manufacturing and R&D . associates) is present in over 80 countries, has capabilities. In early 2017, it divested its animal

43 manufacturing facilities worldwide and mar- health business (operated by subsidiaries Cipla ● Total revenue ● India kets over 1,500 products across various thera- Agrimed SA and Cipla Vet SA, primarily in ● Rest of World peutic areas, with a major focus on respiratory sub-Saharan Africa (SSA)) to Ascendis Pharma. ● USA ● South Africa health, API development and Global Access. Its Cipla sells antimicrobial medicines in Australia, business areas are: respiratory health, APIs and India, South Africa and the USA, as well as in Cipla Global Access. Cipla Global Access is an low- and middle-income countries* such as Sri international tender-based institutional busi- Lanka, Nepal, Myanmar, and in some regions of ness that concentrates on five key therapy areas: the Middle East, Latin America and SSA. HIV/AIDS, malaria, multidrug-resistant tuberculo-

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Cipla markets at least 25** antimicrobial med- remainder of the company’s portfolio comprises icines, 23 of which are listed on the WHO EML 13 antivirals (indicated for HIV/AIDS, hepatitis B (Section 6). The remaining two medicines are or hepatitis C) and two antiprotozoals indicated the antivirals lamivudine and efavirenz/lamivu- for the treatment of malaria. dine/tenofovir (listed on the EML with different doses than those marketed by Cipla). All ten of the company’s antibiotics appear on the WHO EML (Section 6), including two antibiotics in the EML’s Reserve group (colistin and linezolid). The ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited medicines ● Reserve group ** Cipla provided only a sample of its global antimicro- ● Not grouped bial portfolio † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017; regional breakdown by business unit provided by company

92 Access to Medicine Foundation

OPPORTUNITIES

Develop an environmental risk-management cational activities for HCPs include conflict of Increase engagement in R&D innovation. Cipla strategy. Cipla has stated a commitment interest mitigations. Cipla has conducted sev- is currently engaged in adapting generic antimi- to develop and implement an environmen- eral AMR surveys, and can engage in the devel- crobial medicines. For example, the company is tal risk-management strategy. It can ensure its opment of long-term AMR surveillance pro- currently engaged in developing new formula- strategy includes discharge limits and auditing grammes. tions for HIV/AIDS and for malaria in collabora- processes, which apply to the company’s own tion, respectively, with the Drugs for Neglected manufacturing sites, to the sites of third-party Improve access through the registration of Diseases Initiative (DNDi) and the Medicines suppliers and to external waste-treatment sites. antibiotics in more countries. Cipla can file its for Malaria Venture (MMV). It can continue to new and existing antimicrobials for registration engage in incremental R&D, and ensure access Increase engagement in antimicrobial steward- in more low- and middle-income countries. Cipla and stewardship provisions are in place for these ship. Cipla can engage in appropriate promotion has reported that it has not filed its newest anti- projects. activities. It can ensure that current AMR edu- biotics for registration in countries in scope.*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Cipla was developing taste-masked granules of an abaca- final stages in WHO prequalification. Cipla aims not eligible for this Research Area. However, the vir/lamivudine/lopinavir/ritonavir combination to make RAS available to rural areas in Africa company is active in antimicrobial R&D. for paediatric patients with HIV/AIDS in collabo- and to national community health programmes, ration with DNDi. This project is currently in pre- with the support of international donors that Three R&D projects, most being developed clinical stage. The company has developed its have already pledged to procure it. Cipla is also with public partners. Rectal Artesunate Suppositories (RAS) together the first generic medicine manufacturer to The company reports that it has three anti- with MMV. The Global Fund’s Expert Review develop a combination of isoniazid/pyridoxine microbial R&D projects, targeting HIV, P. falci- Panel (ERP) authorized procurement of RAS hydrochloride/sulfamethoxazole/trimethoprim, parum (malaria) and M. tuberculosis. Regarding for pre-referral management of severe malaria which received WHO prequalification in 2016 for R&D collaborations with public partners, Cipla is in 2016 and the medicine is moving through its preventing tuberculosis in HIV/AIDS patients.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• abacavir/lamivu- • Rectal Artesu- dine/lopinavir/ nate Supposi- ritonavir (LPV/r/ tories (RAS) – ABC/3TC) – HIV P. falciparum – Adaptation – Adaptation (4-in-1 taste- (new formu- masked gran- lation) – Pae- ules) – Paediat- diatrics – ERP rics reviewed 2016 • Isoniazid/pyridoxine hydrochloride/sulfamethoxazole/ trimethoprim – M. tuberculosis – Adapta- tion (new FDC) – Opportunis- tic infections in HIV-Infected patients – WHO prequalification 2016

93 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Commits to developing environmental B.2 No transparency on environmental risk B.3 Commits to following GMP. risk-management strategy. management. Cipla reports that it has mechanisms for main- Cipla currently has no environmental risk-man- Cipla does not publish any element looked for taining a high quality of antibiotic production — agement strategy in place to minimise the by the Benchmark, namely: antibiotic discharge namely following GMP standards. This commit- impact of antibiotic manufacturing discharge. levels, audit results, and the identities of its ment applies to its own manufacturing sites but Notably, however, it has committed to develop- third-party suppliers of antibiotic APIs and drug the company does not report any commitment ing one in 2018 in an effort to be in line with the products, or of its external waste-treatment relating to how GMP standards apply to its third- commitments in the Industry Roadmap. plants. It has, however, committed to develop party suppliers of antibiotic drug products. an environmental risk-management strategy in 2018 in line with its commitments as a signatory to the Industry Roadmap.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Newest antibiotics not filed for report on whether it has processes in place to medicine manufacturers that reports taking registration. respond to stock-outs in countries in scope.* action in this regard by reflecting AMR trends Cipla reports that it has not filed its five newest After the period of analysis, Cipla reported to in its marketing materials, including informa- antibiotics for registration in countries in scope.* the Benchmark that it does have a mechanism tion about resistance trends. However, the com- in place for responding to stock-outs: namely it pany’s appropriate promotion practices do not C.2 Inter-country equitable pricing for has a standard operating procedure in place that include the decoupling of its sales force’s incen- antimicrobials. results in a safety stock being held in India. tives from volume of antibiotic sales. Cipla discloses inter-country equitable pricing approaches, taking gross national income (GNI) C.4 Some involvement in AMR-related C.6 Provides information on treatment into account, for its five highest-volume anti- education. duration. microbial medicines. These pricing approaches Cipla is the only generic medicine manufac- The company adapts its packaging to facili- reportedly apply in all countries in scope* where turer that reports different approaches to edu- tate appropriate use of antibiotics by patients, Cipla markets these products. This covers Latin cate HCPs on AMR. These activities are focussed by providing information on treatment duration. America, sub-Saharan Africa and a subset of on raising awareness of the rational use of anti- This can help to improve patient adherence to other countries. biotics. The company provides limited informa- treatment. tion on conflict of interest (COI) mitigation and C.3 General commitment to ensuring supply content development. After the period of analy- C.7 Conducted several AMR surveys. chain efficiency. sis, Cipla stated that its speaker contracts do not Cipla has stated that it has conducted some Cipla has made a general commitment to obligate HCPs to purchase, use, recommend or AMR-related prevalence studies. The company improve supply chain efficiency. During the arrange for the use of company products. delivers the results of these studies via confer- period of analysis, the Benchmark identified no ences and peer-reviewed journals. information on how Cipla works with stakehold- C.5 Adopts some appropriate promotion ers (e.g., governments, procurers) to align supply practices. and demand for antimicrobial medicines, specif- The Benchmark measures how companies ically to prevent or minimise stock-outs in coun- address stewardship through appropriate pro- tries in scope. The company also did not then motion practices. Cipla is one of two generic

94 Access to Medicine Foundation

95 Antimicrobial Resistance Benchmark 2018 Dr. Reddy’s Laboratories Ltd. Signatory to Davos Decl.: No Stock exchanges: XNSE; XNYS • Tickers: DRREDDY; RDY • HQ: Hyderabad, India • Employees: 22,681 Signatory to Industry Roadmap: No

Performance by Research Area How Dr.Reddy’s was evaluated: applicable indicators

Dr. Reddy's is a prominent producer of antibiotics globally approach to equitable pricing, where it has filed antibiotics by sales volume. As a generic medicine manufacturer, Dr. for registration, its actions to ensure efficient supply and its Reddy's was evaluated in Manufacturing & Production and involvement in stewardship activities. However, Dr. Reddy’s Appropriate Access & Stewardship only. Its performance is has an environmental risk-management strategy that is based low compared to most other generic medicine manufacturers on a zero-liquid discharge (ZLD) process at all its manufactur- in scope. It reported no information to the Benchmark, and ing sites, including manufacturing sites for antibiotics. publicly available information is limited, specifically regarding its approach to manufacturing high quality antibiotics, its

Dr. Reddy’s Made: Final: no SALES AND OPERATIONS Revenues by product§ Revenues by regionII

Dr. Reddy’s is a generic medicine manufac- R&D facilities: six in India, two in the USA and . turer founded in 1984, with commercial pres- two in Europe. In 2015, Dr. Reddy’s acquired sev- . ence in 26 countries. Its core therapeutic areas eral established brands from UCB for the ter- . . . include oncology, gastroenterology, cardiovascu- ritories of India, Nepal, Sri Lanka and Maldives, bn INR bn INR . lar health, diabetes and anti-infectives. The com- covering dermatology, respiratory diseases, ear, pany’s Global Generics segment manufactures nose and throat disorders, and paediatrics. In ● Total revenue ● USA and markets prescription and over-the-counter 2016, it completed the acquisition of eight prod- ● Rest of World (OTC) medicines (generics and medicines man- ucts from Teva’s US portfolio. In 2017, it signed a ● India ufactured in its biologics unit). Its Proprietary global licensing pact with CHD Bioscience (USA), ● Russia Products segment develops and manufactures to develop and commercialise CHD’s Phase III differentiated formulations in dermatology and clinical candidate DFA-02 for USD 30 million. neurology. It has 25 manufacturing facilities: 18 DFA-02 is a gentamicin/vancomycin extend- in India (including seven for active pharmaceu- ed-release gel indicated for the prevention of tical ingredients), three in the USA, two in the surgical site infection following non-emergency, UK and one each in China and Mexico. It has ten elective colorectal surgery.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Dr. Reddy’s group (linezolid). The remaining six medicines markets at least 22 antimicrobial medicines, are three antivirals and three antifungals. The seven or more of which are listed on the WHO company also markets an influenza vaccine in EML (Section 6). Sixteen of the company’s anti- Germany, via its subsidiary Betapharm. microbial medicines are antibiotics, with at least three listed on the WHO EML (Section 6), including one antibiotic in the EML’s Reserve

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML†,‡ ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited. medicines ● Reserve group † EML Section 6: Anti-Infective Medicines ● Not grouped ‡ Includes antibiotics whose formulation or dose could not be determined § Revenue from operations; FYE 31 March 2017 || Sales (inc. excise duty), license fees, and service income; excluding other operating income; FYE 31 March 2017

96 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. information on discharge limits for its own and and existing antimicrobials, and ensure that they Dr. Reddy’s can engage in stewardship activi- third-party manufacturers’ sites. The company are priced affordably. Currently, the company ties, e.g., through surveillance activities, educa- currently discloses its environmental risk-man- does not disclose such information. tional activities for healthcare professionals on agement activities in its corporate sustainabil- AMR (while mitigating conflict of interest), and ity report. Engage in R&D innovation. Dr. Reddy’s can engage in appropriate promotion practices. engage in incremental R&D innovation to Ensure affordability and registration plans for address resistance, improve adherence and the Improve transparency on environmental risk new and existing antimicrobials. Dr. Reddy’s can appropriate use of antimicrobial medicines. management. Dr. Reddy’s can share informa- seek to improve access in low- and middle-in- tion on how it manages environmental risk, e.g., come countries through the registration of new

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Dr. Reddy’s’ main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Follows Zero-Liquid Discharge at own B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is sites. management. maintained. Dr. Reddy’s environmental risk-management Dr. Reddy’s does not disclose its strategy to min- Dr. Reddy’s makes no statement regarding how approach is based on following a zero-liquid dis- imise the impact of manufacturing discharge it ensures high quality antibiotic production fol- charge (ZLD) process at all its manufacturing of antibiotics. It does not publish any element lowing international manufacturing standards sites, including manufacturing sites for antibi- looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- otics. Dr. Reddy’s reports no information about discharge levels, audit results, and the identities tional authorities (such as GMP). setting discharge limits or auditing this pro- of its third-party suppliers of antibiotic APIs and cess. It does not appear to have extended this drug products, or of its external waste-treat- approach to its third-party manufacturers of ment plants. antibiotic APIs and drug products, or to external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in Dr. Reddy’s reports no information on where it chain efficiency. stewardship activities. has filed its newest antibiotics for registration in Dr. Reddy’s does not disclose how it works with Dr. Reddy’s does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- erwise publicly available. align supply and demand for antimicrobial med- veillance to appropriate promotion practices) icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Dr. Reddy’s does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiotics scope.* and/or antimicrobial medicines.

97 Antimicrobial Resistance Benchmark 2018 Entasis Therapeutics Inc.

Stock exchange: Privately held • HQ: Waltham, MA, US • Number of employees: 30 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Entasis was evaluated: applicable indicators

Entasis is a biopharmaceutical company, selected for having antibiotic candidate. Entasis engages in numerous public-pri- a pipeline that targets priority pathogens. It was evaluated in vate partnerships and agreements with various organisations the area of Research & Development only. Entasis invested to develop its antibiotic candidates. Entasis has one R&D pro- USD 10-20 million in antibiotic drug development in 2016. The ject in late-stage clinical development, for which it has an company is the leader among other biopharmaceutical com- access provision and stewardship commitment in place. panies in scope. It has five projects in its antimicrobial R&D pipeline, all targeting priority pathogens, including one novel

OPERATIONS

Entasis is a privately held US-based biophar- ing, among others, N. gonorrhoeae, P. aerug- was extended in September 2017 by an addi- maceutical company established in 2015 with inosa and A. baumannii. The company’s most tional USD 31.9 million from Pivotal bioVenture start-up funding from AstraZeneca and full advanced drug candidate is zoliflodacin, indi- Partners, Sofinnova Ventures and TPG Biotech. rights to a subset of its small-molecule anti-in- cated for the treatment of uncomplicated gon- fectives pipeline. The company focusses on cre- orrhoea. Entasis has no products on the market. ating innovative medicines to treat diseases In 2016, the company raised USD 50 million in caused by drug-resistant gram-negative bac- a Series B financing round, which was led by teria. Its pipeline includes both clinical and pre- Clarus and included Frazier Healthcare Partners, clinical small-molecule antibacterials, target- Novo Holdings A/S and Eventide Fund. This

ANTIMICROBIAL PORTFOLIO

Entasis does not have any products on the market.

OPPORTUNITIES

Develop stewardship plan for zoliflodacin. Entasis has signed a licensing agreement to ensure access and the responsible use of its antibiotic candidate (zoliflodacin) in late-stage clinical development, that covers 168 countries. It can develop a plan for ensuring appropriate use of the product, on approval, in remaining territories.

98 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1–2.2 One novel antibiotic in the clinical combinations: with sulbactam and with imipe- territories. In March 2017, Entasis received fund- pipeline. nem. ETX0282 is a combination of cefpodoxime ing from CARB-X to develop ETX0282/cefpo- Biopharmaceutical companies in scope were with a broad-spectrum class A and C ß-lacta- doxime through Phase I clinical development. selected based on their pipelines that target pri- mase inhibitor. The company also received a second CARB-X ority bacteria. Entasis invested USD 10-20 mil- award in October 2017 to progress its discov- lion in antibiotic drug development in 2016. A.3 Three R&D projects being developed ery-stage penicillin-binding protein inhibitor pro- The company has five projects in its antimicro- with public partners, including one PDP. gramme from lead optimization through Phase I bial R&D pipeline targeting priority pathogens, Entasis is developing three R&D projects in its clinical trials. largely focussing on gram-negative bacteria. Its priority pathogen pipeline through public-pri- novel antibiotic candidate zoliflodacin is an inno- vate partnership. In July 2017, the company A.4 Access provision and stewardship com- vative bacterial topoisomerase II inhibitor with announced a collaboration with Global Antibiotic mitment in place for zoliflodacin. a new mode of action, for which no cross-re- Research & Development Partnership (GARDP) Entasis reports that it has an access provision in sistance has been described. Although zolif- for the clinical development of zoliflodacin place and stewardship commitment for its anti- lodacin has broad-spectrum activity, it is cur- after successfully finishing Phase II studies that biotic in late-stage development. The access rently in development for the treatment of gon- were funded and conducted by the US National provision for its investigational antibiotic (zoliflo- orrhoea only. Entasis is seeking to optimize Institute of Allergy and Infectious Diseases dacin) has been developed through its collabora- the medicine’s dosing regimen for this indica- (NIAID). Through this PDP, GARDP is responsible tion with GARDP. GARDP is responsible for pro- tion, as well as limit its widespread use for other for the clinical trials, including financing, man- viding access and promoting the responsible use indications to prevent emergence of resist- aging, and coordinating Phase III trials, pharma- of zoliflodacin in their respective territories (168 ance. Additionally, Entasis has particular exper- covigilance and drug registration in the coun- countries identified by GARDP where access to tise in the structure and function of bacterial tries where it has licensing rights. Entasis retains medicine is likely limited). Entasis is committed ß-lactamases, and is involved in the develop- commercial rights in the majority of mature mar- to developing stewardship programmes, as well ment of new and improved ß-lactamase inhib- kets, and grants GARDP an exclusive and royal- as affordable and equitable pricing, in order to itors in combination with existing ß-lactams. ty-free licence (for the treatment of gonorrhoea) ensure access in mature markets. ETX2514 is a broad-spectrum ß-lactamase inhib- with sublicensing rights for global manufactur- itor, which is being developed in two different ing and sale and distribution in 168 countries or

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Gram-negative discovery platform • ETX0282/cef- • ETX2514/sul- • Zoliflodacin – GNB podoxime – bactam – A. (ETX0914) – N. GNB – ß-lacta- baumannii – gonorrhoeae mase inhibitor & ß-lactamase – Topoisomer- existing cepha- inhibitor & exist- ase II inhibitor – losporin ing ß-lactam Novel • ETX2514/imipenem* – GNB – ß-lactamase inhibitor & existing ß-lactam

GNB = Gram-negative bacteria * This project is considered as an adaptation for scoring, as ETX2514 is considered as a new project in the ETX2514/sulbactam combination.

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Entasis was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Entasis was not eligible for this Research Area.

99 Antimicrobial Resistance Benchmark 2018 Fresenius Kabi AG

Stock exchange: XFRA • Ticker: FRE • HQ: Bad Homburg, Germany • Employees: 34,917 • Signatory to Davos Decl.: via MFE • Signatory to Industry Roadmap: No

Performance by Research Area How Fresenius Kabi was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ○ ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Fresenius Kabi is a prominent producer of antibiotics glob- quality standards to their production facilities. Fresenius ally by sales volume. As a generic medicine manufacturer, Kabi reports information on where it files antibiotics for reg- Fresenius Kabi was evaluated in Manufacturing & Production istration; however, there is no information available regard- and Appropriate Access & Stewardship only. The company is ing the company's approach to equitable pricing for its high- among the top performing generic medicine manufacturers. It est-volume antimicrobial medicines. Regarding stewardship, discloses an environmental risk-management strategy for its the company reflects AMR trends in its marketing materials own sites. Fresenius Kabi reports mechanisms for maintain- through leaflets on AMR-related topics for its top marketed ing a high quality of antibiotic production and also requires products. its third-party suppliers of drug products to apply the same

SALES AND OPERATIONS RevenuesFresenius Kabiby product § RevenuesMade: by region§ Final: no

Fresenius Kabi is a wholly owned subsidiary injectable and specialty sterile and non-ster- of Fresenius SE & Co. KGaA, and specialises in ile pharmaceuticals. Also in 2017, the company . medicines and technologies for infusion, trans- completed the acquisition of Merck KGaA’s . . . fusion and clinical nutrition in the field of crit- biosimilars business, whose product pipeline . . . bn EUR bn EUR ical and chronic care. It has four business seg- focussed on oncology and autoimmune dis- . . ments: intravenous (IV) drugs; infusion ther- eases. Fresenius Kabi markets its antimicrobial apy; clinical nutrition; and medical devices & medicines in 34 countries globally, six of which ● IV drugs ● North America transfusion technology. Its IV drugs segment are low- or middle-income countries.* All of the ● Infusion therapy ● Europe includes anti-infectives. In 2017, Fresenius Kabi company’s antimicrobial medicines are infusion ● Clinical nutrition ● Asia Pacic ● Medical devices, ● LATAM, Africa announced that it would acquire Akorn Inc., a or powder-for-injection formulations. Transfusion technology US-based manufacturer and marketer of prescription and over-the-counter ophthalmic,

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Fresenius Kabi markets at least 35 antimicro- The remaining three medicines are an antifun- bial medicines, 21 of which are listed on the gal (fluconazole) and the antivirals aciclovir and WHO EML (Section 6). Thirty-two of the compa- ganciclovir, indicated for infections caused by ny’s antimicrobial medicines are antibiotics, with herpes virus and cytomegalovirus, respectively. 19 listed on the WHO EML (Section 6), including five in the EML’s Reserve group (aztreonam, cefepime, daptomycin, linezolid and tigecycline).

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Sales, FYE 31 December 2016

100 Access to Medicine Foundation

OPPORTUNITIES

Increase engagement in antimicrobial steward- The company can also seek to improve access mental risk-management strategy is extended ship. Fresenius Kabi adopts some appropriate in low- and middle-income countries by ensur- to the sites of third parties who manufacture promotion practices through leaflets on AMR- ing its new and existing antimicrobials are priced antibiotic APIs and drug products on its behalf. related topics for its top marketed products. It affordably. Fresenius Kabi currently has an environmental can engage in more stewardship activities, e.g., risk-management strategy, that includes audit- through surveillance activities, educational activ- Improve transparency regarding environmental ing processes, and is applied to its own manufac- ities for healthcare professionals on AMR (while risk management. Fresenius Kabi can share turing sites. mitigating conflict of interest), and expand on more information on how it manages environ- appropriate promotion practices. mental risk, e.g., the company can publish the Engage in R&D innovation. Fresenius Kabi can results of audits carried out on its environmen- engage further in incremental R&D innovation to Improve access to new and existing antimicro- tal risk-management strategy. Fresenius Kabi address resistance and improve appropriate use bials. Fresenius Kabi can file its new and exist- already discloses environmental risk principles. of antimicrobial medicines. The company already ing antimicrobials for registration in more coun- engages in incremental R&D directed at improv- tries. Fresenius Kabi has filed two of its newest Expand its environmental risk-management ing usability of its medicines by HCPs. antibiotics for registration in countries in scope.* strategy. Fresenius Kabi can ensure its environ-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Fresenius generic products and, as such, was not in scope Kabi’s main focus is the manufacturing of for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Fresenius Kabi has a general environmen- Fresenius Kabi publishes its environmental Fresenius Kabi reports that it has mechanisms tal risk-management strategy to minimise the risk-management principles in its annual report. for maintaining a high quality of antibiotic pro- impact of antibiotic manufacturing discharge. It does not disclose audit results, or the dis- duction — namely following GMP standards. This This applies to its own manufacturing sites and charge levels of antibiotics. The company also commitment applies to its own manufactur- includes audits. There is no information suggest- does not share the identities of its third-party ing sites. Fresenius Kabi requires its third-party ing that the strategy is applicable to third-party suppliers of antibiotic APIs and drug products, or suppliers to apply the same quality standards to manufacturers of antibiotic APIs and drug prod- external waste-treatment plants. their production facilities. ucts or to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ○ ●

C.1 Some newest antibiotics filed in some bial medicines, specifically to prevent or mini- products, leaflets aimed at informing HCPs on countries in scope. mise stock-outs in countries in scope.* The com- AMR-related topics. These leaflets include AMR- Fresenius Kabi reports information about pany also does not report on whether it has related information under the "Special Warnings where it has filed some of its newest antibiot- processes in place to respond to stock-outs in and Precautions for Use" section. There is no ics for registration in some countries in scope.* countries in scope.* information available on decoupling of the com- However, the Benchmark is not able to publish pany's sales force’s incentives from volume of further information, as all details were provided C.4 No information on AMR-related antibiotic sales. on the basis of confidentiality. education. There is no information available regarding C.6 No antibiotics dispensed directly to C.2 No information available on equitable Fresenius Kabi’s involvement in AMR-related patients. pricing approach. educational activities for HCPs. Fresenius Kabi is not eligible for this indicator as There is no information available regarding it does not have any antibiotics in its portfolio Fresenius Kabi’s approach to equitable pricing C. 5 Adopts some appropriate promotion that are directly dispensed to patients. All of its for its highest-volume antibiotics and/or antimi- practices. antibiotics are administered in the hospital. crobial medicines. The Benchmark measures how companies address stewardship through appropriate pro- C.7 No information regarding AMR C.3 No insight into steps addressing supply motion practices. Fresenius Kabi is one of two surveillance programmes. chain efficiency. generic medicine manufacturers that reports There is no information available regarding Fresenius Kabi does not disclose how it works taking action in this regard by reflecting AMR Fresenius Kabi’s efforts to engage in AMR sur- with stakeholders (e.g., governments, procur- trends in its marketing materials. For exam- veillance programmes. ers) to align supply and demand for antimicro- ple, the company created, for its top marketed

101 Antimicrobial Resistance Benchmark 2018 GlaxoSmithKline plc

Stock exchange: XLON • Ticker: GSK • HQ: Brentford, UK • Employees: 99,300 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How GSK was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ● ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

GSK performs well in all three Research Areas, and is one of external waste-treatment plants. GSK has filed its five newest the leaders when compared with other large research-based antibiotics for registration in many countries in scope.* It also pharmaceutical companies in scope. GSK has the largest anti- reports a comparatively broad inter- and intra-country equi- microbial R&D pipeline of all large research-based pharma- table pricing approach for antimicrobial medicines, as well ceutical companies in scope: 55‡ projects, of which 40‡ target as multiple steps to improve supply chain efficiency. In stew- priority pathogens, including several novel candidates and ardship, GSK reports that it engages in several AMR educa- 12 new vaccine candidates. It has access and/or stewardship tion programmes aimed at healthcare professionals, taking provisions in place for most late-stage candidates. GSK dis- action to mitigate conflict of interest in these programmes. It closes the most comprehensive environmental risk-manage- has ceased remunerating sales staff based on sales volume. It ment strategy of all companies evaluated, which includes dis- engages in AMR surveillance and collaborates and shares its charge limits and reportedly applies to all GSK’s third-party data with public health authorities. suppliers of antibiotic APIs and drug products, as well as to

SALES AND OPERATIONS RevenuesGSK by product§ RevenuesMade: by region§ Final: no

GSK is a large research-based pharmaceuti- AIDS medicines. Shionogi joined ViiV Healthcare cal company with three divisions: pharmaceuti- in 2012. Equity positions in ViiV Healthcare are . . . cals, vaccines and consumer healthcare. In 2016, GSK: 76.5%, Pfizer: 13.5% and Shionogi: 10%. In . . . . GSK sold the largest volume of antibiotics of all 2015, GSK completed the acquisition of Novartis’ bn GBP bn GBP companies in scope of the Benchmark. During vaccine business (excluding influenza vaccines) . . 2016, the company’s leading antibiotics were and in return divested its marketed oncology sold in 126 countries, 57 of which were low- and portfolio to Novartis. In the same year, GSK sold ● Vaccines ● USA middle-income countries*. In 2009, GSK and two of its meningococcal vaccines to Pfizer ● Antimicrobials ● Rest of World Pfizer established ViiV Healthcare, a joint ven- (Mencevax® and Nimenrix®). ● Other pharmaceuticals ● Europe ● Consumer healthcare ture solely focussed on the development of HIV/

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

GSK markets at least 30 antimicrobial medi- minthics, as well as 15 antivirals (12 of which cines, 14 of which are included in the WHO EML target HIV). The company also markets a chlor- (Section 6). The majority of the company’s anti- hexidine antiseptic gel for umbilical cord care in microbial medicines are established products. neonates and has a large and diverse vaccines Nine of its medicines are antibiotics, includ- portfolio, which includes the vaccines Hiberix®, ing the amoxicillin/clavulanic acid formulation targeting Haemophilus influenzae type B, and Augmentin™, a 35-year old top-selling antibiotic Synflorix®, targeting S. pneumoniae. (by volume). The remainder (21) of the company’s portfolio includes antiprotozoals and anthel- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited. medicines ● Reserve group ** GSK is involved in the COMBACTE-CDI network, a ● Not grouped recently launched project within the IMI COMBACTE research consortium. † EML Section 6: Anti-Infective Medicines § Group turnover; FYE 31 December 2016

102 Access to Medicine Foundation

OPPORTUNITIES

Develop access plans for gepotidacin. GSK has ments regarding its environmental risk-manage- and take further language and literacy needs a stewardship plan in place for its antibiotic can- ment strategy, as well as its safety data sheets. It into consideration. didate (gepotidacin) in late-stage clinical devel- has also disclosed its PNECs to the Benchmark opment. GSK can ensure that access plans are under a non-disclosure agreement. Expand practices for aligning supply and also in place for this candidate. demand. GSK can work with relevant stakehold- Expand on stewardship activities. GSK has ers (e.g., suppliers, procurers and payers) to align Improve transparency regarding environmen- established its SOAR surveillance programme supply and demand for all antimicrobials, espe- tal risk management. GSK can build on its cur- for monitoring resistance trends in respiratory cially for its antibiotics, in countries in scope.* rent level of transparency, e.g., by adding its tract infections. It can expand this programme to GSK has a general mechanism in place for align- Predicted No Effect Concentrations (PNECs) for include other diseases and territories, and inte- ing demand and supply, as well as product-spe- resistance selection to its safety data sheets. It grate its activities within existing structures such cific mechanisms for five products including can also work with suppliers to publish PNECs as WHO’s GLASS programme. GSK has adapted albendazole (Zendel®). that apply to its third-party manufacturers of its brochures in South Africa to facilitate the antibiotic APIs and drug products. The com- appropriate use of antibiotics by patients. It can pany currently publishes several policy docu- expand this practice to more countries in scope*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 55 projects scored on ● ● ● ● ● ● pipeline 40 target priority pathogens

A.1 Comparatively high antimicrobial R&D pipeline, 28‡ of which are in clinical stage devel- ing adaptations) are considered novel, making investments. opment. Forty‡ of the company’s projects target the company’s clinical pipeline the most innova- GSK reports investments in antimicrobial R&D priority pathogens. It has the largest pipeline of tive among large research-based pharmaceutical in 2016, which are high compared to other large the large research-based pharmaceutical com- companies included in the Benchmark. GSK has research-based pharmaceutical companies in the panies assessed by the Benchmark, and the 11 antimicrobial vaccines in clinical development Benchmark. However, the Benchmark is not able highest number of projects that focus on pri- (excluding adaptations), six of which are devel- to publish further information, as all details were ority pathogens (for both medicines and vac- oped against diseases caused by a priority path- provided on the basis of confidentiality. cines). In antimicrobial R&D, GSK’s major focus ogen, including HIV, Shigella spp. and non-typea- is on HIV and gram-negative bacteria and, to a ble H. influenzae (for which no vaccines currently A.2.1-2.3 Largest priority pathogens pipeline, smaller extent, M. tuberculosis and gram-positive exist). GSK is also investigating the development including six novel clinical candidates. bacteria. Six out of seven‡ of GSK’s investiga- of a meningococcal vaccine (Bexsero®) for pro- GSK has 55‡ antimicrobial R&D projects in its tional medicines in clinical development (exclud- tection against gonorrhoea.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Active Transport project – GNB – • Confidential pro- • GSK3342830 • Gepotidacin – • Dolutegravir/ • Dolutegra- In partnership with Sanofi ject – GNB & GPB ‡ – Enterobac- N. gonorrhoea, lamivudine – vir/rilpivir- • FimH inhibitors – GNB ▶Salmonella iNTS teriaceae, P. GPB – Gonor- HIV – Adapta- ine (Juluca®) – • Antibiotics early discovery project – vaccine – non-ty- aeruginosa, A. rhoea, ABSSSI – tion (new FDC) HIV – Adapta- GNB phoidal Salmo- baumannii Novel • Cabotegra- tion (new FDC) • Phenotypic screening and tar- nella enterica • GSK3036656 – ▶S. pneumoniae vir/rilpivirine – In partnership get-based programme for NMT ▶Enteric fever M. tuberculosis next generation long-acting – with Johnson & and ProRS – P. falciparum bivalent conju- – Novel vaccine HIV – Adapta- Johnson – FDA ▶Malaria next generation vaccine – gate vaccine – • MI254 – HIV – ▶COPD vaccine tion (new for- approval 2017 P. falciparum Salmonella enter- Novel – Hib mulation) – In • Chlorhex- ica Typhi & ▶Shigella GMMA partnership idine (Umbi- Stage: not published Paratyphi A vaccine – S. son- with Johnson & pro) – antisep- ▶ C. difficile vaccine nei Johnson tic – GNB & GPB • M. tuberculosis ▶S. aureus vaccine ▶Shigella conju- • Fostemsavir – – Adaptation • M. tuberculosis • GSK3488917 – gates vaccine – HIV – Novel (new formula- • M. tuberculosis HIV S. flexneri • Cabotegra- tion for umbil- • M. tuberculosis • Confidential ▶M. tuberculosis vir long-acting ical cord infec- • HIV project – HIV vaccine (PrEP) – HIV – tion) – EMA • HIV • Confidential • GSK2838232 – Novel approval 2016 ▶ Gr. B Streptococcus hexavalent project – HIV HIV – Novel ▶N. gonorrhoea vaccine • pfATP4 inhibitors ▶HIV vaccine – In vaccine – Adap- – P. falciparum partnership with tation (addi- ▶Vaccine • Malaria drug Sanofi tional indication GNB = Gram-negative bacteria discovery of Bexsero®) GPB = Gram-positive bacteria FDC = Fixed dose combination programme – ‡ GSK3342830 has been terminated after the P. falciparum period of analysis.

103 Antimicrobial Resistance Benchmark 2018

A.3 Twenty-four R&D projects being devel- is partially funded by both BARDA and the US try to improve affordability. Furthermore, the oped with public partners, including Defense Threat Reduction Agency under “Other company has stewardship provisions in place for eight PDPs. Transaction Authority” (OTA) agreements, which seven out of eight of its medicines in late-stage GSK is developing 24 R&D projects in its pri- are cost-sharing reimbursement contracts. development. Stewardship for GSK’s HIV candi- ority pathogen pipeline through public-pri- dates will be managed by ViiV Healthcare, which vate partnership.** The company is involved in A.4 Access and/or stewardship provisions in sponsors HIV drug resistance surveillance stud- eight PDPs and one open research consortium, place for most late-stage candidates. ies that are executed via several independent the highest number reported among all compa- GSK reports that it has access and/or steward- consortia. Moreover, GSK has a company-wide nies assessed by the Benchmark. Of these nine ship provisions in place for most of its R&D can- commitment to decouple sales force incentives projects, seven are in preclinical stage and two didates targeting priority pathogens in late-stage from volume of sales, an important steward- are in clinical stage. For the development of its development. It has access provisions for 11 out ship incentive in combating AMR. Only one out Phase II HIV vaccine, GSK partners with the Pox- of its 15 antimicrobial candidates in late-stage of seven of its vaccine candidates has an access Protein Public Private Partnership (P5), a pro- development. GSK states that it will market provision, while three have an access commit- ject that includes the US National Institute of its HIV candidates via ViiV Healthcare, which ment. For example, the agreement with the non- Allergy and Infectious Diseases (NIAID), the Bill has a general access to medicine policy that profit biotechnology organisation Aeras, for the & Melinda Gates Foundation, the South African includes a commitment to voluntary licensing development of an anti-tuberculosis vaccine Medical Research Council, the HIV Vaccine Trials to allow supplies of generic versions of its prod- includes a global access commitment clause, and Network (HVTN), the US Military HIV Research ucts in least-developed, low- and lower-middle WHO prequalification is foreseen. For this indi- Program and Sanofi. The company also collab- income countries and all sub-Saharan African cator, countries in scope are 106 low- and mid- orates with Aeras, a non-profit biotechnology countries. In addition, the policy includes a flex- dle-income countries where access to medicine organisation, on the development of its tubercu- ible pricing procedure in middle-income coun- is likely limited. losis vaccine, currently in Phase II clinical devel- tries that factors in the gross domestic product opment. GSK’s antibiotic candidate gepotidacin (GDP) and impact of the epidemic in each coun-

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Most comprehensive environmental B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at risk-management strategy. mental risk management. 3rd-party sites. GSK is the only company in the Benchmark to GSK publishes several of its environmental GSK reports that it has mechanisms for main- undertake every environmental risk-manage- risk-management policy documents on its web- taining a high quality of antibiotic production ment activity that the Benchmark examines. site. It does not disclose audit results, or the dis- — namely following GMP standards. This com- Namely, the company applies an environmen- charge levels of antibiotics. The company also mitment applies to its own manufacturing sites. tal risk-management strategy to minimise the does not share the identities of its third-party GSK requires its third-party suppliers to apply impact of antibiotic manufacturing discharge. suppliers of antibiotic APIs and drug products or the same quality standards to their production It includes auditing and limits on antibiotic dis- external waste-treatment plants. facilities. charge, for its own manufacturing sites, third- party manufacturers of antibiotic APIs and drug products, and external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed five newest antibiotics in countries highest-volume antimicrobial medicines. These C.4 Multiple activities in AMR-related educa- in scope. approaches cover >50% of countries in scope.* tional programmes. GSK leads in this area, as it reports that it has For albendazole (Zentel™), GSK has commit- GSK reports that it is involved in educational filed its five newest antibiotics for registra- ted to applying intra- and inter-country equitable programmes for healthcare professionals (HCPs) tion in up to 71 countries in scope.* Three of its pricing (including donations) in endemic coun- that include AMR stewardship and rational use most recently introduced antibiotics were filed tries in scope.* of antibiotics, with conflicts of interest (COI) for registration in more than half of the coun- mitigation measures in place. Programmes tries in scope.* Its amoxicillin/clavulanic acid C.3 Taking multiple steps to improve supply such as “Surveillance of Antibiotic Resistance” antibiotic (Augmentin™) was filed for registra- chain efficiency. (SOAR) deliver content through ‘active learn- tion in the highest number of countries in scope* GSK engages with WHO and various Ministries ing channels’ (e.g., conferences and courses) to a (71). Another two of its antibiotics were regis- of Health of countries in scope* to align broad spectrum of HCPs, such as doctors, phar- tered in nine and 31 countries in scope.* GSK’s supply and demand forecasting for albenda- macists, and microbiologists. A general COI mit- five newest antibiotics were introduced between zole (Zentel™), aiming to ensure a continuous igation policy applies to all of the company's 1981 and 2007. exchange of information on, e.g., outbreaks. For programmes. Under this policy, GSK no longer five of its nine highest-volume antimicrobials, pays HCPs to participate in its educational pro- C.2 Leader in inter- and intra-country GSK has mechanisms in place to respond effi- grammes, and uses an external body to select equitable pricing. ciently in the event of stock-outs in countries in HCPs for sponsorship to attend congresses. GSK discloses that it applies an equitable pric- scope.* These mechanisms include inter-market Most educational programmes are not product ing strategic framework to all products includ- (e.g., country-level) stock transfers, and for cef- specific. GSK’s commercial teams are, in some ing antimicrobials. In addition, it discloses prod- tazidime (Fortum®) the prioritisation of emerg- cases, not involved in developing materials. uct-specific inter- and intra-country equitable ing markets over established markets. pricing approaches for seven out of nine of its

104 Access to Medicine Foundation

C.5 Comprehensive involvement in appropri- C.6 Implements brochure and/or packaging C.7 International programme for AMR ate promotion practices. adaptations to facilitate appropriate use. surveillance. The Benchmark measures how companies GSK has adapted its brochures in South Africa GSK runs one international programme, address stewardship through appropriate pro- to facilitate appropriate use of antibiotics by focussed on AMR trends for community-ac- motion practices. GSK reports that it takes patients. The company is also developing a digi- quired respiratory tract infections. The company action in this regard: it reflects AMR trends in its tal solution that provides product information to shares the results with public health authori- marketing materials and has decoupled all sales patients, taking illiteracy into account. ties, through conferences and multiple peer-re- force incentives from sales volumes for all its viewed journals. Additionally, the company is products. This approach is unique in the industry. collaborating with other organisations (such The company now remunerates its sales force as the Open Data Institute and the Wellcome based on their technical knowledge, and the Trust) to explore the possibility of developing quality of service they deliver through in-clinic a single industry-sponsored antibiotic surveil- evaluation and monitoring. lance database, with harmonised measurements and results.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the While GSK does not have its own diagnostics work that addresses the diagnostic challenges Benchmark. This information is provided given division, the company reports that it works with for the epidemiological and clinical studies of the importance of animal health and diagnostics third parties to complement AMR product devel- carbapenem-resistant bacteria. on the topic of AMR. opment with diagnostic tests whenever possible. Additionally, the company reports that it GSK does not market antibiotics for animal use. provides scientific advice and seed-funding for It has a public policy in place which, states that public-private partnerships and for awards for the company will not license its new antibiotics the development of point-of-care diagnostics to for agricultural use. be used in conjunction with antibiotics. GSK also supports COMBACTE-CARE, a European net-

105 Antimicrobial Resistance Benchmark 2018 Johnson & Johnson

Stock exchange: XNYS • Ticker: JNJ • HQ: New Brunswick, NJ, US • Employees: 127,100 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Johnson & Johnson was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ● ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S . AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Johnson & Johnson is one of the leaders when compared environmental risk-management strategy, which includes with other large research-based pharmaceutical compa- discharge limits and reportedly applies to all Johnson & nies in scope, driven by strong performances in Research & Johnson’s third-party suppliers of antibiotic APIs and drug Development, Manufacturing & Production and Appropriate products. It has filed its three newest antibiotics for registra- Access & Stewardship, largely centred around tuberculo- tion in some countries in scope.* It also reports equitable pric- sis-related activities. The company has one of the largest anti- ing strategies for some antibiotics, as well as multiple steps microbial R&D pipelines of the large research-based phar- to improve supply chain efficiency. In stewardship, Johnson maceutical companies in scope: 48** projects, of which 15** & Johnson engages in several tuberculosis-related educa- target priority pathogens, including one novel antimalarial tional programmes aimed at healthcare professionals, taking candidate and at least three new vaccine candidates. It has action to mitigate conflict of interest in these programmes. It access and stewardship provisions in place for some late- engages in tuberculosis-related surveillance programmes, and stage candidates. The company discloses a comprehensive collaborates and shares its data with public health authorities.

SALES AND OPERATIONS RevenuesJohnson & by Johnson product § RevenuesMade: by region§ Final: no

Johnson & Johnson is a large research-based developed and produced by Janssen Vaccines & . . pharmaceutical company with operations in Prevention BV (part of Janssen Pharmaceutical . . three segments: consumer healthcare, pharma- Companies), which divested its oral typhoid and . . ceuticals and medical devices. Its pharmaceuti- oral cholera vaccines to PaxVax and Valneva in bn USD . bn USD cals segment focusses on therapeutic areas such 2014 and 2015 respectively. . . as cardiovascular health and metabolism, immunology, infectious diseases and vaccines, neuro- ● Vaccines ● USA science and oncology. The company sells anti- ● Antimicrobials ● Rest of world ● Other pharmaceuticals microbial medicines or vaccines in 108 countries ● Consumer healthcare globally, 38 of which are low- to middle-income ● Medical devices countries.* Johnson & Johnson’s vaccines are

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Johnson & Johnson markets at least 22 antimi- HIV, two are used in the treatment of hepatitis crobial medicines, seven of which are listed on C, five are antifungals and four are anthelminth- the WHO EML (Section 6). Five of the compa- ics or antiprotozoals. The company has two vac- ny’s antimicrobial medicines are antibiotics. This cines on the market: Quinvaxem®, indicated for includes levofloxacin (Elequine®, Levaquin®), protection against five major childhood infec- listed on the EML's Watch group, and bedaqui- tious diseases, and Hepavax-Gene®, a recom- line (Sirturo®), included in the EML's comple- binant vaccine against hepatitis B. Johnson & mentary list of reserve second-line drugs for Johnson reports that these are being phased the treatment of multidrug-resistant tuberculo- out, citing availability of other products. ● Antibiotics on WHO EML† WHO EML Categories sis. Out of the remaining 17 medicines, six target ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group * Countries in scope are 106 low- and middle-income ● Not grouped countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § FYE 1 January 2017

106 Access to Medicine Foundation

OPPORTUNITIES

Plan ahead for access and stewardship during ronmental risk, e.g., the company can publish such programmes is made publicly available. The R&D. Johnson & Johnson has stated a com- information regarding the levels of antibiotic dis- company does not report stewardship activities mitment to ensure access and stewardship charge. Currently Johnson & Johnson discloses for other antibiotics and can consider such activ- plans are in place for all of its candidates in the several policy documents regarding its environ- ities for these antibiotics as well. pipeline. It can ensure that this commitment mental risk-management strategy. is followed through with specific plans apply- Improve access through the registration of new ing to all of its candidates in late-stage clinical Expand on stewardship activities. Johnson & antibiotics. Johnson & Johnson can improve development. Johnson engages in the DREAM surveillance access in low- and middle-income countries* programme, covering first- and second-line by filing its antimicrobials, particularly bedaqui- Improve transparency regarding environmental anti-tuberculosis medicines. The company can line (Sirturo®) for registration in these countries. risk management. Johnson & Johnson can consider to expand this to more countries, e.g., Johnson & Johnson has currently filed to regis- share more information on how it manages envi- in sub-Saharan Africa, and ensure data from ter this product in 23 countries in scope.*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 48 projects scored on ● ● ● ● ● ● pipeline 15 target priority pathogens

A.1 Comparatively high antimicrobial R&D consist of two medicines, three vaccines and types resistant to at least three antibiotics). No investments. five** adaptations to existing pharmaceuticals, vaccines currently exist for either pathogen. Johnson & Johnson reports investments in anti- including the adaptation of its anti-tuberculo- microbial R&D in 2016, which are high com- sis medicine bedaquiline (Sirturo®) for paediatric A.3 Three R&D projects being developed pared to other large research-based pharmaceu- use. One of the investigational medicines is the with public partners, including two PDPs. tical companies in the Benchmark. However, the antibiotic cadazolid, an oxazolidinone-quinolone Johnson & Johnson is developing three R&D Benchmark is not able to publish further infor- hybrid targeting C. difficile, which was adopted projects in its priority pathogen pipeline through mation, as all details were provided on the basis through the acquisition of Actelion in 2017 and public-private partnership. The company is of confidentiality. is now in Phase III of clinical development. The developing an HIV vaccine in clinical stage other is a novel antimalarial medicine, a dihy- through a consortium of partners, including, A.2.1-2.3 Fifteen R&D projects that target pri- drofolate reductase inhibitor, in Phase I clini- the National Institutes of Health (NIH), the Bill ority pathogens, including one novel clinical development. The company is collaborat- & Melinda Gates Foundation, the International cal antimalarial medicine. ing with ViiV Healthcare on the combination of AIDS Vaccine Initiative (IAVI), the United States Johnson & Johnson has 48** antimicrobial R&D its HIV/AIDS medicine rilpivirine (Edurant®) with Military HIV Research Program (MHRP) and the projects in its pipeline, 23** of which are in clin- ViiV Healthcare’s HIV/AIDS medicines: dolutegra- Beth Israel Deaconess Medical Center (BIDMC), ical-stage development. Fifteen** of the com- vir (Tivicay®)/rilpivirine (Edurant®) combination, among others. Additionally, the company is pany’s projects target priority pathogens. Ten as well as a cabotegravir/rilpivirine (Edurant®) developing an antimalarial medicine through of these are in clinical-stage development, long-acting nanosuspension for injection. The a PDP with the Medicines for Malaria Venture making it the second-largest clinical-stage pipe- company has two vaccines in clinical develop- (MMV). line that targets priority pathogens, among the ment targeting HIV, and a third vaccine targeting large research-based pharmaceutical companies multidrug-resistant extra-intestinal E. coli (spe- assessed by the Benchmark. These ten projects cifically, targeting the four most prevalent sero-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• P218 (DHFR ▶HIV preventive • Cabotegra- • Dolutegra- inhibitor) – P. vaccine vir/rilpivirine vir/rilpivir- Stage: not published falciparum – ▶ExPEC4v vac- long-acting – ine (Juluca®) – Novel cine – ETEC: HIV – Adapta- HIV – Adapta- • Five confidential projects ▶HIV therapeutic CRE, ESBL tion (new for- tion (new FDC) vaccine • Rilpivirine mulation) – In – In partnership long-acting partnership with with GSK – FDA nanosuspension ViiV Healthcare approval 2017 for injection** – • Cadazolid – C. • Darunavir/cobi- HIV – Adapta- difficile cistat/emtricit- tion (new for- abine/tenofo- mulation) vir alafenamide • Bedaquiline for (Symtuza®) – ▶Vaccine paediatrics – HIV – Adapta- ETEC = Extraintestinal Pathogenic E. coli M. tuberculo- tion (new FDC) FDC = Fixed dose combination sis – Adaptation – EMA approval GNB = Gram-negative bacteria GPB = Gram-positive bacteria (new formula- 2017 ** Rilpivirine long-acting nanosuspension has been terminated after the period of analysis tion)

107 Antimicrobial Resistance Benchmark 2018

A.4 Access and stewardship provisions in entails a managed access programme through Johnson & Johnson is responsible for delivery place for some late-stage candidates. the Global Drug Facility and its own subsidiaries, of the long-acting injectable cabotegravir/rilpi- Johnson & Johnson reports that it commits and medical education on the use of bedaquiline virine (Edurant®) regimen to developing coun- to having access and stewardship provisions (Sirturo®) to paediatric healthcare professionals. tries. Only one of the remaining four candidates in place for all its candidates in development In addition, Johnson & Johnson has access pro- in late-stage development (ExPEC4v vaccine) before regulatory approval. To the Benchmark, visions in place for three other R&D candidates has an access commitment in place. For this indi- the company reports that it will expand the targeting priority pathogens in late-stage devel- cator, countries in scope are 106 low- and mid- access and stewardship activities currently in opment, including its HIV vaccine candidate and dle-income countries where access to medicine place for bedaquiline (Sirturo®) to its paediat- the antiretroviral combinations, developed in is likely limited. ric formulation in Phase II development. This collaboration with ViiV Healthcare.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- does not set discharge limits for these plants nor B.3 Commits to following GMP, including at agement strategy. audits implementation of the strategy. 3rd-party sites. Johnson & Johnson undertakes almost all envi- Johnson & Johnson reports that it has mech- ronmental risk-management activities that the B.2 Limited transparency regarding environ- anisms for maintaining a high quality of antibi- Benchmark examines. Namely, it applies an envi- mental risk management. otic production — namely following GMP stand- ronmental risk-management strategy to mini- Johnson & Johnson publishes elements of its ards. This commitment applies to its own manu- mise the impact of antibiotic manufacturing dis- environmental risk-management strategy on its facturing sites. Johnson & Johnson requires its charge. It includes auditing and limits on antibi- website. It does not disclose audit results, or the third-party suppliers of drug products to apply otic discharge, for its own manufacturing sites discharge levels of antibiotics. The company also the same quality standards to their production and those of third-party manufacturers of antibi- does not share the identities of its third-party facilities. otic APIs and drug products. Johnson & Johnson suppliers of antibiotic APIs and drug products or states that its strategy applies to external external waste-treatment plants. waste-treatment plants, yet it also reports that it

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed three newest antibiotics in some C.3 Taking multiple steps to improve supply address stewardship through appropriate pro- countries in scope. chain efficiency. motion practices. Johnson & Johnson’s new Johnson & Johnson reports that it has filed Johnson & Johnson engages with PAHO, the anti-tuberculosis drug, bedaquiline (Sirturo®), its three newest antibiotics for registration in Global Drug Facility, WHO and others to align is provided solely through national tuberculosis some countries in scope* (between 7–23 coun- supply and demand forecasting for three of its programmes and therefore does not require any tries). Two of these antibiotics are licensed from seven highest-volume antimicrobial medicines: marketing materials. The company reports that Daiichi Sankyo for sale in Latin America only. bedaquiline (Sirturo®), darunavir (Prezista®) it does not deploy any sales organisations for the Johnson & Johnson has filed these two antibi- and mebendazole (Vermox®). It also has mech- sale of Sirturo® in countries in scope.* otics (introduced in 1990 and 1996) for registra- anisms in place (i.e., it maintains safety stocks) tion in seven and ten of the countries in scope* to respond efficiently in the event of stock-outs C.6 Implements packaging adaptation for in Latin America. Johnson & Johnson’s bedaqui- in countries in scope.* These mechanisms cover bedaquiline to facilitate appropriate use. line (Sirturo®) is the only product introduced in bedaquiline (Sirturo®), darunavir (Prezista®) and The company collaborated with Stop TB the past five years (2012) that has been filed for simeprevir (Olysio®). Partnership to adapt bedaquiline (Sirturo®) registration in more than ten countries in scope*. packaging by creating a six-month presentation Indeed, it has been filed in 23 such countries. It is C.4 Multiple activities in tuberculosis-related and a blister preparation of the medicine. The also worth noting that through the Global Drug educational programmes. former aims to improve patient adherence to Facility, more than 70 countries have approved Johnson & Johnson has provided tuberculo- treatment in Directly Observed Treatment (DOT) importation of bedaquiline prior to regulatory sis-related stewardship information only. The programmes, while the latter aims to facilitate approval. company reports that it is involved in tubercu- usage in different environmental conditions. losis educational programmes for HCPs that C.2 Product-specific equitable pricing. include AMR stewardship and rational use of C.7 Engages with WHO reference lab- Johnson & Johnson discloses equitable pricing antibiotics, with conflicts of interest (COI) miti- oratories and national tuberculosis approaches for four of its seven highest-volume gation measures in place. The company collabo- programmes. antimicrobial medicines: bedaquiline (Sirturo®), rates with third parties such as the International Johnson & Johnson runs one multi-country sur- darunavir (Prezista®), mebendazole (Vermox®) Union against Tuberculosis and Lung Disease veillance programme, focussed on tuberculo- and simeprevir (Olysio®). It applies inter-coun- and USAID on the appropriate use of anti-tu- sis resistant trends. It engages numerous labo- try equitable pricing to three of these (not berculosis drugs, pharmacovigilance and multi- ratories to support the surveillance of tubercu- mebendazole), and intra-country equitable pric- drug-resistant tuberculosis management. The losis resistance trends via the Drug Resistance ing to bedaquiline, mebendazole and simeprevir. company supports these initiatives with unre- Emergence Assessment in multidrug-resistant Its inter-country pricing policy for bedaquiline stricted educational grants, which ensures inde- tuberculosis programme (DREAM). Although reflects countries’ ability to pay (measured by pendent content development. results are to be published in peer-reviewed GNI per capita) and disease burden (of multid- journals, the company is also sharing data with rug-resistant tuberculosis). C.5 No active promotion of bedaquiline. national tuberculosis programmes. The Benchmark measures how companies

108 Access to Medicine Foundation

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the infrastructure. In December 2015, Johnson & form. The technology is aimed to improve rou- Benchmark. This information is provided given Johnson and the Foundation of Innovative New tine viral load testing of HIV/AIDS patients on the importance of animal health and diagnostics Diagnostics (FIND) entered into a collaboration antiretroviral therapy. on the topic of AMR. for the discovery of point-of-care diagnostics for tuberculosis case detection, including multid- Johnson & Johnson reports that it is develop- rug-resistant strains. ing bedaquiline sensitivity diagnostic plates and The company has also formed a partnership panels that are to be deployed on the Becton with Cue Inc. to develop an HIV viral load test on Dickinson and Thermo Fisher Scientific Inc. lab Cue’s Lab-In-A-Box molecular diagnostic plat-

109 Antimicrobial Resistance Benchmark 2018 Lupin Limited Signatory to Davos Decl.: via MFE Stock exchange: XNSE • Ticker: LUPIN • HQ: Mumbai, India • Number of employees: 16,792 • Signatory to Industry Roadmap: No

Performance by Research Area How Lupin was evaluated: applicable indicators

Lupin is a prominent producer of antibiotics globally by sales reports that it has mechanisms in place for maintaining a high volume. As a generic medicine manufacturer, Lupin was eval- quality of antibiotic production and requires its third-party uated in Manufacturing & Production and Appropriate Access suppliers to apply the same quality standards to their pro- & Stewardship only. The company’s performance in the duction facilities. Lupin does not report any information on Benchmark is lower compared to most other generic med- its access strategies regarding antimicrobial medicines, or its icine manufacturers in scope. Lupin does not report having involvement in stewardship activities that promote appropri- an environmental risk-management strategy. The company ate antibiotic use.

SALES AND OPERATIONS RevenuesLupin by product§ RevenuesMade: by region§ Final: no

Lupin is an Indian-based generic medicine man- 18 manufacturing facilities across India, Japan, ufacturer founded in 1968. It produces active the USA, Mexico and Brazil (five for active phar- . pharmaceutical ingredients (APIs), as well as maceutical ingredient production). The com- . . . generic medicines. The company develops pany invests in R&D for biosimilars, mainly in bn INR bn INR advanced drug-delivery systems and has a highly immunology, endocrine health and oncology. It . differentiated pipeline. It has operations in more has nine R&D facilities, in India and elsewhere, than 100 countries, with key markets for finished including the USA, Japan and the Netherlands. ● Total revenue ● USA drug products in the USA, India, Japan, Europe, In 2016, Lupin acquired Gavis Pharmacauticals, ● India South Africa, Philippines and Australia. The com- whose portfolio includes cardiovascular, cen- ● Rest of World ● Japan pany focusses on cardiovascular health, diabe- tral nervous system (CNS) and anti-infective tes and anti-infectives, with a strong history in medicines, among others. Also in 2016, Lupin anti-tuberculosis medicines and cephalosporin reached an agreement with Shionogi to acquire antibiotics. Its anti-tuberculosis formulations are 21 branded products coming off-patent in Japan, sold globally. Within the company’s India busi- for approx. USD 150 million. These cover ther- ness (contributing approx. 22% to global reve- apeutic areas such as the CNS, oncology and nues), the anti-infectives and anti-tuberculosis anti-infectives. business segments made up 18% of revenues in 2016 (fiscal year). Lupin (and subsidiaries) have

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Lupin mar- ny’s portfolio comprises the antifungal voricona- kets at least 25 antimicrobial medicines, 18 of zole, listed on the WHO EML (Section 6) for which are listed on the WHO EML (Section 6). the treatment of aspergillosis, the antiproto- Nineteen of the company’s antimicrobial medi- zoal tinidazole and four medicines containing the cines are antibiotics, with 13 listed on the WHO antiretroviral lamivudine. EML (Section 6), including six in the EML’s Watch group. The remainder (six) of the compa-

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group * Countries in scope are 106 low- and middle-income ● Not grouped countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017

110 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Lupin can company can publish information regarding the existing antimicrobials, and ensure that they are engage in stewardship activities, e.g., through levels of antibiotic discharge. Currently the com- priced affordably. Currently, the company does surveillance activities, educational activities for pany does not demonstrate evidence of having not disclose such information. healthcare professionals on AMR (while mitigat- an environmental risk-management strategy in ing conflicts of interest), and engage in appropri- place. Engage in R&D innovation. Lupin can engage in ate promotion practices. incremental R&D innovation to address resist- Ensure affordability and registration plans for ance, improve adherence and the appropriate Ensure transparency regarding environmental new and existing antimicrobials. Lupin can seek use of antimicrobial medicines. risk management. Lupin can share information to improve access in low- and middle-income on how it manages environmental risk, e.g., the countries through the registration of new and

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Lupin’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Reports no environmental risk- B.2 No transparency on environmental risk B.3 Commits to following GMP, including at management strategy. management. 3rd-party sites. Lupin does not report having an environmental Lupin does not disclose its strategy to minimise Lupin reports that it has mechanisms for main- risk-management strategy in place to minimise the impact of manufacturing discharge of anti- taining a high quality of antibiotic production the environmental impact of manufacturing dis- biotics. It does not publish any element looked — namely following GMP standards. This com- charge of antibiotics. for by the Benchmark, namely: antibiotic dis- mitment applies to its own manufacturing sites. charge levels, audit results, and the identities of Lupin requires its third-party suppliers to apply its third-party suppliers of antibiotic APIs and the same quality standards to their production drug products, or of its external waste-treat- facilities. ment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Lupin reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Lupin does not disclose how it works with stake- Lupin does not report any involvement in stew- countries in scope.* This information is not oth- holders (e.g., governments, procurers) to align ardship activities (from education to surveillance erwise publicly available. supply and demand for antimicrobial medicines, to appropriate promotion practices) that pro- specifically to prevent or minimise stock-outs in mote appropriate antibiotic use. C.2 No disclosure on equitable pricing countries in scope.* The company also does not approach. report on whether it has processes in place to Lupin does not disclose an equitable pricing respond to stock-outs in countries in scope.* approach for its highest-volume antibiotics and/ or antimicrobial medicines.

111 Antimicrobial Resistance Benchmark 2018 Macleods Pharmaceuticals Ltd.

Stock exchange: Privately held • Ticker: - • HQ: Mumbai, India • Employees: > 13,500 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Macleods was evaluated: applicable indicators

Macleods is a prominent producer of antibiotics glob- report its approach to assuring high quality antibiotic produc- ally by sales volume. As a generic medicine manufacturer, tion consistent with international standards. Macleods has Macleods was evaluated in Manufacturing & Production and provided information on where it has filed two of its newest Appropriate Access & Stewardship only. Although the com- antibiotics for registration, but does not disclose an equita- pany’s performance in the Benchmark is lower compared to ble pricing approach for its antibiotics and antimicrobial medi- most other generic medicine manufacturers in scope, it dis- cines, or actions to ensure efficient supply. The company does closes an environmental risk-management strategy for its not report any involvement in stewardship activities that pro- own sites, which includes an auditing process. It does not mote appropriate antibiotic use.

SALES AND OPERATIONS RevenuesMacleods by product§ Made: Final: no

Macleods is an Indian-based privately-held man- wide range of therapeutic indications, including ufacturer of generic medicines focussing on tuberculosis, malaria, bacterial infections, dia- essential pharmaceuticals. The company is pres- betes and respiratory and cardiovascular dis- . ent in more than 100 countries worldwide, eases. The company has an in-house bioequiva- mn USD including in Southeast Asia, Africa and North lence centre and an R&D centre, and it is active America. It has a total of 14 manufacturing facil- in the development of incremental innovations ities: one for active pharmaceutical ingredients for antimicrobial medicines. Its antimicrobial ● Total revenue (APIs) and 13 for drug products. Current drug medicines are sold in over 52 countries globally, formulations include tablets, hard and soft gel- 43 of which are low- or middle-income coun- atine capsules and dry powder injections. The tries.* According to publicly available data, reve- company is actively seeking to expand its man- nues for the fiscal year 2016 amounted to USD ufacturing capabilities to include, among other 782 million. things, metered dose inhalation products and liquid injectables. Macleods’ products cover a

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Macleods markets at least 83 antimicrobial med- portfolio comprises eight antimalarials (all listed icines, 51 of which are listed on the WHO EML on the WHO EML) and 21 antivirals (including 19 (Section 6). Fifty-four of the company’s antimi- indicated for HIV/AIDS). crobial medicines are antibiotics, with 29 listed on the WHO EML (Section 6), including three in the EML’s Reserve group (cefepime, colistin and linezolid). The remainder (29) of the company’s

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. † EML Section 6: Anti-Infective Medicines § Turnover 2016-2017

112 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Macleods registration of new and existing antimicrobials. on its behalf, as well as to external waste-treat- can engage in stewardship activities, e.g., Macleods has filed two of its newest anti-tuber- ment sites. Macleods currently has a general through surveillance activities, educational activ- culosis medicines for registration in 30 countries environmental risk-management strategy that it ities for healthcare professionals on AMR (while in scope.* It can seek to improve access in low- applies to its own manufacturing sites. mitigating conflicts of interest), and engage in and middle-income countries through the regis- appropriate promotion practices. tration of more antimicrobials, and ensure that Increase engagement in R&D innovation. these are priced affordably. Macleods is currently engaged in adapting Ensure transparency regarding environmental generic antimicrobial medicines. For example, risk management. Macleods can share informa- Expand environmental risk-management strat- the company is developing paediatric formulation on how it manages environmental risk, e.g., egy. Macleods can ensure that antibiotic dis- tions containing lower doses of anti-tubercu- by disclosing its environmental risk-management charge limits are added to its environmental losis medicines (in collaboration with the TB strategy and the levels of antibiotic discharge. risk-management strategy. It can also extend Alliance). It can continue to engage in incremen- this strategy to the sites of third parties who tal R&D, and ensure access and stewardship pro- Improve access through the affordability and manufacture antibiotic APIs and drug products visions are in place for these projects.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Macleods its antimicrobial R&D pipeline targeting priority has a general access to medicine policy that was not eligible for this Research Area. However, pathogens. This includes ten lower-dose formu- includes global adoption, availability and afforda- the company is active in antimicrobial R&D. lations of tuberculosis medicines for paediatric bility. Macleods is also developing a dolutegravir/ use and an additional indication for clofazimine, lamivudine/tenofovir fixed dose combination for Several R&D projects being developed with currently indicated for leprosy. The company col- the treatment of HIV/AIDS. public partners. laborates with TB Alliance and UNITAID on the Macleods reports that it has twelve projects in development of these formulations. TB Alliance

Pipeline targeting priority pathogens

Stage unknown Preclinical Phase I Phase II Phase III Approval

• Clofazimine – • Cycloserine – M. tuberculosis – Adap- M. tuberculo- tation (new formulation: capsules 125 sis – Adaptation mg) – Paediatrics – ERP reviewed (Additional indi- • Ethionamide – M. tuberculosis – cation) Adaptation (new formulation: dispers- • Ethambutol – ible tablets 125 mg) – Paediatrics – M. tuberculo- WHO prequalified 2017 sis – Adaptation • Levofloxacin – M. tuberculosis – (new formula- Adaptation (new formulation: dispers- tion: dispersible ible tablets 100 mg) – Paediatrics – tablets 100 mg) ERP reviewed – Paediatrics • Moxifloxacin – M. tuberculosis – • Linezolid – M. Adaptation (new formulation: dispers- tuberculosis ible tablets 100 mg) – Paediatrics – – Adaptation ERP reviewed (new formula- • Pyrazinamide – M. tuberculosis – tion: dispersible Adaptation (new formulation: dispers- tablets 150 mg) ible tablets 150 mg) – Paediatrics – – Paediatrics WHO prequalified 2016 • Isoniazid – M. • Rifampicin/isoniazid – M. tuberculo- tuberculosis sis – Adaptation (new formulation: – Adaptation dispersible tablets 75 mg + 50 mg) – (new formula- WHO prequalified 2017 tion: dispersible • Rifampicin/isoniazid/pyrazina- tablets 100 mg) mide – M. tuberculosis – Adaptation – Paediatrics (new formulation: dispersible tablets • Dolutegravir/ 75+50+150 mg) – WHO prequalified lamivudine/ten- 2017 ofovir disoproxil fumarate – HIV – Adaptation FDC = Fixed dose combination (new FDC) ERP = Expert Review Panel

113 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is strategy for own sites. management. maintained. Macleods has an environmental risk-manage- Macleods does not disclose its strategy to min- Macleods makes no statement regarding how ment strategy to minimise the impact of anti- imise the impact of manufacturing discharge it ensures high quality antibiotic production fol- biotic manufacturing discharge. This applies to of antibiotics. It does not publish any element lowing international manufacturing standards its own manufacturing sites and includes audit- looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- ing. There is no evidence that the strategy is discharge levels, audit results, and the identities tional authorities (such as GMP). applicable to third-party manufacturers of anti- of its third-party suppliers of antibiotic APIs and biotic APIs and drug products or to external drug products, or of its external waste-treat- waste-treatment plants. The company reports ment plants. no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed two newest antibiotics in some C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- countries in scope. chain efficiency. ship activities. Macleods has provided filing information on two Macleods does not disclose how it works with Macleods does not report any involvement in of its newest antibiotics: isoniazid/rifampicin stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- and isoniazid/pyrazinamide/rifampicin. These align supply and demand for antimicrobial med- veillance to appropriate promotion practices) two products both target tuberculosis and have icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. now been filed for registration in 30 countries in outs in countries in scope.* The company also scope,* mainly in sub-Saharan Africa. does not report on whether it has processes in place to respond to stock-outs in countries in C.2 No disclosure on equitable pricing scope.* approach. Macleods does not disclose an equitable pricing approach for its highest-volume antibiotic and/ or antimicrobial medicines. The company states that its approach to affordability is through tenders.

114 Access to Medicine Foundation Melinta Therapeutics, Inc.

Stock exchange: XNAS • Ticker: MLNT • HQ: New Haven, CT, USA • Number of employees: 11-50 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Melinta was evaluated: applicable indicators

Melinta is a biopharmaceutical company, selected for having pany has five projects in its antimicrobial R&D pipeline, four a pipeline that targets priority pathogens. At the end of of which target priority pathogens. Melinta has one antibiotic 2017, Melinta merged with Cempra and, in January 2018, approved by the FDA for the treatment of acute bacterial skin acquired The Medicines Company's infectious disease busi- and skin structure infections (ABSSSI), and has licensed the ness. The company was evaluated in the area of Research & commercialisation and co-development rights of this product Development only. It is a mid-performing company compared to partners in various geographic areas. to the biopharmaceutical companies in scope. The com-

SALES AND OPERATIONS

Melinta is a US-based biopharmaceutical com- lish its preclinical research programme targeting Pharmaceuticals, Inc. and Malin Corporation pany focussing on the development of antibiot- the ‘ESKAPE’ pathogens: E. faecium, S. aureus, plc. At the end of 2017, Melinta merged with ics for infections caused by drug-resistant bac- K. pneumoniae, A. baumannii, P. aeruginosa, and Cempra and announced the acquisition of the teria. The company was founded in 2000 (as Enterobacteriaceae. The company’s only anti- infectious disease business of The Medicines Rib-X Pharmaceuticals), by Yale University fac- microbial medicine on the market, delafloxa- Company, both biopharmaceutical companies in ulty, including a co-winner of the 2009 Nobel cin (Baxdela™), was acquired from Wakunaga scope of the Benchmark. The latter acquisition Prize for Chemistry for studies on the function Pharmaceutical in 2006 and approved by the was completed in January 2018 and included of the ribosome, a cellular structure responsi- FDA for the treatment of ABSSSI in 2017. It is three antimicrobial medicines marketed by The ble for protein synthesis. Based on these studies, available in both intravenous and oral formula- Medicines Company: the recently launched mer- the company’s drug discovery platform allows tions. The latter is expected to offer advantages openem/vaborbactam (Vabomere™) and estab- for atomic-level analysis of interactions between in terms of administration and reduced hospi- lished products oritavancin (Orbactiv®) and min- drug candidates and their bacterial targets at tal admission rates. Recent funding rounds for ocycline (Minocin®). On merging with Cempra, the ribosome, thereby aiding the design of anti- the company have been led by Vatera Holdings Melinta became listed on the NASDAQ stock biotics capable of bypassing resistance mecha- LLC (e.g., USD 67 million in 2015), together exchange with ticker MLNT. nisms. Melinta has used this platform to estab- with Quadrant Capital Advisors, Inc., Arisaph

ANTIMICROBIAL PORTFOLIO

Melinta has one antibiotic on the market, dela- ture infections (ABSSSI) and is available in both floxacin (Baxdela™), currently not included in intravenous and oral formulations. The oral for- the WHO EML (Section 6). Delafloxacin was mulation is expected to offer advantages in approved by the US FDA in June 2017 for the terms of ease of administration and reduced treatment of acute bacterial skin and skin struc- hospital admission rates.

OPPORTUNITIES

Develop access and stewardship plans for prod- Melinta has signed licensing agreements to help now has a total of three antibiotic candidates in ucts on the market. Regarding products on ensure access to a range of countries in scope.* late-stage clinical development. The company the market, e.g., meropenem/vaborbactam Melinta can develop a strategy for ensuring can ensure access and stewardship provisions (Vabomere™), part of The Medicines Company's appropriate use of the product in all countries. are in place for these candidates, for example, acquisition, Melinta can plan for access and through partnerships. stewardship provisions, e.g., through part- Plan ahead for access and stewardship during nerships. Regarding delafloxacin (Baxdela™), R&D. Melinta merged with Cempra in 2017 and

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. 115 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 4 target priority pathogens

A.2.1-2.2 Four R&D projects that target a A.3 No public-private partnerships reported. ment with Eurofarma Laboratórios, one of the priority pathogen. Melinta conducts R&D in-house and with pri- largest pharmaceutical companies in Brazil, for Biopharmaceutical companies in scope were vate-sector partners. It does not participate in the development and commercialisation of the selected based on their pipelines that target public-private partnerships, or in partnerships medicine in Brazil and other Latin American priority bacteria. Melinta has five projects in with non-profit organisations, for antimicro- countries where Eurofarma operates. For this its antimicrobial R&D pipeline, four of which bial R&D. indicator, countries in scope are 106 low- and target priority bacteria. Its antibiotic, delaflox- middle-income countries where access to medi- acin (Baxdela™), is a fluoroquinolone targeting A.4 Access provision in place, but no infor- cine is likely limited. Regarding stewardship pro- both gram-negative and gram-positive bacteria mation regarding stewardship. visions, Melinta signed the Davos Declaration, (including methicillin-resistant S. aureus), many Melinta reports that it has an access provision which includes a general commitment to support of which are resistant to other quinolones. The in place for its recently approved antibiotic, but the appropriate and responsible use of antimi- compound was approved by the FDA in 2017 for reports no information on stewardship provi- crobial medicines and vaccines. the treatment of ABSSSI, in both oral and intra- sions. In 2017, Melinta licensed the commer- venous formulations. It is currently in Phase III cialisation and co-development rights of dela- clinical trials for community-acquired bacterial floxacin (Baxdela™) to the Menarini Group in pneumonia. Additionally, Melinta has two preclin- 68 countries in Europe, Asia-Pacific, and the ical R&D projects for the development of new Commonwealth of Independent States (CIS). drug classes (such as pyrrolocytosines) through Additionally, Melinta and Malin Corporation plc its ESKAPE pathogen programme, and one mac- entered into an agreement for the commer- rolide discovery programme. cialisation and distribution of the drug in certain countries in the Middle East and Africa. The company has also entered into a similar agree-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• ESKAPE patho- • Delafloxa- • Delafloxacin gen programme cin (Baxdela™) (Baxdela™) – – GNB & GPB – – Adaptation ESBL, P. aerugi- pyrrolocytosines (new indication) nosa, S. aureus, • Macrolide pro- – CABP S. pneumoniae gramme – GNB – ABSSSI – FDA approval 2017

ABSSSI = Acute bacterial skin and skin structure infections CABP = Community-acquired bacterial pneumonia GNB = Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

Melinta is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

C APPROPRIATE ACCESS & STEWARDSHIP

Melinta is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

116 Access to Medicine Foundation Merck & Co., Inc.

Stock exchange: XNYS • Ticker: MRK • HQ: Kenilworth, NJ, US • Employees: 68,000 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Merck & Co., Inc. was evaluated: applicable indicators

Merck & Co., Inc. is active in many important areas related to APIs and drug products. The company reports no information AMR, reflected in its good performance in certain areas of about setting discharge limits. Regarding access, Merck & Co., the Benchmark. Due to a lack of publicly available information Inc. has not publicly disclosed where it has filed its newest and engagement with the Benchmark, it performs less well antibiotics for registration. It has, however, publicly commit- in areas evaluating depth of engagement in AMR. The com- ted to engaging in equitable pricing for some antimicrobials. pany has a relatively small antimicrobial R&D pipeline: 16 pro- Regarding stewardship, the company reports that it engages jects of which nine target priority pathogens, including two in several AMR educational activities aimed at healthcare pro- new vaccine candidates. The company discloses an environ- fessionals. It has also established a long-running AMR surveil- mental risk-management strategy that reportedly also applies lance programme. to all Merck & Co., Inc.’s third-party suppliers of antibiotic

SALES AND OPERATIONS RevenuesMerck & Co., by Inc.product § RevenuesMade: by region§ Final: no

Merck & Co., Inc. (known as MSD outside of the specialising in the development and supply of . . . US and Canada) is a large research-based phar- antibiotics to treat infections arising in acute .II . maceutical company with three business seg- care settings, frequently caused by drug-resist- . . ments: pharmaceuticals, vaccines and animal ant bacteria. At the end of 2016, Merck & Co., bn USD bn USD health. The company sells its products in more Inc. and Sanofi Pasteur ended their vaccines . than 140 countries worldwide. Its core thera- joint venture in Europe (Sanofi Pasteur MSD, peutic areas include infectious diseases and vac- established 1994) to independently manage ● Vaccines & ● USA antimicrobials ● Europe, Middle East, Africa cines. In 2015, Merck & Co., Inc. acquired Cubist their product portfolios. ● Other human ● Asia Paci c, Japan Pharmaceuticals for USD 9.5 billion, a company pharmaceuticals ● Rest of World ● Other revenue (inc. Animal Health)

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Merck & The company also markets an antibody, bezlo- Co., Inc. markets at least 19 antimicrobial medi- toxumab (Zinplava®), indicated, in conjunction cines, nine of which are listed on the WHO EML with antibacterial therapy, to reduce recurrence (Section 6). Nine of the company’s antimicrobials of of C. difficile infections. The company’s vac- are antibiotics, with four listed on the WHO EML cines portfolio includes both traditional child- (Section 6), including two in the EML’s Reserve hood immunisations (such as a measles, mumps group: daptomycin (Cubicin®) and ceftolozane/ and rubella combination vaccine) and newer tazobactam (Zerbaxa®). Out of the remain- additions, such as Gardasil®/ Gardasil®9 for use ● Antibiotics on WHO EML† WHO EML Categories ing ten medicines, seven are antivirals used for against certain strains of human papillomavirus ● Antibiotics not on ● Access group only ® treating HIV/AIDS or hepatitis C, two are antifun- (HPV), and RotaTeq for use against rotavirus. WHO EML† ● Access & Watch groups gals, and one is an anthelminthic. ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § FYE 31 December 2016 || For 16 top-selling products

117 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during its own and third-party manufacturing sites. Expand on stewardship activities. Merck & Co., R&D. Merck & Co., Inc. discloses no information Inc. engages in educational activities for health- regarding access and stewardship provisions for Improve access through the registration and care professionals on AMR globally. It also devel- its candidates. Merck & Co., Inc. can develop and affordability of new and existing antimicrobi- oped the SMART surveillance programme, which implement access and stewardship plans for all als. Merck & Co., Inc. discloses information on has been measuring resistance trends globally its candidates in late-stage clinical development. its registration approach for six antimicrobials, since 2002. The company can collaborate with including antimicrobial medicines and vaccines. public health authorities, and can ensure that Expand environmental risk-management strat- It can seek opportunities to ensure greater the data is made publicly available via an open egy. Merck & Co., Inc. can ensure that it sets and access in more low- and middle-income coun- database. Merck & Co., Inc. can also engage in applies discharge limits for antibiotic manufac- tries through the registration of new and exist- improving appropriate promotion practices. turing. The company publishes its environmental ing antimicrobials, and ensure that these are risk-management policies that it applies to both priced affordably.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 16 projects scored on ● ● ● ● ● ● pipeline 9 target priority pathogens

A.1 No information on antimicrobial R&D adaptation of the existing medicines ceftolo- the company collaborates with the University investments. zane/tazobactam (Zerbaxa™) and tedizolid of Granada and the regional government of Merck & Co., Inc. reports no information on its (Sivextro®) for Hospital-Acquired and Ventilator- Andalusia, Spain, in a research alliance called antimicrobial R&D investments. Associated Bacterial Pneumonia (HABP/VABP). Medina Discovery, which focusses on the screen- Its clinical-stage projects consist of a next-gen- ing and validation of drug targets for infectious A.2.1-2.3 Nine candidates targeting priority eration HIV/AIDS medicine, a ß-lactamase inhib- diseases. Merck & Co., Inc. also collaborates with pathogens. itor targeting gram-negative bacteria, and a vac- Rutgers University, USA, for the discovery of Merck & Co., Inc. does not publicly report infor- cine against S. pneumoniae. novel antimicrobial medicines, with funding from mation on candidates in Phase I development. the National Institutes of Health (NIH). According to publicly available information, the A.3 Some preclinical R&D projects being company has 16 antimicrobial R&D projects in its developed with public partners. A.4 Access and stewardship commitment in pipeline, including ten projects in clinical-stage Merck & Co., Inc. is developing three preclini- place. development. Nine of the company’s projects cal R&D projects in its priority pathogen pipe- Merck & Co., Inc. has a Global AMR Action Plan target priority pathogens. Although its priority line through public-private partnerships (includ- which describes the company’s commitment pathogen pipeline is relatively small compared to ing non-profit organisations). It is developing to support access and stewardship for its novel other large research-based pharmaceutical com- a vaccine for shigellosis through its joint ven- antimicrobials portfolio. It has signed the Davos panies assessed by the Benchmark, eight of the ture with the Wellcome Trust called Hilleman Declaration, which includes a general commit- nine projects that target priority pathogens are Laboratories. Hilleman Laboratories focusses on ment to ensuring access to antimicrobial medi- focussed on multidrug-resistant bacteria (the developing affordable vaccines and addressing cines and vaccines, and to support the appropri- remaining project targets HIV). This includes the R&D gaps for low-resource settings. In addition, ate and responsible use of these products.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Discovery programmes through ▶ Shigella vaccine ▶ S. pneumoniae • Cilastatin/imi- Medina Discovery – GNB, P. falci- conjugate vac- penem/relebac- parum, M. tuberculosis cine V114 tam (MK7655A) • Partnership with Orchid Pharma, – P. aeruginosa, India – Bacteria & fungi CRE – cIAI, cUTI, • Partnership with Rutgers University – HABP/VABP Bacteria • Ceftolozane/ tazobactam (Zerbaxa™) – GNB – Adapta- tion (Additional indication) – HABP/VABP • Tedizolid phosphate (Sivex- tro®) – GPB ▶ Vaccine cIAI = Complicated intra-abdominal infections – Adaptation cUTI = Complicated urinary tract infections (Additional indi- FDC = Fixed dose combination cation) – HABP/ GNB = Gram-negative bacteria VABP GPB = Gram-positive bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial • Doravirine pneumonia (MK1439) – HIV

118 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk management at own B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at and external sites. mental risk management. 3rd-party sites. Merck & Co., Inc. has an environmental risk-man- Merck & Co., Inc. publishes elements of its envi- Merck & Co., Inc. reports that it has mechanisms agement strategy to minimise the impact of ronmental risk-management strategy on its for maintaining a high quality of antibiotic pro- antibiotic manufacturing discharge. The strategy website. It does not disclose audit results, or the duction — namely following GMP standards. This applies to its own manufacturing sites and to discharge levels of antibiotics. The company also commitment applies to its own manufacturing third-party manufacturers of antibiotic APIs and does not share the identities of its third-party sites. Merck & Co., Inc. requires its third-party drug products. The company commits to audit- suppliers of antibiotic APIs and drug products or suppliers of drug products to apply the same ing the implementation of this strategy at both external waste-treatment plants. quality standards to their production facilities. types of site. There is no evidence of the strategy being applicable to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Some newest antibiotics filed in some tries in scope. tices in its marketing materials or decoupling its countries in scope. sales force’s incentives from volume of antibi- Merck & Co., Inc. has filed some of its newest C.4 Multiple activities in AMR-related educa- otic sales. antibiotics, cilastatin/imipenem (Primaxin®) and tional programmes. ertapenem (Invanz®), for registration in some Merck & Co., Inc. is involved in educational pro- C.7 International programme for AMR countries in scope.* However, further details are grammes for HCPs that include AMR steward- surveillance. not publicly available. ship and rational use of antibiotics, with con- Merck & Co., Inc. runs a global surveillance pro- flicts of interest (COI) mitigation measures in gramme focussed on AMR trends, namely the C.2 Makes general commitment to equitable place. Programmes include its recently launched “Study for Monitoring Antimicrobial Resistance pricing. knowledge platform that provides direct links Trends” (SMART), which has a global scope Merck & Co., Inc. discloses a general (not prod- to high-quality information and educational and has been measuring resistance trends in uct-specific) inter- and intra-country equitable resources on AMR. The company also reports intra-abdominal samples since 2002. The data pricing approach covering countries in scope.* working with relevant stakeholders (e.g., CDC has been published in several peer- reviewed and a Colombian public health institute) to publications over the years. The company also C.3 Some insight into approach to supply develop stewardship guidelines and programme publicly commits to providing updated data by chain efficiency. metrics and support antimicrobial stewardship country and region. The company also engages Merck & Co., Inc. does not disclose how it works programmes in hospitals. in two other AMR-related surveillance pro- with stakeholders (e.g., governments, procur- grammes, the Program to Assess Ceftolozane- ers) to align supply and demand for its high- C.5-C.6 No information regarding brochure Tazobactam Susceptibility (PACTS) and est-volume antimicrobial medicines, specifi- and/or packaging adaptations, or Surveillance of Tedizolid Activity and Resistance cally to prevent or minimise stock-outs in coun- appropriate promotion practices. (STAR). tries in scope.* It does, however, publish a set Merck & Co., Inc. does not report any language, of Supply Chain Standards, including the capac- cultural or literacy adaptations made to its bro- ity to respond to changing demand. The com- chures or packaging that would promote appro- pany also does not report on whether it has propriate use. Furthermore, the company does cesses in place to respond to stock-outs in coun- not report any appropriate promotion prac-

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the develop alternatives to antibiotics for animal and feed companies with guidelines on resist- Benchmark. This information is provided given use and to facilitate the appropriate use of anti- ance management, appropriate dosage, and the importance of animal health and diagnostics biotics in animals. Merck & Co., Inc. runs a sur- length of usage to support the appropriate use on the topic of AMR. veillance programme that monitors the emer- of antibiotics. gence of bacterial resistance to Merck & Co., Inc. Merck & Co., Inc. is the only company in scope Animal Health antibiotics. Additionally, the com- that is involved in antibiotics for use in animal pany reports that it provides veterinarians, com- health. The company conducts research to mercial production operations, farmers, ranchers

119 Antimicrobial Resistance Benchmark 2018 MGB Biopharma

Stock exchange: Privately held • Ticker: - • HQ: Bellshill, Scotland, UK • Employees: 2-10 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How MGB Biopharma was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ● ● ○ ● ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ○ ○ ○ ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ○ ○ ○ ○ ○ ○ ○ overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

MGB Biopharma is a biopharmaceutical company, selected in its antimicrobial R&D pipeline, all targeting priority patho- for having a pipeline that targets priority pathogens. It was gens, including one novel antibiotic candidate. The company evaluated in the area of Research & Development only. The engages in numerous public-private partnerships and agree- company performs well compared to other biopharmaceu- ments with various organisations to develop its antibiotic tical companies in scope. MGB Biopharma has four projects candidates.

OPERATIONS

MGB Biopharma, founded in 2010, is a biop- didate, MGB-BP-3, is active against gram-posi- of the company in the development of its MGB harmaceutical company focussing on a new tive bacteria and has recently completed a Phase pipeline. MGB Biopharma has no products on the class of anti-infectives, the DNA Minor Groove I clinical safety study in the oral treatment of C. market. In 2017, the company closed a USD 1 mil- Binders (MGBs), which interact with microbial difficile infection. The compound is an analogue lion financing round to fund the development cell DNA and interfere with its replication. MGBs of the naturally occurring antibiotic (and anti- and production of MGB-BP-3 for a Phase II clin- were originally developed at the University of viral) distamycin. MGB Biopharma has plans to ical study in C. difficile infection. The financing Strathclyde in Glasgow, which licensed the tech- extend the therapeutic indications of this com- round was led by Archangel Investors Limited nology to MGB Biopharma, granting the compound and is currently developing MGBs that are and included contributions from TRI Capital Ltd, pany exclusive global rights in all fields except active against viruses, fungi and parasites. The Barwell plc and Scottish Investment Bank. cancer. The company’s most advanced drug can- University of Strathclyde remains a close partner

ANTIMICROBIAL PORTFOLIO

MGB Biopharma does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. MGB Biopharma has one antibiotic candidate (MGB-BP-3) in clinical development, currently in Phase I. MGB Biopharma is encouraged to implement access and stewardship plans for this candidate as it moves into Phase II clinical development.

120 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 4 projects scored on ○ ● ● ○ ● ○ pipeline 4 target priority pathogens

A.2.1-2.2 One novel antibiotic in the clinical also active against other gram-positive bacteria, A.4 No R&D candidates in late-stage pipeline. such as methicillin-resistant S. aureus (MRSA), development. Biopharmaceutical companies in scope were vancomycin-resistant Enterococcus (VRE) and MGB Biopharma is not eligible for this indicator selected based on their pipelines that target pri- Streptococci. The company is also developing as it does not have any R&D candidates in late- ority bacteria. MGB Biopharma has four pro- intravenous and topical formulations of the com- stage development. jects in its antimicrobial R&D pipeline, all target- pound in preclinical stages, and has discovery ing priority pathogens. MGB Biopharma is cur- platforms for gram-negative bacteria and fungi. rently developing its MGB-BP-3 antibiotic for the treatment of C. difficile infections. MGB-BP-3’s A.3 All R&D projects being developed with antimicrobial activity is based on a new mode of public partner. action, namely its activity as a DNA Minor Groove MGB Biopharma is developing all three R&D pro- Binder (MGB). Despite being in development for jects in its priority pathogen pipeline in collabo- treatment of C. difficile infections, MGB-BP-3 is ration with the University of Strathclyde.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Gram-negative platform – GNB • MGB-BP-3 – S. • MGB-BP-3 – C. • Antifungal platform – Candida aureus, S. pneu- difficile – DNA moniae – Adap- Minor Groove tation (addi- Binder – Novel tional indication) – GPB infections

GNB = Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, MGB Biopharma was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, MGB Biopharma was not eligible for this Research Area.

121 Antimicrobial Resistance Benchmark 2018 Motif Bio plc

Stock exchanges: XLON; XNAS • Ticker: MTFB • HQ: London, United Kingdom • Employees: 7 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No Performance by Research Area How Motif Bio was evaluated: applicable indicators

Motif Bio is a biopharmaceutical company, selected for having During the period of analysis, the company did not engage a pipeline that targets priority pathogens. It was evaluated in in public-private partnerships but conducted R&D in-house the area of Research & Development only. Motif Bio invested and/or with private-sector partners to develop its candidate USD 35 million in antibiotic drug development in 2016. Its per- compounds. Motif Bio has one R&D project in late-stage clin- formance in the Benchmark is low compared with other bio- ical development, and reports that it has both an access and pharmaceutical companies in scope. It has two projects in its stewardship commitment in place for this candidate. antimicrobial R&D pipeline, both targeting priority pathogens.

OPERATIONS

Motif Bio is a biopharmaceutical company in 2015 following the merger of the two compa- ronments in Europe regarding R&D, approval which specialises in developing novel antibiot- nies. In 2017, it was granted ‘orphan drug’ status and market viability of products combating anti- ics against infections caused by multidrug-re- by the FDA (for developing a drug or biologi- microbial resistance. Motif Bio has no products sistant bacteria. The company’s most advanced cal product to treat a rare disease or condition) on the market. In 2016, the company raised USD antibiotic drug candidate, iclaprim, is active for treating S. aureus lung infections in patients 25 million from UK and US investors through a against gram-positive bacteria. It is currently with cystic fibrosis. The company aims to collab- NASDAQ IPO. being developed for the treatment of acute orate with universities and other pharmaceuti- bacterial skin and skin structure infections and cal companies to expand its pipeline of antibi- hospital-acquired pneumonia, including infec- otics against gram-positive and gram-negative tions caused by methicillin-resistant S. aureus bacteria. Motif Bio is a member of the BEAM alli- (MRSA) and multidrug-resistant S. pneumoniae. ance, a group of biopharmaceutical companies The compound was acquired from Nuprim Inc. addressing the regulatory and commercial envi-

ANTIMICROBIAL PORTFOLIO

Motif Bio does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Motif Bio has stated a commitment to ensure access and stewardship provisions are in place for its antibiotic candidate (iclaprim) in late-stage clinical development. It can ensure that these provisions are applied and implemented accordingly.

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 2 projects scored on ○ ● ● ○ ● ● pipeline 2 target priority pathogens

A.2.1-2.2 Two candidates targeting priority lin-resistant S. aureus (MRSA). Iclaprim is cur- strains of Burkholderia, Stenotrophomonas and pathogens. rently in Phase III clinical development and is Achromobacter, in partnership with the Cystic Biopharmaceutical companies in scope were being developed for acute bacterial skin and skin Fibrosis Foundation. selected based on their pipelines that target pri- structure infections (ABSSSI) and hospital-ac- ority bacteria. Motif Bio invested USD 35 mil- quired bacterial pneumonia (HABP). Motif Bio is A.4 Access and stewardship commitments lion in antibiotic drug development in 2016. The also developing another antibiotic in the preclini- for iclaprim. company has two projects in its antimicrobial cal stage, targeting MRSA. Motif Bio reports that it has both an access and R&D pipeline targeting priority pathogens, both a stewardship commitment in place for its anti- in development for the treatment of gram-pos- A.3 No public-private partnerships reported biotic candidate in late-stage development. The itive bacterial infections. The company’s most during the period of analysis. company commits to filing iclaprim for registra- advanced antibiotic candidate is iclaprim, an anti- Motif Bio conducts R&D in-house and/or with tion based on public health needs and disease biotic designed to be effective against bacteria private-sector partners. During the period of prevalence. It also commits to ensuring access to that are resistant to other antibiotics, including analysis, it did not participate in public-private its product in low- and middle-income countries, trimethoprim, a commonly used antibiotic with partnerships, or in partnerships with non-profit with pricing strategies that take affordability into the same mechanism of action. Iclaprim is an organisations, for antimicrobial R&D. After the account. For this indicator, countries in scope antibiotic of the dihydrofolate reductase (DHFR) period of analysis, the company announced in are 106 low- and middle-income countries where inhibitor class that is active against methicil- vitro testing of iclaprim’s activity against various access to medicine is likely limited.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• MTF101 – GPB • Iclaprim – S. aureus, S. pneumoniae – Dihy- drofolate reductase inhibitor – ABSSSI, HABP/ VABP*

ABSSSI = Acute bacterial skin and skin structure infections GPB = Gram-positive bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial pneumonia * After the period of analysis, Motif Bio stated that Phase III trials for iclaprim in patients with HABP/VABP have started

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Motif Bio was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Motif Bio was not eligible for this Research Area.

123 Antimicrobial Resistance Benchmark 2018 Mylan NV Signatory to Davos Decl.: Yes Stock exchange: XNAS • Ticker: MYL • HQ: Canonsburg, PA, US • Number of employees: > 35,000 Signatory to Industry Roadmap: No

Performance by Research Area How Mylan was evaluated: applicable indicators

Mylan is one of the largest producers of antibiotics globally by the same quality standards to their production facilities. The sales volume. As a generic medicine manufacturer, Mylan was company reports no information on where it files products evaluated in Manufacturing & Production and Appropriate for registration; however, it discloses a general intra-coun- Access & Stewardship only. It has the highest performance try equitable pricing approach. The company also engages in among generic medicine manufacturers in scope. The com- stakeholder engagement to ensure efficient supply. Regarding pany discloses an environmental risk-management strategy stewardship, Mylan adapts its packaging with symbols and that is applied to its own manufacturing sites. Mylan reports pictograms illustrating the necessary antibiotic dosage sched- mechanisms for maintaining a high quality of antibiotic pro- ule for patients. duction and also requires its third-party suppliers to apply

SALES AND OPERATIONS RevenuesMylan by product§ RevenuesMade: by regionII Final: no

Mylan, founded in 1961, is a US-based global pro- (UNAIDS), the Clinton Health Access Initiative vider of generic and specialty pharmaceuticals. and the Bill & Melinda Gates Foundation (BMGF), . The company produces and markets innova- among others. Under the agreement, the com- . . . tive and generic medicines, active pharmaceuti- pany will supply a generic fixed dose combina- bn USD bn USD cal ingredients and consumer healthcare prod- tion of dolutegravir/lamivudine/tenofovir diso- ucts in approximately 165 countries and territo- proxil fumarate (developed as part of a licens- ries worldwide. The company's key therapeutic ing agreement with Gilead Sciences Inc. and ● Total revenue ● North America areas include cardiovascular, CNS and anaes- ViiV Healthcare) for a maximum price of about ● Europe thesia, infectious disease, immunology, res- USD 75 per patient per year. In return, the BMGF ● Rest of World piratory and allergy, dermatology and oncol- will guarantee minimum sales volumes of the ogy. In 2017, Mylan announced a multilateral drug. Since 2015, Mylan has made several large agreement to provide a new class of antiretro- acquisitions, including those of Meda, Abbott's virals (ARVs) to low- and middle-income coun- non-US developed markets specialty and tries. This agreement includes the South African branded generics business and the non-sterile, government, the Kenyan government, the topicals-focussed specialty and generics busi- Joint United Nations Programme on HIV/AIDS ness of Renaissance Acquisition Holdings.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Mylan markets at least 49 antimicrobial medi- The remainder (28) of the company’s portfo- cines, 38 of which are listed on the WHO EML lio comprises two antifungals and 26 antivirals, (Section 6). Twenty-one of the company’s anti- including 22 indicated for HIV/AIDS, the largest microbial medicines are antibiotics, with 19 listed anti-HIV portfolio in the Benchmark. on the WHO EML (Section 6), including one on the EML’s Reserve group (linezolid).

● Antibiotics on WHO EML† WHO EML Categories * Countries in scope are 106 low- and middle-income ● Antibiotics not on ● Access group only countries where access to medicine is likely limited WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines ● Other antimicrobial ● Watch group only § Net sales and other revenues from third-parties; FYE 31 medicines ● Reserve group December 2016 ● Not grouped || Third-party net sales; FYE 31 December 2016

124 Access to Medicine Foundation

OPPORTUNITIES

Expand engagement in antimicrobial steward- Expand environmental risk-management strat- cally for its antiretrovirals. It can seek to improve ship. Mylan adapts its packaging with symbols egy. Mylan can ensure antibiotic discharge limits access in low- and middle-income countries and pictograms illustrating the necessary dosage are added to its environmental risk-manage- through registration of new and existing anti- schedule for patients. It can expand this prac- ment strategy. It can also extend this strategy microbials, and ensure that more products are tice to more countries in scope* and take further to the sites of third parties who manufacture priced affordably. language and literacy needs into consideration. antibiotic APIs on its behalf, as well as to exter- Mylan can engage in more stewardship activi- nal waste-treatment sites. Mylan has a general Increase engagement in R&D innovation. Mylan ties, e.g., through surveillance activities, educa- environmental risk-management strategy that it is currently engaged in developing new fixed tional activities for healthcare professionals on applies to its own manufacturing sites. dose combinations of antiretroviral medicines. It AMR (while mitigating conflict of interest), and can continue to engage in incremental R&D, and engage in appropriate promotion practices. Ensure affordability and registration plans for ensure access and stewardship provisions are in new and existing antimicrobials. Mylan dis- place for these projects. closed its approach to equitable pricing specifi-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Mylan was the Fixed Dose Combination (FDC) efavirenz/ antiretrovirals from Gilead Sciences Inc., Bristol- not eligible for this research area. However, the lamivudine/tenofovir disoproxil fumarate, which Myers Squibb Co. and ViiV Healthcare. Mylan company is active in antimicrobial R&D. has been shown to be non-inferior while con- commits to pricing these generics affordably. In taining a reduced drug dose, and can be sold at particular, Mylan has announced a new agree- Two new fixed dose combinations for HIV/AIDS. a lower price. The other project involves dolute- ment with UNAIDS and other partners to make Mylan reports that it has two projects in its anti- gravir/lamivudine/tenofovir disoproxil fumarate, the dolutegravir/lamivudine/tenofovir disoproxil microbial R&D pipeline targeting a priority path- a new FDC for the treatment of HIV/AIDS. In fumarate combination available to public sector ogen, namely HIV. One project involves a dose 2017, Mylan received FDA tentative approval for purchasers in low- and middle-income countries reduction to efavirenz (600 mg to 400 mg), in both of these FDCs, as they consist of patented at around USD 75 per person, per year.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Efavirenz/lamivudine/tenofovir disoproxil fumarate – HIV – Adaptation (new FDC with reduced dose: 400 mg efavirenz instead of 600 mg in the existing FDC) – FDA tentative approval 2017* • Dolutegravir/ lamivudine/ tenofovir disoproxil fumarate – HIV – Adapta- tion (new FDC) – FDA tentative approval 2017

125 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Mylan has an environmental risk-management Mylan reports some of its environmen- Mylan reports that it has mechanisms for main- strategy that includes minimising the impact of tal risk-management initiatives in its Global taining a high quality of pharmaceutical pro- antibiotic manufacturing discharge. The strat- Sustainability Report, published on its website. It duction that includes antibiotic production — egy applies to its own sites and includes audit- does not disclose audit results, or the discharge namely following GMP standards. This commit- ing. At a number of sites in India, Mylan fol- levels of antibiotics. The company also does not ment applies to its own manufacturing sites. lows a Zero-Liquid Discharge process (ZLD, a share the identities of its third-party suppliers of Mylan requires its third-party suppliers to apply water treatment process in which all wastewa- antibiotic APIs and drug products, or of external the same quality standards to their production ter is cleaned and reused). The company's envi- waste-treatment plants. facilities. ronmental risk-management strategy has not been extended to Mylan's third-party manufacturers of antibiotic APIs and drug products, or to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 Taking multiple steps to improve supply C.4-C.7 Some involvement in AMR steward- Mylan reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Mylan engages with the Global Fund, PEPFAR Mylan adapts its packaging with symbols and countries in scope.* This information is not oth- and the South African government to align pictograms illustrating the necessary dosage erwise publicly available. supply and demand forecasting for five of its schedule for patients. This can help to improve highest-volume antimicrobials. These are all HIV/ patient adherence to treatment. However, it C.2 Intra-country equitable pricing for AIDS medicines. The company also has response does not report of any activities in HCP educa- antimicrobials. mechanisms in place for its HIV/AIDS medicines tion, appropriate promotion practices, or surveil- Mylan discloses a general (not product-spe- in order to respond efficiently in the event of lance programmes. cific) intra-country equitable pricing approach. stock-outs in countries in scope.* These mecha- It reports that this applies to at least its 5 high- nisms are designed to enable Mylan to anticipate est-volume antimicrobial medicines (all HIV/AIDS and respond to competing suppliers’ stock-outs. medicines) in countries in scope.* Under this general approach, the lowest prices are reserved for Global Fund, PAHO and PEPFAR.

126 Access to Medicine Foundation Nabriva Therapeutics plc

Stock exchange: XNAS • Ticker: NBRV • HQ: Dublin, Ireland • Number of employees: 66 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Nabriva was evaluated: applicable indicators

Nabriva is a biopharmaceutical company, selected for having does not provide evidence of engaging in public-private part- a pipeline that targets priority pathogens. It was evaluated nerships and agreements to develop and commercialise its in the area of Research & Development only. Nabriva has candidate compounds. Nabriva has no access or steward- invested USD 48 million in antibiotic drug development in ship provisions in place for its late-stage clinical antimicrobial 2016. The company performs well compared to other biop- candidates. harmaceutical companies in scope. Nabriva’s R&D pipeline consists of five projects, all of which target priority pathogens, including one novel antibiotic candidate. The company

OPERATIONS

Nabriva is a biopharmaceutical company The company then became public in 2015. In addressing the regulatory and commercial envi- engaged in research and development of novel 2017, it relocated its corporate headquarters to ronments in Europe regarding R&D, approval and antibiotics to treat bacterial infections, with Ireland. Nabriva is currently developing lefam- market viability of products combating antimi- a focus on the pleuromutilin class of antibiot- ulin, a semi-synthetic compound that inhib- crobial resistance. Nabriva has no products on ics. Pleuromutilins were discovered in the 1950s its the synthesis of bacterial protein. Lefamulin the market. In 2016, the company had USD 6.5 and have since been used systemically in ani- has recently completed a Phase III trial eval- million worth of revenues from research premi- mals and topically in humans. In 2006, Nabriva uating its safety and efficacy in patients with ums and grants. was incorporated as a spin-off from the Sandoz CABP. Nabriva is a member of the BEAM alli- GmbH Antibiotics Research Institute in Austria. ance, a group of biopharmaceutical companies

ANTIMICROBIAL PORTFOLIO

Nabriva does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Nabriva is developing one antibiotic candidate (lefamulin) in late-stage clinical development. Nabriva can ensure access and stewardship provisions are in place for lefamulin, e.g., through partnerships.

127 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1-2.2 Pipeline focussed on pleuromutilin and for paediatric use. Lefamulin is seen by A.4 No information on access or stewardship antibiotics. WHO as a new innovative antibiotic, as this is the provisions. Biopharmaceutical companies in scope were first pleuromutilin for systemic use in humans. Nabriva reports no information on access or selected based on their pipelines that target pri- Additionally, Nabriva is developing a pleuromuti- stewardship provisions for its antibiotic candi- ority bacteria. Nabriva invested USD 48 mil- lin in topical form (BC7013) for the treatment of date in late-stage development. It has signed lion in antibiotic drug development in 2016. The uncomplicated skin and skin structure infections the Davos Declaration, which includes a gen- company has five projects in its antimicrobial (uSSSI). The company also owns a pleuromutilin eral commitment to ensuring access to antimi- R&D pipeline, all targeting priority pathogens, discovery platform. crobial medicines and vaccines, and to support including one topical formulation. Currently, the appropriate and responsible use of these Nabriva has one systemic pleuromutilin antibi- A.3 No public-private partnerships reported. products. otic (lefamulin) in Phase III clinical trials to eval- Nabriva conducts R&D in-house and/or with pri- uate the safety and efficacy of intravenous to vate-sector partners. It does not participate in oral lefamulin in patients with CABP. Nabriva public-private partnerships, or in partnerships intends to develop lefamulin for additional indi- with non-profit organisations, for antimicro- cations, including for the treatment of acute bac- bial R&D. terial skin and skin structure infections (ABSSSI)

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Pleuromutilin molecule platform – • Lefamulin (IV/ • BC7013 – S. • Lefamulin (IV/ • Lefamulin (IV/ GNB & GPB oral) – Adapta- aureus, VRE, oral) – Adapta- oral) – Hib, S. tion (new for- CRE, ESBL, P. tion (additional aureus, S. pneu- mulation) – Pae- aeruginosa – indication) – moniae, VRE – diatrics Pleuromutilin ABSSSI Pleuromutilin – topical formula- CABP – Novel tion

ABSSSI = Acute bacterial skin and skin structure infections CABP = Community-acquired bacterial pneumonia GNP= Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Nabriva was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Nabriva was not eligible for this Research Area.

128 Access to Medicine Foundation Novartis AG

Stock exchange: XSWX • Ticker: NOVN • HQ: Basel, Switzerland • Employees: 118,393 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Novartis was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S . AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Novartis is among the top performing large research-based its newest antibiotics in some countries in scope* and com- pharmaceutical companies, following close behind the lead- mits to engaging in inter-country equitable pricing for its ers. This is driven by strong performance in Manufacturing & antimicrobials. The company reports that it widely applies Production and Appropriate Access & Stewardship. Its per- intra-country equitable pricing for one product. It also reports formance in Research & Development is on par with the aver- engaging with local healthcare facilities to align supply and age for this group of companies. The company has an antimi- demand. Regarding stewardship, Novartis engages in numer- crobial R&D pipeline of 32** projects, of which 16 target a pri- ous AMR educational activities aimed at healthcare profes- ority pathogen, including two novel antimalarial candidates. sionals, taking steps to mitigate conflict of interest, and is cur- It has an access commitment in place for four of its R&D can- rently adjusting incentives for its sales teams to increase the didates. The company discloses a comprehensive environ- weight of fixed pay in overall compensation and to reduce the mental risk-management strategy, which includes discharge variable component. In contrast to other large research-based limits and reportedly applies to all Novartis’ third-party sup- pharmaceutical companies in scope, Novartis does not report pliers of antibiotic APIs and drug products. Novartis has filed engaging in antibiotic-specific AMR surveillance programmes.

SALES AND OPERATIONS RevenuesNovartis by product§ RevenuesMade: by region§ Final: no

.II Novartis is a large research-based pharmaceu- Sandoz also sells other drug products, pharma- . . tical company with three divisions: Innovative ceutical intermediates and active pharmaceutical . . . Medicines, Alcon (eye-care products) and ingredients (APIs). It sold and/or donated 2,425 . . Sandoz (generic medicines). The Innovative million doses of antimicrobial medicines during bn USD bn USD Medicines division has two business units: phar- the fiscal year 2016. In 2015, Novartis divested . maceuticals (primary care and specialty medi- its vaccine business (excluding influenza vac- . cines) and oncology. The bulk of antimicrobial cines) to GSK in an asset swap that included the ● Antimicrobials ● USA ● Other generics ● Europe medicines in the company's portfolio are mar- acquisition of GSK’s marketed oncology portfo- ● Other branded ● Asia, Africa, Australasia keted by Sandoz. Sandoz markets antimicrobi- lio. The influenza vaccines unit ceased operation medicines ● Rest of World als in about 140 countries globally, of which 71 in 2014 and was finally acquired by CSL Limited ● Alcon or more are low- or middle-income countries.* in 2015 (including its development pipeline).

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Novartis markets at least 67 antimicrobial med- by its generics division Sandoz. Of 41 antibiotics icines, the second largest reported antimicro- on the market, 36 are listed on the WHO EML bial portfolio among the large research-based (Section 6), including three antibiotics in the pharmaceutical companies assessed by the EML’s Reserve group (cefepime, daptomycin and Benchmark. Sixty of these 67 medicines are linezolid). The remainder (26) of the company’s listed on the WHO EML (Section 6). The bulk of portfolio includes antivirals, antifungals, anti- the company’s antimicrobial medicines are clas- protozoals and anthelminthics, the majority of sical fermentation-derived antibiotics (penicil- which are listed on the WHO EML (Section 6). ● Antibiotics on WHO EML† WHO EML Categories lins, cephalosporins and macrolides), marketed ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only * Countries in scope are 106 low- and middle-income medicines ● Reserve group countries where access to medicine is likely limited. ● Not grouped † EML Section 6: Anti-Infective Medicines § Net sales; FYE 31 December 2016 || Approximately

129 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during of antibiotic discharge. Currently, Novartis dis- Engage in more stewardship activities. Novartis R&D. Novartis has a general registration proce- closes several elements of its environmental engages in several stewardship activities. The dure in place for candidates that reach Phase III risk-management strategy. company can engage in antibiotic resistance sur- clinical development, and has specifically stated veillance programmes, collaborate with public a commitment to apply this to its late-stage can- Expand environmental risk-management strat- health authorities and ensure that data is made didates. Novartis can ensure that this proce- egy. Novartis can apply its antibiotic discharge publicly available through open databases. dure is applied, while also implementing further limits to third parties who manufacture antibi- access and stewardship plans for all its candi- otic APIs on its behalf. Novartis has set discharge Expand its SMS for Life programme to more dates in late-stage clinical development. limits for its own manufacturing sites and exter- countries. Novartis can expand its SMS for Life nal waste-treatment plants as part of its envi- (2.0) programme, a public-private partnership Improve transparency regarding environmental ronmental risk-management strategy. between Novartis and local public health facil- risk management. Novartis can share more ities to track medicines stock levels, to more information on how it manages environmen- countries in scope.* The programme is already tal risk, e.g., the company can disclose the levels operating in six African countries.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 32 projects scored on ● ● ● ○ ● ● pipeline 16 target priority pathogens

A. 1 Average antimicrobial R&D investments. antimalarial medicines (both imidazolopipera- A.4 Access commitment in place, but no Novartis reports investments in antimicrobial zines); LFF571 (an antibiotic targeting C. difficile information regarding stewardship. R&D in 2016, which are average compared to in Phase II development); and LYS228 (an antibi- Novartis reports that it has an access commit- other large research-based pharmaceutical com- otic with activity against carbapenem-resistant ment in place for its four R&D candidates tar- panies in the Benchmark, however the exact Enterobacteriaceae spp. (CRE), currently start- geting priority pathogens in late-stage develop- amount is confidential. These investments cover ing Phase II clinical trials). Additionally, Novartis ment, but reports no information on steward- antimicrobial medicines only, as Novartis is not is awaiting approval for the inclusion of tuber- ship provisions. In the 2016 Access to Medicine involved in vaccine development. culosis as an additional indication for its leprosy Index, Novartis was a leader in registering prod- medicine, clofazimine (Lamprene®). ucts in countries in scope.* The company com- A.2.1-2.2 Pipeline focussed on gram-negative mits to applying the same strategy to its late- bacteria and malaria. A.3 Six R&D projects being developed with stage investigational candidates. For exam- Novartis has 32** antimicrobial R&D projects in public partners, including two PDPs. ple, the PDP funding agreements for its anti- its pipeline, seven of which are in clinical stage Novartis is developing six R&D projects in its malarial candidates include clauses to ensure development. Sixteen of the company’s projects priority pathogen pipeline through public-pri- broad access. Regarding stewardship provisions, target priority pathogens. It has an average-sized vate partnership (including non-profit organisa- Novartis signed the Davos Declaration, which pipeline compared to other large research- tions). Two antimalarial candidates, cipargamin includes a general commitment to support the based pharmaceutical companies assessed and KAF156/lumefantrine, are being developed appropriate and responsible use of antimicro- by the Benchmark. The company has a strong through PDPs with the Medicines for Malaria bial medicines and vaccines. After the period of focus on malaria and bacteria, mostly gram-neg- Venture (MMV). Development of KAF156/lume- analysis, Novartis stated its practice of initiat- ative. It has nine drug candidates in preclini- fantrine is co-funded by the Bill & Melinda Gates ing global surveillance for potential resistance to cal development (eight of which target bacte- Foundation and development of cipargamin is its novel antimicrobial agents a minimum of four ria), and four drug candidates in clinical develop- co-funded by the Wellcome Trust. The other years prior to expected launch (in line with FDA ment. Novartis’ clinical pipeline consists of four four projects are in preclinical stage and involve recommendations). investigational medicines including: two novel public research institutes.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Inhibitors/modulators of bacterial • JA-43-AO00 – • LYS228 ‡ – GNB • LFF571 – C. dif- • Clofazimine outer membrane biogenesis – GNB GNB & GPB ficile, S. aureus, (LAM320) – • Bacterial cell wall inhibitors – GNB • EE-67-VB84 – P. VRE M. tuberculo- • Inhibitors/modulators of bacterial aeruginosa • KAF156/lume- sis – Adaptation cell envelope biogenesis and func- • FB-11-AR48 – fantrine – P. fal- (additional indi- tion – GNB GNB & GPB ciparum – Novel cation) – Await- • Phenotypic screening of natural • Cipargamin • Cipargamin ing approval products – GNB (KAE609) – (KAE609) – P. • Discovery of new combinations of P. falciparum falciparum – existing and new chemical entities – Adaptation Novel – GNB (new formula- • Uncomplicated malaria – P. falci- tion: intrave- parum nous) • Confidential GNB = Gram-negative bacteria project – GNB GPB = Gram-positive bacteria ** After the period of analysis, Novartis submitted an – Adaptation ‡ This candidate moved to Phase II clinical adaptive project of tobramycin for the treatment of development after the period of analysis. (new formula- bronchiectasis-related Pseudomonas, including the tion) assessment of resistance. 130 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at agement strategy. mental risk management. 3rd-party sites. Novartis undertakes almost all environmental Novartis publishes elements of its environmen- Novartis reports that it has mechanisms for risk-management activities that the Benchmark tal risk-management strategy on its website. It maintaining a high quality of antibiotic produc- examines. Namely, it applies an environmen- does not disclose audit results, or the discharge tion — namely following GMP standards. This tal risk-management strategy to minimise the levels of antibiotics. The company also does not commitment applies to its own manufactur- impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers ing sites. Novartis requires its third-party suppli- This includes auditing at its own manufacturing of antibiotic APIs and drug products or external ers of drug products to apply the same quality sites and those of third-party manufacturers of waste-treatment plants. standards to their production facilities. antibiotic APIs and drug products. Novartis sets limits on antibiotic discharge for its own manufacturing sites and external waste-treatment plants, yet not to third-party manufacturers of antibiotic APIs and drug products.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed newest antibiotics in some coun- Nigeria and Tanzania. Alignment of supply and example, the company has started to increase tries in scope. demand for these products is managed through the weight of fixed pay in overall compensation Novartis reports information about where it has SMS For Life, a public-private partnership and to reduce the variable component. filed five of its newest antibiotics for registra- between Novartis and local healthcare facilities tion in some countries in scope* (between one set up to track stock levels. Initially established C.6 Implements brochure and/or packaging and eight countries). These products were intro- for mobile phones, the programme was updated adaptations to facilitate appropriate use. duced between 2011 and 2017. in Nigeria in 2016 to include a tablet- and smart- Novartis has adapted several brochures (to phone-based version of its stock-level tracking include demographic and literacy considera- C.2 Inter- and intra-country equitable platform. tions) to facilitate appropriate use of antibiotics pricing. by patients. For example, paediatric brochures Novartis discloses a general (not product-spe- C.4 Multiple activities in AMR-related educa- have been incorporated to illustrate the appro- cific) commitment to applying inter-coun- tional programmes. priate dosage of amoxicillin, and the packaging try equitable pricing to its highest-volume Novartis reports that it is involved in educational for its penicillin G antibiotic in Africa has been antimicrobials including antibiotics. It applies programmes for HCPs that include AMR stew- adapted for patients who may be illiterate. intra-country equitable pricing approaches for ardship and rational use of antibiotics, with con- artemether/lumefantrine (Coartem®) in the flicts of interest (COI) mitigation measures in C.7 No apparent involvement in surveillance majority of countries in scope.* This approach place. Programmes include topics on diagnosis, programmes. was first developed and implemented in part- treatment and management of multidrug-resist- Novartis reports no involvement in antibi- nership with WHO in 2001. Novartis has inde- ant bacterial infections. The company provides otic resistance-specific programmes aimed at pendently extended this approach beyond its ini- a protocol to mitigate COI. All educational activ- increasing global surveillance capabilities. tial ten-year term. ities reported were developed in collaboration with third parties. C.3 Local engagement to align supply and demand. C.5 Comprehensive involvement in appropri- Novartis engages with primary and local health- ate promotion practices. care facilities to align supply and demand fore- The Benchmark measures how companies casting for two of its highest-volume antimi- address stewardship through appropriate pro- crobial medicines: artemether/lumefantrine motion. Novartis reports that it takes action in (Coartem®) and efavirenz. This applies in the this regard: it reflects AMR trends in its market- following countries in scope*: Cameroon, the ing materials and is currently adjusting incen- Democratic Republic of Congo, Ghana, Kenya, tives for its sales teams around the world. For

131 Antimicrobial Resistance Benchmark 2018 Pfizer Inc.

Stock exchange: XNYS • Ticker: PFE • HQ: New York, NY, US • Employees: 96,500 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Pfizer was evaluated: applicable indicators

Pfizer** is among the top performing large research-based Pfizer discloses a comprehensive environmental risk-man- pharmaceutical companies, following close behind the lead- agement strategy, which includes discharge limits and report- ers. It performs well in Manufacturing & Production and edly applies to all Pfizer’s third-party suppliers of antibiotic Appropriate Access & Stewardship, achieving an average per- APIs and drug products. Pfizer has filed four of its five newest formance in Research & Development. The company does not antibiotics in countries in scope.* It also reports having mech- report its antimicrobial R&D investments and its R&D pipe- anisms in place for responding efficiently to stock-outs in line is comparatively small compared to other large research- countries in scope.* Regarding stewardship, Pfizer is engaged based pharmaceutical companies assessed by the Benchmark: in a number of AMR educational and training activities for seven antimicrobial projects. Notably, six of these target pri- healthcare professionals, taking steps to mitigate conflicts of ority pathogens, including four vaccines. It has access pro- interest, as well as engaging in established AMR surveillance visions in place for its vaccines in late-stage development. programmes that have an emphasis on data-sharing.

SALES AND OPERATIONS RevenuesP zer by product§ RevenuesMade: by region§ Final: no

Pfizer is a large research-based pharmaceuti- and biosimilars. In 2016, the company acquired cal company with two business segments: Pfizer AstraZeneca’s small-molecule anti-infectives . . . . Essential Health and Pfizer Innovative Health, business and late-stage pipeline, including com- . . . which includes vaccines. Pfizer sells antimicro- mercialisation rights to avibactam/ceftazi- bn USD bn USD bial medicines in at least 122 countries globally, dime (Zavicefta™).** In 2017, Pfizer and Basilea . . of which 53 or more are low- to middle-income Pharmaceutica Ltd. entered into an agreement countries.* In 2016, the company sold more than whereby Pfizer was granted exclusive rights to ● Vaccines ● USA 160 million doses of vaccines, including 61 mil- develop and commercialise the antifungal isavu- ● Antimicrobials ● Developed Rest of World lion doses of Prevnar 13® in partnership with conazole (Cresemba®) in several European ● Other pharmaceuticals ● Developed Europe ● Emerging markets Gavi, the Vaccines Alliance. In 2009, GSK and countries, China and 16 Asian-Pacific countries Pfizer established ViiV Healthcare (GSK: 76.5%, (exc. Japan).** Pfizer purchased two meningo- Pfizer: 13.5% and Shionogi: 10%), a joint ven- coccal vaccines, Mencevax® and Nimenrix®, from ture solely focussed on the development of HIV/ GSK in 2015. It had previously purchased from AIDS medicines. In 2015, Pfizer completed the Baxter, in 2014, the vaccines NeisVac-C® and acquisition of Hospira — a provider of generic FSME-IMMUN®/TicoVac®, indicated for meningi- injectable medicines (including antimicrobials) tis and tick-borne encephalitis, respectively.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Pfizer markets at least 114 antimicrobial med- 6), including seven in the EML’s Reserve group. icines, the largest reported antimicrobial port- The remainder (31) of the company’s portfo- folio among the large research-based pharma- lio includes antifungals (systemic and topical), ceutical companies assessed by the Benchmark. antiprotozoals and anthelminthics, as well as Sixty of these 114 medicines are listed on the eight antivirals. Pfizer also markets two antisep- WHO EML (Section 6). Eighty-three of the com- tic irrigation solutions and six vaccines, including pany’s antimicrobial medicines are antibiot- Prevnar 13® for pneumococcal pneumonia, and ics, with 45 listed on the WHO EML (Section four meningococcal vaccines. ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only ** Assets, specifically marketed products, acquired from * Countries in scope are 106 low- and middle-income WHO EML† ● Access & Watch groups AstraZeneca in 2016, and Basilea in 2017, remain subject countries where access to medicine is likely limited. ● Other antimicrobial ● Watch group only to integration into the Pfizer portfolio (including MAA † EML Section 6: Anti-Infective Medicines medicines ● Reserve group § transfer process in several markets). These assets have FYE 31 December 2016 ● Not grouped therefore been excluded from this analysis.

132 Access to Medicine Foundation

OPPORTUNITIES

Plan ahead for access and stewardship during biotic discharge, and publish the identities of Ensure access to more antimicrobials. Pfizer is R&D. Pfizer has registration and affordability third parties who manufacture antibiotic APIs currently committed to engaging in inter-coun- plans in place for all of its vaccine candidates. It and drug products on its behalf. Currently, Pfizer try equitable pricing for its antimicrobial med- also has stewardship plans in place for its anti- discloses several policy documents on its envi- icines. Pfizer can expand its affordability strat- biotic candidate (avibactam/aztreonam) in the ronmental risk management. egy by engaging in intra-country equitable pric- form of AMR surveillance programmes and edu- ing for its antimicrobial medicines, and improv- cational activities for HCPs. Pfizer can ensure Expand environmental risk-management strat- ing access to recently acquired assets from that access plans are also in place for avibactam/ egy. Pfizer has set discharge limits for its own AstraZeneca and Basilea such as avibactam/ aztreonam. manufacturing sites and third parties who manu- ceftazidime (Zavicefta®) and isavuconazole facture antibiotic APIs and drug products as part (Cresemba®). Improve transparency regarding environmental of its environmental risk-management strategy. risk management. Pfizer can share more infor- It can ensure these antibiotic discharge limits are mation on how it manages environmental risk, applied to external waste-treatment sites. e.g., the company can disclose the levels of anti-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 7 projects scored on ● ● ● ● ● ● pipeline 6 target priority pathogens

A.1 No information on antimicrobial R&D clinical development targeting S. aureus, C. dif- A.4 Access provisions in place for its investments. ficile and group B Streptococcus (for which no vaccines in late-stage development. Pfizer reports no information on its antimicrobial vaccines currently exist) and a 20-valent pneu- Pfizer reports that it has access provisions in R&D investments. mococcal vaccine. place for both of its vaccines in late-stage development. It reports that it has a stewardship pro- A.2.1-2.3 Six R&D projects focussed on prior- A.3 Two R&D projects being developed with vision in place for its antibiotic candidate in late- ity pathogens. public partners. stage development, and commits to plan access Pfizer has seven antimicrobial R&D projects in its Pfizer is developing two R&D projects in its pri- plans during R&D but does not provide informa- pipeline, six of which are in clinical stage devel- ority pathogen pipeline through public-pri- tion on details of such action plans. For its two opment. Six of the company’s projects target private partnerships (including non-profit organ- vaccines in Phase II and III clinical stage, it will ority pathogens. Although Pfizer has a smaller isations).*** After acquiring avibactam from apply an equitable pricing policy that is based on pipeline compared to leaders in this area, all of AstraZeneca in 2016, Pfizer continued the devel- countries’ ability to pay, while covering research its projects focus on multidrug-resistant bac- opment of avibactam/aztreonam in collabora- and development costs. It is unknown if this terial infections. Pfizer has one project in pre- tion with Allergan, currently in Phase II clinical policy applies to its avibactam/aztreonam com- clinical development that focusses on new fixed development, through the COMBACTE-CARE bination. Furthermore, Pfizer plans to continue dose combinations (FDCs) of existing ß-lactam programme (IMI’s New Drugs 4 Bad Bugs con- its AMR surveillance programmes, as well as and ß-lactamase inhibitors. Pfizer is involved in sortium). The project also includes funding from launch educational initiatives regarding the risks the clinical development of new vaccines and BARDA. In 2016, Pfizer received funding from of AMR and how vaccines could play a role in new FDCs of existing antibiotics. This includes the Bill and Melinda Gates Foundation to con- addressing this public health threat. For this indi- the development of a new combination of the duct a Phase I/II clinical trial to evaluate the cator, countries in scope are 106 low- and mid- existing ß-lactam aztreonam and the ß-lacta- investigational group B Streptococcus (GBS) vac- dle-income countries where access to medicine mase inhibitor avibactam, a project that was cine in South Africa. Moreover, Pfizer is part of is likely limited. obtained with the acquisition of AstraZeneca’s a public-private consultation group led by WHO antibiotics division, in collaboration with on group B Streptococcus vaccine development, Allergan. Pfizer has no new chemical entities in which aims to develop standardised antibody its pipeline. Nevertheless, it has four vaccines in assays to identify correlates of protection.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Discovery of ▶Pneumococ- ▶S. aureus 4-anti- ▶C. diffi- FDCs with exist- cal conju- gen vaccine cile vaccine ing small mol- gate 20-valent (PF06290510) (PF06425090) ecules – GNB vaccine – Adaptation (PF06482077) • Avibactam/ (new FDC) – S. pneumo- aztreonam ▶Vaccine niae (PF06947387) cIAI = Complicated intra-abdominal infection FDC = Fixed dose combination – MBL – cIAI, GNB = Gram-negative bacteria ▶Group B Strep- HABP/VABP GPB = Gram-positive bacteria tococcus – Adaptation HABP/VABP = Hospital-acquired/Ventilator- *** Pfizer is involved in the COMBACTE- 6‑valent con- (new FDC) – In associated bacterial pneumonia CDI network, a recently launched pro- MBL = metallo-ß-lactamase jugate vaccine partnership with ject within the IMI COMBACTE research ‡ This candidate moved to Phase III clinical devel- (PF06760805) Allergan plc‡ consortium. opment after the period of analysis.

133 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at management strategy. mental risk management. 3rd-party sites. Pfizer undertakes many of the environmental Pfizer publishes elements of its environmen- Pfizer reports that it has mechanisms for main- risk-management activities that the Benchmark tal risk-management strategy on its website. It taining a high quality of antibiotic production examines. Namely, it applies an environmen- does not disclose audit results, or the discharge — namely following GMP standards. This com- tal risk-management strategy to minimise the levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers Pfizer requires its third-party suppliers of drug It includes auditing and limits on antibiotic dis- of antibiotic APIs and drug products or external products to apply the same quality standards to charge, at its own manufacturing sites and those waste-treatment plants. their production facilities. of third-party manufacturers of antibiotic APIs and drug products. Pfizer's manufacturing sites include primary waste treatment. Secondary waste treatment occurs on- and off-site. The environmental risk-management strategy does not apply to off-site waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed four of five newest antibiotics in procurers) to align supply and demand for anti- force from sales volume. In addition to provid- countries in scope. microbial medicines, specifically to prevent or ing AMR-related trends in its marketing mate- Pfizer reports that it has filed four of its five minimise stock-outs in countries in scope.* It has rials, Pfizer’s materials are reviewed by medi- newest antibiotics, introduced in 1991-2005, launched a website on supply status of injecta- cal experts to ensure they are aligned with anti- for registration in countries in scope* (between bles, including antimicrobial medicines such as biotic stewardship principles. Moreover, sales 30-63 countries). The fifth antibiotic, introduced piperacillin/tazobactam (Zosyn®). force training includes topics such as challenges in 1999, has not been filed for registration in in AMR and stewardship. any country in scope.* Pfizer did not report filing C.4 Multiple activities in AMR-related educa- information about newer antibiotics acquired tional programmes. C.6 Provides information on treatment recently (i.e., from AstraZeneca in 2016 and from Pfizer reports that it is involved in educational duration. Basilea in 2017), as these products are still being programmes for HCPs that include AMR stew- Pfizer adapts its packaging to facilitate appropri- integrated into the Pfizer portfolio (e.g., ongoing ardship and rational use of antibiotics, with con- ate use by providing information on treatment MAA transfer processes in several markets). flict of interest (COI) mitigation measures in duration. This can help to ensure that patients place. Programmes such as “Sharing Hospital complete the treatment course. C.2 Makes general commitment to equitable Anti-infectives Perspectives and Experience” pricing. (SHAPE) and the “Infectious Disease Education C.7 Open source surveillance programme. Pfizer discloses a general (not product-specific) and Learning” (IDEAL) support the implemen- Pfizer reports that is involved in several surveil- commitment to applying inter- and intra-country tation of local antimicrobial stewardship pro- lance programmes, focussed on AMR trends. equitable pricing to antimicrobials in countries grammes. Its COI mitigation strategy consists Pfizer’s ATLAS programme stands out among in scope.* Pfizer is also committed to long-term of external content development and SOPs to all AMR surveillance programmes identified by public-private donation programmes for azithro- review content and potential COIs. The company the Benchmark, as it is completely accessible to mycin (Zithromax®) and fluconazole (Diflucan®). participates in various interactive courses and the public. The company is highly active in sur- massive open online courses (MOOCs) in col- veillance activities globally, some of which have C.3 Mechanisms in place to respond to laboration with third parties, aiming at chang- been running for over 14 years. Pfizer reports stock-outs. ing the behaviour of HCPs in stewardship and that it collaborates with public health agencies Pfizer reports that it has mechanisms in place resistance. for its surveillance programme in Latin America. for responding efficiently to stock-outs of all of its antimicrobial medicines and vaccines in C.5 Comprehensive involvement in appropri- countries in scope.* These are based on a set of ate promotion practices. demand and supply principles, such as ensuring The Benchmark measures how companies supplies are distributed equitably between coun- address stewardship through appropriate pro- tries, sharing information on shortages with pur- motion. Pfizer reports that it takes action in this chasers, and assigning additional resources in regard: it reflects AMR trends in its marketing the event of delays. Pfizer does not disclose how materials and is currently working on a pilot pro- it works with stakeholders (e.g., governments, ject to decouple the remuneration of its sales

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Pfizer does not market antimicrobials for use in ies of carbapenem-resistant bacteria. The com- Benchmark. This information is provided given animals. pany has also entered into collaborations with the importance of animal health and diagnostics diagnostic manufacturers to support commer- on the topic of AMR. Pfizer supports COMBACTE-CARE, a European cial availability of susceptibility tests for its new network that addresses the diagnostic chal- antibiotics. lenges for the epidemiological and clinical stud-

134 Access to Medicine Foundation Polyphor Ltd.

Stock exchange: Privately held • Ticker: - • HQ: Allschwil, Switzerland • Employees: approx. 100 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Polyphor was evaluated: applicable indicators

Polyphor is a biopharmaceutical company, selected for having Polyphor engages in public-private partnerships to develop its a pipeline that targets priority pathogens. It was evaluated in candidate compounds. The company has one R&D project in the area of Research & Development only. It invested more late-stage clinical development, but reports no information on than USD 5 million in antibiotic drug development in 2016. access or stewardship provisions for this candidate. The company performs well when compared with other biopharmaceutical companies in scope. It has three projects in its antimicrobial R&D pipeline, all targeting priority pathogens.

OPERATIONS

Polyphor, founded in 1996, is a privately-held ard-of-care treatment. Polyphor also develops platform, frequently used in research collabora- Swiss-based biopharmaceutical company, focus- an inhaled formulation of murepavadin for cystic tions with other pharmaceutical companies. sing on the development of macrocycle drugs fibrosis as part of a consortium, funded by the Polyphor is a member of the BEAM alliance, a that address antibiotic resistance and severe Innovative Medicines Initiative (IMI), a public-pri- group of biopharmaceutical companies address- pulmonary diseases. Polyphor discovered a new vate partnership of EFPIA and the EU. ing the regulatory and commercial environments class of antibiotics effective against gram-neg- While murepavadin is selective for P. aeruginosa, in Europe regarding R&D, approval and market ative bacteria, the Outer Membrane Protein the next generation of OMPTAs are broad-spec- viability of products combating antimicrobial Targeting Antibiotics (OMPTA). The most trum antibiotics, which target most important resistance. advanced drug candidate is murepavadin, indi- gram-negative pathogens, including extensively Polyphor has no products on the market. In 2017, cated for the treatment of infections caused by drug-resistant (XDR) and multidrug-resistant the company announced that it had successfully P. aeruginosa. Murepavadin recently entered (MDR) strains. In early 2017, Polyphor received a completed a CHF 40 million private financing Phase III clinical studies, after showing encour- CHF 2.3 million award from the Wellcome Trust round, 98% of which came from existing inves- aging results in a Phase II study in patients to advance the development of its broad-spec- tors, with substantial contributions from Varuma with ventilator-associated bacterial pneumo- trum, gram-negative preclinical candidates. The AG and Ingro Finanz AG. nia (VABP), when co-administered with stand- company has a proprietary macrocycle discovery

ANTIMICROBIAL PORTFOLIO

Polyphor does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Polyphor is developing one antibiotic candidate (murepavadin) in late-stage clinical development. Polyphor can ensure access and stewardship provisions are in place for murepavadin, for example, through partnerships.

135 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 Novel antibiotics that address teins. This makes Polyphor one of the few com- 2013, the company signed an exclusive world- cross-resistance. panies developing innovative antibiotics that wide licence agreement with Roche to develop Biopharmaceutical companies in scope were address cross-resistance. and commercialise murepavadin. In 2015, Roche selected based on their pipelines that target pri- decided to discontinue its involvement and ority bacteria. Polyphor invested more than USD A.3 At least one R&D project being devel- Polyphor continues the clinical development of 5 million in antibiotic drug development in 2016. oped with public partners.* the compound. The company has three projects in its antimicro- Polyphor is developing one R&D project in its bial R&D pipeline targeting priority pathogens, priority pathogen pipeline through a public-pri- A.4 No information on access or stewardship focussed on gram-negative bacteria. Polyphor’s vate partnership*: this is its preclinical OMPTA provisions novel antibiotic murepavadin (POL7080) tar- platform, developed in collaboration with the Polyphor reports no information on access or geting P. aeruginosa is entering Phase III clini- University of Zürich and with financial sup- stewardship provisions for its antibiotic candi- cal trials. Murepavadin is a synthetic macrocy- port from the Swiss government (amount date in late-stage development. It has signed clic protein that binds to a specific protein in not known). In 2017, the development of this the Davos Declaration, which includes a gen- the outer membrane of P. aeruginosa, interfer- broad-spectrum platform targeting gram-neg- eral commitment to ensuring access to antimi- ing with its proper functioning and ultimately ative pathogens also received funding from the crobial medicines and vaccines, and to support killing the pathogen. The company has more Wellcome Trust (CHF 2.3 million). Polyphor the appropriate and responsible use of these compounds in preclinical stage using the same is not developing its clinical stage candidate, products. molecular target class, outer membrane pro- murepavadin, via public-private partnership. In

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• POL7080 • Murepavadin inhaled – P. (POL7080 IV) – aeruginosa P. aeruginosa – • Broad spectrum HABP/VABP – OMPTA com- Novel ‡ pounds – GNB (inc. MDR and XDR)

GNP = Gram-negative bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial pneumonia ‡ Phase III clinicaI trials are expected to commence in the first months of 2018.

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Polyphor was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Polyphor was not eligible for this Research Area.

* After the Benchmark’s period of analysis, Polyphor entered into collaboration with the public-private partnership Innovative Medicines Initiative (IMI), as part of the iABC consortium, to co-fund and advance the development of its inhaled formulation of murepavadin.

136 Access to Medicine Foundation Roche Holding AG

Stock exchange: XSWX • Ticker: ROG • HQ: Basel, Switzerland • Employees: 94,052 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Roche was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Roche has relatively low sales of antibiotics compared to environmental risk-management strategy, which includes dis- the other large research-based pharmaceutical companies charge limits and reportedly applies to all Roche’s third-party in scope. The company is currently making efforts to re-en- suppliers of antibiotic APIs and drug products. Roche, cur- ter the antibiotics market and performs less well in the rently actively marketing antibiotics only in China, has filed Benchmark compared to other large research-based phar- two of its newest antibiotics in some countries in scope.* It maceutical companies. It performs well in Manufacturing makes no information available regarding equitable pricing & Production, but falls behind in the areas of Research & for antimicrobials. Roche reports engaging in some steward- Development and Appropriate Access & Stewardship. It has a ship activities, including ad hoc AMR educational activities for comparatively small antimicrobial R&D pipeline of eight pro- healthcare professionals. It provides funding to two surveil- jects, three of which target priority pathogens, including one lance programmes in China. novel biological antibiotic. Roche discloses a comprehensive

SALES AND OPERATIONS Revenues by product§ Revenues by regionII Roche Made: Final: no

Roche is a large research-based pharmaceuti- ment with Polyphor (ended in 2015), a company . . cal company with two divisions: pharmaceuti- also in scope of the Benchmark, and agreements . cals and diagnostics. Its pharmaceutical business with two different biotechnology companies, . includes therapeutic areas such as oncology, Discuva and Warp Drive Bio, for use of their bio- . . neuroscience, infectious diseases and immunol- informatics platforms to search for new classes bn CHF bn CHF . ogy. Although it is the third-largest company in of antibiotics. Roche also develops and com- . . scope of the Benchmark (based on total rev- mercialises a wide array of point-of-care diag- ● Antimicrobials ● North America enues), its antibiotic sales are low compared nostic tests for viruses (e.g. HIV, HBV and HCV) ● Other pharmaceuticals ● Europe, Middle East, Africa to several other large research-based pharma- and bacteria (e.g., M. tuberculosis, C. difficile and ● Diagnostics ● Asia Paci c and Japan ceutical companies in scope. The company had methicillin-resistant S. aureus). ● Other revenues ● Rest of World reduced its antimicrobial research at the turn of the century but has since sought to rebuild it by collaborating with smaller biopharmaceutical companies. Examples include a licensing agree-

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Roche markets at least 11 antimicrobial med- group, and ceftriaxone (Rocephin®), in both the icines, seven of which are listed on the WHO Access and Watch groups. The remaining nine EML (Section 6). Two of the company’s antimi- medicines are two antiprotozoals and seven crobial medicines are antibiotics, both listed on antivirals (including one PEGylated and one the WHO EML (Section 6): sulfamethoxazole/ non-PEGylated interferon for the treatment of trimethoprim (Bactrim®), in the EML’s Access viral hepatitis).

● Antibiotics on WHO EML† WHO EML Categories * Countries in scope are 106 low- and middle-income ● Antibiotics not on ● Access group only countries where access to medicine is likely limited WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines ● Other antimicrobial ● Watch group only § Revenues from external customers, inc. sales, royalties medicines ● Reserve group and other operating income; FYE 31 December 2016 ● Not grouped || Sales; FYE 31 December 2016

137 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during Engage in antimicrobial stewardship. Roche on its behalf. Roche currently discloses several R&D. Roche has two candidates in clinical devel- currently supports some education and surveil- policies on environmental risk management. opment, both in Phase I. Roche is encouraged lance programmes. It can engage more actively to implement access and stewardship plans for in stewardship activities, e.g., through strength- Expand environmental risk-management strat- these candidates as they move into Phase II clin- ening its role in more surveillance activities, edu- egy. Roche has set discharge limits for its own ical development. cational activities for healthcare professionals on and third party manufacturing sites as part of its AMR (while mitigating conflicts of interest) and environmental risk-management strategy. Roche Ensure access by addressing affordability for engage in appropriate promotion practices. can ensure these discharge limits are applied to antimicrobial medicines. Roche has reported its external waste treatment plants. that it has low-priced generic antibiotics availa- Improve transparency regarding environmental ble on the market, and that the price of its orig- risk management. Roche can share more infor- inators has also decreased. Roche can improve mation on how it manages environmental risk, the affordability of its antimicrobial medicines e.g., disclose the levels of antibiotic discharge by developing an equitable pricing strategy that and publish the identities of third parties who takes socio-economic factors into account. manufacture antibiotic APIs and drug products

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 8 projects scored on ● ● ● ○ ● ○ pipeline 3 target priority pathogens

A. 1 No information on antimicrobial R&D Roche is developing a new ß-lactamase inhib- A.3 One R&D project being developed with investments. itor, nacubactam, which is currently in Phase I public partners. Roche reports no information on its antimicro- clinical development. Roche is engaged in a col- Roche is developing one R&D project in its pri- bial R&D investments. laborative antibiotics discovery project with ority pathogen pipeline through public-private drug discovery company Discuva. This collabo- partnership. The company received funding from A.2.1-2.2 One novel biological agent in the ration involves the use of Discuva’s proprietary BARDA (potentially up to USD 150 mn) to fur- clinical pipeline. SATIN technology platform, a novel technology ther develop its ß-lactamase inhibitor nacubac- Roche has eight** antimicrobial R&D projects in that identifies the molecular targets of chemi- tam and accelerate the development of tests for its pipeline, seven of which are in clinical stage cal compounds that affect bacterial growth and detecting specific viral and bacterial infections. development. Three of the company’s projects genes. The platform comprises several different Roche also conducts R&D with private-sector target priority pathogens, the lowest number varieties of transposons — genes that are spe- partners.‡ of projects targeting priority pathogens among cifically engineered for each target pathogen, large research-based pharmaceutical compa- coupled with high-throughput Next Generation A.4 No R&D candidate in late-stage nies. However, all three of these projects are Sequencing (NGS) technology, bioinformat- development. focussed on bacteria. Roche also focusses its ics and machine learning. This allows for ongo- Roche is not eligible for this indicator as it does R&D activities on influenza and hepatitis B. The ing genome-wide analysis of bacterial events not have any R&D candidates in late-stage company has at least one project in preclinical throughout the chemistry optimisation process. development. stage.*** Roche is developing an antibody-drug Roche does not have any drug candidates tar- conjugate, a novel antibody bound to a rifamy- geting a priority pathogen beyond Phase II of cin analogue, against S. aureus. It is a highly spe- clinical development. cific and innovative biological agent. Additionally,

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• SATIN (Selective Antibiotic Target • Nacubactam IdentificatioN) – Bacteria – In part- (RG6080) – nership with Discuva Ltd CRE • S. aureus therapeutic antibody conjugate (RG7861) – Novel

** After the Benchmark’s period of analysis, Roche ‡ After the Benchmark’s period of analysis, Roche reported termination of one of these projects reported having 13 active research collaborations with (MHAA4549A). academic groups globally to support novel antibiotic dis- *** After the Benchmark’s period of analysis, Roche covery focussing on multidrug-resistant gram-nega- entered into collaboration with Warp Drive Bio around tive bacteria. the Genome Mining™ Platform, which provides access to over one hundred novel classes of natural antibiotics.

138 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at agement strategy. mental risk management. 3rd-party sites. Roche undertakes almost all environmental Roche publishes elements of its environmen- Roche reports that it has mechanisms for main- risk-management activities that the Benchmark tal risk-management strategy on its website. It taining a high quality of antibiotic production examines. Namely, it applies an environmen- does not disclose audit results, or the discharge — namely following GMP standards. This com- tal risk-management strategy to minimise the levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers Roche requires its third-party suppliers of drug It includes auditing and limits on antibiotic dis- of antibiotic APIs and drug products or external products to apply the same quality standards to charge, both for its own manufacturing sites and waste-treatment plants. their production facilities. those of third-party manufacturers of antibiotic APIs and drug products. Roche states that its strategy applies to external waste-treatment plants, yet it also reports that it does not set discharge limits for these plants nor audits implementation of the strategy.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed two newest antibiotics in some in scope.* After the period of analysis, Roche quired infections. The company reports that it countries in scope. reported to the Benchmark that it does have a only actively markets and promotes this antibi- Roche has provided filing information on two of global expert group to allocate available supply otic in China. its newest antibiotics: ceftriaxone (Rocephin®) to prevent stock-outs from happening. was introduced in 1984 and has now been C.6 No information regarding brochure and/ filed for registration in 49 countries in scope.* C.4 Some involvement in AMR-related or packaging adaptations. Sulfamethoxazole/trimethoprim (Bactrim®) was education. Roche does not provide sufficient information introduced in 1969 and has now been filed for Roche has provided information for its China on linguistic, cultural or literacy adaptations registration in 34 countries in scope,* mainly in headquarters, the only country where it actively made to its brochures or packaging to facilitate Latin America and sub-Saharan Africa. markets antibiotics. The company reported that appropriate use of antibiotics by patients. its China headquarters provides on-demand C.2 No equitable pricing approach. educational materials for rational use of antibi- C.7 Supports academic surveillance pro- Roche does not disclose an equitable pricing otics for self-learning purposes, but stated that grammes financially. approach for its highest-volume antibiotics and/ due to limited resources, it does not initiate edu- Roche has only provided information for sur- or antimicrobial medicines. It does report that cational programmes independently. veillance activities taking place in China, the it views competition from generic medicines as only country where it actively markets antibiot- the main mechanism triggering price reductions. C.5 No involvement in appropriate promo- ics. The company supports two surveillance pro- tion practices. grammes focussed on AMR trends in China. It C.3 No insight into steps addressing supply The Benchmark measures how companies provides funding for these two programmes, chain efficiency. address stewardship through appropriate pro- which focus on community-acquired E. coli and Roche does not disclose how it works with motion. The company does not report taking pneumonia infections in secondary and ter- stakeholders (e.g., governments, procurers) to action in this regard either through reflect- tiary care hospitals in China. The sharing of the align supply and demand for antimicrobial med- ing AMR trends in its marketing materials or results from these studies is the sole respon- icines, specifically to prevent or minimise stock- decoupling its sales force’s incentives from sibility of the researchers; however, the lead- outs in countries in scope*. The company also volume of antibiotic sales. Roche has only pro- ing researchers have stated plans to publish the does not report on whether it has processes vided information for the antibiotic ceftriaxone results in peer-reviewed journals. in place to respond to stock-outs in countries (Rocephin®), which is used in community-ac-

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Additionally, since 2014, Roche has partnered Benchmark. This information is provided given with UNAIDS and the Clinton Health Access the importance of animal health and diagnostics Initiative (CHAI), among others, to help diagnose on the topic of AMR. and combat HIV infections in children and adults in 82 developing countries with a high burden Roche develops and commercialises a wide array of disease. of diagnostic tests for viruses (e.g., HIV, HBV and HCV) and bacteria (e.g., M. tuberculosis, C. difficile and methicillin-resistant S. aureus). For example, the cobas® Liat® system is an in vitro diagnostic platform where results can be made available in less than 30 minutes for viruses (e.g., influenza A/B) and bacteria (e.g., C. difficile).

139 Antimicrobial Resistance Benchmark 2018 Sanofi

Stock exchange: XPAR • Ticker: SAN • HQ: Paris, France • Employees: 106,859 • Signatory to Davos Decl.: Yes• Signatory to Industry Roadmap: Yes

Performance by Research Area How Sanofi was evaluated: applicable indicators

Sanofi is among the top performing large research-based reportedly applies to all the company’s third-party suppliers pharmaceutical companies in scope, following close behind of antibiotic APIs and drug products, as well as mechanisms the leaders. This is driven by strong performance in Research to assure quality of antibiotic manufacturing is maintained. & Development with average performance in Manufacturing Sanofi reports that it has filed its five newest antibiotics in & Production and Appropriate Access & Stewardship. The some countries in scope.* The company engages in equitable company’s R&D pipeline consists of 32‡ antimicrobial pro- pricing strategies on non-antibiotic antimicrobials only. Sanofi jects, of which 18‡ target priority pathogens, including one reports having mechanisms in place for responding efficiently novel antimalarial candidate and six new vaccine candidates. to stock-outs in countries in scope.* The company engages It has access provisions in place for three out of five of its in a number of AMR educational activities, as well as surveil- vaccines in late-stage development. Sanofi discloses a com- lance programmes. prehensive environmental risk-management strategy, which

SALES AND OPERATIONS RevenuesSano by product§ RevenuesMade: by region§ Final: no

Sanofi is a large research-based pharmaceutical Sanofi Pasteur. In 2016, the company sold more company organised into five business units: gen- than 1 billion doses of vaccines globally. At the . . . eral medicines and emerging markets; diabetes end of 2016, Sanofi Pasteur and Merck & Co., . . . and cardiovascular; consumer healthcare; spe- Inc. ended their vaccines joint venture in Europe bn EUR bn EUR cialty care; and vaccines. Its specialty care busi- (Sanofi Pasteur MSD, established 1994) to inde- . . ness unit develops treatments for rare diseases, pendently manage their product portfolios. At multiple sclerosis, oncology and immunology. the same time, the company completed the ● Vaccines ● USA The company sells antimicrobial medicines and acquisition of Boehringer Ingelheim’s consumer ● Pharmaceuticals ● Europe vaccines in 140 countries globally, including 72 healthcare business, in exchange for its animal ● Emerging Markets ● Rest of World low- and middle-income countries.* health business (Merial). Sanofi’s vaccine business is run via subsidiary

Antimicrobial portfolio breakdown ANTIMICROBIAL PORTFOLIO

Sanofi markets at least 31** antimicrobial med- cated for the treatment of malaria. Its vaccines icines, 18 of which are listed on the WHO EML portfolio is one of the largest of the companies (Section 6). Twenty-one of the company’s anti- assessed by the Benchmark and covers a wide microbial medicines are antibiotics, with 11 range of indications, including pneumococcal listed on the WHO EML (Section 6), includ- disease (Pneumo™ 23), meningococcal disease ing five in the EML’s Watch group. The remain- (e.g., Menomune®) and infections caused by der (ten) of the company’s portfolio consists of Haemophilus influenzae type B (ActHib®). antiprotozoal medicines, including seven indi- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped

Plan ahead for access and stewardship during e.g., apply for WHO prequalification. Sanofi Increase engagement in stewardship activities. R&D. Sanofi discloses no information regarding can implement further access and stewardship Sanofi engages in some stewardship activities. access and stewardship provisions for its anti- plans for all its candidates in late-stage clinical Sanofi can take steps to ensure that its current microbial medicines in late-stage clinical devel- development. AMR educational activities for healthcare pro- opment. For its vaccine candidates, it plans to, fessionals include processes to mitigate conflicts * Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. 140 † EML Section 6: Anti-Infective Medicines § Net sales not inc. the held-for-exchange Animal Health segment; FYE 31 December 2016 ** Sanofi provided only a sample (approx. 50%) of its global antimicrobial portfolio. Access to Medicine Foundation

of interest. It can also expand its current surveil- microbial medicines. Sanofi can seek to improve facturers of antibiotic APIs and drug products. lance activities to more countries, collaborating access for more antimicrobial medicines (spe- Sanofi currently discloses several policies on with public health authorities and ensuring that cifically antibiotics) by expanding its affordabil- environmental risk management. the data is made publicly available via an open ity strategy to more products and more coun- database. Sanofi can also engage in appropriate tries in need. Expand environmental risk-management strat- promotion practices. egy. Sanofi has set discharge limits for its own Improve transparency regarding environmental manufacturing sites as part of its environmental Ensure access by addressing affordability for risk management. Sanofi can share more infor- risk-management strategy. It can ensure these antimicrobial medicines. Sanofi currently states mation on how it manages environmental risk, discharge limits are applied to third parties who a commitment to applying product-specific e.g., disclose the levels of antibiotic discharge, manufacture APIs on its behalf, as well as to inter-country equitable pricing to two of its anti- and publish the identity of third party manu- external waste-treatment sites.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 32 projects scored on ● ● ● ● ● ● pipeline 18 target priority pathogens

A.1 Comparatively high vaccine R&D cene-containing compound active against both organisation, on the development of its tubercu- investments. chloroquine-susceptible and chloroquine-re- losis vaccine, currently in Phase II clinical devel- Sanofi reports that it invested more than USD sistant P. falciparum, while artefenomel dis- opment. The remaining three R&D projects (two 500 million in the development of vaccines in plays important chemical dissimilarities to other preclincial, one clinical) involve public research 2016, which is high compared to other large artemisinins, making it likely to remain effective institutes. research-based pharmaceutical companies in the against artemisinin-resistant strains. Six out of Benchmark. The company reports no informa- 12 of Sanofi’s innovative vaccines in development A.4 Access provisions in place for most tion on investments made for the development target priority pathogens. Four of these are clin- vaccines in late-stage development. of antimicrobial medicines. ical-stage projects, including an HIV vaccine can- Sanofi reports that it has access provisions in didate (for which no vaccines currently exist). place for three out of five of its vaccines in late- A.2.1-2.3 Eighteen R&D projects in priority stage development. It reports that it has an pathogen pipeline, with broad focus. A.3 Eleven R&D projects being developed access commitment in place for its antimalarial Sanofi has 32‡ antimicrobial R&D projects in with public partners, including seven candidate in late-stage development, but does its pipeline, 19‡ of which are in clinical stage PDPs. not report information on access provisions. development. Eighteen‡ of the company’s pro- Sanofi is developing 11 R&D projects in its pri- For its three vaccines in late-stage develop- jects target priority pathogens. Its pipeline size ority pathogen pipeline through public-pri- ment, Sanofi plans to file for WHO prequalifica- is above average when comparing it to other vate partnerships (including non-profit organ- tion and/or for the European Medicines Agency large research-based pharmaceutical companies isations).*** Eight of these R&D projects are in (EMA) article 58 (a scientific assessment of a assessed by the Benchmark. Its pipeline covers development through a PDP or open research medicine for use outside the EU). For the anti- a broad range of priority pathogens, includ- consortium. Seven projects are in development malarial candidate in late-stage development ing both gram-negative and gram-positive bac- through a PDP, five are in preclinical stage and (artefenomel/ferroquine), the company commits teria, HIV, P. falciparum (malaria) and M. tuber- two are in clinical stage. For the development of to ensuring sufficient supply, but does not pro- culosis. Looking only at R&D for multidrug-re- its Phase II HIV vaccine, Sanofi partners with the vide a clear strategy for achieving this goal. For sistant bacteria, the company has seven discov- Pox-Protein Public Private Partnership (P5), a this indicator, countries in scope are 106 low- ery-stage projects, one vaccine in preclinical project that includes the US National Institute of and middle-income countries where access to stage and three vaccines in clinical development, Allergy and Infectious Diseases (NIAID), the Bill medicine is likely limited. Regarding stewardship including one that targets M. tuberculosis. The & Melinda Gates Foundation, the South African provisions, Sanofi signed the Davos Declaration, company has one novel antimalarial medicine in Medical Research Council, the HIV Vaccine Trials which includes a general commitment to support clinical development (artefenomel/ferroquine), Network (HVTN), the US Military HIV Research the appropriate and responsible use of antimi- in collaboration with the Medicines for Malaria Program and GSK. The company also collab- crobial medicines and vaccines. Venture (MMV). Ferroquine is a promising ferro- orates with Aeras, a non-profit biotechnology

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Novel natural product discovery – ▶S. pneumoniae ▶S. pneumoniae ▶DTP-HepB-Po- ▶C. difficiletox - GNB vaccine paediatric vac- lio-Hib hexava- oid bivalent vac- • Influx enhancement – GNB – In part- • Malaria blood cine (PPrV) lent paediatric cine‡ nership with GSK stage inhibitor – vaccine (Shan6, ▶DTP-Polio-Hib • Phenotypic Screening – GNB P. falciparum PR5I) – Adap- paediatric pen- • Staphylococcus project – S. aureus tation tavalent vaccine • Tuberculosis growth inhibitors (mac- ▶M. tuberculosis (Pentaxim®) rolides) – M. tuberculosis bivalent vaccine – Adaptation • Tuberculosis growth inhibitors (H4:IC31®) (new target (Griselimycin) – M. tuberculosis ▶HIV Vaccine – In demographic: • Tuberculosis growth Inhibitors (Per- partnership with Japan) sisters) – M. tuberculosis GSK • Malaria project – P. falciparum • Artefenomel/ ▶Malaria vaccine – P. falciparum Ferroquine – P. falciparum – Novel ▶Vaccine 141 GNB = Gram-negative bacteria *** Sanofi is involved in the COMBACTE-CDI network, a ‡ C. difficile vaccine has been terminated recently launched project within the IMI COMBACTE after the period of analysis. research consortium. Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at management strategy. mental risk management. 3rd-party sites. Sanofi undertakes almost all of the environ- Sanofi publishes elements of its environmen- Sanofi reports that it has mechanisms for main- mental risk-management activities that the tal risk-management strategy on its website. It taining a high quality of antibiotic production Benchmark examines. Namely, it applies an envi- does not disclose audit results, or the discharge — namely following GMP standards. This com- ronmental risk-management strategy to mini- levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. mise the impact of antibiotic manufacturing dis- share the identities of its third-party suppliers Sanofi requires its third-party suppliers of drug charge. It includes auditing for its own manufac- of antibiotic APIs and drug products or external products to apply the same quality standards to turing sites and those of third-party manufactur- waste-treatment plants. their production facilities. ers of antibiotic APIs and drug products, and for external waste-treatment plants. Sanofi has also set antibiotic discharge limits for its own manufacturing sites.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed five newest antibiotics in some its antibiotics and non-antibiotic antimicrobial its non-product-specific materials. However, the countries in scope. medicines. The company demonstrates no evi- company’s appropriate promotion practices do Sanofi reports that it has filed its five newest dence of engaging with relevant stakeholders not include the decoupling of its sales force’s antibiotics, introduced between 1989 and 1997, (e.g., governments, procurers) to align the supply incentives from volume of antibiotic sales. for registration in some countries in scope* and demand for antimicrobial medicines. It does (between 20-45 countries). Two of these anti- report informing and following-up on stock-outs C.6 Provides information on treatment biotics are on the WHO EML (Section 6): cefix- with local or regional authorities. duration. ime (Oroken®), which is registered in 20 coun- Sanofi adapts its packaging to facilitate appro- tries mainly in sub-Saharan Africa; and levoflox- C.4 Some involvement in AMR-related priate use of antibiotics by patients, by providing acin (Tavanic®), which is registered in 45 coun- education. information on treatment duration. This can help tries across multiple regions. Sanofi reports that it is engaged in several edu- to improve patient adherence to treatment. cational activities, focussing on infectious dis- C.2 Inter-country equitable pricing for ease management and appropriate use and pre- C.7 Public health partnership to monitor antimicrobials. scription of antibiotics, running e.g., in France, AMR trends in France. Sanofi discloses inter-country equitable pric- China, India and Vietnam. Content is delivered Sanofi is engaged in one surveillance pro- ing approaches for two of its highest-volume via websites, conferences and meetings to a gramme. Sanofi partners with public health insti- antimicrobial medicines in some countries in wide range of healthcare professionals, including tutions to monitor AMR trends in France, for scope.* The two approaches cover: (1) meglu- medical doctors, microbiologists and pharma- example. Sanofi cooperates with French national mine (Glucantime®) indicated for Leishmaniasis, cists. It is not clear, however, how the company institutes in the monitoring of antimicrobial mainly in Latin American countries; and (2) amo- ensures content is developed independently or resistance trends. The company does not own diaquine/artesunate (ASAQ Winthrop®) indi- how it mitigates possible conflicts of interest. the data, and depends on its partners to publish cated for malaria, mainly in Africa. For amodi- results in journals or at congresses. aquine/artesunate, the pricing approach is being C.5 Adopts some appropriate promotion implemented in cooperation with partners such practices. as the Global Fund, WHO and MSF. The Benchmark measures how companies address stewardship through appropriate pro- C.3 Global mechanisms in place for respond- motion practices. Sanofi reports that it takes ing to stock-outs. action in this regard by reflecting AMR trends Sanofi reports that it has global mechanisms in in its marketing materials, including informa- place for responding efficiently to stock-outs of tion about resistance trends and guidelines in

142 Access to Medicine Foundation Shionogi & Co., Ltd.

Stock exchange: XTKS • Ticker: 4507 • HQ: Osaka, Japan • Number of employees: 5,896 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Shionogi was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ○ ○ ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Shionogi is the smallest research-based pharmaceutical com- ers of antibiotic APIs and drug products. The company pro- pany in scope, with sales mostly in Japan. The company’s per- vides no evidence of activities related to facilitating access. formance is lower compared to large research-based phar- Shionogi's commitment to stewardship is driven by engage- maceutical companies in scope in Research & Development, ment in a number of stewardship educational activities, as Manufacturing & Production and Appropriate Access & well as surveillance programmes in partnership with academic Stewardship. The company's R&D pipeline consists of 25 anti- institutions in Japan. It does not remunerate sales staff based microbial projects, of which 15 target priority pathogens. on sales volume of antibiotics. Shionogi discloses an environmental risk-management strategy, which is not applied to the company's third-party suppli-

Shionogi Made: Final: no SALES AND OPERATIONS Revenues by product§ Revenues by regionII

Shionogi is a large research-based pharmaceu- eight antimicrobial medicines in Japan, Taiwan . . tical company headquartered in Japan. Its core and the US. During the fiscal year 2016, it sold therapeutic areas are infectious diseases and approximately 15 million doses of antimicrobial . . pain/central nervous system disorders, though medicines. In 2012, following a long-term col- bn JPY bn JPY . its portfolio also covers additional areas, such laboration on the development of several novel . as cardiovascular health and paediatrics. Within integrase inhibitors for the treatment of HIV/ ● Antimicrobials ● Japan the infectious diseases area, the company is AIDS, Shionogi joined ViiV Healthcare, a joint ● Other pharmaceuticals ● Europe especially focused on three areas of research: venture originally established by GSK and Pfizer, ● USA severe bacterial and fungal infections, HIV/AIDS solely focused on the development of HIV/AIDS ● Other and viral respiratory infections and emerging/ medicines. Equity positions in ViiV Healthcare re-emerging infections. The company markets are GSK: 76.5%, Pfizer: 13.5% and Shionogi: 10%.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Shionogi markets eight antimicrobial medi- other antiretroviral agents, for the treatment of cines, two of which are listed on the WHO EML HIV/AIDS. Dolutegravir was developed in collab- (Section 6). Six of the company’s antimicrobial oration with ViiV Healthcare and is listed on the medicines are antibiotics, including the combina- WHO EML (Section 6). tion sulfamethoxazole/trimethoprim (Baktar®), listed on the EML’s Access group. The remaining two medicines are antivirals: one indicated for influenza A/B infections and the other, dolute- ● Antibiotics on WHO EML† WHO EML Categories ® gravir (Tivicay ), indicated, in combination with ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Net sales; FYE 31 March 2017 || Net sales; FYE 31 March 2016

143 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Improve access to antimicrobial medicines. Ensure transparency on its approach to envi- Continue developing early-stage projects. Shionogi can develop an access strategy for ronmental risk management. Shionogi has Shionogi has a large early-stage pipeline of R&D countries in scope,* that includes the filing stated a commitment to disclose its environ- projects targeting priority pathogens. It can of its newest antibiotics (including flomoxef mental risk-management strategy, the identi- ensure that these early-stage projects move (Flumarin®)), for registration. Currently, Shionogi ties of its third-party suppliers and its external along the pipeline into clinical development. has not filed its antibiotics for registration in waste-treatment sites. countries in scope.* Increase engagement in stewardship activities. Expand environmental risk-management strat- Shionogi has engaged with academic institutes Plan ahead for access and stewardship during egy. Shionogi can ensure its environmental for several short-term surveillance programmes. R&D. Shionogi is developing one antibiotic can- risk-management strategy is applied to third It can ensure the development of long-term didate (cefiderocol) in late-stage clinical devel- parties who manufacture antibiotic APIs on its AMR surveillance programmes, and ensure that opment. It is currently seeking partners to behalf, as well as to external waste-treatment data is made publically available through open plan for its commercialisation, through licens- sites. It currently has an environmental risk-man- databases and collaboration with public health ing. Shionogi can ensure that these partner- agement strategy that includes discharge limits, authorities. ship agreements include access and stewardship which are applied to its own manufacturing sites. provisions.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 25 projects scored on ● ● ● ○ ● ● pipeline 15 target priority pathogens

A.1 Comparatively high antimicrobial R&D including bacteria, fungi, HIV and M. tuberculo- tion on access provisions. Shionogi commits to investments. sis. Cefiderocol, a new cephalosporin, is its most providing its investigational antibiotic (cefidero- Shionogi reports that it invested more than advanced compound which is currently in Phase col) only for indications for which limited or no USD 200 million in antimicrobial R&D in 2016, III clinical development. Shionogi is also develop- alternative treatment options are available and which is relatively high compared to other large ing an antibody against P. aeruginosa. where cefiderocol is likely to be an appropri- research-based pharmaceutical companies in ate treatment option. This would include infec- the Benchmark. The company’s antimicrobial A.3 Some preclinical R&D projects being tions caused by, e.g., carbapenem-resistant and/ R&D investments are almost as high as its rev- developed with public partners. or multidrug-resistant gram-negative pathogens. enues earned from antimicrobial medicines. Shionogi is developing four preclinical projects Shionogi plans to commercialise cefiderocol in These investments cover antimicrobial medi- in its priority pathogen pipeline through pub- the countries in which it has affiliate companies cines only, as Shionogi is not involved in vaccine lic-private partnerships. Three of these projects (the USA, China, Singapore, EU countries and development. involve collaboration with universities, which are Taiwan), and is currently in talks with partners focused on the discovery of novel medicines that to commercialise it outside of these countries. A.2.1-2.2 Fifteen R&D projects in priority target HIV and multidrug-resistant gram-posi- For this indicator, countries in scope are 106 low- pathogen pipeline, one in clinical stage. tive bacteria. The remaining project involves the and middle-income countries where access to Shionogi has 25 antimicrobial R&D projects in screening of Shionogi’s compound libraries for medicine is likely limited. There is no informa- its pipeline, two of which are in clinical stage candidates with activity against M. tuberculosis tion available on whether these countries are development. Fifteen of the company’s pro- through the PDP with TB Alliance. included in Shionogi’s commercialisation plans. It jects target priority pathogens. It has an aver- has signed the Davos Declaration, which includes age-sized pipeline when comparing it to other A.4 Stewardship commitment in place, but a general commitment to ensuring access to large research-based pharmaceutical companies no information regarding access. antimicrobial medicines and vaccines, and to assessed by the Benchmark. Shionogi is the only Shionogi reports that it has a stewardship com- support the appropriate and responsible use of company engaged in antifungal drug develop- mitment in place for its antibiotic candidate in these products. ment. Its preclinical activities have a broad focus late-stage development, but reports no informa-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Antibacterial programme 1 – GNB • Antibody – P. • Cefiderocol • Antibacterial programme 2 – GNB aeruginosa (S649266) – • Antibacterial programme 3 – GPB • YF-49-92 – M. CRE, ESBL, P. • Anti-tuberculosis programme – M. tuberculosis aeruginosa, A. tuberculosis baumannii – • Anti-tuberculosis programme 2 – M. BSI, cUTI, HABP/ tuberculosis VABP, Sepsis • Anti-HIV programme 1 – HIV • Anti-HIV programme 2 – HIV • Anti-HIV programme 3 – HIV BSI = Bloodstream infections • Anti-HIV programme 4 – HIV cUTI = Complicated urinary tract infection GNB = Gram-negative bacteria • Anti-HIV programme 5 – HIV GPB = Gram-positive bacteria • Antifungal programme 1 – Candida HABP/VABP = Hospital-acquired/Ventilator- • Antifungal programme 2 – Candida associated bacterial pneumonia

144 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management strat- B.2 Commitment to increase transpar- B.3 Commits to following GMP, including at egy for own sites. ency regarding environmental risk 3rd-party sites. Shionogi has an environmental risk-management management. Shionogi reports that it has mechanisms for strategy to minimise the impact of antibiotic Shionogi does not currently disclose its strat- maintaining a high quality of antibiotic produc- manufacturing discharge that includes audit- egy to minimise the impact of manufacturing tion — namely following GMP standards. This ing and discharge limits. The strategy currently discharge of antibiotics. Notably, however, it has commitment applies to its own manufacturing applies to Shionogi’s own sites. Shionogi has made a commitment to publish this strategy as sites. Shionogi requires its third-party suppli- committed to extending it, within a year, to its well as the identities of its third-party manu- ers of drug products to apply the same quality third-party manufacturers of antibiotic APIs and facturers. It currently does not publish any ele- standards to their production facilities. drug products. The company has made no state- ments looked for by the Benchmark, namely: ment about extending the strategy to external antibiotic discharge levels, audit results, and the waste-treatment plants. identities of its third-party manufacturers of antibiotic APIs and drug products, or of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ○ ○ ● ● ● ●

C.1 Newest marketed antibiotics not filed C.4 Some involvement in AMR-related C.6 No information regarding brochure and/ for registration. education. or packaging adaptations. Shionogi reports that it has not filed its newest Shionogi reports that it is involved in educational Shionogi does not provide sufficient information marketed antibiotics for registration in countries programmes for HCPs that include AMR stew- on any language, cultural or literacy adaptations in scope.* ardship, with conflict of interest (COI) mitigation made to its brochures or packaging that would measures in place. It has strategies in place for promote appropriate use. C.2-C.3 No marketed products in countries in independent content development. Half of the scope. programmes disclosed were delivered through C.7 Surveillance programmes focused on Shionogi reports that it is not marketing any courses, while the remaining programmes are Japan. antimicrobials in any countries in scope.* delivered via web pages and leaflets. Shionogi has engaged with academic institutes Hence, in these countries, Shionogi does not for several short-term surveillance programmes. report having equitable pricing approaches C.5 Adopts appropriate promotion practices. These programmes are aimed at measuring or processes in place to improve supply chain The Benchmark measures how companies the current AMR landscape in different regions efficiency and prevent and/or respond to address stewardship through appropriate pro- across Japan. All Shionogi’s studies will be pub- stock-outs. motion practices. Shionogi reports that it takes lished in peer-reviewed journals. After the period action in this regard: it reflects AMR trends in its of analysis, the company reported engagement marketing materials and does not remunerate its in further surveillance programmes in more sales teams based on antibiotic sales volume. countries, details of which are not available.

145 Antimicrobial Resistance Benchmark 2018 Summit Therapeutics plc

Stock exchanges: XLON; XNAS • Tickers: SUMM; SMMT • HQ: Abingdon, UK • Employees: 40 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Summit was evaluated: applicable indicators

Summit is a biopharmaceutical company, selected for having lic-private partnerships to develop its antibiotic candidates. a pipeline that targets priority pathogens. It was evaluated in The company reports that it has an access commitment in the area of Research & Development only. It invested USD 5 place for its antibiotic candidate in late-stage development, million in antibiotic drug development in 2016. The company but reports no information on stewardship provisions. performs well compared to other biopharmaceutical companies in scope. It has one project in its antimicrobial R&D pipeline targeting priority pathogens. Summit engages in pub-

OPERATIONS

Summit is a biopharmaceutical company focus- tively target C. difficile bacteria without disrupt- ogy company with a proprietary genetics-based sing on the development of novel medicines for ing the gut flora, thereby reducing CDI recur- platform facilitating the discovery and develop- indications for which current therapies are lack- rence rates—a common clinical issue in this ment of differentiated antibiotics. Summit was ing or inadequate. The company was founded in disease. The company plans to start Phase III listed on the AIM market of the London stock 2003 as a spin-off from the University of Oxford trials for ridinilazole in the first half of 2018. exchange in 2004, after raising GBP 15 mil- and is currently conducting two clinical pro- Summit has no products on the market. In lion from investors. In 2015, it was listed on the grammes: one on the genetic disease Duchenne September 2017, the company was awarded NASDAQ stock exchange, where it raised USD muscular dystrophy and the other on C. difficile a contract from BARDA of up to USD 62 mil- 34 million. infections (CDI). Its only antimicrobial drug can- lion for the development of ridinilazole for the didate is ridinilazole, currently in Phase II devel- treatment of CDI. In December 2017, Summit opment. The compound is designed to selec- acquired UK-based Discuva Ltd, a biotechnol-

ANTIMICROBIAL PORTFOLIO

Summit does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Summit has committed to ensure access and stewardship provisions are in place for its antibiotic candidate (ridinilazole), through its agreement with the Wellcome Trust. It can ensure that these plans are applied and implemented accordingly.

146 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 1 project scored on ○ ● ● ○ ● ● pipeline 1 target priority pathogens

A.2.1-2.2 One novel antibiotic in the clinical lion from the Wellcome Trust for the preclinical stage development, but reports no information pipeline. and clinical development of ridinilazole. Under on stewardship provisions. The access commit- Biopharmaceutical companies in scope were the agreement, Summit is solely responsible for ment for its investigational antibiotic (ridinila- selected based on their pipelines that target pri- the preclinical and clinical development of the zole) has been made through an agreement with ority bacteria. Summit invested USD 5 million in CDI programme. The Wellcome Trust is eligi- the Wellcome Trust. If the company or its licen- antibiotic drug development in 2016. The com- ble to receive a tiered portion of the net revenue sees do not develop, commercialise or exercise pany has one project in its antimicrobial R&D made by Summit or its affiliates (of up to a low- their IP rights in underserved markets within a pipeline targeting a priority pathogen. Summit’s to mid-single digit percentage) following sign- specified timeframe, the Wellcome Trust is per- antimicrobial pipeline consists of the antibiotic ing of a revenue share agreement in 2017. The mitted to take over exploitation of the IP in ridinilazole, currently in clinical Phase II devel- Wellcome Trust is also eligible to receive a mile- those markets. The IP rights were granted to opment for the treatment of CDI. The drug can- stone of a specified amount if cumulative net Summit for a number of major territories includ- didate is a bis-benzimidazole, a new class of revenues exceed a specified amount. In addition, ing the United States, Europe and Japan. No spe- antibiotics for which the mode of action is yet in September 2017, the company was granted up cific strategy has been made for lower- and mid- unknown. to USD 62 million by BARDA for advancing the dle-income countries. For this indicator, coun- clinical and regulatory development of ridinila- tries in scope are 106 low- and middle-income A.3 One R&D project being developed with zole, including through Phase III clinical trials. countries where access to medicine is likely public partners. limited. Summit is developing one R&D project in its A.4 Access commitment in place, but no priority pathogen pipeline through public-pri- information regarding stewardship. vate partnership (including non-profit organisa- Summit reports that it has an access commit- tions). The company has received GBP 6.3 mil- ment in place for its antibiotic candidate in late-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Ridinilazole – C. difficile – Bis-benzimidazole – Novel

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Summit was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Summit was not eligible for this Research Area.

147 Antimicrobial Resistance Benchmark 2018 Sun Pharmaceutical Industries Ltd.

Stock exchange: XNSE • Ticker: SUNPHARMA • HQ: Mumbai, India • Employees: > 30,000 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Sun Pharma was evaluated: applicable indicators

Sun Pharma is a prominent producer of antibiotics glob- publicly available information is limited, specifically regard- ally by sales volume. As a generic medicine manufacturer, ing its approach to manufacturing high quality antibiotics, its Sun Pharma was evaluated in Manufacturing & Production approach to equitable pricing, where it has filed antibiotics and Appropriate Access & Stewardship only. Its performance for registration, its actions to ensure efficient supply and its is low compared to other generic medicine manufacturers involvement in stewardship activities. in scope. It reported no information to the Benchmark, and

SALES AND OPERATIONS RevenuesSun by product§ RevenuesMade: by regionII Final: no

Sun Pharma, founded in 1983, is an Indian-based central nervous system (CNS). The company has generic medicine manufacturer focussing on the 42 manufacturing sites spread across six conti- . production of generic medicines, specialty prod- nents and markets its products in more than 150 . . . ucts, over-the-counter (OTC) products, antiret- countries worldwide. bn INR bn INR rovirals (ARVs) and active pharmaceutical ingre- In 2015, Sun Pharma completed the acquisi- . . dients (APIs). The company’s business segmen- tion of Ranbaxy Laboratories Limited, an Indian- tation is based on a mix of geographical and based company focussed on generic medicines ● Total revenue ● USA therapeutic areas. It listed its anti-infectives seg- with international operations, and a member of ● India ment as its fourth-biggest therapeutic segment the Daiichi Sankyo group (at the time of acqui- ● Emerging Markets ● Rest of World by revenue, after cardiology, neuropsychiatry sition). The merger combined Sun Pharma’s and gastroenterology. The company’s specialty established specialty business with Ranbaxy’s business focusses on the therapeutic areas of global operations in generic medicines. dermatology, ophthalmology, oncology and the Antimicrobial portfolio breakdown

ANTIMICROBIAL PORTFOLIO According to publicly available data, Sun Pharma The remainder (27) of the company’s portfo- markets at least 69 antimicrobial medicines, 35 lio is diverse, comprising antifungals, anthelmin- of which are listed on the WHO EML (Section thics, antiprotozoals and antivirals, 13 of which 6). Forty-two of the company’s antimicro- target HIV. bial medicines are antibiotics, with 18 listed on ● Antibiotics on WHO EML† WHO EML Categories the WHO EML (Section 6), including two in the ● Antibiotics not on ● Access group only EML’s Reserve group (colistin and tigecyclin). WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped OPPORTUNITIES

Engage in antimicrobial stewardship. Sun levels of antibiotic discharge. Currently, the company does not disclose such information. Pharma can engage in stewardship activi- pany does not report having an environmental ties, e.g., through surveillance activities, educa- risk-management strategy. Engage in R&D innovation. Sun Pharma can tional activities for healthcare professionals on engage in incremental R&D innovation to AMR (while mitigating conflicts of interest), and Ensure affordability and registration plans for address resistance, improve adherence and the engage in appropriate promotion practices. new and existing antimicrobials. Sun Pharma appropriate use of antimicrobial medicines. can seek to improve access in low- and mid- Ensure transparency regarding environmental dle-income countries through the registration of risk. Sun Pharma can share information on how new and existing antimicrobials, and ensure that it manages environmental risk, e.g., disclose the they are priced affordably. Currently, the com- * Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited 148 † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017 || Sales; FYE 31 March 2017 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Sun Pharma’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Reports no environmental risk- B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is management strategy. management. maintained. Sun Pharma does not report having an environ- Sun Pharma does not disclose its strategy to Sun Pharma makes no statement regarding how mental risk-management strategy in place to minimise the impact of manufacturing discharge it ensures high-quality antibiotic production fol- minimise the environmental impact of manufac- of antibiotics. It does not publish any element lowing international manufacturing standards turing discharge of antibiotics. looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- discharge levels, audit results, and the identities tional authorities (such as GMP). of its third-party suppliers of antibiotic APIs and drug products, or of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Sun Pharma reports no information on where it chain efficiency. ship activities. has filed its newest antibiotics for registration in Sun Pharma does not disclose how it works with Sun Pharma does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- erwise publicly available. align supply and demand for antimicrobial med- veillance to appropriate promotion practices) icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Sun Pharma does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiotics scope.* and/or antimicrobial medicines.

149 Antimicrobial Resistance Benchmark 2018 Tetraphase Pharmaceuticals, Inc.

Stock exchange: XNAS • Ticker: TTPH • HQ: Watertown, MA, USA • Employees: 66 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Tetraphase was evaluated: applicable indicators

Tetraphase is a biopharmaceutical company, selected for jects in its antimicrobial R&D pipeline, all targeting priority having a pipeline that targets priority pathogens. It was evalu- pathogens. Tetraphase engages in public-private partnerships ated in the area of Research & Development only. It invested to develop its antibiotic candidates. The company has one USD 64 million in antibiotic drug development in 2016, which antibiotic in late-stage clinical development. Tetraphase is the is high compared to other biopharmaceutical companies in only biopharmaceutical company identified by the Benchmark the Benchmark. The company performs well compared with to have both an access and stewardship provision in place for other biopharmaceutical companies in scope. It has three pro- an antibiotic in late-stage clinical development.

OPERATIONS

Tetraphase, founded in 2006, is a biopharma- is currently undergoing Phase III trials for the TP6076, an investigational synthetic fluorocy- ceutical company focussing on the design and treatment of complicated intra-abdominal infec- cline antibiotic that targets multidrug-resist- development of fully synthetic tetracycline anti- tions and complicated urinary tract infections. ant gram-negative bacteria. The company is also biotics targeting multidrug-resistant bacte- Tetraphase has no products on the market. exploring the use of its tetracycline candidate ria. The company’s proprietary chemistry plat- In recent years, Tetraphase has secured sev- compounds in other therapeutic areas, includ- form has resulted in a library of tetracycline ana- eral grants from various partners, including the ing oncology and inflammatory diseases. In 2013, logues containing more than 2,500 compounds. US National Institute of Allergy and Infectious Tetraphase was listed on the NASDAQ stock The company’s most advanced drug candidate, Diseases (NIAID) and BARDA. The latter cur- exchange, where it raised USD 75 million. eravacycline, is a broad-spectrum antibiotic rently supports the joint development of erava- being developed in both oral and intravenous cycline with the R&D company CUBRC. In 2017, formulations for the treatment of resistant and Tetraphase was awarded USD 4 million (over an multidrug-resistant infections. The compound 18-month period) by CARB-X, to further develop

ANTIMICROBIAL PORTFOLIO

Tetraphase does not have any products on the market.

OPPORTUNITIES

Expand stewardship provisions for eravacycline. Tetraphase is the only company to have access and stewardship provisions (involving a surveillance programme), for an antibiotic in late-stage clinical development. It can ensure that further stewardship provisions are in place, e.g., appropriate promotion practices.

150 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 Pipeline focussed on tetracycline organisation). Tetraphase has received funding Eastern Europe, India, Middle East, North Africa antibiotics. from BARDA for the development of eravacy- and South America. For this indicator, coun- Biopharmaceutical companies in scope were cline, NIAID for TP271 and CARB-X for TP6076. tries in scope are 106 low- and middle-income selected based on their pipelines that target pri- Through CARB-X, Tetraphase also shares IP countries where access to medicine is likely lim- ority bacteria. Tetraphase invested USD 64 mil- rights with the Wellcome Trust for TP6076. ited. Tetraphase has an ongoing global surveil- lion in antimicrobial R&D in 2016. The company This enables the Wellcome Trust to commer- lance programme in collaboration with IHMA, has three projects in its antimicrobial R&D pipe- cialise the medicine in underserved markets, if Inc., which monitors the susceptibility to erava- line targeting priority pathogens, all of which necessary. cycline of gram-negative and gram-positive bac- are broad-spectrum fluorocycline candidates. Its teria and anaerobes in all types of hospitals (gov- leading candidate is eravacycline, a broad-spec- A.4 Only biopharmaceutical company to have ernment, teaching, community, etc.). 1.5 full-time trum antibiotic in development for compli- both an access and stewardship provi- equivalent employees (FTEs) are dedicated to cated intra-abdominal infections and compli- sion in place. the surveillance programme and its Antimicrobial cated urinary tract infections. Its two other tet- Tetraphase reports that it has both an access Voluntary Evaluation Program (AVEP). AVEP racycline compounds (TP271 and TP6076) are in and stewardship provision in place for its antibi- provides strips and disks that enable hospitals to Phase I clinical development for the treatment of otic in late-stage development. It is the only bio- test susceptibility of pathogens to the antibiotic. gram-negative bacterial infections. pharmaceutical company to have these provi- The annual cost of the global surveillance pro- sions in place for an investigational antibiotic gramme is USD 750,000, and the annual cost of A.3 All R&D projects being developed with (eravacycline). Following approval, the company AVEP is USD 350,000 (for US and EU markets). public partners. intends to commercialise eravacycline directly Tetraphase is developing all three R&D projects in the USA and the EU. The company is actively in its priority pathogen pipeline through pub- seeking partners to develop and commercial- lic-private partnership (including a non-profit ise eravacycline in regions including Asia-Pacific,

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• TP271 – ESBL, • Eravacycline – A. baumannii, CRE, ESBL, A. VRE, S. aureus, baumannii, VRE, C. difficile – Flu- S. aureus, C. dif- orocycline – ficile – Fluorocy- CABP cline – cIAI, cUTI • TP6076 – CRE, ESBL, A. bau- CABP = Community-acquired bacterial pneumonia mannii, VRE, S. cIAI = Complicated intra-abdominal infection aureus, C. diffi- cUTI = Complicated urinary tract infection cile – Fluorocy- cline

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Tetraphase was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Tetraphase was not eligible for this Research Area.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Tetraphase supports the Antimicrobial Voluntary didate eravacycline. Benchmark. This information is provided given Evaluation Program (AVEP), which provides the importance of animal health and diagnostics strips and disks that enable hospitals to test the on the topic of AMR. susceptibility of pathogens to its antibiotic can-

151 Antimicrobial Resistance Benchmark 2018 Teva Pharmaceutical Industries Ltd.

Stock exchanges: XNYS; XTAE • Ticker: TEVA • HQ: Petach Tikva, Israel • Employees: 56,960 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Teva was evaluated: applicable indicators

Teva is a prominent producer of antibiotics globally by sales nal waste-treatment plants. The company reports that it has volume. As a generic medicine manufacturer, Teva was evalu- mechanisms for maintaining a high quality of antibiotic pro- ated in Manufacturing & Production and Appropriate Access duction, and requires its third-party suppliers to apply the & Stewardship only. The company performs well when com- same quality standards to their production facilities. Teva pared with the other generic medicine manufacturers in reported no information on its access strategies regarding scope. It discloses a comprehensive environmental risk-man- antimicrobial medicines in countries in scope* or its involve- agement strategy, which it does not apply to third-party man- ment in stewardship activities that promote appropriate anti- ufacturers of antibiotic APIs and drug products or to exter- biotic use.

SALES AND OPERATIONS RevenuesTeva by product§ RevenuesMade: by region§ Final: no

Teva is an Israeli-based generic medicine man- Gamble called PGT Healthcare. Teva has the ufacturer founded in 1901. The company oper- highest revenue among the generic medicine . . ates in two business segments: generic and spe- manufacturers included in the Benchmark. The . . cialty medicines. Its specialty medicines seg- company markets its antimicrobial medicines in bn USD bn USD ment focusses on delivering medicines, devices 54 countries globally, seven of which are low- or . and services in the core therapeutic areas of res- middle-income countries.* piratory illness, central nervous system (includ- In 2016, Teva acquired Actavis Generics, the ● Total revenue ● USA ing pain, migraine, movement and neurodegen- global generic pharmaceuticals business from ● Europe erative disorders), oncology and women’s health. Allergan plc, for approximately USD 33.4 billion ● Rest of world It engages in R&D activities within both its busi- cash and 100 million Teva shares. The acquisition ness segments, focussing on the development required the divestment of certain assets and of complex technologies and formulations. Teva operations in the USA and Europe to meet anti- is active in 80 countries and has 87 manufactur- trust regulatory requirements. Later in 2016, the ing facilities, manufacturing and supplying active company completed the acquisition of Anda Inc., pharmaceutical ingredients on a global scale. It a US-based distributor of generic pharmaceuti- also has a global over-the-counter (OTC) busi- cals from Allergan for USD 500 million. ness, including a collaboration with Procter &

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Teva markets at least 44 antimicrobial medi- ing 16 medicines consist of nine antivirals, four cines, 30 of which are listed on the WHO EML antifungals and three antiprotozoals indicated (Section 6). Twenty-eight of the company’s anti- for treatment of malaria. microbial medicines are antibiotics, with 17 listed on the WHO EML (Section 6), including one on the EML’s Reserve group (linezolid). The remain-

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited medicines ● Reserve group † EML Section 6: Anti-Infective Medicines ● Not grouped § Net revenues; FYE 31 December 2016

152 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Teva can Improve transparency regarding environmental ment strategy is applied to external waste treat- engage in stewardship activities, e.g., through risk management. Teva can share more informa- ment plants and can apply its discharge limits surveillance activities, educational activities for tion on how it manages environmental risk, e.g., and auditing processes to third-party suppliers healthcare professionals on AMR (while mitigat- disclose the levels of antibiotic discharge and of antibiotic APIs and drug products. ing conflicts of interest), and engage in appropri- publish the identities of third parties who manu- ate promotion practices. facture antibiotic APIs and drug products on its Engage in R&D innovation. Teva can engage in behalf. Teva currently discloses its environmen- incremental R&D innovation to address resist- Ensure affordability and registration plans for tal risk-management principles. ance, improve adherence and the appropriate new and existing antimicrobials. Teva can seek use of antimicrobial medicines. to improve access in low- and middle-income Expand environmental risk-management strat- countries through the registration of new and egy. Teva has an environmental risk-manage- existing antimicrobials, and ensure that they are ment strategy that includes discharge limits, priced affordably. Currently, the company does which are applied to its own manufacturing sites. not disclose such information. It can ensure its environmental risk-manage-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Teva’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Teva applies an environmental risk-management Teva publishes its environmental risk-manage- Teva reports that it has mechanisms for main- strategy to minimise the impact of antibiotic ment strategy in its CSR report. It does not dis- taining a high quality of antibiotic production manufacturing discharge that includes audit- close audit results, or the discharge levels of — namely following GMP standards. This coming and discharge limits. The strategy applies antibiotics. The company also does not share the mitment applies to its own manufacturing sites. to Teva’s own sites and to its third-party manu- identities of its third-party suppliers of antibiotic Teva requires its third-party suppliers to apply facturers of antibiotic APIs and drug products; APIs and drug products or external waste-treat- the same quality standards to their production however, the discharge limits and auditing pro- ment plants. facilities. cesses are applicable to its own manufacturing sites only. The strategy does not apply to external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Teva reports no information on where it has filed chain efficiency. ship activities. its newest antibiotics for registration in coun- Teva does not disclose how it works with stake- Teva does not report any involvement in stew- tries in scope.* This information is not otherwise holders (e.g., governments, procurers) to align ardship activities (from education to surveillance publicly available. supply and demand for antimicrobial medicines, to appropriate promotion practices) that pro- specifically to prevent or minimise stock-outs in mote appropriate antibiotic use. C.2 No disclosure on equitable pricing countries in scope.* The company also does not approach. report on whether it has processes in place to Teva does not disclose an equitable pricing respond to stock-outs in countries in scope.* approach for its highest-volume antibiotics and/ or antimicrobial medicines.

153 Antimicrobial Resistance Benchmark 2018 The Medicines Company

Stock exchange: XNAS • Ticker: MDCO • HQ: Parsippany, NJ, USA • Employees: 410 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How The Medicines Company was evaluated: applicable indicators

The Medicines Company* is a biopharmaceutical company, received FDA approval for its meropenem/vaborbactam selected for having a pipeline that targets priority pathogens. combination in August 2017. The company engages in pub- At the end of 2017, the company announced that it would lic-private partnerships to develop its antibiotic candidates. divest its infectious disease business to Melinta, another The company reports no information on access or steward- biopharmaceutical company in scope of the Benchmark. ship provisions for its recently FDA-approved antibiotic. The The divestment was completed in January 2108. The Medicines Company was not evaluated in the Manufacturing Medicines Company was evaluated in the area of Research & Production area; however, it is the only company in scope & Development only, although it has a number of antibiot- to disclose identities of third-party manufacturers of its ics on the market. It performs well compared to other biop- antibiotics. harmaceutical companies in scope. The Medicines Company

§ § SALES AND OPERATIONS RevenuesThe Medicines by product Company RevenuesMade: by region Final: no

The Medicines Company is a US-based biophar- tions. The compound was developed with fund- . maceutical company with core therapeutic areas ing from BARDA, first under a contract of USD . in infectious disease care, cardiovascular care, 90 million and, starting in 2016, under a new surgery and perioperative care. The company’s five-year contract of up to USD 132 million. . . mn USD mn USD revenues in the past three years have come pri- At the end of 2017, The Medicines Company marily from the US sales of its cardiovascular announced that it would divest its infectious dis- . medicine bivalirudin (Angiox® or Angiomax®), ease business to Melinta, another biopharma- ● Total revenue ● USA a direct thrombin inhibitor. These revenues ceutical company in scope of the Benchmark. ● Europe include approximately USD 71.2 million in roy- The divestment was completed in January 2018 ● Rest of World alties derived from the authorised sale of the and included three marketed antimicrobial med- generic version of bivalirudin (Angiomax®) by icines: meropenem/vaborbactam (Vabomere™), Sandoz. In August 2017, the company received minocycline (Minocin®) and oritavancin FDA approval to commercialise its intrave- (Orbactiv®). The company’s two other marketed nous formulation of meropenem/vaborbac- antimicrobial medicines (azithromycin and clin- tam (Vabomere™), which is active against mul- damycin) are generic medicines comercialised tidrug-resistant gram-negative bacteria, for the via a licensing and supply agreement with APP treatment of complicated urinary tract infec- Pharmaceuticals, LLC.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, The lations of two other antibiotics: the broad-spec- Medicines Company’s portfolio of antimicro- trum agent minocycline (Minocin®), approved to bial medicines consists of five antibiotics. treat Acinetobacter species infections, and the One of these antibiotics, clindamycin, is listed antibiotic oritavancin (Orbactiv®), active against on the WHO EML (Section 6), in the Access gram-positive pathogens and indicated for the group. The remaining four medicines are the treatment of acute bacterial skin and skin struc- recently approved meropenem/vaborbactam ture infections in adults, including those due to (Vabomere™), azithromycin (for intravenous methicillin-resistant S. aureus (MRSA). administration) and powder-for-injection formu- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines * In January 2018, The Medicines Company completed ● Other antimicrobial ● Watch group only § Net revenues; FYE 31 December 2016 the divestment of its infectious disease business to medicines ● Reserve group Melinta Therapeutics, Inc. ● Not grouped

154 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 1 projects scored on ○ ● ● ○ ● ● pipeline 1 target priority pathogens

A.2.1-2.2 One antibiotic recently approved. A.3 One R&D project being developed with A.4 No information on access or stewardship Biopharmaceutical companies in scope were public partners. provisions. selected based on their pipelines that target pri- The Medicines Company developed merope- The Medicines Company reports no informa- ority bacteria. The Medicines Company received nem/vaborbactam (Vabomere™) in partnership tion on access or stewardship provisions for its FDA approval for its meropenem/vaborbac- with BARDA, which began with a five-year con- recently FDA-approved antibiotic. It has signed tam (Vabomere™, formerly Carbavance™) in tract in 2014, followed by a new five-year con- the Davos Declaration, which includes a gen- August 2017. Vaborbactam is a ß-lactamase tract in 2016 (≤ USD 132 million). eral commitment to ensuring access to antimi- inhibitor (BLI) with a novel chemical struc- crobial medicines and vaccines, and to support ture. Meropenem is an existing carbapenem the appropriate and responsible use of these ß-lactam. Vaborbactam restores susceptibil- products. ity to meropenem in carbapenem-resistant Enterobacteriaceae (CRE).

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Meropenem/ vaborbactam (Vabomere™) – CRE – Novel ß-lactamase inhibitor vaborbactam and existing ß-lactam – cUTI cUTI = Complicated urinary tract infection – FDA approval 2017 – Novel

B MANUFACTURING & PRODUCTION

The Medicines Company is a biopharmaceutical B.2 Only company to disclose identities of company that did not meet the criteria for eval- third-party suppliers. uation in this Research Area. It does, however, On reviewing publicly available information, the have products on the market, and notable prac- Benchmark found that The Medicines Company tices relevant to this area are mentioned. has disclosed the identities of third-party manufacturers of its antibiotics, per product, in its annual report. It is the only company to publish this information.

C APPROPRIATE ACCESS & STEWARDSHIP

The Medicines Company is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

155 Antimicrobial Resistance Benchmark 2018 Wockhardt Limited

Stock exchange: XNSE • Ticker: WOCKPHARMA • HQ: Mumbai, India • Employees: 6,768 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Wockhardt was evaluated: applicable indicators

Wockhardt is a biopharmaceutical company, selected for in-house and/or with private-sector partners to develop its having a pipeline that targets priority pathogens. It was eval- antibiotic candidates. The company reports no information on uated in the area of Research & Development only, although access or stewardship provisions for its five antibiotic candi- it has a number of antimicrobials on the market. Although its dates in late-stage development. Wockhardt was not evalu- performance in the Benchmark is lower compared to other ated in the Appropriate Access & Stewardship area. However, biopharmaceutical companies in scope, all five of its R&D pro- it engages in patient and community educational programmes jects target priority pathogens. Wockhardt does not engage in India and also coordinates an AMR surveillance programme in public-private partnerships; however, it conducts R&D to monitor resistance trends in India.

SALES AND OPERATIONS RevenuesWockhardt by product§ RevenuesMade: by region§ Final: no

Wockhardt is an Indian-based biopharmaceutical susceptibility testing (AST) relevant to its novel company with a focus on R&D. Besides pharma- antibacterial drugs under development. ceutical research, the company’s research pro- Wockhardt sells antimicrobial medicines in . . gramme includes areas such as genomics, bio- the USA, the UK, Ireland, Puerto Rico, Russia, mn USD mn USD technology and novel drug delivery systems. Norway, India and Vietnam. The latter two are Wockhardt is currently developing a new drug considered low- or middle-income countries.* Its discovery programme focussing on unmet needs vaccines are sold exclusively in India. In the fiscal ● Vaccines & ● India in bacterial infections (both gram-negative and year 2016, Wockhardt sold 142 million Standard antimicrobials ● Europe gram-positive). The company is also involved in Units (SUs) of antimicrobial medicines and 1.1 ● Other revenue ● USA ● Rest of World the development of diagnostics for antibiotic million SUs of vaccines.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Wockhardt markets at least 25 antimicrobial listed on the WHO EML (Section 6). The compa- medicines, 19 of which are listed on the WHO ny’s vaccines target hepatitis A (Biovac A®) and EML (Section 6). Twenty-one of the compa- chickenpox (Biovac V®). ny’s antimicrobial medicines are antibiotics, with 15 listed on the WHO EML (Section 6), including one in the EML’s Reserve group (colistin, Wockstin®). The remainder (four) of the company’s portfolio consists of two antifungals, the antimalarial quinine and the antiviral aciclovir, all ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped Plan ahead for access and stewardship during R&D. Wockhardt is developing five antibiotic candidates in late-stage clinical development. Wockhardt can ensure access and stewardship provisions are in place for these candidates, for * Countries in scope are 106 low- and middle-income example, through partnerships. countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1-2.2 Five broad-spectrum antibiotics biotic. The other four medicines in the compa- private-sector partners. It does not participate targeting priority pathogens. ny’s pipeline are: one macrolide (nafithromycin); in public-private partnerships, or in partner- Biopharmaceutical companies in scope were two broad-spectrum antibiotic fluoroquinolones ships with non-profit organisations, for antimi- selected based on their pipelines that target (alalevonadifloxacin and levonadifloxacin), which crobial R&D. priority bacteria. Wockhardt has five antibiot- are being developed specifically for gram-posi- ics that target priority pathogens, one of which tive bacterial infections (including MRSA infec- A.4 No information on access or stewardship is a combination of two existing agents. All five tions and community-acquired bacterial pneu- provisions. medicines are in Phase III clinical stage devel- monia); and a new high-dose combination of Wockhardt reports no information on access or opment. The company’s pipeline includes a new cefepime/tazobactam, which is active against stewardship provisions for its five antibiotic candi- ß-lactam enhancer (zidebactam), developed in multidrug-resistant Enterobacteriaceae, includ- dates in late-stage development. It has signed the combination with ß-lactam cefepime for the ing ESBL-, KPC- and OXA-181-expressing strains. Davos Declaration, which includes a general com- treatment of multidrug-resistant gram-nega- mitment to ensuring access to antimicrobial med- tive bacterial infections. In 2017, the FDA agreed A.3 No public-private partnerships reported. icines and vaccines, and to support the appropri- to an abridged Phase III clinical trial for this anti- Wockhardt conducts R&D in-house and/or with ate and responsible use of these products.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Cefepime/zidebactam (WCK5222) – CRE, ESBL, P. aeruginosa, A. baumannii – New ß-lactam enhancer & existing ß-lactam – BSI, CABP/HABP cIAI, cUTI • Levonadifloxacin (WCK771) – S. pneumoniae, S. aureus, Hib – Fluoro- quinolone – ABSSSI, HABP/VABP, DFI • Alalevonadifloxacin (WCK2349) – S. pneumoniae, S. aureus, Hib – Oral prodrug of levonadifloxacin – ABSSSI, ABSSSI = Acute bacterial skin and skin structure CABP/HABP, DFI infections • Nafithromycin (WCK4873) – S. pneu- BSI = Bloodstream infection moniae, S. aureus, Hib – Macrolide – CABP/HABP = Community-/Hospital-acquired bacterial pneumonia CABP/HABP, chlamydial urethritis, oti- cIAI = Complicated intra-abdominal Infection tis media, URTI cUTI = Complicated urinary tract infection • Cefepime/tazobactam (WCK4282) – DFI = Diabetic foot infection CRE, ESBL, P. aeruginosa – Adaptation FDC = Fixed dose combination URTI = Upper respiratory tract infection (new FDC of existing ß-lactam & ß-lacta- VABP = Ventilator-associated bacterial pneumonia mase inhibitor) – BSI, cIAI, cUTI, HABP

B MANUFACTURING & PRODUCTION

Wockhardt is a biopharmaceutical company that Research Area. It does, however, have products did not meet the criteria for evaluation in this on the market.

C APPROPRIATE ACCESS & STEWARDSHIP

Wockhardt is a biopharmaceutical company that Wockhardt was not eligible for this indicator, C.7 Only biopharmaceutical company did not meet the criteria for evaluation in this and does not provide any information in AMR- to report running a surveillance Research Area. It does, however, have products related education for HCPs. Notably, however, programme. on the market, and notable practices relevant to the company engages in patient education with Wockhardt was not eligible for this indica- this area are mentioned. its Mobile 1000 programme in India through tor. Notably, however, the company coordi- the Wockhardt Foundation. This programme nates a surveillance programme in India, which C.4 No apparent involvement in AMR-related includes Water, Sanitation and Hygiene (WASH) works with hospitals and laboratories to monitor education for HCPs. education and other health promotion activities. resistance trends. This programme is completely funded by Wockhardt.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Wockhardt is involved in the development of Benchmark. This information is provided given diagnostics for antibiotic susceptibility testing the importance of animal health and diagnostics (AST) relevant to its novel antibacterial drugs on the topic of AMR. under development. 157 Antimicrobial Resistance Benchmark 2018

158 Access to Medicine Foundation Appendices

I - Methodology scopes 160

II - Priority pathogens for R&D 163

III - Products for access 164

IV - Countries for access 169

V - Analysis, scoring and review 170

VI - Limitations 173

VII - Scoring guidelines 174

VIII - Guide to report cards 179

IX - List of figures 180

X - Definitions 181

XI - Acronyms 183

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APPENDIX I Methodology scopes

The Antimicrobial Resistance Benchmark assesses pharmaceutical company behaviour regarding specific diseases and product types and in a specific geographic scope, depending on the Research Area in question. The following pages set out the rationale for these analytical scopes and how they have been defined.

COMPANY SCOPE

The Benchmark covers pharmaceutical coming characteristic. The Foundation acknowl- on their readiness to engage with the data-col- panies with antimicrobial medicines and/or edges that several companies in scope could be lection process. R&D projects and the ability and a commit- placed in more than one group. Where possible ment to address AMR. Thirty companies are in and appropriate, in the Benchmark report, such Large research-based pharmaceutical compa- scope, selected based on a combination of fac- nuances are used to inform the analysis of com- nies were selected based on their antibiotic tors, including R&D focus and experience, anti- pany performance. Each company is evaluated in business volume and revenue, their antimicro- biotic market share and public commitment to those areas where it has relevant products and/ bial pipelines and portfolios and/or public com- address AMR. or activities. mitments to tackling AMR (i.e., they had signed, per September 2016, the Davos Declaration and The landscape of pharmaceutical companies Criteria for inclusion Industry Roadmap on AMR).1,2,3 Generic medi- with antimicrobials for human health can be The companies in scope have been selected cine manufacturers were selected if they ranked divided into three broad and overlapping groups: based on a combination of factors. Companies within the global top ten by antibiotics sales large research-based pharmaceutical compa- with an antibiotics focus have been prioritised volume and/or if they are signatories to the nies; generic medicine manufacturers; and bio- in this first iteration of the Benchmark. Bacteria Industry Roadmap on AMR.2,4 Biopharmaceutical pharmaceutical companies. There are key dif- represent the greatest number of resistant path- companies were identified as having at least ferences in the expertise and capacities of each ogens, the widest geographic scope of resist- one drug in clinical development targeting a type, notably in the size and nature of their prod- ance, and the bulk of the interventions at the priority pathogen as overviewed by The Pew uct portfolios and their R&D focus and expertise. government, manufacturer, healthcare provider Charitable Trusts’ report⁶ on antibiotics regis- As a result, each group can address AMR in dif- and patient levels. The final selection of com- tered at clinicaltrials.org. All of the companies ferent ways. panies was based on several size and opportu- selected from this list for inclusion have signed nity criteria, including: (1) relevance of marketed the Davos Declaration, except one (Summit With this in mind, the Foundation used these portfolio, (2) relevance of antimicrobial pipeline, Therapeutics). Industry associations represent- broad categorisations to structure its analyt- and (3) commitment to addressing AMR. A small ing these and other companies have signed the ical framework. The 30 companies in scope number of companies were selected following Davos Declaration. have been grouped according to their key defin- clear stakeholder recommendations and based

2018 Antimicrobial Resistance Benchmark – companies in scope

LARGE RESEARCH-BASED PHARMACEUTICAL COMPANIES Signatory to the Revenue Global antibiotic Davos Industry Country Ticker Stock exchange (bn USD)1 sales Kgs2 Decl.3 Roadmap4 GlaxoSmithKline plc GBR GSK XLON 34.4 28,810.0 ● ● Johnson & Johnson USA JNJ XNYS 71.9 2,053.6 ● ● Merck & Co., Inc. USA MRK XNYS 39.8 12,273.1 ● ● Novartis AG CHE NOVN XSWX 47.6 3,000.0 ● ● Pfizer Inc. USA PFE XNYS 52.8 9,028.9 ● ● Roche Holding AG CHE ROG XSWX 49.6 349.5 ● ● Sanofi FRA SAN XPAR 35.6 unknown ● ● Shionogi & Co., Ltd. JPN 4507 XTKS 3.0 unknown ● ●

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GENERIC MEDICINE MANUFACTURERS Global antibiotic Signatory to the Revenue sales International Davos Industry Country Ticker Stock exchange (bn USD)1 Units5 Decl.3 Roadmap4 Aspen Pharmacare Holdings Limited ZAF APN XJSE 2.4 3.2 ● ● Aurobindo Pharma Limited IND AUROPHARMA XNSE 2.3 unknown ● ● Cipla Limited IND CIPLA XNSE 2.3 unknown ● ● Dr. Reddy’s Laboratories Ltd. IND DRREDDY; RDY XNSE; XNYS 2.2 2.1 ● ● Fresenius Kabi AG DEU FRE XFRA 6.3 8.3 ●** ● Lupin Limited IND LUPIN XNSE 2.6 2.7 ●** ● Macleods Pharmaceuticals Ltd.* IND n/a n/a unknown unknown ● ● Mylan NV USA MYL XNAS 11.0 11.5 ● ● Sun Pharmaceutical Industries Ltd. IND SUNPHARMA XNSE 4.7 5.5 ● ● Teva Pharmaceutical Industries Ltd. ISR TEVA XNYS; XTAE 21.9 13.3 ● ●

BIOPHARMACEUTICAL COMPANIES Signatory to the Revenue Priority R&D Davos Industry Country Ticker Stock exchange (mn USD)1 projects6 Decl.3 Roadmap4 Achaogen Inc. USA AKAO XNAS 41.8 1 ● ● Cempra Inc. USA CEMP XNAS 18.0 2 ● ● Entasis Therapeutics Inc. USA n/a n/a unknown 2 ● ● Melinta Therapeutics Inc. USA MLNT XNAS unknown 1 ● ● MGB Biopharma GBR n/a n/a unknown 1 ● ● Motif Bio plc GBR MTFB XLON; XNAS 0.0 1 ● ● Nabriva Therapeutics plc IRL NBRV XNAS 6.5 1 ● ● Polyphor Ltd. CHE n/a n/a unknown 1 ● ● Summit Therapeutics* GBR SUMM; SMMT XLON; XNAS 3.0 1 ● ● Tetraphase Pharmaceuticals Inc. USA TTPH XNAS 5.1 3 ● ● The Medicines Company USA MDCO XNAS 167.8 1 ● ● Wockhardt Ltd. IND WOCKPHARMA XNSE 619.0 4 ● ●

* Company included on basis of stakeholder recommen- 2 Mordor Intelligence. (2016). Global Antibiotics Market 4 Industry Roadmap for Progress on Combating dations and willingness to participate. Leaders – Top 10 by value, volume and company pro- Antimicrobial Resistance. September 2016. ** via Medicines for Europe (MFE) files. 5 Mordor intelligence (2016). Top 10 Generic Antibiotic 1 Revenue = fiscal year 2016/17 (Exchange rates from 3 Declaration by the Pharmaceutical, Biotechnology and Manufacturers by Volume – Custom Study. www.x-rates.com, the exchange rate of the last day of Diagnostics Industries on Combating Antimicrobial 6 The PEW Charitable Trusts. (March, 2016). Antibiotics the fiscal year was used) Resistance. Signatories as at January, 2017. Currently in Clinical Development.

DISEASE SCOPE

The disease scope is deliberately broad. This is curb AMR, particularly for R&D. Priority path- infectious disease: as occurring when microbial to ensure the Benchmark can capture the full ogens identified by the Benchmark are listed in pathogens invade a host and harm tissues, and range of companies’ AMR-related policies and Appendix II. These are drug-resistant pathogens can be transmitted to other individuals. It encap- practices. All infectious diseases are in scope for as defined by WHO’s R&D Priority List and by sulates diseases caused by the five main groups analysis. Certain pathogens have been deemed CDC’s Biggest Threat List. of infectious microorganisms relevant to AMR: by stakeholders to be a priority for efforts to The Benchmark applies a wide definition of bacteria, viruses, fungi, helminths, and protozoa.

PRODUCT SCOPE

The product scope covers antimicrobial med- Manufacturing & Production: marketed antibiot- any health system. Access to these medicines, icines on the market and in development, and ics; the potential impact of companies’ manufac- particularly in low- and middle-income coun- vaccines in development. Vaccines are undoubt- turing processes on AMR mainly relate to antibi- tries, is a continued priority that must be con- edly critical for limiting AMR. See the 2017 otic discharge into the environment and parame- sidered alongside efforts to curb AMR. Access to Vaccines Index for an assessment of ters that promote antibacterial resistance. • For Stewardship indicators (C.4 – C.8): mar- vaccine companies’ practices for improving vacci- keted antibiotics. Stewardship practices to nation coverage. Each of the Benchmark’s three Access & Stewardship: prevent overuse can limit the emergence and Research Areas has a tailored product scope: • For Access indicators (C.1 – C.3): antibiot- spread of resistance. ics for indicator C.1; antimicrobial medicines Research & Development: antimicrobial medi- on the WHO Model List of Essential Medi- cines and vaccines in discovery, preclinical and cines 2017 (EML), Section 6, for indicators C.2, clinical phases I-III, or approved (or awaiting C.3 (see Appendix III). These medicines are approval) in 2016–17. deemed essential to the basic functioning of

161 Antimicrobial Resistance Benchmark 2018

How products are assessed per Research Area The table shows which products are relevant to each Research Area. Whether a particular product group is relevant has been determined AMR Benchmark Research Areas through stakeholder consultation. Research & Manufacturing & Appropriate Development Production Access & Stewardship Products Access Stewardship

Innovative and adaptive antimicrobial ● medicines and vaccines in development

Antimicrobial medicines on WHO Model ● List of Essential Medicines 2017

Antibiotics ● ● ●

GEOGRAPHIC SCOPE

The geographic scope is global. Access indica- Access metrics focus on low- and middle-in- been defined using three criteria: (1) countries’ tors have an exclusive focus on low- and mid- come countries level of income (gross national income [GNI] per dle-income countries. The challenges of sufficient access and afforda- capita); (2) their levels of development; and (3) Antimicrobial resistance is emerging across the bility are significantly higher in poorer coun- the scope and scale of inequality in each country. globe. The need for new antimicrobials and sus- tries.6 A group of indicators (A.4, C.1, C.2 , C.3) These assessments are based on data from the tainable antibiotic production are global priori- measure how companies either plan for or World Bank, the United Nations Development ties. The rational use of antibiotics in particular already address access to prioritised antimi- Programme (UNDP), and the United Nations is needed wherever antibiotics are available. crobial medicines in 106 low- and middle-in- Economic and Social Council (ECOSOC).7,8,9 come countries. This group of countries has

162 Access to Medicine Foundation

APPENDIX II Priority pathogens for R&D

In the Research & Development Research Area, the Benchmark assessed companies’ R&D projects that target priority pathogens. The pathogens deemed priority by the Benchmark are listed here and comprise (emerging) drug-resistant pathogens as defined by WHO’s R&D Priority List and by the Centers for Disease Control’s US Biggest Threat List.

Stakeholder prioritisation

Pathogen WHO Priority CDC Biggest List¹ Threats²

BACTERIA Carbapenem-resistant Enterobacteriaceae (CRE) Critical Urgent

Extended-spectrum ß-lactamase Enterobacteriaceae (ESBL) Critical Serious

Multidrug-resistant Acinetobacter spp. (including A. baumannii) Critical Serious

Multidrug-resistant Pseudomonas aeruginosa Critical Serious

Neisseria gonorrhoeae High Urgent

Drug-resistant Campylobacter spp. High Serious

Vancomycin-resistant Enterococcus (VRE) High Serious (E. faecalis & E. faecium) Drug-resistant Salmonella spp. High Serious (including non-typhoidella Salmonella enterica & Salmonella enterica sero- type Typhimurium Drug-resistant Staphylococcus aureus High Serious / (methicillin-resistant S. aureus & vancomycin-resistant S. aureus) Concerning Clarithromycin-resistant Helicobacter pylori High

Drug-resistant Shigella spp. Medium Serious

Drug-resistant Streptococcus pneumoniae Medium Serious

Ampicillin-resistant Haemophilus influenzae type b (Hib) Medium

Drug-resistant Mycobacterium tuberculosis WHO AMR Serious priority area Clostridium difficile Urgent

Erythromycin-resistant group A Streptococcus Concerning

Clindamycin-resistant group B Streptococcus Concerning

VIRUSES Human immunodeficiency virus (HIV) WHO AMR priority area

PROTOZOA Multidrug-resistant Plasmodium falciparum WHO AMR priority area

FUNGI Fluconazole-resistant Candida spp. Serious

1. WHO. (2017). Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. Retrieved from http://www. who.int/medicines/areas/rational_use/antibacterial_agents_clinical_development/en/ 2. U.S. Centers for Disease Control and Prevention (CDC). (April, 2013). Antibiotic resistance threats in the United States, 2013. Retrieved from http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf

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APPENDIX III Products for access

Only anti-infective medicines on the WHO Model List of Essential Medicines 2017 (EML), Section 6, are in scope for indicators C.2 and C.3. They are deemed essential by WHO to the basic functioning of any health system. Access to these medicines, particularly in low- and middle-income countries, must be considered alongside to curb AMR.

WHO MODEL LIST OF ESSENTIAL MEDICINES (MARCH 2017). SECTION 6. ANTI-INFECTIVE MEDICINES.

6.1 ANTHELMINTHICS albendazole Tablet: (chewable): 400 mg ivermectin Tablet: (scored): 3 mg levamisole Tablet: 50 mg; 150 mg (as hydrochloride) mebendazole Tablet (chewable): 100 mg; 500 mg niclosamide Tablet (chewable): 500 mg praziquantel Tablet: 150 mg; 600 mg pyrantel Oral liquid: 50 mg (as embonate or pamoate)/mL Tablet (chewable): 250 mg (as embonate or pamoate) diethylcarbamazine Tablet: 50 mg; 100 mg (dihydrogen citrate) triclabendazole Tablet: 250 mg oxamniquine Capsule: 250 mg Oral liquid: 250 mg/5 mL

6.2 ANTIBACTERIAL MEDICINES amikacin Injection: 250 mg (as sulfate)/mL in 2-mL vial Powder for injection: 100 mg; 500 mg; 1 g (as sulfate) in vial amoxicillin Powder for oral liquid: 125 mg (as trihydrate)/5 mL; 250 mg (as trihydrate)/5 mL Solid oral dosage form: 250 mg; 500 mg (as trihydrate) Powder for injection: 250 mg; 500 mg; 1 g (as sodium) in vial amoxicillin + clavulanic acid Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic acid/5 mL; 250 mg amoxicillin + 62.5 mg clavulanic acid/5 mL Tablet: 500 mg (as trihydrate) + 125 mg (as potassium salt) Powder for injection: 500 mg (as sodium) + 100 mg (as potassium salt); 1000 mg (as sodium) + 200 mg (as potassium salt) in vial ampicillin Powder for injection: 500 mg; 1 g (as sodium salt) in vial azithromycin Capsule: 250 mg; 500 mg (anhydrous) Oral liquid: 200 mg/5 mL aztreonam Powder for injection: 1 g; 2 g in vial bedaquiline Tablet: 100 mg benzathine benzylpenicillin Powder for injection: 900 mg benzylpenicillin (= 1.2 million IU) in 5-mL vial; 1.44 g benzylpenicillin (= 2.4 million IU) in 5-mL vial benzylpenicillin Powder for injection: 600 mg (= 1 million IU); 3 g (= 5 million IU) (sodium or potassium salt) in vial capreomycin Powder for injection: 1 g (as sulfate) in vial cefalexin Powder for reconstitution with water: 125 mg/5 mL; 250 mg/5 mL (anhydrous) Solid oral dosage form: 250 mg (as monohydrate) cefazolin Powder for injection: 1 g (as sodium salt) in vial cefixime Capsule or tablet: 200 mg; 400 mg (as trihydrate) Powder for oral liquid: 100 mg/5 mL cefotaxime Powder for injection: 250 mg per vial (as sodium salt) ceftazidime Powder for injection: 250 mg or 1 g (as pentahydrate) in vial ceftriaxone Powder for injection: 250 mg; 1 g (as sodium salt) in vial chloramphenicol Capsule: 250 mg Oily suspension for injection: 0.5 g (as sodium succinate)/mL in 2-mL ampoule Oral liquid: 150 mg (as palmitate)/5 mL Powder for injection: 1 g (sodium succinate) in vial

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ciprofloxacin Oral liquid: 250 mg/5 mL (anhydrous) Solution for IV infusion: 2 mg/mL (as hyclate) Tablet: 250 mg (as hydrochloride) clarithromycin Solid oral dosage form: 500 mg Powder for oral liquid: 125 mg/5 mL; 250 mg/5 mL Powder for injection: 500 mg in vial clindamycin Capsule: 150 mg (as hydrochloride) Injection: 150 mg (as phosphate)/mL Oral liquid: 75 mg/5 mL (as palmitate) clofazimine Capsule: 50 mg; 100 mg. cloxacillin □ Capsule: 500 mg; 1 g (as sodium salt) Powder for injection: 500 mg (as sodium salt) in vial Powder for oral liquid: 125 mg (as sodium salt)/5 mL cycloserine Solid oral dosage form: 250 mg dapsone Tablet: 25 mg; 50 mg; 100 mg daptomycin Powder for injection: 350 mg; 500 mg in vial delamanid Tablet: 50 mg doxycycline Oral liquid: 25 mg/5 mL; 50 mg/5 mL (anhydrous) Solid oral dosage form: 50 mg; 100 mg (as hyclate) Powder for injection: 100 mg in vial Tablet (dispersible): 100 mg (as monohydrate) ethambutol Oral liquid: 25 mg/mL Tablet: 100 mg to 400 mg (hydrochloride) ethambutol + isoniazid Tablet: 400 mg + 150 mg ethambutol + isoniazid + Tablet: 275 mg + 75 mg + 400 mg + 150 mg pyrazinamide + rifampicin ethambutol + isoniazid + rifampicin Tablet: 275 mg + 75 mg + 150 mg ethionamide Tablet: 125 mg; 250 mg fifth-generation cephalosporins (with Powder for injection: 400 mg; 600 mg (as fosamil) in vial or without beta-lactamase inhibitor) e.g., ceftaroline fosfomycin Powder for injection: 2 g; 4 g (as sodium) in vial fourth-generation cephalospor- Powder for injection: 500 mg; 1g; 2g (as hydrochloride) in vial ins (with or without beta-lactamase inhibitor) e.g., cefepime gentamicin Injection: 10 mg; 40 mg (as sulfate)/ mL in 2-mL vial isoniazid Oral liquid: 50 mg/5 mL Tablet: 100 mg to 300 mg Tablet (scored): 50 mg isoniazid + pyrazinamide + rifampicin Tablet: 75 mg + 400 mg + 150 mg; 150 mg + 500 mg + 150 mg Tablet (dispersible): 50 mg + 150 mg + 75 mg isoniazid + rifampicin Tablet: 75 mg + 150 mg; 150 mg + 300 mg; 60 mg + 60 mg; 150 mg + 150 mg Tablet (dispersible): 50 mg + 75 mg kanamycin Powder for injection: 1 g (as sulfate) in vial levofloxacin Tablet: 250mg; 500 mg; 750 mg linezolid Injection for intravenous administration: 2 mg/mL in 300 mL bag Powder for oral liquid: 100 mg/5 mL Tablet: 400 mg; 600 mg meropenem Powder for injection: 500 mg (as trihydrate); 1 g (as trihydrate) in vial metronidazole Injection: 500 mg in 100-mL vial Oral liquid: 200 mg (as benzoate)/5 mL Suppository: 500 mg; 1 g Tablet: 200 mg to 500 mg moxifloxacin Tablet: 400 mg nitrofurantoin Oral liquid: 25 mg/5 mL Tablet: 100 mg oxazolidinones Injection for intravenous administration: 2 mg/mL in 300 mL bag e.g., linezolid Powder for oral liquid: 100 mg/5 mL Tablet: 400 mg; 600 mg p-aminosalicylic acid Granules: 4 g in sachet Tablet: 500 mg phenoxymethylpenicillin Powder for oral liquid: 250 mg (as potassium salt)/5 mL Tablet: 250 mg (as potassium salt) piperacillin + tazobactam Powder for injection: 2 g (as sodium salt) + 250 mg (as sodium salt); 4 g (as sodium salt) + 500 mg (as sodium salt) in vial polymyxins Powder for injection: 1 million IU (as colistimethate sodium) in vial e.g., colistin procaine benzylpenicillin Powder for injection: 1 g (=1 million IU); 3 g (=3 million IU) in vial

□ Primarily intended to indicate similar clinical performance within a pharmacological class.

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pyrazinamide Oral liquid: 30 mg/mL Tablet: 400 mg Tablet (dispersible): 150 mg Tablet (scored): 150 mg rifabutin Capsule: 150 mg rifampicin Solid oral dosage form: 150 mg; 300 mg Oral liquid: 20 mg/mL rifapentine Tablet: 150 mg spectinomycin Powder for injection: 2 g (as hydrochloride) in vial streptomycin Powder for injection: 1 g (as sulfate) in vial sulfamethoxazole + trimethoprim Injection: 80 mg + 16 mg/mL in 5-mL ampoule; 80 mg + 16 mg/mL in 10-mL ampoule Oral liquid: 200 mg + 40 mg/5 mL Tablet: 100 mg + 20 mg; 400 mg + 80 mg; 800 mg + 160 mg tigecycline Powder for injection: 50 mg in vial vancomycin Capsule: 125 mg; 250 mg (as hydrochloride) Powder for injection: 250 mg (as hydrochloride) in vial

6.3 ANTIFUNGAL MEDICINES amphotericin B Powder for injection: 50 mg in vial (as sodium deoxycholate or liposomal complex) clotrimazole Vaginal cream: 1%; 10% Vaginal tablet: 100 mg; 500 mg fluconazole Capsule: 50 mg Injection: 2 mg/mL in vial Oral liquid: 50 mg/5 mL flucytosine Capsule: 250 mg Infusion: 2.5 g in 250 mL griseofulvin Oral liquid: 125 mg/5 mL Solid oral dosage form: 125 mg; 250 mg itraconazole Capsule: 100 mg Oral liquid: 10 mg/mL nystatin Lozenge: 100,000 IU Oral liquid: 50 mg/5 mL; 100,000 IU/mL Pessary: 100,000 IU Tablet: 100,000 IU; 500,000 IU potassium iodide Saturated solution voriconazole Tablet: 50 mg; 200 mg Powder for injection: 200 mg in vial Powder for oral liquid: 40 mg/mL

6.4 ANTIVIRAL MEDICINES abacavir Tablet: 300 mg (as sulfate) Tablet (dispersible, scored): 60 mg (as sulfate) abacavir + lamivudine Tablet (dispersible, scored): 600 mg (as sulfate) + 300 mg*; 60 mg (as sulfate) + 30 mg; 120 mg (as sulfate) + 60 mg aciclovir □ Oral liquid: 200 mg/5 mL Powder for injection: 250 mg (as sodium salt) in vial Tablet: 200 mg atazanavir Solid oral dosage form: 100 mg; 300 mg (as sulfate) atazanavir + ritonavir Tablet (heat stable): 300 mg (as sulfate) + 100 mg daclatasvir Tablet: 30 mg; 60 mg (as hydrochloride) darunavir Tablet: 75 mg; 400 mg; 600 mg; 800 mg dasabuvir Tablet: 250 mg dolutegravir Tablet: 50 mg efavirenz Tablet: 200 mg (scored); 600 mg efavirenz + emtricitabine + tenofovir Tablet: 600 mg + 200 mg + 300 mg (disoproxil fumarate equivalent to 245 mg tenofovir disoproxil) efavirenz + lamivudine + tenofovir Tablet: 400 mg + 300 mg + 300 mg (disoproxil fumarate equivalent to 245 mg tenofovir disoproxil) emtricitabine + tenofovir Tablet: 200 mg + 300 mg (disoproxil fumarate equivalent to 245 mg tenofovir disoproxil) entecavir Oral liquid: 0.05 mg/mL Tablet: 0.5 mg; 1 mg

□ Primarily intended to indicate similar clinical performance within a pharmacological class. * Corrected based on page 153 of ‘Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access Recommendations for a public health approach’ 2010 revision and page 15 of ‘The Selection and Use of Essential Medicines’ Report of the WHO Expert Committee, 2013.

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isoniazid + pyridoxine + sulfamethox- Tablet (scored): 300 mg + 25 mg + 800 mg + 160 mg azole + trimethoprim lamivudine Oral liquid: 50 mg/5 mL Tablet: 150 mg lamivudine + nevirapine + zidovudine Tablet: 30 mg + 50 mg + 60 mg; 150 mg + 200 mg + 300 mg lamivudine + zidovudine Tablet: 30 mg + 60 mg; 150 mg + 300 mg ledipasvir + sofosbuvir Tablet: 90 mg + 400 mg lopinavir + ritonavir Oral liquid: 400 mg + 100 mg/5 mL Tablet (heat stable): 100 mg + 25 mg; 200 mg + 50 mg Capsule containing oral pellets: 40 mg + 10 mg nevirapine Oral liquid: 50 mg/5 mL Tablet: 50 mg (dispersible); 200 mg ombitasvir + paritaprevir + ritonavir Tablet: 12.5 mg + 75 mg + 50 mg oseltamivir Capsule: 30 mg; 45 mg; 75 mg (as phosphate) Oral powder: 12 mg/mL pegylated interferon alfa (2a or 2b) Vial or prefilled syringe: 180 micrograms (peginterferon alfa-2a); 80 microgram, 100 microgram (peginterferon alfa-2b) raltegravir Tablet (chewable): 25 mg; 100 mg Tablet: 400 mg ribavirin Injection for intravenous administration: 800 mg and 1 g in 10-mL phosphate buffer solution Solid oral dosage form: 200 mg; 400 mg; 600 mg ritonavir Oral liquid: 400 mg/5 mL Tablet (heat stable): 25 mg; 100 mg simeprevir Capsule: 150 mg sofosbuvir Tablet: 400 mg sofosbuvir + velpatasvir Tablet: 400 mg + 100 mg tenofovir disoproxil fumarate Tablet: 300 mg (tenofovir disoproxil fumarate – equivalent to 245 mg tenofovir disoproxil) valganciclovir Tablet: 450 mg Powder for oral solution: 50 mg/mL zidovudine Capsule: 250 mg Oral liquid: 50 mg/5 mL Solution for IV infusion injection: 10 mg/mL in 20-mL vial Tablet: 300 mg Tablet (dispersible, scored): 60 mg (as sulfate)

6.5 ANTIPROTOZOAL MEDICINES amodiaquine Tablet: 153 mg or 200 mg (as hydrochloride) amphotericin B Powder for injection: 50 mg in vial (as sodium deoxycholate or liposomal complex) artemether Oily injection: 80 mg/mL in 1-mL ampoule artemether + lumefantrine Tablet: 20 mg + 120 mg Tablet (dispersible): 20 mg + 120 mg artesunate Injection: ampoules, containing 60 mg anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution. For use in the management of severe malaria Rectal dosage form: 50 mg; 100 mg; 200 mg capsules (for pre-referral treatment of severe malaria only; patients should be taken to an appropriate health facility for follow-up care) Tablet: 50 mg artesunate + amodiaquine Tablet: 25 mg + 67.5 mg; 50 mg + 135 mg; 100 mg + 270 mg artesunate + mefloquine Tablet: 25 mg + 55 mg; 100 mg + 220 mg artesunate + pyronaridine Tablet: 60 mg + 180 mg tetraphosphate Granules: 20 mg + 60 mg benznidazole Tablet: 12.5 mg; 100 mg Tablet (scored): 50 mg chloroquine Oral liquid: 50 mg (as phosphate or sulfate)/5 mL Tablet: 100 mg; 150 mg (as phosphate or sulfate) dihydroartemisinin + piperaquine Tablet: 20 mg + 160 mg; 40 mg + 320 mg phosphate diloxanide Tablet: 500 mg (furoate) doxycycline Capsule: 100 mg (as hydrochloride or hyclate) Tablet (dispersible): 100 mg (as monohydrate) eflornithine Injection: 200 mg (hydrochloride)/ mL in 100-mL bottle mefloquine Tablet: 250 mg (as hydrochloride) melarsoprol Injection: 3.6% solution, 5-mL ampoule (180 mg of active compound)

□ Primarily intended to indicate similar clinical performance within a pharmacological class.

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metronidazole □ Injection: 500 mg in 100-mL vial Oral liquid: 200 mg (as benzoate)/5 mL Tablet: 200 mg to 500 mg miltefosine Solid oral dosage form: 10 mg; 50 mg nifurtimox Tablet: 30 mg; 120 mg; 250 mg paromomycin Solution for intramuscular injection: 750 mg of paromomycin base (as the sulfate) pentamidine Tablet: 200 mg; 300 mg (as isethionate) Powder for injection: 200 mg (as isetionate) in vial primaquine Tablet: 7.5 mg; 15 mg (as diphosphate) proguanil Tablet: 100 mg (as hydrochloride) pyrimethamine Tablet: 25 mg quinine Injection: 300 mg quinine hydrochloride/mL in 2-mL ampoule Tablet: 300 mg (quinine sulfate) or 300 mg (quinine bisulfate) sodium stibogluconate or meglumine Injection: 100 mg/mL, 1 vial = 30 mL or 30%, equivalent to approximately 8.1% antimony antimoniate (pentavalent) in 5-mL ampoule sulfadiazine Tablet: 500 mg sulfadoxine + pyrimethamine Tablet: 500 mg + 25 mg sulfamethoxazole + trimethoprim Injection: 80 mg + 16 mg/mL in 5-mL ampoule; 80 mg + 16 mg/mL in 10-mL ampoule Oral liquid: 200 mg + 40 mg/5 mL Tablet: 100 mg + 20 mg; 400 mg + 80 mg suramin sodium Powder for injection: 1 g in vial

MEDICINES IN SCOPE, IN ADDITION TO 2017 WHO MODEL LIST OF ESSENTIAL MEDICINES 1,2

I. The WHO Model List of Essential Medicines incorporates ‘fourth gen- Product ATC class eration cephalosporins (with or without beta-lactamase inhibitor)’ and ceftaroline J01DI ‘fifth generation cephalosporins (with or without beta-lactamase inhib- ceftobiprole J01DI itor)’. Based on the examples listed on the 2017 Model List of Essential ceftolozane + tazobactam J01DI Medicines, ceftaroline and cefepime, and using the Anatomical Therapeutic cefepime J01DE Chemical (ATC) Classification system by WHO the following cephalospor- cefpirome J01DE ins were evaluated as if on the WHO Model List of Essential Medicines: cefozopran J01DE

II. The WHO Model List of Essential Medicines incorporates square box Product ATC class Corresponding symbols (□) to indicate similar clinical performance within a pharmaco- product with □ logical class. The listed medicine should be the example of the class for idoxuridine J05AB aciclovir which there is the best evidence for effectiveness and safety. Based on vidarabine J05AB aciclovir the examples listed on the Model List of Essential Medicines and using the ganciclovir J05AB aciclovir Anatomical Therapeutic Chemical (ATC) Classification system by WHO, famciclovir J05AB aciclovir the following antimicrobial medicines, that are not specifically mentioned valaciclovir J05AB aciclovir on the Model List of Essential Medicines, were evaluated as if on the WHO cidofovir J05AB aciclovir Model List of Essential Medicines. penciclovir J05AB aciclovir brivudine J05AB aciclovir dicloxacillin J01CF cloxacillin meticillin J01CF cloxacillin oxacillin J01CF cloxacillin flucloxacillin J01CF cloxacillin nafcillin J01CF cloxacillin tinidazole P01AB metronidazole ornidazole P01AB metronidazole azanidazole P01AB metronidazole propenidazole P01AB metronidazole nimorazole P01AB metronidazole secnidazole P01AB metronidazole

1 WHO. (March, 2017). WHO Model List of Essential Medicines, 20th List. Retrieved from http://www.who.int/medicines/publications/essentialmedicines/en/ 2 WHO. (March, 2017). WHO Model List of Essential Medicines for Children, 6th List. Retrieved from http://www.who.int/medicines/publications/essentialmedicines/en/

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APPENDIX IV Countries for access

The challenges of sufficient access and afforda- defined using three criteria: (1) countries’ level Nations Development Programme (UNDP), and bility are significantly higher in poorer countries. of income (GNI per capita); (2) their levels of the United Nations Economic and Social Council Access indicators (A.4, C.1, C.2, C.3) measure development; and (3) the scope and scale of ine- (ECOSOC). 1,2,3 This is the same geographic how companies address access in 106 low- and quality in each country. These assessments are scope as used by the 2018 Access to Medicine middle-income countries. This group has been based on data from the World Bank, the United Index.

EAST ASIA & PACIFIC Guatemala LMIC Central African Rep. LIC Cambodia LMIC Guyana MHDC Chad LIC China HiHDI Haiti LIC Comoros LIC Indonesia LMIC Honduras LMIC Congo, Dem. Rep. LIC Kiribati LMIC Mexico HiHDI Congo, Rep. LMIC Korea, Dem. Rep. LIC Nicaragua LMIC Côte d’Ivoire LMIC Lao PDR LMIC Paraguay MHDC Equatorial Guinea MHDC Micronesia, Fed. Sts. LMIC Peru HiHDI Eritrea LIC Mongolia LMIC Suriname HiHDI Ethiopia LIC Myanmar LMIC Gabon MHDC Papua New Guinea LMIC MIDDLE EAST & NORTH AFRICA Gambia, The LIC Philippines LMIC Djibouti LMIC Ghana LMIC Samoa LMIC Egypt, Arab Rep. LMIC Guinea LIC Solomon Islands LMIC Iran, Islamic Rep. HiHDI Guinea-Bissau LIC Thailand HiHDI Iraq MHDC Kenya LMIC Timor-Leste LMIC Morocco LMIC Lesotho LMIC Tonga LMIC Palestine, State LMIC Liberia LIC Tuvalu LDC Syrian Arab Rep. LMIC Madagascar LIC Vanuatu LMIC Tunisia LMIC Malawi LIC Vietnam LMIC Yemen, Rep. LMIC Mali LIC Mauritania LMIC EUROPE & CENTRAL ASIA SOUTH ASIA Mozambique LIC Armenia LMIC Afghanistan LIC Namibia MHDC Kosovo LMIC Bangladesh LMIC Niger LIC Kyrgyz Rep. LMIC Bhutan LMIC Nigeria LMIC Moldova LMIC India LMIC Rwanda LIC Tajikistan LMIC Maldives HiHDI São Tomé and Principe LMIC Turkmenistan MHDC Nepal LIC Senegal LIC Ukraine LMIC Pakistan LMIC Sierra Leone LIC Uzbekistan LMIC Sri Lanka LMIC Somalia LIC South Africa MHDC LATIN AMERICA & CARIBBEAN SUB-SAHARAN AFRICA South Sudan LIC Belize HiHDI Angola LHDC Sudan LMIC Bolivia LMIC Benin LIC Swaziland LMIC Brazil HiHDI Botswana MHDC Tanzania LIC Colombia HiHDI Burkina Faso LIC Togo LIC Dominican Rep. HiHDI Burundi LIC Uganda LIC Ecuador HiHDI Cameroon LMIC Zambia LMIC El Salvador LMIC Cape Verde LMIC Zimbabwe LIC

Table legend LIC: Low-income country (World Bank income classifications) 1 World Bank Country and Lending Groups [Online]. Retrieved 15 June 2017 from https://datahelpdesk. LMIC: Lower middle-income country (World Bank income classifications) worldbank.org/knowledgebase/articles/906519 LDC: Least Developed Country (UN Human Development Index) 2 United Nations Development Programme. (2016). LHDC: Low Human Development Country (UN Human Development Index) Global Human Development Report 2016. New York, NY. MHDC: Medium Human Development (Country UN Human Development 3 United Nations Committee for Development Policy. (June, 2017). List of Least Developed Countries (as of Index) June 2017). Retrieved from https://www.un.org/devel- HiHDI: High Human Development Country with high inequality (UN opment/desa/dpad/wp-content/uploads/sites/45/pub- Inequality-adjusted Human Development Index) lication/ldc_list.pdf

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APPENDIX V Analysis, scoring and review process

PROCESS FOR ANTIMICROBIAL dose combinations (FDCs) composed of two group anti-infective medicines in the WHO EML PORTFOLIO ANALYSIS or more single-INN elements – therefore, two (Section 6). For products already listed on the FDCs containing, e.g., the same single-INN com- WHO EML (Section 6), the classification was The Benchmark requested companies to provide ponents but with different doses in one or more exclusively based on this list, whereas for prod- data on their antimicrobial portfolio for anal- of the components, were considered equivalent ucts not on the WHO EML (Section 6) the clas- ysis. Companies were required to list each of and aggregated. The Benchmark also consid- sification was based on the product’s pharma- their antimicrobial products’ International Non- ered that different salts of the same single-INN cological properties and clinical indications. proprietary Name (INN), brand name(s), pri- product or FDC component (e.g. tenofovir diso- Products that fell into more than one of the mary indication(s), formulation(s), dose(s) and proxil and tenofovir disoproxil fumarate, or chlo- five categories above were counted in all rele- route(s) of administration. They were also asked ramphenicol palmitate and chloramphenicol vant categories. Within the five categories, prod- to indicate whether or not the product was as sodium succinate) were considered equiva- ucts were further classified into subcategories. listed on Section 6 of the WHO Model List of lent and aggregated. On the other hand, product Products that fell into more than one subcate- Essential Medicines (EML). modifications that resulted in significantly differ- gory were counted in a separate ‘multiple cate- This request to companies was accompanied ent chemical/pharmaceutical properties were gories’ subcategory. by a pre-populated database of marketed anti- considered non-equivalent to the original prod- The research team also analysed whether microbial medicines which the research team uct (examples include benzathine benzylpenicil- antibacterial medicines (antibiotics) listed on collected from one or more publicly available, lin, benzathine phenoxymethylpenicillin and ten- the WHO EML (Section 6) were part of the EML company-specific sources. The company was ofovir disoproxil alafenamide, relative to ben- Access, Watch or Reserve groups. The Watch asked to verify the database and include addi- zylpenicillin, to phenoxymethylpenicillin and to and Reserve groups include antibiotics and anti- tional necessary information. tenofovir disoproxil fumarate, respectively). The biotic classes that should be priority targets of All products on the market as of 8 Benchmark also considered that combination local, national and global stewardship activities. September 2017 (when the data collection products differing only in components that are These groups also include antibiotics that are period ended) were eligible for inclusion in the not antimicrobials (e.g. oxytetracycline and the not part of the WHO EML, for example, norflox- descriptive analysis of the antimicrobial port- combination hydrocortisone/oxytetracycline) acin (a fluoroquinolone) or teicoplanin (a gly- folio. The research team verified whether were equivalent and hence aggregated. Lastly, copeptide). Only antibiotics listed on the WHO R&D projects included for analysis in the R&D co-packaging of two products already marketed EML (Section 6) were assigned to these groups. Research Area were approved between the date by a company (single-INN or FDC) did not count of submission and the end of data collection. If as an additional product. For the analysis com- so, the product was included in the company’s bining companies’ portfolios (in the Portfolio SUMMARY OF THE SCORING PROCESS portfolio. However, R&D projects with market Analysis section of this report) no further data approval dates between 8 September 2017 and aggregation took place, meaning a product with Companies were assessed and scored by 31 October 2017 (the time period during which a given INN, marketed by more than one com- the Benchmark in three Research Areas: the status of R&D projects was monitored by pany, was counted as many times as the number Research and Development, Manufacturing the Benchmark) were not added to the compa- of companies that market it. The purpose of this and Production and Appropriate Access and ny’s portfolio. was to provide an overview of the antimicrobial Stewardship, with each area composed of sev- In some cases, companies did not submit medicines market. eral indicators. Due to the variation between their entire antimicrobial portfolio during the Information regarding whether or not the companies in scope, not all indicators were data collection period. Products not submit- product was listed on WHO EML (Section 6) was applicable to every company, as shown in the ted may include products with different INNs also verified by the research team. Antimicrobial Indicators and Scoring Eligibility table in this as well as products with the same INN but mar- medicines were determined as being on the Appendix. keted under different brand names (e.g. in differ- WHO EML (Section 6) if they fulfilled any of the The Benchmark included ongoing/active ent countries/regions). For companies that did following four criteria: (a) appeared directly on projects up until 8 September 2017 (when the not participate in the Benchmark’s survey, the the list; (b) were part of a pharmacological class data collection period ended), with two excep- initially pre-populated database was used for all appearing directly on the list (e.g. fourth-gen- tions: (1) for R&D indicators, the status of R&D descriptive portfolio analyses. eration cephalosporins or oxazolidinones); (c) projects included for analysis was monitored To ensure products were within scope and were in the same pharmacological class as a between 8 September 2017 and 31 October eligible for analysis – i.e. antimicrobial medi- medicine listed on the WHO EML (Section 6) 2017 (for termination or changes in clinical cines for human use, both systemic and topi- with a square box (i.e. the antibacterial cloxa- phase); all R&D projects had to be ongoing, cal, but not vaccines – and that there were no cillin, the antiviral aciclovir and the antiproto- approved or awaiting approval on 31 October duplicate products within a company’s submis- zoal metronidazole); (d) were listed on the WHO 2017; however, no additional R&D projects were sion, the research team reviewed and validated EML (Section 6) as an alternative to another included for analysis after 8 September 2017; companies’ submitted portfolios. For analyses directly listed medicine (e.g. imipenem/cilastatin (2) for stewardship indicators, such as C.4 and at the individual company level, product data as alternative to meropenem). The dose, formu- C.7, programmes active at some point during the was aggregated at the INN level, since these lation and route of administration of the medi- period of analysis were included, regardless of were used to showcase the different active anti- cine was taken into consideration for points (a) their ending date. Financial data from fiscal year microbial ingredients that the company mar- and (b) only. 2016 was used for analysis (the exact date mark- keted (formulations, doses, routes of adminis- Antimicrobial medicines were further clas- ing the fiscal year end varies among companies). tration or brand names were not differentiated). sified into five antimicrobial categories: anthel- INN-level aggregation was performed both in minthic; antibacterial; antifungal; antiprotozoal the case of products with a single INN and fixed- and antiviral. These are the categories used to

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Data review Scoring METHODOLOGY DEVELOPMENT Companies were asked to verify the accuracy of All indicators were scored from zero to five and publicly sourced data and to provide additional weighted equally. When scoring a company on To develop the methodology for the 2018 necessary information. Prior to analysis, the a quantitative indicator, such as financial invest- Antimicrobial Resistance Benchmark, the Benchmark team reviewed companies’ submis- ments or R&D pipeline size, the corresponding Foundation applied its proven process for build- sions for each of the Research Areas: number was first scaled across all companies in ing consensus on the role of pharmaceutical scope for relative scoring. This number was then companies in tackling global health priorities. Research & Development: R&D projects con- used to determine scoring tiers from zero to five Strategic guidance was provided by an Expert sisting of antimicrobial medicines and vac- (with possibly non-uniform intervals). Committee for the Benchmark, an independent cines were included for the overall pipeline. When a given indicator was not applicable to body of experts, from top-level academic cen- R&D projects eligible for scoring had to target a company, the company’s maximum attainable tres, donor governments, local governments in at least one of the pre-defined priority path- score in the corresponding Research Area was low- and middle-income countries, investors and ogens (see Appendix II). R&D projects were decreased by an amount equal to the number of companies. The Expert Committee met in June classified as new or adaptive. Adaptive R&D maximum points attainable in that indicator. 2017 to review proposals for the scope, struc- projects do not involve a new chemical or bio- Scoring was carried out based on data ture and analytical approach of the Benchmark. logical entity (NCE or NBE); new R&D pro- from a wide range of information sources Their recommendations helped identify ways jects involve either an NCE or NBE. New medi- including companies themselves, independ- forward where disagreement or uncertainty cines in clinical development were further clas- ent reports and databases or documents from existed regarding areas of research. sified as novel when they fulfilled one or more the WHO, other multilateral organizations and of the following criteria, defined by WHO in Non-Governmental Organisations. For analy- The Expert Committee members: its 2017 analysis of the antibacterial clinical sis and scoring of R&D projects, the Benchmark Hans Hogerzeil (Chair) University of development pipeline¹: (a) it represents a new also reached out, where necessary, to external Groningen chemical class; (b) it aims at a new target; (c) experts and, in the case of projects developed in Greg Frank Biotechnology Inno- it has a new mode of action; (d) it displays no collaboration with other partners, to the latter. vation Organization cross-resistance from existing antimicrobials. For currency conversion to USD, exchange rates Nina Grundmann IFPMA After final submission and any necessary clari- on the website x-rates.com were used. Magdalena Kettis Nordea fications with the companies, all R&D projects Final scoring of the companies was the result Joakim Larsson University of Gothenburg were evaluated according to this standardised of a multi-tiered analysis and quality assurance Marc Mendelson University of Cape Town procedure. process. The quality assurance process included Katarina Nedog Medicines for Europe both systematic verification of scoring con- Evelina Tacconelli University of Tübingen Manufacturing & Production: the Benchmark sistency and spot-checking. For each indicator, Evelyn Wesangula Ministry of Health, Kenya requested companies to share their policies on preliminary scoring results were used to make the manufacturing of antibiotics. For transpar- adjustments in scoring guidelines to ensure Stakeholders by group ency indicator B.2, the research team reviewed maximum variability of final results. These pre- Discussions were held with representatives of a companies’ public information on, e.g., corpo- liminary results also led to the identification of a wide range of organisations, a list of which can rate websites, annual reports and corporate widespread lack of data in companies’ submis- be found in the methodology report for the 2018 social responsibility reports. sions for indicator C.8 in the AA&S Research Antimicrobial Resistance Benchmark, available Area – this indicator was subsequently removed for download at www.amrbenchmark.org. Appropriate Access & Stewardship: the from analysis. Benchmark requested companies to share their access and stewardship policies for anti- Review process biotics. For indicators on access to medicine, Following clarification and cross-check of com- companies were requested to disclose their pany scores, the research team wrote the var- five newest antibiotics, and their five high- ious sections of the Benchmark report. Each est-volume antibiotics and non-antibiotic anti- Research Area was reviewed by two externally microbial medicines listed on the WHO EML appointed expert advisors. In addition to this, (Section 6) (see Appendix III). Companies’ pol- an external editorial review of the Benchmark icies and strategies for these medicines were report was performed. then analysed in the various access-related indicators. For stewardship-related indicators, companies were asked to disclose: (a) product-specific strategies regarding appropriate promotion practices and brochure and packaging adaptations related to their five top-selling antibiotics; (b) non-product specific strategies regarding educational and surveillance activi- 1. WHO. (2017). Antibacterial agents in clinical development: an analysis of the antibacterial clinical develop- ties and over-the-counter sales control. ment pipeline, including tuberculosis. Retrieved from http://www.who.int/medicines/areas/rational_use/ antibacterial_agents_clinical_development/en/

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INDICATORS AND SCORING ELIGIBILITY

IN SCOPE FOR R&D IN SCOPE FOR M&P IN SCOPE FOR AA&S

Company A.1 A2.1 A2.2 A2.3 A.3 A.4 B.1 B.2 B.3 C.1 C.2 C.3 C.4 C.5 C.6 C.7

GSK ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Johnson & Johnson ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Merck & Co., Inc. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Novartis ● ● ● 0* ● ● ● ● ● ● ● ● ● ● ● ● Pfizer ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Roche ● ● ● 0* ● 0** ● ● ● ● ● ● ● ● ● ● Sanofi ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Shionogi ● ● ● 0* ● ● ● ● ● ● 0*** 0*** ● ● ● ● Aspen ● ● ● ● ● ● ● ● ● ● Aurobindo ● ● ● ● ● ● ● ● ● ● Cipla ● ● ● ● ● ● ● ● ● ● Dr. Reddy's ● ● ● ● ● ● ● ● ● ● Fresenius Kabi ● ● ● ● ● ● ● ● 0† ● Lupin ● ● ● ● ● ● ● ● ● ● Macleods ● ● ● ● ● ● ● ● ● ● Mylan ● ● ● ● ● ● ● ● ● ● Sun Pharma ● ● ● ● ● ● ● ● ● ● Teva ● ● ● ● ● ● ● ● ● ● Achaogen ● ● ● ● Cempra ● ● ● ● Entasis ● ● ● ● Melinta ● ● ● ● MGB Biopharma ● ● ● 0** Motif Bio ● ● ● ● Nabriva ● ● ● ● Polyphor ● ● ● ● Summit ● ● ● ● Tetraphase ● ● ● ● The Medicines Company ● ● ● ● Wockhardt ● ● ● ●

Large research-based pharmaceutical compa- research area, with the exception of two sub-in- in this area. Biopharmaceutical companies nies were eligible for scoring in every research dicators: A.1, assessing financial investments, were not eligible for scoring in M&P and AA&S area, with a few exceptions. Generic med- and A.2.3, assessing vaccines in the R&D pipe- because they either did not have products on icine manufacturers were eligible for scor- line. The latter was omitted because none of the the market or had small sales volumes and were ing in the M&P and AA&S research areas but biopharmaceutical companies assessed by the thus excluded in this iteration of the Benchmark. not in R&D, as their main focus is the manufac- Benchmark were active in vaccine R&D, and the Any evaluation of access and stewardship plans turing of generic products. Biopharmaceutical former because financial investments into anti- for R&D projects was done in indicator A.4. companies were eligible for scoring in the R&D microbial R&D are not reflective of their efforts

* No marketed vaccines ** No late-stage clinical projects (Phase II onwards, inc.) targeting priority pathogens *** No marketed products in countries in scope † The company’s antimicrobial medicines are all administered in hospitals, not directly dispensed to patients.

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APPENDIX VI Limitations

In this section we cover the main limitations such as the Pew Charitable Trust findings¹, our ing: biopharmaceutical companies and generic faced in the Benchmark. All limitations, method- findings in this category of companies should medicine manufacturers. These companies were ological, process or otherwise will be reviewed therefore not be taken to be representative of therefore not as familiar to the Foundation as by the Foundation when undertaking future all biotechnology companies involved in antimi- the large research-based pharmaceutical com- Benchmarks. crobial product development given the sheer panies with whom the Foundation has built a volume of such small and medium sized compa- relationship over the last ten years. This may GENERAL METHODOLOGICAL nies coming onto the market in the development have affected these companies’ extent of partic- LIMITATIONS of infectious disease medicines and vaccines. ipation in this first round of the Benchmark, par- As in any survey, main limitations relate to cover- Due to resource limitations, the Benchmark anal- ticularly in the case of generic medicine manage, sampling, non-responder and measurement ysis could only focus on biotechnology compa- ufacturers, whose participation was relatively biases. To the extent possible, the Benchmark nies targeting bacterial pathogens. Future iter- poor in comparison to other company types. research team strove to minimise the impact ations of the Benchmark may include a broader As in all survey and questionnaire methodol- of these biases in the final results. On cover- spectrum of pathogens. ogies, the data of the Benchmark is dependent age and representativeness, we attempted to Among the large research-based pharmaceu- on company submissions as the source data. In ensure that coverage of our survey represented tical companies and generic medicine manufac- order to mitigate any reporting bias, every effort as much as possible the wider antimicrobial turers, companies were selected based on their was made to triangulate company-submitted industry players with relevant activities across antibiotics business volume, signatories to the data by verifying it against public sources such the three Research Areas. The criteria used to Industry Roadmap on AMR or based on stake- as company annual reports, WHO reports and select companies for the Benchmark is outlined holder recommendation and willingness to par- clinical trial websites. The comprehensiveness in detail in our Methodology 2017. On respon- ticipate. The Benchmark findings on this cate- and level of detail available in public sources was siveness, we strove to minimise non-response gory of companies should therefore be taken in thus a limiting factor in the analyses. In so far as rates by making at least three attempts to con- this context. possible, when triangulation was not possible, tact companies included in the Benchmark. Depending on the research area being analysed, data was excluded from scoring. For example, in Whenever necessary, the Benchmark offered different company types might be included in the the R&D research area, only clinical stage prod- companies personalised calls and/or on-site analysis. For instance, within the R&D research ucts could be verified with publicly available data visits in order to improve understanding and area, indicators on the pipeline are applicable to and then scored. Though not scored, preclinical usability of the questionnaire, reduce misinter- both large research-based pharmaceutical com- and discovery stage projects were still included pretation of questions and improve accuracy of panies and smaller biopharmaceutical compa- on the overall reporting in the Benchmark. reporting by companies. nies. These are clearly very different company Furthermore, some information was submit- types with vastly different business models. In ted by companies on the basis of confidential- APPLICABILITY OF FINDINGS the Benchmark analysis, we corrected for these ity, thus making the Benchmark’s ability to ana- variations between company types, company lyse and report conclusions across several indi- Disease and product scopes size and company portfolio whenever relevant cators challenging. The outputs analysed in this study and the and possible. Further, the Benchmark provides findings generated from it relate only to the key information about companies’ antimicrobial disease, and product scopes as outlined in business in several sections of the report, which the Antimicrobial Resistance Benchmark readers should take into account as impor- Methodology 2017. For this first iteration of tant context when interpreting the Benchmark the Benchmark, a broad infectious disease findings. scope was chosen with specific focus on com- Different factors may affect companies’ pany activities for a list of priority pathogens capacity for reporting information. Some com- as determined by the WHO and CDC for the panies have submitted only a selection of their R&D research area. For the Manufacturing and antimicrobial business to the Benchmark. Hence, Production and Stewardship research areas, the the data presented in the “Portfolio Analysis” focus through stakeholder and expert review section of this report and on individual com- committee consensus was to focus on compa- pany report cards may not necessarily repre- ny’s initiatives and activities around antibiotics. sent their entire portfolio. Different companies The Access research area assessed more broadly also use different nomenclature and have differ- antimicrobial activities of included companies. ent ways of categorising information. For example, when calculating the value of antimicrobial Company comparability R&D investments or revenue from antimicrobi- The results and findings of this Benchmark als sales, such disaggregated data might not be relate to a subset of companies especially in readily available. In an effort to minimise variabil- the generic and biotechnology industry. Within ity in interpretation and ensure data consistency, the biotechnology companies, our findings rep- a glossary of definitions was published in the resent a specific subset of companies involved Benchmark Methodology 2017. namely in the clinical development of medicines and vaccines targeting bacterial pathogens in Data Availability an attempt to align our company selection with The Foundation includes for the first time, two ¹The PEW Charitable Trusts. (March, 2016). Antibiotics other international agencies active in this space different categories of companies in its report- Currently in Clinical Development.

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APPENDIX VII Scoring guidelines

A RESEARCH & DEVELOPMENT

A.1 R&D INVESTMENTS [New indicator text] 5 The company reports investments of over USD 1 billion in the develop- R&D investments (financial and in-kind) dedicated to the development of antimicrobial medicines and vaccines. ment of antimicrobial medicines and vaccines in the fiscal year 2016. 4 The company reports investments of USD 200 million to USD 1 billion [Original indicator text] in the development of antimicrobial medicines and vaccines. Financial R&D investments dedicated to the development of anti- 1 The company has an antimicrobial R&D pipeline, but did not report on microbial medicines and vaccines. The denominator is a company’s its investments. (i.e. research-based or generic) total revenue from its pharmaceuti- 0 There is no information that the company invests in the development cal and vaccine products. For biopharmaceutical companies, this is an of antimicrobial medicines and vaccines. absolute measurement. [Explanation for change] For this indicator, only large research-based pharmaceutical companies were scored. Investments were scored as absolute numbers, as this was sufficient to accurately capture a company’s commitment to antimicrobial R&D.

A.2 R&D PROJECTS [Original indicator text] Size of pipeline and public health value of its investigational antimicrobials and vaccines under development. Public health value is evaluated based on criteria such as targeting a priority pathogen and/or new mode of action. [Explanation for change] Following a review of the data, indicator A.2 (R&D projects) was divided into three sub-indicators to enable a more fine-grained comparison of companies’ pipelines. The three sub-indicators focus on: pipeline size (A2.1), number of novel candidates in clinical development (A2.2) and number of vaccines in the pipeline (A2.3).

A.2.1 Pipeline size The size of a company’s R&D pipeline targeting priority pathogens, 5-1 The number of medicines and vaccines in development by a company including medicines, vaccines and adaptations (developed in-house that target priority pathogens. This number is scaled across all com- or through collaborations). panies in the same company group and scored. Preclinical projects are awarded half the points of a clinical project. 0 The company has no relevant R&D activity within the scope of this indicator.

A.2.2 Novelty of pipeline The novelty of investigational clinical antimicrobial medicines tar- 5-1 The number of novel medicines in clinical development by a company geting priority pathogens that the company is developing (in-house that target priority pathogens. This number is scaled across all compa- or through collaborations). A compound is considered novel when nies in the same company group and scored. it meets at least one of the four criteria (as defined by WHO): a 0 The company has new investigational antimicrobial medicines targeting new chemical class; a new target; a new mode of action; and/or an priority pathogens in its pipeline, none of which are novel. absence of cross-resistance to existing antimicrobials.

A2.3 Vaccines in pipeline The number of new vaccines that the company is developing for pri- 5-1 The number of new vaccines in development by a company that target ority pathogens in scope (in-house or through collaborations). priority pathogens. This number is scaled across all companies in the same company group and scored. Preclinical projects are awarded half the points of a clinical project. 0 The company is engaged in vaccine development, but does not report on having new vaccines in development that target priority pathogens. NA The company is not engaged in vaccine development and has no relevant R&D activity within the scope of this indicator.

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A .3 R&D COLLABORATIONS [New indicator text] 5 The company engages in open collaborations and/or PDPs for the The company engages in open collaborations and public-private part- development of most of its projects (≥50%) in scope. nerships (PPP), such as Product Development Partnerships (PDPs), 4 The company engages in open collaborations and/or PDPs for the to overcome the scientific challenges of creating new antimicrobial development of 1-50% of its projects in scope. medicines and vaccines targeting priority pathogens. 3 The company does not engage in open collaborations and/or PDPs, but [Original indicator text] partners with NGOs and governments for the development of some of The company engages in open collaborations to overcome the scien- its projects in scope. tific challenges of creating new antimicrobial medicines and vaccines 2 The company does not engage in open collaborations and/or PDPs, but targeting priority pathogens. partners with universities and/or public institutes for the development [Explanation for change] of some of its projects in scope. Following data collection, the completeness and quality of all data 0 The company does not engage in open collaborations or PPPs. was reviewed and certain indicators refined. For this indicator, the scope of partnerships was broadened to public-private partnership.

A.4 ACCESS PROVISIONS The proportion of late-stage antimicrobial R&D projects that target 5 The company reports having access strategies in place for all its late- priority pathogens for which the company provides information on stage medicines and vaccines AND stewardship plans in place for all its having 1) access provisions for the countries in scope, and 2) global late-stage medicines. stewardship provisions in place. Late-stage R&D includes projects 4 The company reports having access strategies in place for all its late- from Phase II clinical development onwards (developed in-house stage medicines and vaccines OR stewardship strategies in place for all or through collaborations). Access & stewardship provisions refer its late-stage medicines. to plans for ensuring the future availability and affordability of new 3 The company reports having access strategies in place for some of its products in countries in scope, while also ensuring the future appro- late-stage medicines and vaccines AND/OR stewardship strategies for priate use of these products. some of its late-stage medicines. 2 The company reports having general commitments on access AND/OR stewardship in place for some of its late-stage medicines or vaccines. 1 The company reports having neither access nor stewardship provisions in place for any of its late-stage medicines or vaccines, but reports a commitment to it by having signed the Davos Declaration. 0 The company reports having neither access nor stewardship provisions in place for any of its late-stage medicines or vaccines.

B MANUFACTURING & PRODUCTION

B.1 ENVIRONMENTAL RISK MANAGEMENT STRATEGY The company has an environmental risk-management strategy to 5 The company demonstrates an environmental risk-management strat- minimise environmental impact of manufacturing discharge of anti- egy to minimise environmental impact of manufacturing discharge biotics. This strategy: 1) applies to its own facilities, to third-party of antibiotics that meets 9 out of the 9 elements* identified by the manufacturers of antibiotic API and drug products and to exter- Benchmark. nal waste-treatment plants; 2) includes auditing; and 3) includes dis- 4 The company demonstrates an environmental risk-management strat- charge limits. egy to minimise environmental impact of manufacturing discharge of antibiotics that meets 6-8 of the 9 elements identified by the *The 9 elements include: 1. Environmental risk-management strat- Benchmark. egy applicable to 1.1) own manufacturing sites, 1.2) third-party man- 3 The company demonstrates an environmental risk-management strat- ufacturers of API and drug products, 1.3) external waste-treat- egy to minimise environmental impact of manufacturing discharge ment plants; 2. Audits performed on the implementation of its strat- of antibiotics that meets 3-5 of the 9 elements identified by the egy at 2.1) own manufacturing sites, 2.2) third-party manufacturers Benchmark. of API and drug products, 2.3) external waste-treatment plants; 3. 2 The company demonstrates an environmental risk-management strat- Antibiotic discharge limits set and applied to 3.1) own manufacturing egy to minimise environmental impact of manufacturing discharge of sites, 3.2) third-party manufacturers of API and drug products, 3.3) antibiotics that meets 2 of the 9 elements identified by the Benchmark. external waste-treatment plants. 1 The company demonstrates an environmental risk-management strategy to minimise environmental impact of manufacturing discharge of antibiotics that meets 1 of the 9 elements identified by the Benchmark. 0 The company demonstrates no information on an environmental risk-management strategy to minimise environmental impact of manufacturing discharge of antibiotics.

B.2 DISCLOSURE ON ENVIRONMENTAL RISK MANAGEMENT The company publicly discloses: 1) its environmental risk-manage- 5-1 The company publicly discloses: 1. its environmental risk-management ment strategy to minimise environmental impact of manufacturing strategy to minimise environmental impact of manufacturing discharge discharge of antibiotics; 2) results of audits on this strategy of the of antibiotics; 2. results of audits on this strategy of the company’s company’s manufacturing sites; 3) results of audits on this strategy manufacturing sites; 3. results of audits on this strategy of third parties’ of third parties’ manufacturing sites of antibiotic API and drug prod- manufacturing sites of antibiotic API and drug products and of waste- ucts and of wastewater treatment plants; 4) the identities of its third water treatment plants; 4. the identities of its third parties manufac- parties manufacturing antibiotic API and drug products, and antibi- turing antibiotic API and drug products, and antibiotic waste treatment otic waste treatment plants; 5) the levels of antibiotic discharge. plants; 5. the levels of antibiotic discharge. The score is based on the number of these elements that are publicly disclosed. 175 Antimicrobial Resistance Benchmark 2018

0 The company demonstrates no information on public disclosure of any of the defined 5 criteria.

B.3 MANUFACTURING HIGH-QUALITY ANTIBIOTICS The company makes commitments to ensure that its own and third- 5 The company reports a commitment to maintain high quality of anti- party production facilities manufacturing antibiotic drug products biotic production consistent with international standards such as the maintain high quality of antibiotic production consistent with inter- FDA, EU and/or WHO Good Manufacturing Practice that apply to all national standards developed and accepted by recognized national company’s manufacturing sites AND to third-party manufacturers of and international authorities. antibiotic drug products. 2,5 The company reports a commitment to maintain high quality of antibiotic production consistent with international standards such as the FDA, EU and/or WHO Good Manufacturing Practice (GMP) that apply to all company’s manufacturing sites, but not to third-party manufacturers of antibiotic drug products. 0 The company demonstrates no information on commitments to maintain high quality of antibiotic production consistent with international standards such as the FDA, EU and/or WHO Good Manufacturing Practices.

C ACCESS & STEWARDSHIP

C.1 REGISTRATION OF ANTIBIOTICS The company files to register its newest antibiotics in the highest 5 The company provides information on filing to register all five of its number of countries in scope. newest antibiotics in countries in scope. Each antibiotic is reported as filed for registration in >40% of countries in scope. 4 The company provides information on filing to register all five of its newest antibiotics in, on average, >40% of the countries in scope. 3 The company provides information on filing to register some of its newest antibiotics in, on average, 20-40% of the countries in scope. 2 The company provides information on filing to register all its newest antibiotics in, on average, 1-20% of the countries in scope. 1 The company provides information on filing to register some of its newest antibiotics in, on average, 1-20% of the countries in scope. 0 The company demonstrates no information on filing to register any of its newest in any countries in scope.

C.2 PRICING OF ANTIMICROBIALS The company commits to implement an appropriate access strategy 5 The company makes a general commitment that includes inter- and that includes affordability considerations of its highest-volume anti- intra-country equitable pricing on appropriate access for its high- biotics and non-antibiotic antimicrobial medicines for countries in est-volume antibiotics and non-antibiotic antimicrobial medicines that scope. is applied in >50% of the countries in scope as well as a product-specific commitment for more than one of its products. 4,5 The company makes a general commitment that includes inter- and intra-country equitable pricing on appropriate access for its highest-volume antibiotics and non-antibiotic antimicrobial medicines that is applied in >50% of the countries in scope OR has a product-specific commitment for more than one product. 4 The company makes a general commitment that includes inter- and intra-country equitable pricing on appropriate access for its highest-volume antibiotics and non-antibiotic antimicrobial medicines that is applied in ≤50% of countries in scope. 3 The company makes a general commitment that includes inter-country equitable pricing on appropriate access for its highest-volume antibiot-ics and non-antibiotic antimicrobial medicines for countries in scope. 1 The company makes a general commitment on appropriate access for its highest-volume antibiotics and non-antibiotic antimicrobial medicines for countries in scope. 0 The company makes no commitment on appropriate access for its highest-volume antibiotics and non-antibiotic antimicrobial medicines for countries in scope.

C.3 ENSURING CONTINUOUS SUPPLY The company has mechanisms* in place to improve supply chain effi- 5 The company engages with relevant stakeholders to align its supply ciency aimed at preventing stock-outs and improving demand fore- and demand forecasting for (>50%) of its highest-volume antibiotics casting of its highest-volume antibiotics and non-antibiotic antimi- and non-antibiotic antimicrobial medicines for countries in scope AND crobial medicines so as to ensure sustainable delivery to countries has mechanism(s) in place to respond efficiently in the event of stock- in scope. outs for (>50%) of its highest-volume antibiotics and non-antibiotic antimicrobial medicines for countries in scope. 176 Access to Medicine Foundation

*Mechanisms include: 1) engagement with relevant stakehold- 3 The company engages with relevant stakeholders to align its supply ers (e.g., governments, PAHO, UNICEF) to align supply and demand and demand forecasting for (≤50%) of its highest-volume antibiotics forecasting so as to prevent or minimise stock-outs in countries in and non-antibiotic antimicrobial medicines for countries in scope AND scope (i.e. LMIC); and 2) ability to respond efficiently in the event has mechanism(s) in place to respond efficiently in the event of stock- of stock-outs, e.g., faster, more precise and cheaper manufacturing outs for (≤50%) of its highest-volume antibiotics and non-antibiotic approaches, rationalising the manufacture process so that number of antimicrobial medicines for countries in scope. product packs and packaging can be standardised to simplify manu- 2 The company engages with relevant stakeholders to align its supply facture and distribution to poor access areas. and demand forecasting for (>50%) of its highest-volume antibiotics and antimicrobial medicines for countries in scope OR has mechanism(s) in place for (>50%) of its highest-volume antibiotics and non-antibiotic antimicrobial medicines for countries in scope in order to respond efficiently in the event of stock-outs in countries in scope. 1 The company engages with relevant stakeholders to align its supply and demand forecasting for (≤50%) of its highest-volume antibiotics and antimicrobial medicines for countries in scope OR has mechanism(s) in place for (≤50%) of its highest-volume antibiotics and non-antibiotic antimicrobial medicines for countries in scope in order to respond efficiently in the event of stock-outs in countries in scope. 0 The company does not engage with relevant stakeholders to align its supply and demand forecasting for its antibiotics and non-antibiotic antimicrobial medicines for countries in scope and has no mechanism(s) in place to respond efficiently in the event of stock-outs in countries in scope.

C.4 SUPPORTING EDUCATIONAL STEWARDSHIP ACTIVITIES [New indicator text] 5 The company engages in educational activities, most with a clear con- The company engages and/or supports educational activities to edu- flict of interest mitigation strategy and content development inde- cate healthcare professionals on antibiotic stewardship, with a clear pendence, focussed on a combination of: AMR specific topics; stew- conflict of interest mitigation strategy* for its educational materials. ardship topics; and the rational use of antibiotics, all delivered through [Original indicator text] active learning methods. The company engages and/or supports educational activities that are 4 The company engages in educational activities, most with a clear con- non-product specific to educate healthcare professionals (HCP) about flict of interest mitigation strategy and content development inde- antibiotic stewardship. pendence, focussed on a combination of: AMR specific topics; stewardship topics; and the rational use of antibiotics, delivered through pas- *An educational activity has a conflict of interest mitigation strategy sive learning methods. when it does not involve branding materials, product-specific con- 3 The company engages in educational activities, most with a clear contents or commercial teams, amongst others. flict of interest mitigation strategy and content development independence, focussed on AMR specific topics or the rational use of antibiotics. 2 The company engages in educational activities, and provides for some of its projects, evidence of an independent review of the development of its contents as a conflict of interest mitigation strategy. 1 The company engages in educational activities and reported commitment to conflict of interest mitigation, but provided no information on independent content development of its materials. 0 The company does not provide evidence of engaging in any activity to educate healthcare professionals on antibiotic stewardship.

C.5 APPROPRIATE PROMOTIONAL ACTIVITIES [New indicator text] 5 The company reports taking into account AMR trends and guidelines The company adopts appropriate promotion practices that advance in its marketing materials AND has formal processes in place to incen- appropriate use of antibiotics in its promotional activities and has tivise appropriate promotion practices focussed on antibiotic steward- mechanisms in place to incentivise appropriate promotion practices ship, OR deploys no sales agents to promote all of its antibiotics. for its antimicrobial portfolio. 4 The company reports taking into account AMR trends and guidelines [Original indicator text] in its marketing materials AND commits to develop strategies to incen- The company adopts ethical marketing practices that advance appro- tivise appropriate promotion practices focussed on antibiotic steward- priate use of antibiotics in its promotional activities, and has mecha- ship, OR deploys no sales agents to promote some of its antibiotics. nisms in place to incentivise ethical marketing practices by its in-house 2 The company reports taking into account AMR trends and guidelines and/or third-party sales representatives. in its marketing materials, but does not implement appropriate promo- [Explanation for change] tion practices to its sales agents. Following data collection, the completeness and quality of all data 0 The company does not report about engaging in appropriate promo- was reviewed and certain indicators refined. For this indicator, the tion practices that advance appropriate use of its antibiotics. aspect focussing on third-party sales representatives was not scored due to the absence of adequate data.

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C.6 BROCHURE AND PACKAGING [New indicator text] 5 The company provides information on more than two brochure and The company implements brochure and packaging adaptation to packaging adaptations, consisting of at least one general state- facilitate appropriate use of antibiotics by patients, for its high- ment on appropriate use of antibiotics, and one literacy and language est-volume antibiotics. The company considers local needs, such as consideration. literacy and language, when adapting brochure and packaging. 4 The company provides information on two brochure and packaging [Original indicator text] adaptations, consisting of at least one general statement on appropri- The company implements brochure and packaging adaptation to facil- ate use of antibiotics, and one literacy and language consideration. itate appropriate use of antibiotics by patients, beyond local regulatory 3 The company provides information on two brochure and packaging requirements, for its highest-volume antibiotics. The company consid- adaptations, which consist of a general statement on appropriate use ers local needs – literacy, language, cultural, demographic and environ- of antibiotics. mental considerations – when adapting brochure and packaging. 2 The company provides information on one brochure and packaging [Explanation for change] Following data collection, the completeness adaptation, which consists of a general statement on appropriate use and quality of all data was reviewed and certain indicators refined. For of antibiotics. this indicator, the aspect on adaptation beyond regulatory require- 0 The company does not provide information on packaging and brochure ments was not scored due to the absence of adequate data. adaptations.

C.7 ANTIMICROBIAL RESISTANCE SURVEILLANCE The company has/supports/contributes to local and/or global antibi- 5 The company engages or participates in at least one long-term* AMR- otic resistance surveillance programmes. surveillance programme that shares the results publicly in open data- sets and collaborates with Public Health authorities. *Long term AMR-surveillance programmes include programmes 4 The company engages or participates in at least one long-term* AMR- that are periodically repeated at least every two years and/or pro- surveillance programme and provides evidence of sharing the results grammes that are ongoing for at least three years. with Public Health authorities. 3 The company engages or participates in at least one AMR-surveillance programme, providing evidence of sharing the results via peer-reviewed journals or congresses. 2 The company engages or participates in at least one AMR-surveillance programme, but there is no evidence of a clear data-sharing policy. 0 The company does not provide information on engaging or participating in any AMR-surveillance programmes.

C.8 OTC SALES CONTROL The company has innovative models and mechanisms in place with relevant stakeholders to reduce uncontrolled antibiotic purchase, such as over-the-counter (OTC) and non-prescription sales.

Following data collection, all data was reviewed and certain indicators refined. In this case, the completeness and quality of data did not allow for an evaluation of the indicator.

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APPENDIX VIII Guide to Report Cards

This document provides a description of each section of the Report Cards for the 2018 Antimicrobial Resistance Benchmark.

Section Description Source

General company information Company name, Stock exchange(s), Stock exchange ticker(s), Location of head- • Annual report for the fiscal year ending 31 December (header) quarters, Number of employees, Signatory to Davos Declaration, Signatory to 2016 or later (or, equivalently, forms 10-K or 20-F) Industry Roadmap • Company website • Industry Roadmap for Progress on Combating Antimicrobial Resistance (September 2016) • Davos Declaration signatories list (as of January 2017)

Performance by Research This graph shows the company’s scores for each of the RAs in which it was scored. • Benchmark analysis Area (RA) (figure)

How company was evaluated: This figure shows the indicators that were applicable to the company. • Benchmark methodology applicable indicators (by RA)

Performance (text) This section summarises the company’s overall performance in the Benchmark. It • Benchmark analysis covers: • Drivers behind its scores • Main areas where the company scores well or poorly compared to peers

Sales and Operations (text) This section provides a general description of the company’s global operations, • Company’s annual report including recent changes in its business (e.g., acquisitions or divestments), focus- • Company’s website sing on its antimicrobial business. • Press releases by company or other pharmaceutical news websites For biopharmaceutical companies with no products on the market, this section is • Stock exchange communications called “Operations” • Methodology 2017 • Benchmark analysis

Revenues by product (figure) Where possible, this figure shows a breakdown of the company’s revenues into: • Company’s annual report vaccines, antimicrobial medicines, other.

When disaggregated revenue figures were not available, the figure shows the company’s total revenue.

Revenues by region (figure) This figure shows a breakdown of the company’s sales or operating revenues by • Company’s annual report (terminology is as close to geographic region the annual report as possible)

Antimicrobial Portfolio (text) This section provides a description of the number and type of antimicrobial medi- • Benchmark methodology and analysis cines the company markets as of September 2017 and the proportion included on • Registered products identified from the EMA, FDA, the WHO EML (Section 6) PMDA, and the company’s website. • WHO EML (Section 6), 20th List, March 2017 (amended August 2017)

Antimicrobial Portfolio This figure shows a breakdown of the number of antimicrobial medicines the com- • Benchmark methodology and analysis (figure) pany markets as of September 2017 into antibiotics and other antimicrobials, and • Registered products identified from the EMA, FDA, the number of antibiotics on the WHO EML (Section 6). PMDA, and the company’s website This includes a breakdown of the proportion of the company’s EML antibiotic port- • WHO EML (Section 6), 20th List, March 2017 folio that falls into the EML’s Access, Watch, and Reserve groups. (amended August 2017)

Opportunities (text) This section outlines opportunities for the company to do more to address AMR. • Benchmark analysis The opportunities take into account company-specific characteristics as far as possible.

Performance by RA (text) These three sections summarise company performance for each of the RAs, by • Benchmark methodology indicator. The paragraphs describe the company’s performance and highlight • Benchmark analysis (where available) relevant examples of its activities.

Following a review of the data, indicator A.2 (R&D projects) was divided into three sub-indicators to enable a more fine-grained comparison of companies’ pipelines. The three sub-indicators focus on, respectively, pipeline size (A2.1), number of novel medicine candidates (A2.2) and number of vaccines in the pipeline (A2.3). In R&D, access and stewardship provisions are analysed for late-stage projects only. This includes projects in clinical Phase II or III as well as projects awaiting approval or approved by 31 October 2017.

Antimicrobial Pipeline (figure) This figure shows the company’s pipeline of vaccines and antimicrobial R&D pro- • Projects submitted by the company for scoring and jects targeting priority pathogens. analysis in the Benchmark, including verification/ Where applicable, regulatory approvals (including label extensions) are noted, cross-reference with publicly available pipeline infor- including the regulatory body/location and date of approval. mation. Approval data is verified using public sources. Data omissions due to confidentiality agreements are noted, in addition to changes to the status of projects taking place until 31 October 2017.

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APPENDIX IX List of figures

7 Figure 1. Antmicrobial Resistance Benchmark – Company Performances 10 Figure 2. Antibiotic resistance and increased risk of death 12 Figure 3: Change in the Number of New Antibacterial Drug Approvals in USA 1980-2014. 17 Figure 4. Pharmaceutical companies are active in ten AMR priority areas. 18 Figure 5. 30 companies in scope 19, 20 Figure 6. Comparing scores: large research-based pharmaceutical companies. 19, 20 Figure 7. Comparing potential: large research-based pharmaceutical companies. 19, 21 Figure 8. Comparing scores: generic medicine manufacturers. 19, 21 Figure 9. Comparing potential: generic medicine manufacturers. 19, 22 Figure 10. Comparing scores: biopharmaceutical companies. 19, 22 Figure 11. Comparing potential: biopharmaceutical companies. 24 Figure 12. Few late-stage antibiotics with access and stewardship plans. 25 Figure 13a. Nine out of 19 companies support AMR surveillance. 25 Figure 13b. AMR surveillance programmes are being conducted in 147 countries worldwide. 26 Figure 14. Eight companies set discharge limits. No company publishes discharge levels. 27 Figure 15. Decoupling sales volumes from sales agents’ bonuses: four companies are taking action 28 Figure 16. Which antimicrobial medicines are available on the market? 29 Figure 17. Companies in scope have 268 antibiotics on the WHO EML (Section 6). 34 Figure 18. Global coverage of older vaccines exceeds 80% - for newer vaccines coverage remains relatively low 36 Figure 19. More research and development needed on vaccines against priority pathogens. 37 Figure 20. Five companies market and develop vaccines for priority pathogens. 40 Figure 21. Company performance: research & development 42 Figure 22. Companies in scope 45 Figure 23. Antimicrobial pipelines contain 276 R&D projects. 45 Figure 25. Breakdown of the clinical pipeline for priority pathogens. 45 Figure 24. Criteria for WHO and CDC prioritisation of pathogens. 46 Figure 26. GSK is developing the most projects that target priority pathogens. 46 Figure 27. Projects targeting priority pathogens by biopharmaceutical companies. 48 Figure 28. What makes an antibiotic novel? 48 Figure 29. Few novel clinical-stage projects targeting priority bacteria. 50 Figure 30. Half of new R&D projects involve partnerships with public or non-profit partners. 50 Figure 31. Half of the partnering bodies are focussed on antibacterial R&D. 55 Figure 32. Almost half of the companies have at least one access and/or stewardship provision in place for a late-stage clinical candidate. 58 Figure 33. Company performance: Manufacturing & Production 60 Figure 34. Companies in scope 62 Figure 35. Depth and breadth of environmental risk-management strategies vary widely. 64 Figure 36. More than half of companies publicly disclose GMP commitments. 66 Figure 37. Company performance: Access & Stewardship 68 Figure 38. Companies in scope 70 Figure 39. Almost 65% of antibiotics are registered in countries where access is less likely. 70 Figure 40. Four antibiotics have been filed in more than half of the countries in scope. 71 Figure 41. Only three companies have registered new antibiotics in low- and middle-income countries this decade. 74 Figure 42. Companies prefer active learning techniques to educate HCPs. 75 Figure 43. Companies deliver AMR-related content through a mix of activities. 75 Figure 44. Only five of the 29 programmes run educational webcasts. 75 Figure 45. Non-branded educational materials are the most common conflict of interest (COI) mitigation techniques. 77 Figure 46. Nine companies commit to reviewing promotional activities. 79 Figure 47. AMR surveillance: Number, geographical scope and length of surveillance programmes 79 Figure 48. AMR surveillance programmes are being conducted in 147 countries worldwide.

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APPENDIX X Definitions

Access provisions Antibiotic stewardship ally, but not necessarily, in association with one [Working definition, used for analysis] Antibiotic stewardship is a systematic and com- or more other ingredients. Also referred to as Provisions to ensure that within the scope of the prehensive process that aims to ensure that all formulations. Benchmark, public health needs are taken into aspects of prescription (e.g., drug, dose, dura- consideration during R&D. Access provisions tion), dispensing and use of antibiotics follow Environmental risk management can be included in R&D partnerships and/or in the evidence available in order to minimise the [Working definition, used for analysis] in-house R&D. They facilitate availability, acces- emergence of resistance. Environmental risk management seeks to deter- sibility and affordability for patients in countries mine what environmental risks exist from antibi- within the scope of the Benchmark (e.g., equi- AMR surveillance otic production and determines how to manage table pricing strategies, sufficient supply com- [Working definition, used for analysis] those risks in the way best suited to protect mitments, non-exclusivity in specified terri- Continuous, systematic collection, analysis and human health and the environment, in particular tories, waiving for patent rights, royalty-free interpretation of antimicrobial infection and to the emergence of antibiotic resistance. provisions). resistance-trend data needed for the planning, implementation, and evaluation of antimicrobial Equitable pricing strategy Active pharmaceutical ingredient stewardship activities. [Working definition, used for analysis] The active pharmaceutical ingredient (API) is the A targeted pricing strategy, which aims at effective part of any medicine. Some medicines, Antimicrobial medicines improving access to medicines and vaccines for such as combination therapies, have multiple [Working definition, used for analysis] those in need by taking affordability for individ- active ingredients to treat different symptoms or Medicines used to treat infectious diseases by uals and healthcare systems into account in a act in different ways. directly targeting the bacteria, fungi, helminths, manner that is locally appropriate. protozoa or viruses that cause the infection (as Active learning methods opposed to targeting the symptoms of the infec- Falsified medicine Method of learning in which attendees are tion or toxins produced by the pathogen). A medicine which is deliberately and fraudu- actively participating in the learning process, lently mislabelled with respect to identity and/ not only passively listening, such as courses and Antimicrobial resistance or source. Falsified medicines may contain no congresses. Resistance in different types of microorganisms; active ingredient, the wrong active ingredi- encompasses resistance to antibacterial, anti- ent or the wrong amount of the correct active Adaptive R&D viral, antiprotozoal, antifungal and anthelmintic ingredient. [Working definition, used for analysis] medicines. See Antibiotic resistance. R&D adaptations to existing medicines and/or Generic medicine vaccines. This includes new formulations, new Appropriate promotional practices A medicine that is comparable to an origina- fixed dose combinations of existing chemical or [Working definition, used for analysis] tor medicine in dosage form, strength, route of biological entities, a new target demography or Promotional activities targeting the general administration, quality and performance charac- the repurposing of an existing product for addi- public, patients and healthcare professionals in teristics, and intended use. tional indications. such a way that transparency, integrity, accuracy, clarity and completeness of information can be Good Manufacturing Practices Affordability ensured. Good manufacturing practice (GMP) is a system [Working definition, used for analysis] to ensure that products are consistently pro- A measure of the payer’s ability to pay for a Appropriate use of antibiotics duced and controlled according to quality stand- product (whether or not they are the end user). The cost–effective use of antibiotics, which ards. It is designed to minimise the risks involved The Benchmark takes this into account when maximises clinical therapeutic effect while mini- in any pharmaceutical production that cannot be assessing pricing strategies for relevant prod- mising both drug-related toxicity and the devel- eliminated through testing the final product. ucts in scope. opment of antimicrobial resistance (WHO Global Strategy for Containment of Antimicrobial Healthcare Professionals Antibiotic Resistance). Any specialised worker in any branch of health- [Working definition, used for analysis] care that provides preventive, curative or reha- Antimicrobial medicine to treat bacterial infec- Broad-spectrum antibiotics bilitative services to the community. tions by directly targeting the bacteria that Broad-spectrum antibiotics are active against a cause the infection (as opposed to targeting the wider number of bacterial types and, thus, may Herd immunity symptoms of the infection or toxins produced be used to treat a variety of bacterial infections. The resistance to the spread of a contagious dis- by the pathogen). Equivalent to antibacterial ease within a population that results if a suffi- medicine. Conflict of interest ciently high proportion of individuals are immune Situation where the primary interest of protect- to the disease, especially through vaccination. Antibiotic resistance ing and promoting public health conflicts with a Resistance that occurs when bacteria change secondary interest, such as financial incentives Late-stage drug development in response to the use of antibiotics used to or non-financial incentives. [Working definition, used for analysis] treat bacterial infections (such as urinary tract Medicine and vaccine candidates in Phase II or infections, pneumonia, bloodstream infections) Drug product III clinical development. Products approved (or making them ineffective. A finished dosage form, e.g., tablet, capsule, or awaiting approval) in 2016-2017 are also catego- solution that contains a drug substance, gener- rised as late-stage.

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prises Phase I-III clinical development. Products are taken into consideration during R&D. Narrow-spectrum antibiotics approved (or awaiting approval) in 2016-2017 Stewardship provisions can be included in R&D Narrow-spectrum antibiotics are active against are also categorised as clinical stage. partnerships and/or in in-house R&D. They facil- a selected group of bacterial types. Examples itate the appropriate use of antimicrobial med- are colistin, an antibiotic that selectively tar- Predicted no-effect concentration icines and reduce the emergence of resistance gets gram-negative bacteria, and vancomycin, The predicted no-effect concentration (PNEC) (e.g., appropriate promotion and surveillance). an antibiotic that selectively targets gram-posi- is the concentration of a substance in any envi- tive bacteria. ronment below which adverse effects will most Substandard antibiotics likely not occur during long-term or short-term Authorised medical products, in this case antibi- Novel drug candidate exposure. otics, that fail to meet either their quality stand- [Working definition, used for analysis] ards or their specifications, or both. Also called To qualify as novel, a candidate must fulfil one Priority pathogen “out of specification”. or more of the criteria defined by WHO’s report [Working definition, used for analysis] on antibacterial agents in clinical development: it Pathogens for which new innovative medicines represents a new chemical class; aims at a new and vaccines are highly needed. The priority target; has a new mode of action; and/or has an pathogens were identified based on the WHO absence of cross-resistance from existing anti- priority pathogens list as of 25 February 2017 microbials. This classification was applied to can- and CDC’s US Biggest Threats as of April 2013. didates in clinical stage only and validated by WHO and/or external experts. Product Development Partnership [Working definition, used for analysis] One Health Product Development Partnerships (PDPs) take Approach to designing and implementing public the form of centralised non-profit organisations health programmes, policies, legislation and that facilitate financial risk-sharing across the research in which multiple sectors communi- public and private sectors by pooling and sharing cate and work together to achieve better out- resources, both tangible and intangible, for the comes. The areas of work in which a One Health development of medicines, vaccines and other approach is particularly relevant include food health tools. safety, the control of zoonosis, and combating antimicrobial resistance. Public-private partnership [Working definition, used for analysis] Open collaborations A partnership between one or more public [Working definition, used for analysis] organisations and the private sector for provid- A multi-stakeholder partnership that focusses ing a public asset or service, in which the private on pharmaceutical R&D, such as a Product party bears significant risk and management Development Partnership (PDP) and open responsibility, and remuneration is linked to per- research consortia, with an open approach to formance. The Benchmark also considers a part- pooling and sharing resources such as data and nership between a non-profit organisation and expertise between partners. the private sector as a public-private partnership (PPP). Originator medicine The medicine that was first authorised world- Pull incentives wide for marketing, normally as a patented prod- Pull incentives reward a successful result or uct, on the basis of the documentation of its research and development of a new antimi- efficacy, safety and quality, according to require- crobial medicine and provide known return on ments at the time of authorisation. The origina- investment. Examples of pull incentives are tor medicine always has a brand name; this name extended exclusivity periods, higher reimburse- may, however, vary among countries. ment or market entry rewards.

Over-the-counter medicine Push incentives Purchase of a medicine by ordinary retail with- Push incentives lower the cost of and de-risk out prescription from a healthcare professional. research and development of a new antimicrobial drug. Examples of push incentives are Preclinical & clinical drug development stage grants, partnerships or tax credits. [Working definition, used for analysis] Preclinical stage development includes the dis- Stewardship provisions covery and preclinical phase of drug develop- [Working definition, used for analysis] ment. The clinical development stage com- Provisions to ensure that public health needs

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APPENDIX XI Acronyms

AA&S Appropriate Access and Stewardship HiHDI High Human Development Country with High ABSSSI Acute Bacterial Skin and Skin Structure Infection Inequality ACT Artemisinin-based combination therapy HIV Human Immunodeficiency Virus AIDS Acquired immune deficiency syndrome HVTN HIV Vaccine Trials Network AMR Antimicrobial resistance IFPMA International Federation of Pharmaceutical API Active pharmaceutical ingredient Manufacturers & Associations ARV Antiretroviral IP Intellectual property AST Antibiotic susceptibility testing IPO Initial Public Offering ATC Anatomical Therapeutic Chemical classification IV Intravenous BARDA US Biomedical Advanced Research and KOL Key opinion leader Development Authority LDC Least Developed Country BSAC British Society for Antimicrobial Chemotherapy LHDC Low Human Development Country BEAM Alliance Biotech companies in Europe combating LIC Low-Income Country AntiMicrobial Resistance Alliance LMIC Lower-Middle Income Countries BIO Biotechnology Innovation Organization M&P Manufacturing and Production cIAI Complicated intra-abdominal infection MAA Marketing authorization application CARB-X Combating Antibiotic Resistant Bacteria MEB Medicines Evaluation Board Biopharmaceutical Accelerator MGB Minor Groove Binder CABP Community-acquired bacterial pneumonia MHDC Medium Human Development Country CDC US Centers for Disease Control and Prevention MOOC Massive Open Online Courses CDDEP Center for Disease Dynamics, Economics and MRSA Methicillin-Resistant Staphylococcus aureus Policy MSF Médecins Sans Frontières CDI C. difficile infection MMV Medicines for Malaria Venture CHAI Clinton Health Access Initiative ND4BB New Drugs for Bad Bugs CME Continuing medical education NGO Non-governmental organisation CNS Central nervous system NGS Next Generation Sequencing COI Conflict of interest NIAID US National Institute of Allergy and Infectious CRE Carbapenem-resistant Enterobacteriaceae Diseases cUTI Complicated urinary tract infection OECD Organisation for Economic Co-operation and DDD Defined daily dose Development DNA Deoxyribonucleic acid OMPTA Outer Membrane Protein Targeting Antibiotic DNDi Drugs for Neglected Disease Initiative OTC Over-the-counter DRIVE-AB Driving reinvestment in research & development PAHO Pan American Health Organization and responsible antibiotic use PEPFAR President's Emergency Plan for AIDS Relief EC Expert Committee of the AMR Benchmark PDP Product Development Partnership ECOSOC United Nations Economic and Social Council PMDA Japan Pharmaceuticals and Medical Devices EML WHO Model List of Essential Medicine, March 2017 Agency (amended August 2017) R&D Research and Development EMA European Medicines Agency RNA Ribonucleic acid EU European Union SARS Severe Acute Respiratory Syndrome ESBL Extended-spectrum ß-lactamase SOP Standard Operating Procedures FAIRR Farm Animal Investment Risk and Return SSA Sub-Saharan Africa FDA US Food and Drug Administration SU Standard Units FDC Fixed dose combination TGA Australia Therapeutic Goods Administration FYE Fiscal year end The Benchmark The Antimicrobial Resistance Benchmark GARDP Global Antibiotic Research & Development The Foundation Access to Medicine Foundation Partnership The Global Fund The Global Fund to Fight AIDS, Tuberculosis and GBS Group B Streptococcus Malaria GDP Gross Domestic Product UNDP United Nations Development Programme GLASS Global Antimicrobial Resistance Surveillance USAID United States Agency for International System Development GMP Good Manufacturing Practice USSSI Uncomplicated skin and skin structure infection GNI Gross national income VABP Ventilator-associated bacterial pneumonia GUARD Global Union for Antibiotics Research and VRE Vancomycin-resistant Enterococcus Development WHO World Health Organization HABP Hospital-acquired bacterial pneumonia ZLD Zero Liquid Discharge HBV Hepatitis B Virus HCP Healthcare professional HCV Hepatitis C Virus

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