WHO Drug Information Vol. 30, No. 4, 2016

WHO Drug Information Contents

ICDRA for rare diseases; Japan joins international collaboration on GMP inspections; Mapping of 547 17th International Conference of Drug global medicines regulatory initiatives; MHRA Regulatory Authorities and Swissmedic sign agreement 586 Use of medicines Report on sales of veterinary antibiotics in Regulatory collaboration Europe; Indian FDC ban reversed 558 Collaboration, not competition: 586 Under discussion developing new reliance models Approved

587 Obeticholic acid : for rare, chronic liver disease; Insulin aspart : for diabetes mellitus; Insulin

Medicines regulation glargine/lixisenatide : for diabetes mellitus; Lonoctocog alfa : for haemophilia

567 Comparison of medicines legislation in the A; Etelcalcetide : for secondary hyperparathyroidism; Tenofovir alafenamide :

East African Community for chronic hepatitis B; Olaratumab : for soft tissue sarcoma; Palbociclib : for breast cancer; Eteplirsen :

for Duchenne muscular dystrophy; Baricitinib :: for rheumatoid arthritis; Naloxone nasal spray : for opioid overdose;

Edotreotide : for diagnosis of gastro-entero-pancreatic neuroendocrine tumours; Safety news 589 Biosimilars

577 Safety warnings Insulin glargine; Teriparatide; Rituximab;

DPP-4 inhibitors : Pemphigoid; Polaprezinc : copper deficiency; Brimonidine Adalimumab-atto

gel : worsening of rosacea symptoms ; Levonorgestrel emergency 590 Extension of indications

contraceptives : interactions with liver enzyme inducers; Direct-acting antivirals : hepatitis B reactivation; HIV Empagliflozin : to reduce cardiovascular risk in diabetes; Maraviroc : for use in children; Nivolumab: for Hodgkins lymphoma;

treatment-boosting agents and steroids : systemic adverse Canakinumab : for rare and serious auto-inflammatory diseases;

effects; Nivolumab : immune thrombocytopenic purpura, myocarditis, rhabdomyolysis; Eculizumab : interaction with meningococcal vaccine; Anaesthetics and sedatives in young children and pregnant women Publications and events 580 Known risks 591 Research and ethics

Pioglitazone : bladder cancer; Warfarin and miconazole : Revised CIOMS ethical guidelines

contraindicated; Statins: immune-mediated necrotizing myopathy ; Daptomycin : acute generalized exanthemous pustulosis; NSAIDs: increased risk of 591 Access to medicines

miscarriage; Paracetamol : updated labelling to address risk of liver injury; Lurasidone and certain ARVs : contraindicated; UN High Level Panel report on access to 581 Labelling changes health technologies; Report of the Lancet

Metformin : for patients with moderate kidney impairment; Etoricoxib : lower recommended dose; Commission on Essential Medicines; Access 582 Improved dosing instructions to Medicine Index 2016; High price of Levetiracetam oral solution hepatitis C treatment; Medicines patent 583 Unchanged recommendations and licences database upgraded; Updated

Urine- and plasma-derived medicines : safe regarding Zika; paediatric ARV formulary and list 583 Non-compliance with good practices 594 Quality of medicines

Pharmaceutics International Inc., U.S.: import stop to EU; Sample testing survey on medicines for 583 Safety reviews started women and children ; Fighting poor-quality medicines in low- and middle-income countries Regulatory news 595 Antimicrobial resistance 584 Pre-market assessment Landmark UN declaration on antimicrobial EMA publishes clinical reports resistance; The economic threat of drug- 584 Post-market surveillance resistant infections Social media campaign on reporting of 596 Clinical use of medicines medicines side effects; EU project to Mentoring programme strengthen market surveillance for medical 596 Disease updates

devices ; EU–U.S. collaboration on medicines Tuberculosis : WHO global report; Measles : immunization gap persists; Malaria : funding secured for vaccine pilots; Zika: end of public health emergency;

Continued

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Continued

598 WHO matters ATC/DDD classification Model prequalification dossier; New medicines invited for prequalification; Seminar 600 ATC/DDD classification (temporary) for laboratories held in China; “Green” 603 ATC/DDD classification (final) procurement of health commodities; New prequalification fee structure 599 Upcoming events International Nonproprietary 2017 joint UNICEF-UNFPA-WHO Names (INN) manufacturers meeting 605 Proposed INN: List 116

Abbreviations and websites

CHMP Committee for Medicinal Products for Human Use (EMA) EMA European Medicines Agency (www.ema.europa.eu) EU European Union FDA U.S. Food and Drug Administration (www.fda.gov) Health Canada Federal department responsible for health product regulation in Canada (www.hc-sc.gc.ca) MHLW Ministry of Health, Labour and Welfare, Japan MHRA Medicines and Healthcare Products Regulatory Agency, United Kingdom (www.mhra.gov.uk) Medsafe New Zealand Medicines and Medical Devices Safety Authority (www.medsafe.govt.nz) PRAC Pharmacovigilance Risk Assessment Committee (EMA) PMDA Pharmaceuticals and Medical Devices Agency, Japan (www.pmda.go.jp/english/index.htm) Swissmedic Swiss Agency for Therapeutic Products (www.swissmedic.ch) TGA Therapeutic Goods Administration, Australia (www.tga.gov.au) U.S. United States of America

Note: The online version of this issue (freely available at www.who.int/medicines/publications/druginformation) has direct clickable hyperlinks to the documents and web pages referenced.

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ICDRA

17th International Conference of Drug Regulatory Authorities

“Patients are waiting: How regulators collectively make a difference” Present challenges and opportunities - roadmap for the future

The 17th International Conference of Drug Regulatory Authorities (ICDRA) was held in Cape Town, South Africa, on 29 November–2 December 2016. The event was co-hosted by the Medicines Control Council (MCC) of South Africa and WHO.

More than 360 delegates from regulatory authorities of WHO Member States participated in the 17th ICDRA. The recommendations as presented at the end of the conference are set out on the following pages. They are reproduced here as provided by the moderators in the closing plenary session. Feedback, particularly from non-participating authorities, is welcome.

Several common cross-cutting themes emerged from the discussions. These can be further grouped and consolidated and include e.g. improving coordination, reliance, work- sharing and use of regional networks; promoting greater transparency, awareness and communication; enabling preparedness to facilitate crisis management; development of international standards; and provision of technical assistance to support implementation.

WHO intends to develop a further more concise iteration of these recommendations in the form of a work plan, integrating any feedback received and ensuring greater alignment and consistency across the various work streams. This work plan will be prepared later in 2017, and the outcomes of the deliverables will be presented to the 18th ICDRA in September 2018.

WHO will also conduct a general survey seeking feedback on the 17th ICDRA to help inform the structure and content of the next ICDRA. More information on this survey will be published in the next issue of WHO Drug Information.

►►Please send your feedback on the 17th ICDRA recommendations to: [email protected]

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17th ICDRA sessions: Recommendations Page

THEME: Regulatory systems strengthening 549 Plenary 3 Strengthening of regulatory systems: Follow-up on WHA Resolution 67.20 Plenary 5 Good regulatory practices: Why are they important? Plenary 7 Global scenery of regulatory convergence initiatives: linking opportunities Workshop B Model regulatory framework for medical devices: how to take steps for successful implementation Workshop C Harmonization and work-sharing in pharmacovigilance: What does this mean in practice?

THEME: Public health emergencies 551 Plenary 4 Regulatory preparedness for public health emergencies Workshop I Regulators’ response to shortages of supplies Workshop J Regulators’ role in addressing antimicrobial resistance

THEME: Biologicals 553 Workshop A Similar biotherapeutic products Workshop D Blood products – old and new challenges Workshop G Update on vaccines regulation

THEME: Substandard and falsified medical products 555 Plenary 6 SSFFC medical products and supply chain integrity Workshop F Effective communications for preventing, detecting and responding to SSFFC medical products

THEME: Special topics 556 Workshop E Regulatory challenges of medical products for maternal & child health Workshop H Safety of herbal medicines: present challenges and opportunities

►►17th ICDRA website: www.icdra.co.za Information on past ICDRA conferences is available at: www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra/en/

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THEME: Regulatory systems strengthening

Plenary 3: Strengthening of regulatory systems: Follow-up on WHA Resolution 67.20

Recommendations to WHO Recommendations to Member States 1. Implement a unified policy and 1. Work towards attaining at least minimal harmonized global benchmarking tool, capacity (functionality) of “regulatory applicable for all medical products; systems”, which includes the concept streamline processes where possible to of reliance and collaborative decision- increase efficiency of benchmarking and making. capacity building 2. Encourage best use of existing networks 2. Incorporate an innovative and more for capacity building – e.g., the African coordinated approach to regulatory Vaccines Regulatory Forum (AVAREF), systems strengthening such as coalition the Developing Country Vaccine of interested partners and centres of Regulators’ Network (DCVRN), the Pan excellence American Network for Drug Regulatory 3. Promote the concept of reliance, where Harmonization (PANDRH) – to foster appropriate, and collaborative decision- collaboration in regulatory activities, making at regional level including work-sharing. 4. Increase transparency in the outcome 3. Invest in human resources with the of benchmarking activities, thereby goal of achieving more systemic and facilitating reliance. predictable outputs from assessors and 5. Consider moving away from using the promote documentation of training and term “Stringent national regulatory maintaining competency records. authority”.

Plenary 5: Good regulatory practices

Recommendations to WHO Recommendations to Member States 1. Develop a training curriculum for 1. Concerned bodies including promotion and implementation of the parliamentarians, policy makers and WHO Good regulatory practices (GRP) regulators (supranational, national and guideline for all layers of regulatory subnational levels) to be informed/ bodies (supranational, national and educated on aspects of good regulatory subnational levels) practices 2. Incorporate the use of information 2. National/subnational levels of regulatory technology (websites, mobile applications, authorities to harmonize legal frameworks etc.) and emphasize staff competency and implementation of GRP, requiring and training as enablers for promoting both sufficient and competent human and implementing GRP resources.

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Plenary 7: Global scenery of regulatory convergence initiatives: linking opportunities

Recommendations to WHO Recommendations to Member States 1. Encourage communication and 1. Prioritize initiatives regarding different information/ work-sharing across existing areas of regulations that will result in initiatives in order to optimize their outputs. facilitating access to medicines for 2. Explore opportunities to identify technical patients. platforms that would facilitate interactions 2. Focus on appropriate resourcing models in and acquisition of existing knowledge. order to build a regulatory system that is fit 3. Leverage all opportunities for collaboration for purpose. and de-duplication of work. 3. Look for opportunities to obtain 4. Start working on indicators of medicinal technical support and capacity building products’ regulation systems in order to across existing initiatives and networks. capture progress made in the area of 4. Take into full consideration the existing access to medicines. technical standards, while respecting national realities and contexts.

Workshop B: Model regulatory framework for medical devices: how to take steps for successful implementation

Recommendations to WHO Regulatory Framework in their national 1. Create a technical working group on regulatory system. medical devices. 2. Strengthen regulation capacity of 2. Collaborate with partners – International regulators on medical devices, both in Medical Device Regulators Forum countries that do have regulation in place (IMDRF), Pan African Harmonization as well as countries that start regulating. Working Party (PAHWP), Asian Harmonization Working Party (AHWP) – in Ideas from the pre-ICDRA workshop strengthening medical device regulatory Regulating medical devices: the functions as well as in capacity building for involvement of stakeholders regulators on medical devices. Implementing regulation is more effective and efficient if regulators and stakeholders Recommendations to Member States interact in a timely and interactive manner. 1. Between 2016-2018, ten Member States Patients would want a plan with clear implement the basic level of regulatory steps to have safe and accessible medical control as set in the WHO Global Model devices.

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Workshop C: Harmonization and work-sharing in pharmacovigilance

Recommendations 4. Avoid duplication, in particular share 1. Take stock of work-sharing solutions from information and existing assessments established cooperation initiatives (like on signals and safety issues in a timely EU) or bilateral agreements (like ARFA manner. and ANVISA/Infarmed) and strengthen 5. Consider integrating vigilance systems and maintain a pharmacovigilance system across different types of products including based on clear and transparent rules, medical devices and cosmetics. engagement of all stakeholders and 6. Maintain and further improve centralized coordinated by an established platform system of signal detection, providing a such as WHO. tailored service to Member States on their 2. Promote and take advantage of emerging specific requests. opportunities and harmonization 7. Strengthen collaboration with existing frameworks (such as the African centralized systems/databases (e.g. Medicines Regulatory Harmonization Eudravigilance and WHO’s global African Medicines Regulatory Individual Case Safety Reports database, Harmonization, AMRH) including common Vigibase), in order to avoid duplication. standards, definitions, instruments and 8. Support an integrated pharmaco­vigilance channels of communication. strategy that engages key stakeholders 3. Pharmacovigilance systems should in an open, transparent and collaborative be able to act locally, addressing way to strengthen systems, avoids appropriately any emerging safety duplication of efforts and promotes concerns. effective use of the limited resources.

THEME: Public health emergencies

Plenary 4: Regulatory preparedness for public health emergencies

Recommendations to WHO 4. Develop guidance, and appropriate 1. Consider the formation of a special WHO forums for dialogue, for developed led task force on medicine regulation that and developing country regulators, can be deployed during a public health on regulatory pathways, platform crisis to provide advice to countries on technologies and novel clinical trial issues that may arise. designs for products against emerging 2. Ensure that regulatory support is a priority infectious disease pathogens, ensuring area of activity as the R&D Blueprint that the guidance includes more for emerging infectious diseases is vulnerable populations such as pregnant implemented. women and children. 3. Consult on the needs for further 5. Report back at the 18th ICDRA development of the Emergency Use on progress made on regulatory Approval and Listing mechanisms preparedness for public health established through the Prequalification emergencies and the integration of this programme. activity into NRA systems strengthening.

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Recommendations to Member States 4. Public health emergencies require 1. Preparedness for public health rapid, extensive regulatory collaboration emergencies is key, so all NRAs should and cooperation so development and ensure they proactively participate maintenance of appropriate platforms for in national preparedness planning this purpose is a high priority processes. 5. Timely sample and data-sharing remain 2. Regulators should help drive product barriers to product evaluation, so development for public health regulators should help drive change emergencies, not only for diagnostics, through advocacy for the national benefits vaccines and therapeutics but also for of sample and data-sharing. relevant infection control products. 6. Member States should improve their 3. Crisis communications are particularly pharmacovigilance systems to ensure challenging and NRAs need to proactively that safety of investigational products is develop a general communication plan effectively monitored during public health that would include crises, and to develop emergencies. their capacity, overall, to communicate more effectively

Workshop I: Regulatory responses to shortages of supplies

Recommendations to Member States 2. Governments/regulators should consider 1. Regulators should encourage and enable shortage reporting systems which feed the authorization of alternative active to national, to regional and to global pharmaceutical ingredient (API) sources, systems. manufacturing processes and sites for 3. Governments/regulators should consider all medicines identified as vulnerable or the process for special access (including critical. donations) to meet the particular needs of patients.

Workshop J: Regulatory role in addressing anti-microbial resistance

Recommendations to WHO Recommendations to Member States 1. Continue to support countries on 1. Regulators should consider ways that monitoring antimicrobial consumption will facilitate the development of new and use in human and animals. Increase antibiotics such as harmonized technical the systems of gathering data on anti- standards, scientific advice, accelerated microbial resistance in the health care pathways and incentivized research. setting. 2. Member States/regulators should 2. Continue supporting countries in promote the rational use and prescribing strengthening their regulatory systems of medicines. Actions can include: to ensure that the quality of antibiotics / prohibiting the dispensing of medicines antimicrobials can be assured. without a prescription, information campaigns, requirements for proper diagnostics, considering the indications for which medicines are indicated.

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THEME: Biologicals

Workshop A: Similar biotherapeutic products

Recommendations to WHO Recommendations to Member States 1. Expand support to Member States in 1. Given the number of available guidelines implementing guiding principles for for biosimilars (e.g, WHO, EMA, national regulatory evaluation of biotherapeutics, guidance), the focus should be on the including biosimilars, for example to implementation of the existing guidelines. Russian-speaking countries and low- and 2. Collaboration is the key for overcoming middle-income countries. lack of expertise and experience in many 2. Foster collaboration and use of existing NRAs. For that purpose, better use of regulatory networks to promote existing resources through the networks information and work-sharing among (e.g. AVAREF and Zazibona in the African regulators and provide technical support region and other relevant networks in to enable regulatory evaluation on the other regions) is the way forward. basis of up-to-date scientific principles and 3. Training as part of long term strategy evidence. for building capacity should be 3. Further development, and communication accelerated and all relevant training about use, of public standards should opportunities should be used. For be prioritized to help assure quality of example, the European Network Training biotherapeutics including biosimilars. Center will soon become available to 4. Provide technical assistance and guidance non-EU regulators. for regulatory oversight of biosimilars 4. Regulators should provide relevant and developed through technology transfer. useful information to enable health care 5. Develop mechanisms to assist countries providers to prescribe and patients to use in linking regulation with guidance on the biosimilars with confidence. appropriate use of similar biotherapeutic products.

Workshop D: Blood products – old and new challenges

Recommendations to Member States quality of plasma suitable for use in 1. Member States are encouraged to fractionation. implement regulation of blood and 2. Member States are encouraged to blood components for transfusion as implement regulation of reagents and essential medicines covering all steps devices essential to the preparation “from vein to vein and back” based on of blood and blood components (e.g. current WHO Guidelines including “Good anticoagulant solutions, donor screening Preparation Practices (GPP)” analogous assays, compatibility tests, etc.). to pharmaceutical good manufacturing 3. Member States are encouraged to model practices and to assure availability and new blood regulations on those already established in other countries and to seek

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any necessary assistance from such 2. WHO, at the request of Member States, countries and from WHO. should offer specific training for inspectors 4. Member States are encouraged to and assessors in the regulation of blood regulate snake antivenoms as biological and blood components and related products and to assess the quality, reagents and devices, including a focus on effectiveness and specificity of these strengthening of regional networks. products in the context of the country`s 3. WHO should regularly update the specific needs, making use of tools global data base on snake species and available from WHO including the revised antivenoms. WHO Guidelines for the Production, 4. WHO, at the request of Member States, Control and Regulation of Snake should assist in the development of Antivenom Immunoglobulins and the regional reference standards for venoms. updated WHO database on snake species 5. WHO should take steps towards eventual and antivenoms. inclusion of snake antivenoms in its prequalification programme. The current Recommendations to WHO assessment programme should be 1. WHO, at the request of Member States, continued, with consideration of expansion should continue to provide assistance for of support for NRA inspections, critical assessments of national blood regulatory laboratory testing and promotion of quality- systems. assured manufacturing.

Workshop G: Vaccine regulation

Recommendations to WHO 5. Establish a global network of national 1. Assist Member States to build capacity at vaccine control laboratories involved in the regional level (e.g., regional blocks and testing of WHO-prequalified vaccines networks) for regulation of vaccine 2. Assist Member States that will transition Recommendations to Member States from vaccine procurement through GAVI 1. Consider using regional level approaches to self-procurement of vaccines to prepare (e.g., regional blocks and networks) for adequately and in a timely way for the regulation of vaccines change. 2. For efficient lot release testing of vaccines, 3. Assist Member States to build consider a risk-based approach or pharmacovigilance capacity for vaccine networking (reliance) approach 4. Consider removal of the innocuity test 3. Utilize opportunities through WHO, and as a requirement for lot release from links with international regulatory platforms WHO vaccine guidelines but encourage (e.g., PAHO, ASEAN, AVAREF and maintenance of some capacity to perform DCVRN), to build capacity for vaccine this test, if needed. regulation.

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THEME: Substandard and falsified medical products

Formerly known as substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC) medical products

Plenary 6: SSFFC medical products and supply chain integrity

Recommendations to WHO policy and decision makers, relevant 1. WHO is urged to continue regulatory stakeholders and most importantly strengthening, with particular emphasis civil society of the threat posed by on training in relation to all aspects of substandard and falsified medical the prevention, detection and response products. to substandard and falsified medical 2. Member States and regulatory authorities products. are encouraged to set and implement 2. WHO is urged to publish data on the national/regional strategies to prevent, scope, scale and harm caused by detect and respond to substandard and substandard and falsified medical falsified medical products, embedded products. within core regulatory functions. 3. WHO is urged to examine all available 3. Member States are requested to and emerging technologies to assist in nominate regulatory technical experts the tracking, tracing and authentication of to participate in the WHO Member State medical products, and where necessary Mechanism, and specifically national screening, testing and reporting of regulatory focal points to engage with the substandard and falsified medical WHO Global surveillance and monitoring products. system for substandard and falsified medical products. Recommendations to Member States 1. Heads of regulatory agencies are encouraged to raise awareness amongst

Workshop F: Effective communications – SSFFC

Recommendations to WHO falsified medical products discovered in 1. WHO is encouraged to provide best the supply chain. practice communications guidance to 3. WHO is encouraged to provide a central Member States, including templates and communications hub with access models for communication, education and available to communications experts in awareness campaigns. Member States which will house all the 2. WHO is encouraged to provide guidance advice, knowledge and experience gained on communication strategies specifically from the communications programme in relation to reacting to substandard and developed by WHO.

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Recommendations to Member States the knowledge base of communications 1. Member States are encouraged to play activities globally, and to enable this an active role in the Communications experience and learning to be shared with Working Group of the WHO Member other Member States. State Mechanism to ensure the proposals 3. Member States are encouraged to deliver developed reflect the needs of all national communication and awareness countries. campaigns, offering accurate information, 2. Member States are encouraged to share sound advice and reassurance to relevant examples of communication campaigns stakeholders specifically civil society and implemented in their countries to the the young. Member State Mechanism, to improve

THEME: Special topics

Workshop E: Regulatory challenges of medical products for maternal and child health

Recommendations to Member States 4. All national regulatory authorities should review their current language in package For maternal immunization inserts/labelling to accurately reflect data Maternal immunization is a field of growing while avoiding misleading statements. importance to reduce neonatal, infant and maternal mortality, and new vaccines are For paediatric medicines in development for Group B Streptococcus 1. Member States are still facing challenges (GBS) and respiratory syncytial virus to get optimal formulations for children, (RSV). and there is a need to incentivize 1. Implementation of recently developed research and licensure of paediatric WHO guidelines on influenza vaccine formulations. labelling was recognized as an important 2. It is good to see an increase of the step towards wider immunization of number of ongoing studies and pregnant women, and women during the registration, but problems still exist in lactation period, with inactivated influenza treating children in countries. Every effort vaccines. should be made to define regulatory 2. Collection and review of safety data from requirements for involvement of children post-marketing surveillance and post- in clinical trials. licensure studies of existing vaccines 3. Member States should consider putting would contribute to better understanding in place post-marketing surveillance and of the safety in the field. pharmacovigilance when new paediatric 3. For new vaccines to be used for maternal formulations are introduced. immunization, randomized, controlled designs with pre-specified clinical and Recommendations to WHO immunological outcomes are the gold 1. WHO guidelines on quality, safety and standard, with consideration in the trial efficacy of RSV vaccines: standardization design of correlates of protection.

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and coordination in reaching consensus clinical trials and licensure (particularly on that matter is critical. important for medicines used in 2. Guidelines for paediatric medicines used oncology). in emergency situations (such as the 4. Registry practices need to be Ebola outbreak) should be developed. standardized. Good practices for 3. There is a need for a clear definition registries need to be developed by WHO. of a child and an adolescent, and 5. Regulation of paediatric medicines should consideration of what this means for be a permanent theme for ICDRA.

Workshop H: Safety of herbal medicines

Recommendations to Member States information on safety of herbal medicines 1. Member States are encouraged to and on public awareness campaigns adopt and subsequently monitor the relating to herbal medicines, through implementation of existing WHO relevant mechanisms, such as the guidelines pertaining to herbal medicines, International Regulatory Cooperation for according to national circumstances, Herbal Medicines. to define/determine the scope of the 2. In order to strengthen the national effective regulation and safety monitoring capacity at the regulatory authorities of herbal medicines. in conducting comprehensive effective 2. Member States are encouraged to regulation of herbal medicines, WHO identify and develop tools to implement should: appropriate communication strategies a) identify and coordinate with aimed at consumers, health care possible partners to provide tailored providers, manufacturers and distributors capacity-building opportunities to the of herbal medicines, in order to facilitate concerned regulatory authorities; them to make informed decision/choice in b) support exchange among Member their use and clinical application. States of technical expertise 3. Member State are encouraged to share and technical resources that are good practices in setting key objectives, required in the assessment of herbal and/or action taken to overcome safety medicines for inclusion in the national concerns of herbal medicines, among registration; and Member States. c) further support Member States in developing methodologies in Recommendations to WHO setting required national standards 1. WHO should further coordinate and and reference sources (such as support Member States in order to pharmacopoeia) taking into account strengthen and facilitate collaboration particulars of herbal medicines, in and communication among national order to enhance mutual reliance regulatory authorities in the area of basis for convergence of standards herbal medicines, especially in sharing among Member States. å

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Regulatory collaboration

Collaboration, not competition: developing new reliance models Exchange of assessment reports (ARs) with regulators outside the European Union (EU)1

At a time when modern medicines manufacture and distribution are increasingly globalized, cooperation between medicine regulators has become essential, and multiple models of regulatory collaboration are being implemented in all regions of the world. The European regulatory system for medicines is unique in the global regulatory environment and may serve as a model for other countries or regions for building trust and mutual reliance. The EU Medicines Agencies Network Strategy to 2020 highlights the strong international role that the EU network can play in promoting reliance and work-sharing with other regulators. This paper provides a discussion of the programmes and initiatives in which medicines regulators rely on collaboration and on assessment work carried out by other regulators while retaining responsibility for their own regulatory decisions. It also proposes some tools and suggestions to make these approaches more systematic. The paper concentrates on assessment of applications for marketing authorization, but many concepts expressed here can be applied to other regulatory areas such as inspections and pharmacovigilance. Although the focus is on exchange of documents produced by the European Medicines Agency (EMA) and other agencies in the EU network with regulators outside the EU, it is recognized that the EU regulatory system also has much to gain by exchanging experience with, and receiving information from, regulators in other regions of the world.

1 The 28 EU Member States plus Iceland, Liechtenstein and Norway form the European Economic Area (EEA). Most of the EU rules, procedures and practices described in this article apply to all the EEA countries.

Authors: Riccardo Luigetti, European Medicines Agency (EMA) Peter Bachmann, Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Germany, and Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) Emer Cooke, European Medicines Agency (EMA); since 15 November 2016: Department of Essential Medicines and Health Products (EMP), World Health Organization Tomas Salmonson, Läkemedelsverket (MPA), Sweden, and EMA Committee for Medicinal Products for Human Use (CHMP)

Any feedback on ways to achieve or improve cooperation would be very much appreciated by the EMA and the other agencies in the EU network, and can be addressed to EMA through the mailbox: [email protected].

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Introduction 1965. It has a long history of developing effective cooperation within Europe and Current regulatory challenges may serve as a model for other countries Modern medicines manufacture and or regions for building trust and mutual distribution are becoming more and reliance. The EU Medicines Agencies more globalized. As a consequence the Network Strategy to 2020 (1), published in manufacturing processes and supply December 2015, highlights collaboration chains of pharmaceutical products, in the global regulatory environment as a including generics, are increasingly strategic priority area and aims at further complex. The same medicinal product developing a strong international role is often distributed in several countries for the network by, among other things, or world regions and used by patients capacity building and promoting reliance all over the world. It is also common and work-sharing with other regulators. that different manufacturing phases for A number of other countries and regions the same product take place in different have also developed or are developing countries, often very far away from formal and informal frameworks for each other. At the same time more and cooperation and work-sharing, helping more common elements are present avoid duplication and use resources in the dossiers submitted in different efficiently. A few examples are given jurisdictions. below; the list is far from being exhaustive. In addition, new medicines coming to In the Region of the Americas, which the market are often complex products comprises 55 countries, the Pan such as biotechnology, gene therapy American Network for Drug Regulatory or cell therapy products, or have Harmonization (PANDRH) is a forum of sophisticated formulations involving national medicine regulatory agencies e.g. micellar systems or nanoparticles. whose aim is to promote regulatory Some regulators may lack the resources harmonization between them, including or specific competences to carry out technical guidelines and regulatory assessments of these products before processes, while the Caribbean they are put on their markets. Community (CARICOM) is advancing a In this environment, collaboration project to develop a regional regulatory among regulators is essential to avoid system. duplication of work, release scarce In Africa, several regional communities resources for more critical areas and and projects are in place to develop speed up patients access to new and/or cooperation mechanisms, such as the affordable products. East African Community (EAC) and the Southern African Development New models of cooperation Community (SADC), which are working The growing awareness of the need for towards harmonization among the regulators to work together has led to the participating authorities, and the emergence of new models of cooperation. ZaZiBoNa project, which connects the The European medicines system is regulatory systems of the four participating probably the best-established example of countries (Zambia, Zimbabwe, Botswana regulatory cooperation between medicines and Namibia) with a view to expanding authorities, with a legal basis dating from the project to other countries. The African

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Vaccine Regulatory Forum (AVAREF) is An alternative way to achieve developing mechanisms and pathways cooperation and avoid duplication of work for expedited regulatory review of clinical is what is often referred to as reliance. trials for products being developed to Reliance is a broad concept and can be address public health emergencies and achieved in real life in different ways. In neglected diseases, including joint review general, reliance implies that the work by regulators and ethics committees. A done is shared by the trusted authority timeline for the establishment of an African (e.g. through assessment or inspection Medicines Agency has been recently reports), while the receiving authority uses established (2). this work according to its own scientific The Association of Southeast Asian knowledge and regulatory procedures and Nations (ASEAN), the Asia-Pacific retains its own regulatory responsibilities. Economic Cooperation (APEC) and For example when an assessment report the Gulf Central Committee for Drug for a medicine authorized in the EU is Registration (GCC-DR) are among the shared with a regulatory authority in Africa, regional initiatives in Asia working towards the receiving authority might still need to harmonization for medicinal products. consider differences in conditions of use, patient population and other parameters. Collaboration and reliance In many cases reliance on the Regulatory collaboration can be achieved assessment or inspection work carried out in a variety of ways, including information by another trusted regulatory authority can and/or work-sharing and mutual be the best way to cooperate effectively. recognition of assessment and inspection Reliance can be unilateral, bilateral results. (mutual) or multilateral. Forms of cooperation such as mutual recognition agreements, which require EU registration pathways establishment of a strong legal framework, The EU regulatory model has evolved are desirable and should be implemented significantly over time, particularly since whenever possible. However, they take the creation of the European Medicines a long time to set up, as the regulatory Agency (EMA), the Centralised Procedure systems involved need to be mutually and the Mutual Recognition Procedure assessed and shown to be equivalent in 1995. The various routes to medicines before implementation. approval in the EU system (Table 1) are

Table 1. Routes to medicines approval in the EU system* Centralised Procedure Assessment via EMA, resulting in a single marketing authorization (CP) throughout the EU Decentralised Procedure Assessment of a new (not previously authorized) medicine by a (DCP) Reference Member State on behalf of a group of other Member States Mutual Recognition Assessment of a medicine authorized in at least one Member State by a Procedure (MRP) Reference Member State on behalf of a group of other Member States National procedures Assessment by a Member State of a medicine for approval in its own jurisdiction *More information is available in the Notice to Applicants published by the European Commission at: http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm

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based on a single assessment system for marketing authorization. The receiving so that any assessment report (AR) from authorities benefit from the information any of the agencies in the EU network can in the EU ARs but maintain their own be used as a basis for reliance by other regulatory responsibilities for decision- regulators. making. Exchange of complete, unredacted Currently the pilot involves EU ARs plays an important role in regulatory authorities as well as Health Canada, cooperation. EU regulators share their Swissmedic, the Taiwan Food and unredacted ARs with regulators outside Drug Administration (TFDA) and the the EU in several established initiatives Therapeutic Goods Administration (TGA) and other contexts, as described of Australia. Other members of the IGDRP below. This exchange is often based on may decide to take part at a later stage. confidentiality agreements, but in the spirit In January 2015, the information-sharing of regulatory collaboration ARs can also pilot was extended to include applications be exchanged where there is no such for generics submitted through the agreement in place and the applicant Centralised Procedure, allowing EMA for marketing authorization consents to to share its ARs relating to these this sharing. This allows the extensive submissions with the collaborating non-EU assessment work carried out by EU regulatory agencies in real time. experts to be used by other international The EU is leading this initiative with regulators for the benefit of patients. The the aim of strengthening the scientific different means used to achieve such assessment, increasing consistency in the sharing of ARs in practice are explained assessment of generics and saving global later in this paper. assessment resources.

Information-sharing initiatives WHO collaborative registration pilot for involving EU ARs stringently authorized products, including through the EU’s Article 58 Procedure IGDRP information-sharing pilots with The World Health Organization (WHO) EU’s Decentralised and Centralised collaborative registration pilot for Procedures medicines approved by a stringent The information-sharing pilot of the regulatory authority (SRA)3 was initiated International Generic Drug Regulators in 2015 as an extension of a WHO Programme (IGDRP)2 was launched in procedure that facilitates and accelerates July 2014 using the EU Decentralised the national registration of products Procedure (DCP) as a model for already assessed and prequalified by cooperation. It provides a mechanism for WHO. The pilot aims at facilitating the sharing of information during the scientific registration of SRA-approved essential assessment phases of the procedure. medicines in countries where regulatory During Decentralised Procedures for 3 generics participating in the pilot, ARs are Defined in WHO guidance(3) as a regulatory authority in a country that is a member of the shared by the EU agencies in real time International Conference on Harmonisation with the participating non-EU authorities, (ICH) or an ICH observer country, or a upon request from the company applying regulatory authority associated with an ICH country through a legally binding mutual 2 https://www.igdrp.com/ recognition agreement

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resources may be limited. Here as well, would for Centrally Authorised Products the receiving competent authorities retain authorized for marketing in Europe, taking their regulatory responsibilities and make into account possible different conditions their own decisions.4 of use. Experts and observers from WHO Since November 2014 EMA has or from WHO Member States (appointed participated in the development and by WHO) are part of the assessment implementation of the pilot. In this context, process. The CHMP, after consultation EMA ARs are shared with regulators in with WHO, adopts a scientific opinion, African countries by companies holding following the process in place for the EU marketing authorizations who wish to Centralised Procedure.5 market their products in these countries. An Article 58 Procedure followed by EMA confirms, upon request from the collaborative registration provides a useful company, that it has no objections to the approach to speeding up patient access sharing of its ARs and, in accordance to essential medicines, including new or with WHO procedures, confirms that the improved therapies for unmet medical Quality Information Summary provided by needs, without compromising on the the company complies with the information quality of assessment. in the dossier assessed by EMA. EMA can provide the receiving authority with further Other uses of EU assessment information or clarification on any aspect reports by non-EU regulators of the assessment and promotes dialogue Non-EU regulators often request between the receiving authority and the applicants to provide EU ARs in contexts relevant EMA assessors as required. other than the information-sharing At the time of writing, EMA participation initiatives described above. The use of has involved three Centrally Authorized EU ARs in the receiving country may be Products and one assessed under Article included in the legislation, guidelines or 58 (see below), for the treatment of HIV, procedures of these countries. Some malaria or tuberculosis. examples are given below. Article 58 of Regulation (EC) No. 726/2004 (4) allows EMA’s Committee Switzerland for Medicinal Products for Human Use The Swiss legislation (5) foresees that for (CHMP) to give opinions, in co-operation a medicinal product which has already with the WHO, on medicinal products for been granted an authorization in a country human use that are intended exclusively with a comparable control system for for markets outside the EU. This includes medicinal products, the assessment vaccines used in the WHO Expanded by the reference authority will be taken Programme on Immunization, medicines into account by Swissmedic during used to treat public health priority the authorization procedure, provided diseases, and medicines for WHO target that the applicant explicitly requests diseases such as HIV/AIDS, malaria or Swissmedic to do so. The goal is to make tuberculosis. Under Article 58 the CHMP medicinal products already authorized in carries out a scientific assessment according to the same standards as it 5 More information on Article 58 is available at: www.ema.europa.eu/ema/index. 4 More information is available at http://apps.who. jsp?curl=pages/regulation/document_listing/ int/prequal/ under “Collaborative Registration”. document_listing_000157.jsp

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foreign countries available to patients in Singapore Switzerland as rapidly as possible while Legislation in Singapore (7) allows for ensuring a targeted, risk-assessed use of leveraging of foreign reports to grant Swissmedic’s resources. marketing authorizations. The reference Use of an existing EU AR in this way has agencies accepted by the Singapore decreased the review time by up to about Health Sciences Authority (HSA) are 20%. In 2015, about 15% of medicinal EMA, U.S. FDA, Health Canada, TGA products with known active substances and MHRA (for national products or authorized in Switzerland were authorized Decentralised and Mutual Recognition taking into account ARs produced by products where MHRA is the Reference EMA or an EU Reference Member State.6 Member State). For applications that In addition, there are products for which have obtained prior approval from these the approval decision is not based solely reference agencies, HSA has a system on shared EU reports. Applicants are that enables leveraging of assessments encouraged to always submit any such performed by these agencies, called the ARs as they are considered a valuable Verification Route (VR). To be eligible source of information. for the VR, one of the criteria is that the product is authorized for marketing in any Canada two of the HSA’s reference agencies. In Canada, a draft guideline was The VR takes 60 days (excluding published in 2012 (6) which details how clock-stops) as opposed to the 270 days information submitted by applicants on necessary for products not previously reviews carried out by foreign authorities authorized by any other authority (Full can be used by Health Canada during the Route) or to the 180 days for products assessment of applications. The guideline authorized by at least one drug regulatory recognizes that the Canadian law does authority (Abridged Route). 5% of the not prevent Health Canada from using, products authorized in Singapore in 2015 where appropriate, foreign reviews to have been authorized via the VR using perform part of the evaluation or to inform EMA assessment reports.7 Health Canada’s decision-making. Health Canada however cannot grant (or refuse Mexico to grant) marketing authorization based In 2012, EMA was approached by the solely on the existence of a foreign review Mexican medicines regulator COFEPRIS and its corresponding regulatory decision. to facilitate an assessment of legal Different levels of reliance on foreign equivalence between the Mexican and reviews are detailed in the guideline, EU pharmaceutical legislation. After allowing for the possibility that a critical dialogue with EMA lawyers, the result assessment of the foreign review is used was a unilateral agreement (“acuerdo”) as a basis for the Canadian regulatory (8) through which Mexico uses the work decision on the entire data package or on carried out at EMA during assessment one or more of its components. of Centrally Authorised Products to expedite approval of new medicines in Mexico. Similar arrangements are in place between Mexico and some other 6 Personal communication received from Swissmedic 7 Personal communication received from HSA

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countries, including the United States, in these cases confidential information is Canada, Australia and Switzerland. redacted. When marketing authorization holders Modalities for exchange of are requested by a non-EU authority to information with non-EU regulators share EU ARs for their products, they may ask the relevant EU agency to confirm Sharing of assessment reports (ARs) in writing that it has no objection to the EMA ARs (for both the Centralised and the sharing. Unless there are serious reasons Article 58 procedures) and ARs from other to object, the EU agency indicates to agencies in the EU network are shared the company concerned that it does not with non-EU regulators directly or through object. A standard wording for responding the marketing authorization holder. to such requests has been developed and Although EU ARs include commercially published on the EMA website.9 confidential information, they can be exchanged by EMA and the other Public ARs agencies in the EU network with other Notwithstanding the measures identified regulators when there is a Confidentiality above the EU assessment process Arrangement8 in place between the EU is exceptionally transparent, and the and the receiving authority. Through these possibility of taking advantage of what arrangements the parties agree not to is made public on the websites of EMA disclose confidential information. and the other agencies in the EU network In the absence of such an should not be underestimated. The EMA agreement, unredacted EU ARs can website, for example, is continuously still be exchanged directly with non-EU updated with information on the quality, regulators, provided that the marketing safety and efficacy of Centrally Authorised authorization holder for the products Products. For every medicine, including consents to the exchange. EMA is those with a positive opinion under encouraging such direct exchanges as far Article 58, a European Public Assessment as possible, and a template to be used Report (EPAR) is published,10 which gives by companies to consent to exchange of a wealth of information on the product, ARs has been made public on the EMA its use and its assessment. EMA also website9. EU ARs can also be provided publishes information on medicines by EU authorities without consent from which receive a negative opinion from the the marketing authorization holder, but CHMP. Similar public ARs are published by other agencies in the European network. 8 Confidentiality Arrangements are in place Public ARs for products assessed through between the EU and the following organizations: US Food and Drug Administration (FDA); Health the Mutual Recognition Procedure are Canada (HC); Japan Ministry of Health, Labour published in the MR Product Index on the and Welfare (MHLW) and Pharmaceutical and Heads of Medicines Agencies website.11 Medical Devices Agency (PMDA); Swissmedic; Australia Therapeutic Goods Administration (TGA); World Health Organization (WHO) 10 More information on EPARs is available 9 Available in the EMA questions and answers on at: www.ema.europa.eu/ema/index. pre-submission guidance, Question No. 68 at: jsp?curl=pages/medicines/landing/epar_search. www.ema.europa.eu/ema/index.jsp?curl=pages/ jsp&mid=WC0b01ac058001d125 regulation/general/general_content_000157.jsp 11 Available at: www.hma.eu/mriproductindex.html

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Additional approaches Pharmaceutical Inspection Co-operation Exchange or publication of ARs are not Scheme (PIC/S) and the International the only ways in which cooperation on Generic Drug Regulators Programme medicine assessment among regulators (IGDRP) among others provide excellent can be achieved or information on platforms for working together to assessment can be exchanged. Other overcome remaining difficulties. possibilities are being explored, such as allowing regulators from other Conclusion jurisdictions to listen to, or participate The challenges faced by regulators in, relevant product-specific meetings in an increasingly complex regulatory and discussions. The possibility of environment are shared and recognized post-authorization webinars, where the by the EU agencies network, and the scientific rationale for the decisions taken need for cooperation is emphasized in the by an agency is explained and discussed recently published EU network strategy with other regulators, may also be (1). EMA and the other agencies in the considered. EU network are willing to provide support and to cooperate with other international Remaining barriers regulators as much as possible, while There are still barriers to overcome in at the same time benefiting from the furthering the exchange of assessment work done by other authorities as far as and inspection information among possible. regulators worldwide. Such barriers can As demonstrated by examples from be legal (e.g. lack of legal framework, other regions of the world, the EU confidentiality issues), technical (e.g. lack authorities are not alone in favouring of secure IT platforms for information- and promoting sharing of ARs and other sharing), and non-technical (e.g. political regulatory documents (e.g. inspection issues, lack of trust). However, none of reports). However, such cooperation is them should be big enough to prevent currently mainly carried out at regional cooperation and sharing of information level. It makes little sense that the work among regulators, given the benefits it can carried out by regulators in one part of the bring to patients worldwide. world is not shared with regulators in other EMA and the other agencies in the EU regions. The cooperation and sharing network are committed to finding ways to need to be more global in order to be overcome such barriers wherever they more effective. exist. For example, in the absence of a It has become increasingly clear that globally accepted secure IT platform, they forms of cooperation requiring a strong share unredacted ARs through the EU legal framework often require a very secure email system, Eudralink, which long time to be achieved. An alternative is encrypted and password-protected. approach is that of reliance, in which Multilateral cooperation forums such regulatory authorities make use of shared as WHO groups and committees, the information but retain their decision- International Conference of Drugs making responsibilities. Reliance can be Regulatory Authorities (ICDRA), the unilateral, bilateral or multilateral, can be International Coalition of Medicines achieved in a short timeframe, does not Regulatory Agencies (ICMRA), the require a heavy legal framework, and can

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be the prelude to more formalized forms 3 WHO. Procedure for prequalification of pharmaceutical products. Annex 10. In: of cooperation such as mutual recognition WHO Expert Committee on Specifications agreements. for Pharmaceutical Preparations. Forty-fifth To promote reliance and work-sharing in report. Geneva: World Health Organization; line with the EU network strategy to 2020, 2011 (WHO Technical Report Series No. EMA and the other agencies in the EU 961). network will continue to share unredacted 4 European Commission. Regulation (EC) EU assessment and inspection reports No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying with other regulators worldwide as much down Community procedures for the as possible, and will actively develop new authorisation and supervision of medicinal and better ways to facilitate cooperation products for human and veterinary use and and exchange of information to realize the establishing a European Medicines Agency. greatest possible benefits for patients. 5 Swiss Confederation. Federal Act on Medicinal Products and Medical Devices References (Therapeutic Products Act, TPA) of 15 December 2000. Article 13, Medicinal 1 EMA. EU Medicines Agencies Network products authorised in foreign countries, Strategy to 2020. Working together and Ordinance of 17 October 2001 to improve health. London: European concerning Medicinal Products (Medicinal Medicines Agency; 17 December 2015. Products Ordinance), Articles 5a - 5d. Available at: nd 6 Health Canada. The Use of Foreign Reviews 2 AMRH. 2 Task Team meeting to facilitate by Health Canada. Draft guidance document. the establishment of African Medicines Published by authority of the Minister of Agency (AMA) successful. AMRH Health. Draft Date: 2012/09/11. Newsletter January–June 2016: pp. 5-6. 7 Health Sciences Authority (HSA). Guidance on medicinal product registration in Singapore. Effective 1 April 2011. 8 Government of Mexico. Diario oficial. Tercera secciòn. Secretaría de Salud. (Official gazette. Section Three. Department of Health). 5 October 2012. å

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Medicines regulation

Comparison of medicines legislation in the East African Community

Efficient and aligned regulatory systems are crucial in ensuring access to medical products of assured quality. However, marketing authorizations of needed products are often delayed as researchers and manufacturers must navigate multiple regulatory requirements to register their products across countries. In the East African Community (EAC), efforts are under way for harmonization of technical requirements for medicines regulation. This article presents a comparison of legal and regulatory frameworks for the regulation of medicines in EAC partner states. The findings show some commonalities but also differences and gaps, underlining the need for convergence towards a common medicines regulatory framework in line with international standards.

Background a population of 161.3 million people in 2015 it is home to approximately 14% of East African Community the population of the African continent. The East African Community (EAC) was Life expectancies are below the global established in 1999 among the Republics average, and all EAC partner states except of Kenya, Uganda, Rwanda, Burundi and Kenya are low-income countries according the United Republic of Tanzania. With to the World Bank classification(Table 1).

Table 1: Demographic characteristics of EAC partner states Partner Land size, Population, Gross domestic Gross national income Life expectancy state km3 million product (GDP), (GNI) per capita*, at birth**, years World Bank million US$ US$ World Bank data data, 2015 World Bank data 2015 (World Bank data 2015) (WHO data, 2015) Kenya 569 140 46.1 63 398 1 340 63.4 Tanzania 855 800 53.5 44 895 910 61.8 Rwanda 24 670 11.6 8 096 700 66.1 Uganda 200 520 39.0 26 369 670 62.3 Burundi 25 680 11.2 3 085 260 59.6 * The World Bank defines low-income economies as those with a GNI per capita of up to US$ 1 025. Lower middle-income economies are those with a GNI per capita of US$ 1 026-4 035. ** Global average 2015: 71.4 years.

This article was authored by Mr. Hiiti B Sillo, Tanzania Food and Drugs Authority (TFDA), with input from Mr Sunday Kisoma, TFDA, and Mrs Monika Zweygarth. We thank Professor Eliangiringa Kaale and Professor Veronica Mugoyela from Muhimbili University of Health and Allied Sciences, Tanzania, and Dr Lembit Rägo from the Council for International Organizations of Medical Sciences (CIOMS), Switzerland, for helpful comments on the manuscript.

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Medicines regulatory harmonization authorizations are still available for Harmonization initiatives for regulation medicinal products to be marketed in one of medicines started in 1990 when the EU member state only. medicines regulators and the research- Other regional harmonization initiatives based industry of Europe, Japan and are under way in the Association of the United States of America established the Southeast Asian Nations (ASEAN), the International Conference on Harmonization Gulf Cooperation Council (GCC), the Pan of Technical Requirements for Registration American Network for Drug Regulatory of Pharmaceuticals for Human Use (ICH, Harmonization (PANDRH) and the now known as the International Council on Southern African Development Community Harmonisation of Technical Requirements (SADC). for Registration of Pharmaceuticals for Human Use). The objectives of ICH are to EAC medicines regulation harmonization improve the efficiency of drug development Chapter 21, Article 118 of the EAC and registration processes. To date, ICH Treaty (3) provides for co-operation has published guidelines in all areas of on health and specifically asks partner medicines regulation including 12 quality states to harmonize drug registration guidelines, 11 safety guidelines, 18 procedures so as to achieve good control efficacy guidelines and 8 multidisciplinary of pharmaceutical standards without guidelines (1). impeding or obstructing the movement One example of a functioning and of pharmaceutical products, and hence successful regional harmonization facilitate access to pharmaceutical initiative is that implemented by the products within the Community. This is European Union (EU), which offers several expected to increase access to medicinal registration pathways (2). Under the EU products needed to treat health conditions centralized procedure, pharmaceutical that are prevalent in the region. companies submit a single marketing The beginnings of harmonization of authorization application to the EMA. The medicines regulation in the EAC region relevant Committee carries out a scientific go back to 2001, when the technical assessment of the application and gives a requirements for registration of veterinary recommendation on whether or not to grant drugs were approved by the EAC a marketing authorization. Once granted by national medicines regulatory authorities the European Commission, the centralized (NMRAs) as exemplified by the Tanzanian marketing authorization is valid in all EU guidelines. This was followed by a member states. Under the decentralized situation analysis of partner states (4), procedure, applications are submitted and which highlighted some differences in subsequently approved simultaneously regulatory capacity and scope of activities in several member states, one of which as well a lack of institutional mechanisms is designated as the “reference member to share information for example on drug state”. Under the mutual recognition registration or product recalls. procedure, which is applicable to the The EAC Medicines Regulation majority of conventional medicinal Harmonization (MRH) Programme products, already existing national was launched in March 2012. It was marketing authorizations are recognized by the first programme to receive funding one or more EU member states. National under the African Medicines Regulatory

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Harmonization (AMRH) initiative through EAC medicines regulatory systems a trust fund established by an agreement between the Bill & Melinda Gates Medicines laws Foundation and the World Bank. The An overview of the medicines regulatory ultimate goal of the EAC MRH programme framework in EAC partner states is shown is to establish a harmonized regulatory in Table 2. Some specific aspects are system in the region that enables approval compared below. of medicines through various regulatory pathways, similar to the regulation model Scope of regulation implemented by the EU Member States. The national medicines regulatory authority (NMRA) of Uganda regulates medicines only, and this includes oversight

Table 2: Legal framework for medicines regulation in EAC partner states Partner Medicines law Year of Amend­ Regulatory authority Organizational set-up state Enact­ment ments Burundi* Décret n° 100/150 du 1980 None Department of Department under 30 septembre 1980 Pharmacy, Medicines the Ministry of Public portant Organisation and Laboratory Health and the Fight de l’exercice de la (DPML) against HIV and AIDS, Pharmacie au Burundi Head: Director Kenya The Pharmacy and 1957 2009 Pharmacy and Statutory body under Poisons Act, Chapter Poisons Board (PPB) the Department of 244 www. Ministry of Health; pharmacyboardkenya. Head: Registrar and org Chief Pharmacist Rwanda Law No. 47/2012 of 2013 None Pharmaceutical Unit of the 14/01/2013 relating Services (Pharmacy Department of to the Regulation and Taskforce) Clinical Services Inspection of Food in the Ministry of and Pharmaceutical Health; Head: Head Products of Pharmaceutical Services Tanzania Tanzania Food, Drugs 2003 2004, Tanzania Food and Government (Mainland) and Cosmetics Act, 2014 Drugs Authority Executive Agency, Cap 219 (TFDA) Head: Director- www.tfda.or.tz General Tanzania The Zanzibar Food, 2006 None Zanzibar Food and Statutory Board under (Zanzibar) Drugs and Cosmetics Drugs Board (ZFDB) the Ministry of Health; Act www.zfdb.go.tz Head: Registrar Uganda The National Drug 1993 None National Drug Semi–autonomous Policy and Authority Authority (NDA) www. organization under Act nda.or.ug the Ministry of Health; Head: Executive Director/Registrar * In Burundi a law relating to regulation of medicines was at the draft stage at the time of writing. This text was obtained from the national medicines regulatory officer and was reviewed for this comparison. No major changes were anticipated until its entry into force. In addition, provisions for medicines registration were published in 2013 in a ministerial order (see Footnote 3 on Page 570 for details).

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of the national drug policy and essential importation and exportation, whereas the medicines list. In Kenya the NMRA also regulation of wholesalers and retail outlets regulates poisons. The NMRAs of Tanzania is governed by the Pharmacy Act, 20112 (Mainland and Zanzibar) regulate food, with the controls being implemented by the medical devices, cosmetics and herbal Pharmacy Council. The draft medicines drugs in addition to pharmaceuticals. The law of Burundi does not include provisions law of Rwanda relates to the regulation for licensing of activities. and inspection of food and pharmaceutical products; however no food regulation Provisions for registration of medicines is actually carried out. The draft law Five of the six medicines laws reviewed of Burundi mandates the NMRA to include detailed provisions for registration regulate drugs and other products whose of medicinal products before they are consumption can harm health. placed on the market. The draft law of Burundi mentions the registration function Regulation of the pharmacy profession as part of the Department’s mandate, Regulation of pharmacy professionals – while details were published in 2013 in a pharmacists, pharmaceutical technicians ministerial order3. and pharmacy assistants – is included Provisions for importation of unlicensed in the medicines laws of Kenya and medicines in special circumstances Tanzania (Zanzibar). The laws of Uganda, are found in the laws of Tanzania (both Rwanda, and Tanzania (Mainland) and Mainland and Zanzibar), Kenya and the draft medicines law of Burundi focus Rwanda and in the 2013 ministerial order on regulation of medicinal products, while of Burundi. The law of Uganda is silent on the pharmacy profession is governed by this issue. separate laws1 and is regulated by the professional associations or councils. Compliance with good manufacturing practice (GMP) Licensing of activities and premises Kenya, Tanzania (Mainland and Zanzibar) The laws of Kenya, Uganda, Rwanda and and Uganda have national guidelines Tanzania (Zanzibar) contain provisions for on GMP based at a minimum on WHO licensing of retail and wholesale outlets as GMP standards, and compliance with well as manufacturers of pharmaceuticals. these guidelines is required for medicines The law of Tanzania (Mainland) covers registration in these countries. In Uganda, licensing of manufacturing facilities compliance with GMP guidelines is and wholesale premises engaged in required for licensing of premises under the regulations on Certificate of Suitability 1 Uganda: Pharmacy and Drugs Act of 1970, of Premises, 20144 of the National Drug Chapter 280. Available at: www.ulii.org/ug/ legislation/consolidated-act/280 2 see Footnote 1 United Republic of Tanzania: Pharmacy 3 Gouvernement du Burundi. Ordonnance Act, 2011 (No. 1 of 2011). Available at: Ministérielle Conjointe numéro 630/540/750/11 http:// parliament.go.tz/polis/uploads/bills/ du 02/8/2013 portant mode et conditions acts/1452070670-ActNo-1-2011.pdf. d’homologation des médicaments à usage Rwanda: Law No 45/2012 of 14/01/2013 relating humain et autres intrants pharmaceutiques au to the organization, functioning and competence Burundi. Available at: http://www.minisante.bi/ of the National Pharmacy Council. documents/homologation.pdf. Burundi: Decrèt no 100/150 du 30 septembre 4 Available at: http://www.nda.or.ug/files/ 1980, see also Table 1. downloads/Drug%20Certificate%20of%20

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Act. The guidelines are detailed and in is a core department of the NMRA. The line with WHO’s current GMP standards, quality control laboratories of Kenya, and the NMRA of Uganda is the lead Uganda and Tanzania (Mainland) were the agency on inspections of manufacturing first in the EAC region, and all three are facilities within the framework of EAC- WHO-prequalified. Rwanda has a quality MRH, which signifies the country’s level of control laboratory under the Rwanda strength in this area. The law of Rwanda Standards Board under the Ministry of requires that “pharmaceutical products Trade, Industry and EAC Affairs. Burundi ... are manufactured in compliance has a quality control laboratory under the with relevant principles relating to their National Institute of Public Health (INSP), manufacture” and prohibits manufacture of but according to the national strategic plan pharmaceutical products without a license for laboratory services 2015-20196 it does granted under the law; GMP compliance is not currently serve as a national reference mentioned in a comprehensive guideline laboratory. on registration of medicines compiled by the Technical Working Group on Pharmacovigilance Medicines Evaluation and Registration Although the laws of Kenya, Rwanda of the EAC MRH Programme, which was and Tanzania (Mainland and Zanzibar) approved by the Minister and published mention the follow-up of medicines safety on the website of the Ministry of Health as one of the functions of the regulatory of Rwanda in 20145. In Burundi, GMP authority, they do not contain specific certificates and GMP inspection are provisions for pharmacovigilance activities mentioned in the registration application by the regulatory agencies. Nevertheless, forms, but not in the draft medicines law in Kenya pharmacovigilance is being itself or in the 2013 ministerial order. executed by the Pharmacy and Poisons Board of Kenya in line with specific Quality control laboratories guidelines found on the authority’s In Tanzania (Mainland and Zanzibar) website7, and in Uganda and Tanzania the laboratory is part of the NMRA with pharmacovigilance activities are also appropriate legal provisions. In Kenya carried out by the respective NMRAs. In there is a legal basis for the quality control Tanzania (Zanzibar) medicines safety laboratory, which is however set up as an is monitored by the Zanzibar Food and independent body corporate with its own Drugs Board, while the TFDA is mandated organizational structure and management, to perform this function throughout the where the head of the laboratory does not Mainland. The Pharmacy Task Force report directly to the head of the NMRA. performs pharmacovigilance in Rwanda, In Uganda the legal provisions are not although the medicines law of Rwanda is explicit but implied and the laboratory silent on this issue, as is the draft law of Burundi. Suitability%20of%20premises%20Regulation. pdf 6 Ministère de la santé publique et de la lutte 5 Available at: http://moh.gov.rw/ contre le SIDA. Plan stratégique national de fileadmin/templates/protocols/ laboratoire de biologie medicale du Burundi. APPROVED_MOH_GUIDELINES_ON_ June 2015. Available at: https://www.minisante. SUBMISSION_OF_DOCUMENTATION_ bi/documents/plan_strategique_labo.pdf FOR_REGISTRATION_OF_HUMAN_ 7 Available at: http://pharmacyboardkenya.org/ PHARMACEUTICAL_PRODUCTS.pdf downloads/?file=national_pv_guidelines.pdf

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Control of clinical trials contravene provisions made under the The laws of Tanzania (Mainland and respective laws. The medicines laws of Zanzibar) describe the approval Kenya, Uganda, Tanzania (Mainland and process for clinical trials and include Zanzibar) contain specific provisions for some provisions for informed consent, sanctions including monetary penalties, trial monitoring and reporting. Related revocation of professional and/or product regulations and guidelines are published permits, confiscation of consignments on the TFDA’s website8. Similarly, the law and deportation and imprisonment. The of Kenya mentions the need to conduct maximum fines under the respective clinical trials as a condition for registration medicines laws are five million Tanzania of medicines to establish their safety, Shillings (approx. 2 350 US$), 1 million efficacy or bioequivalence as applicable, Kenya Shillings (approx. 9 800 US$) while a comprehensive guideline on and 1 million Uganda Shillings (approx. clinical trials is available on the PPB’s 300 US$), and the maximum terms of website9. The law of Rwanda contains imprisonment are five years in Uganda, a general statement about the need for two years in Kenya and Tanzania imported and domestically produced (Mainland), and six months in Tanzania pharmaceutical products to undergo (Zanzibar). clinical trials to identify their effectiveness and potential adverse effects related to Discussion their use. However detailed provisions NMRAs are entrusted with ensuring the could not be found in the public domain efficacy, safety and quality of medicines, either for Rwanda or for Burundi. and they are expected to carry out these tasks by applying the best available Provisions to make specific regulations scientific knowledge and skills without The laws of both Tanzania Mainland and bias. A recent achievement that can Zanzibar enable the Minister of Health, support regulatory strengthening on advice of the regulatory authorities, to and convergence in the region is the make regulations pertaining to products publication of the African Union Model and activities regulated under the Law on Medical Products Regulation respective medicines laws. The laws of (5), which covers the key principles of Uganda (Section 61) and Kenya (Section effective medicines regulation. The review 44) provide for making special regulations. of the medicines laws of EAC countries The medicines laws of Rwanda and presented here has identified some Burundi do not contain provisions to make differences and gaps that need to be regulations. addressed.

Sanctions Organizational set-up The medicines laws of Burundi and Good governance including accountability Rwanda do not contain specific provisions and transparency, sufficient competent for sanctions to individuals or entities that human resources to carry out the required 8 Available at: http://www.tfda.or.tz/ tasks, adequate financial resources index/?q=clinical_trials_downloads and freedom from undue influence of 9 Available at: http://pharmacyboardkenya.org/ politics and the interests of individuals, downloads/?file=Guidelines for Conduct of groups and the public are critical for Clinical Trials in Kenya 2016.pdf

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effective medicines regulation. Efficient, Pre-marketing control of products independent and unbiased decision- Medicines registration is at the centre making therefore requires that a sound of the medicines regulatory functions. It organizational structure is in place, involves the pre-marketing assessment giving the authority the power to acquire of data submitted by applicants to and use resources and to appoint and establish the compliance of products with dismiss staff and determine the level of standards of quality, safety and efficacy. their remuneration. The AU Model Law A clear presentation of the technical recommends that authorities should be requirements for registration is important autonomous, although they should remain for effective enforcement, as it gives functionally and financially accountable NMRAs the power to refuse registration to their Ministries. However, of the six or to remove products from registers. The regulatory bodies in EAC partner states laws of Kenya, Tanzania (Mainland and only those of Tanzania (Mainland) and Zanzibar) and Uganda contain detailed Uganda have autonomy in decision-making provisions for registration of medicines on staffing and finances. The other NMRAs with defined standards to be met in terms are Boards or Departments that are of quality, safety and efficacy. In Burundi dependent on resource allocation from the and Rwanda the law contains a general Ministry of Health, an arrangement that can clause, while detailed provisions were affect the efficiency of regulatory activities. subsequently published in an Order of the Minister. These dispositions enable Control of activities the EAC countries in principle to control Through licensing of activities, NMRAs the quality, safety and efficacy of the are able to ensure that medicines are medicines placed on their markets. manufactured, stored, distributed and sold To facilitate convergence of practices in premises complying with regulations and a detailed Medicines Evaluation and that they comply with the specifications Registration Compendium was developed of their marketing authorization until they under the EAC-MRH programme (7). The reach the end users. The NMRAs of compendium is based on the Modules of Kenya, Uganda and Tanzania (Zanzibar) the ICH Common Technical Document are in charge of licensing the full range (CTD) format and can be adapted for of activities and can institute appropriate national use, as has been done in the measures to safeguard the quality of guidelines published in 2014 in Rwanda. pharmaceuticals. In Tanzania (Mainland) Currently, Tanzania through TFDA the responsibilities are divided between serves as a lead agency in Medicines the regulatory authority, which controls Evaluation and Registration in the manufacturing and wholesale (importers’) EAC, and so far work-sharing has been premises, and the Pharmacy Council, successfully demonstrated. Despite which controls wholesalers and retail the effort made, technical capacity in outlets. While this arrangement offers assessment and registration especially of clustering of regulatory activities, it may new chemical entities and biotechnology result in loopholes and inefficiency in derived products still poses a challenge regulation, as the two parties have different towards effective regulation. objectives, standards, processes and Compliance with GMP was found reporting lines (6). to be a requirement for registration of

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medicines in only three of the six laws No quality control laboratory exists in reviewed. In the other countries provisions Burundi. Regional collaboration could offer for GMP compliance were in the form a solution, although cross-border shipment of recommendations and guidance and of samples under controlled conditions may hence not be legally enforceable. and communication of results may pose This increases the risk that medicines are significant logistic and organizational assessed and registered even though they challenges. The absence of quality control are manufactured in facilities that do not laboratories can therefore delay regulatory comply with GMP. In such facilities there actions and impact the patients. is a higher risk of mix-ups and cross- Pharmacovigilance is important to contamination of products, among other detect adverse events observed with threats, with serious potential impact on medicines on the market. Although the health of patients. pharmacovigilance activities are being carried out in EAC countries, the absence Post-market control of products of specific legal provisions in this area Quality control laboratories form an is likely to hinder the effective control important component in effective of safety of registered medicines, as regulation of medicines. Their role is to guidelines published by individual partner offer pre- and post-registration testing of states may not be legally enforceable. product samples in order to confirm that a product conforms with its specifications Control of clinical trials at all times. Functional quality control Effective regulatory control of clinical laboratories are in place in Kenya, trials is another important aspect of Tanzania, Uganda and Rwanda. While medicines regulation. For this purpose, in Tanzania and Uganda both functions laws must contain detailed provisions on are under the same roof, in Kenya the how pharmaceutical companies should laboratory is independent of the NMRA apply for permission to carry out clinical and in Rwanda it is under the Rwanda trials, and how NMRAs in collaboration Standards Board. The latter arrangement with Ethics Committees should perform facilitates independent analysis and ethical and regulatory review, approve reporting of analytical results without clinical trials, inspect clinical trial sites, undue influence by findings from dossier and follow-up periodically on the conduct assessment and inspections. However, it of the trials according to the approved may affect the efficiency of communication protocols. The full range of the above- and delay product registration, since pre- mentioned provisions was not found in all registration testing is a requirement for all the medicines laws reviewed. However, an pharmaceutical products in Kenya10. approval process for clinical trials exists in 10 Pre-registration testing can serve to verify EAC countries, with detailed regulations that the manufacturer’s testing methods for and guidelines available in some of the the product give valid results at the national partner states. Cooperation and capacity- laboratory, but has otherwise been found to building were stepped up when the need have little added benefit as it is rare to find product deficiencies in registration samples for clinical testing was urgent. During submitted by applicants. In recent years it has been recognized that the focus should products circulating in countries comply with the be on targeted, risk-based testing as part specifications of their marketing authorization of post-market surveillance to ensure that on an ongoing basis.

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the Ebola crisis the African Vaccines have to go through the often bureaucratic Regulatory Forum (AVAREF) served as a process of amendment of the main laws common platform for regulators and ethics every time an update is necessary. The committee in reviewing and approving resulting loopholes may encourage acts of clinical trial applications (8). unlawful dealing in medicines, especially as the general statutory laws of EAC Enforcement of legal provisions countries do not have adequate sanctions Enforcement of medicines legislation in place compared to the potential profit to depends to a large extent on the be made by illegal activities. deterrent effect of sanctions. The fines and jail terms specified in the laws of Limitations of this comparison EAC partner states are relatively low The comparison presented in this article compared to the profits often realized by focused on the medicines laws of EAC unlawful dealers of medicines, and are in partner states. It did not systematically no way commensurate to the risks that take into account other laws or the full substandard and counterfeit medicines range of regulations that affect the control pose for the population. By contrast, of medicines. Nevertheless, the findings in a small EU country with 1.4 million identify the main gaps and opportunities inhabitants, Estonia, dealers of medicines for achieving effective regulation through who contravene the provisions of the harmonization and can thus be useful Medicines Act11 are liable to pay fines in improving the legal systems in EAC of up to 32 000 Euro (approximately partner states as part of the ongoing EAC US$ 35 700), and certain offenses are harmonization process. subject to prosecution and punishment The review focused on the main under other laws, for example criminal law. regulatory functions. In addition to providing for these, the AU Model Law Adaptation to change includes some “Miscellaneous provisions” Provisions to make specific regulations on management of conflicts of interest, enable governments to accommodate the the extent of liability of NMRAs for loss or need for new regulatory functions as they damage arising from their decisions, and emerge. The AU Model Law on medical protection of and access to information. products regulation gives the supervisory These aspects were not considered in this authority (i.e. the Ministry in charge of article, although they can have a direct health) the power to make regulations impact on the control of medicines. For and guidelines necessary to pursue example, a review of WHO assessment the objectives of the medicines law, in reports of regulatory systems in African consultation with the regulatory authority. countries (9) found that in many cases Clauses to this effect are included in the medicines regulation is not sufficiently laws of Uganda, Kenya and Tanzania independent from the procurement (Mainland and Zanzibar). The laws of function, and that there is limited Rwanda and Burundi are silent on this public access to up-to-date registers of aspect, and this means that the agencies authorized products, licenced premises and professionals. 11 Republic of Estonia. Agency of Medicines: Medicinal Products Act. https://www.riigiteataja. ee/en/eli/525112013005/consolide

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Conclusion References The medicines laws in EAC partner states 1 International Council for Harmonization cover most of the key regulatory functions, (ICH). ICH guidelines. www.ich.org/ and NMRAs are in place. The laws are at products/guidelines.html different stages of implementation, with 2 EMA. The European regulatory system for some partner states having significantly medicines and the European Medicines Agency. A consistent approach to more regulatory capacity and experience medicines regulation across the European than others. On the other hand, some Union. EMA/437313/2016. London, United of the older laws have not been recently Kingdom: European Medicines Agency, reviewed or amended to keep up with the 2016. pace of pharmaceutical innovation and 3 EAC: Treaty for the Establishment of East technology. Some NMRAs conduct key African Community. August 2007. functions that are not provided for in their 4 Situation analysis study on medicines respective medicines laws. registration harmonisation in Africa. Final Differences were found in the legal report for the East African Community. November 2010. provisions for key regulatory functions as well as in regulatory practices of EAC 5 NEPAD / PATH. Increasing access to high quality, safe health technologies partner states, potentially creating delays across Africa. African Union Model Law on in bringing needed medicines to the Medical Products Regulation. Policy brief. populations and presenting legal loopholes (Undated). that can easily be exploited. The sanctions The full text of the model law is available stipulated in the laws are generally not at http://www.hst.org.za/publications/ african-union-model-law-medical-products- severe enough, nor enforced to a sufficient regulation. extent, to deter unlawful dealing in 6 Mori AT, Kaale EA, Risha. Reforms: a medicines across the EAC region. quest for efficiency or an opportunity The differences and gaps need to be for vested interests’? A case study of addressed in collaboration, since all pharmaceutical policy reforms in Tanzania EAC partner states are faced with similar BMC Public Health. 2013 Jul 13;13:651. health and economic challenges. Future doi: 10.1186/1471-2458-13-651 challenges are likely to be experienced 7 EAC. Compendium of Medicines Evaluation across the region as globalization and Registration for Medicine Regulation Harmonization in the East African and cross-border trade and travel Community. Document No: EAC/TF-MED/ increase. These developments call for MER/FD/COM/N1R0. Version September convergence of regulatory practices in 2014. the region by streamlining the existing 8 The African Vaccine Regulatory Forum legal and regulatory frameworks towards (AVAREF): A platform for collaboration in a common medicines law in the region. a public health emergency. WHO Drug The medicines regulatory harmonization Information 2016; 29(3):127-31. programme in EAC partner states is 9 WHO. Assessment of Medicines Regulatory a good start towards achieving this Systems in Sub-Saharan African Countries. An Overview of Findings from objective. 26 Assessment Reports. Geneva: World Health Organization, 2010. å

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Safety news

Safety warnings Brimonidine gel: worsening of rosacea symptoms DPP-4 inhibitors: Pemphigoid United Kingdom – Prescribing advice Japan – A warning about the risk of for brimonidine gel (Mirvaso®) has been pemphigoid has been added to the updated following an EU-wide review that approved product information in Japan found worsened rosacea symptoms in up for antidiabetics containing the dipeptidyl to 16% of patients treated with brimonidine peptidase 4 (DPP-4) inhibitors alogliptin, gel in clinical studies. In most cases, the linagliptin or teneligliptin. Health erythema and flushing resolved after the professionals are advised to refer patients treatment was stopped. with blisters, erosions or other signs Treatment should be initiated with less or symptoms of this skin condition to a than the maximum dose for at least one dermatologist, and to consider treatment week, and the dose should be increased discontinuation. gradually based on tolerability and ►►PMDA Summary of investigation results response to treatment. The maximum and MHLW Revision of precautions, daily dose (1 g of gel in total weight, 22 November 2016. approximately 5 pea-sized amounts) should not be exceeded. Patients should be advised to stop treatment and consult a Polaprezinc: copper deficiency doctor if they notice increased redness or Japan – The PMDA has recommended burning during treatment. that the risk of copper deficiency should ►►Drug Safety Update volume 10 issue 4, be included in product information for November 2016: 1. polaprezinc, a medicine used to treat gastric ulcer. Pancytopaenia and anaemia have been Levonorgestrel emergency reported in Japan in poorly nourished contraceptives: interactions with patients treated with polaprezinc. These liver enzyme inducers adverse effect may occur because the United Kingdom – The MHRA has zinc contained in the medicine inhibits the informed health professionals that absorption of copper. Health professionals women seeking emergency contraception should monitor their patients and take who have used cytochrome P450 3A4 appropriate measures if any abnormalities (CYP3A4) enzyme inducers (such as are observed. the antiretrovirals efavirenz and ritonavir, ►►PMDA Summary of investigation results, certain medicines for tuberculosis and and MHLW Revisions of precautions, epilepsy and herbal medicines containing 22 November 2016. St John’s wort) within the last four weeks should use a copper intrauterine device or, if this is not an option, double the dose of levonorgestrel from 1.5 mg

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to 3 mg. Ulipristal acetate emergency patients receiving these medicines for contraception is not recommended for hepatitis B virus. (1) use in these women. Advice should also The EMA, Health Canada and the TGA be provided on highly effective ongoing of Australia have performed their own contraception as described in national reviews and have issued similar warnings guidance. (2, 3, 4).The EMA has confirmed its earlier This follows a review of the emergency recommendation to screen all patients for contraceptive levonorgestrel (Levonelle® hepatitis B before starting treatment with and associated names) by the EMA, which DAAs, and has concluded that further found that medicines or herbal remedies studies are needed to assess the risk of that induce CYP3A4 enzymes lower the liver cancer with these medicines. blood levels of levonorgestrel, which ►►(1) FDA Drug safety communication, 4 may reduce its emergency contraceptive October 2016. efficacy. (2) EMA Press release, 16 December 2016. ►►MHRA Press release, 15 September 2016. (3) Health Canada Advisory, 1 December MHRA Drug Safety Update Volume 10 2016. Issue 2, September 2016: 1. (4) TGA Safety advisory, 19 December 2016. EMA. Referrals. Levonelle 1500 microgram tablets and associated names. HIV treatment-boosting agents and steroids: systemic adverse effects Direct-acting antivirals: hepatitis B United Kingdom – The MHRA has reactivation warned health professionals that the United States of America – The FDA use of steroids metabolized by the has warned health professionals that cytochrome P450 3A (CYP3A) pathway in cases of hepatitis B virus reactivation have to patients treated with a HIV treatment- occurred in patients co-infected with hepatitis boosting agent may increase the risk of C virus while undergoing treatment with systemic corticosteroid-related adverse direct-acting antivirals (DAA). Some cases effects. Although these reactions are have resulted in fulminant hepatitis, hepatic rarely reported, this interaction may failure and death. occur even with steroid formulations A “Boxed Warning” is to be added to administered by intranasal, inhaled, and the product information of daclatasvir intra -articular routes. Coadministration (Daklinza®), sofosbuvir and velpatasvir of these medicines is not recommended (Epclusa®), ledipasvir and sofosbuvir unless the potential benefit to the patient (Harvoni®), simeprevir (Olysio®), outweighs the risk. In such cases use of sofosbuvir (Sovaldi®), ombitasvir and beclomethasone should be considered, paritaprevir and ritonavir (Technivie®), particularly for long-term use, as it is dasabuvir and ombitasvir and paritaprevir less dependent on CYP3A metabolism. and ritonavir (Viekira Pak®, Viekira Pak Patients should be monitored for systemic XR®), and elbasvir and grazoprevir corticosteroid-related reactions. (Zepatier®), directing health care ►►MHRA. Drug Safety Update vol 10 issue 5, professionals to screen and monitor all December 2016: 1.

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Nivolumab: immune when the concentration of eculizumab in thrombocytopenic purpura, the blood is considered to be relatively myocarditis, rhabdomyolysis high. Patients not yet treated with Japan – The PMDA has recommended eculizumab should be vaccinated with a updates to the product information for meningococcal vaccine (against serotypes the anti-cancer medicine nivolumab A, C, Y, W135, and B) before or at the (Opdivo®) to warn about the risk of start of eculizumab treatment, unless immune thrombocytopenic purpura, the risks of delaying therapy outweigh and about the risk of myocarditis and the risks of developing a meningococcal rhabdomyolysis, in addition to myasthenia infection. Patients who started eculizumab gravis and myositis that are already treatment less than two weeks after mentioned as adverse effects. In the receiving a meningococcal vaccine section on precautions, a statement should receive appropriate prophylactic has been added that patients should antibiotics for two weeks after vaccination. continue to be monitored after treatment The Canadian product information has discontinuation as serious adverse effects been updated to include this new safety may still occur at that stage. information. The revisions are based on reports of ►►Health Canada Advisory, 25 October 2016. the above-mentioned events in people treated with nivolumab in Japan, and on reported cases of myocarditis and Anaesthetics and sedatives in rhabdomyolysis in patients treated with young children and pregnant nivolumab in other countries. women ►►PMDA Summary of investigation results and United States of America – Based on MHLW Revision of precautions, 18 October a comprehensive analysis of published 2016. scientific studies, the FDA has issued a Drug Safety Communication to inform health care providers, parents and Eculizumab: interaction with caregivers of children younger than three meningococcal vaccine years, and pregnant women in their third Canada – A Health Canada safety review trimester, that the repeated or lengthy has found that patients with complement- (more than three hours) use of general mediated diseases who were treated with anaesthetic and sedation medicines may eculizumab (Soliris®) had an increased adversely affect children’s developing risk of low haemoglobin, including brains. The FDA is requiring warnings to anaemia or haemolysis, after vaccination be added to the labels of these medicines. with Serogroup B meningococcal vaccine The Agency recognizes that in many (Bexsero®). The risk was highest in cases these exposures may be medically patients whose predicted systemic necessary and that the potential harms eculizumab concentrations were relatively must be carefully weighed against the low. risk of not performing a specific medical Health Canada has recommended that procedure. patients being treated with eculizumab ►►FDA Statement, 14 December 2016. should be vaccinated only after their FDA Drug safety communication, disease has been controlled and within 14 December 2016. one week following eculizumab infusion,

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Known risks The approved product information for topical miconazole in the UK includes a Pioglitazone: bladder cancer warning that caution should be exercised United States of America – The FDA in patients on oral anticoagulants such as has updated the labelling of products warfarin, and anticoagulant effect should containing the type 2 diabetes medicine be monitored. pioglitazone to describe the additional ►►PMDA Summary of investigation results, studies reviewed on the increased risk 18 October 2016. of bladder cancer in patients treated with pioglitazone. This follows warnings issued about this risk in 2010 and 2011. Statins: immune-mediated ►►FDA Drug safety communication, necrotizing myopathy 12 December 2016. Japan – The PMDA has recommended updates to the product information for statin-containing products on the market in Warfarin and miconazole: Japan to warn about the risk of immune- contraindicated mediated necrotizing myopathy. Japan – The PMDA, in consultation with In the EU, the approved product the MHLW, has approved an amendment information for statins was updated to the product information for miconazole in 2015 to include immune-mediated (gel and injection) and for warfarin, to necrotizing myopathy as an adverse effect include a contraindication for the two occurring with unknown frequency. medicines to be used concomitantly due ►►PMDA Summary of investigation results, to the increased risk of bleeding. 18 October 2016. Health professionals have been advised EMA. PRAC recommendations on to prescribe other azole antifungal signals. Adopted at the PRAC meeting of medicines. The product information for 6-9 January 2015. these alternative antifungals has also been updated to advise extreme caution and measures such as more frequent Daptomycin: acute generalized prothrombin time (PT) measurement exanthemous pustulosis and thrombotest, due to the increased Japan – The PMDA has recommended PT-international normalized ratio (INR) in to update the product information for the patients treated with warfarin and other antibacterial medicine daptomycin to azole antifungals. warn about the risk of acute generalized These measures follow reports received exanthemous pustulosis (AGEP). This in Japan of a substantial number of follows cases of AGEP reported both in cases of serious bleeding during or after Japan and elsewhere. concomitant administration of the two Approved product information in the EU drugs. The revision also took into account includes a warning about AGEP, while the reports sent to the MHRA in the United U.S. FDA-approved product information Kingdom about possible interactions mentions that serious skin reactions, of warfarin and miconazole, including including Stevens-Johnson syndrome and haemorrhagic events with fatal outcome. The MHRA is reviewing these data.

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vesiculobullous rash, have been observed injury reported in Canada were associated in the post-marketing phase. with unintentional overdoses. ►►PMDA Summary of investigation results and ►►Health Canada Information update, MHLW Revision of precautions, 18 October 15 September 2016. 2016.

Lurasidone and certain ARVs:

NSAIDs: increased risk of contraindicated; miscarriage United States of America – The FDA Australia – The TGA has completed a has announced that product information safety review on the known association for several antiretrovirals (ARVs) has been between the use of non-steroidal anti- updated to add lurasidone (Latuda®), an inflammatory drugs (NSAIDs) and the antipsychotic medicine, to the section on increased risk of miscarriage. The review contraindications due to the potential for focused on ensuring that consistent serious and life-threatening reactions. information on this risk was available for The ARVs concerned are: tipranavir, all products. The findings confirmed a indinavir, saquinavir, ritonavir (also in potential increased risk of miscarriage with combination with lopinavir), fosamprenavir non-aspirin NSAIDs, particularly when (if co-administered with ritonavir), the medicine is taken close to the time of darunavir, atazanavir (if co-administered conception. For aspirin the evidence was with ritonavir), nelfinavir, and fixed-dose not sufficient to confirm an association combinations of elvitegravir, cobicistat, with the risk of miscarriage. emtricitabine and tenofovir. Lurasidone The TGA is working with sponsors is already included as a contraindicated of non-aspirin NSAIDs to harmonize medication in the product information the warnings included in the product of atazanavir/cobicistat and darunavir/ information in line with the conclusions of cobicistat. the review. In the EU, approved product information ►►TGA Safety advisory, 11 October 2016. for lurasidone includes a contraindication with strong CYP3A4 inhibitors, mentioning some of the above ARVs, and product Paracetamol: updated labelling to information for the ARVs warns against address risk of liver injury co-administration of certain substances Canada – Health Canada has released that are highly dependent on the CYP3A4 an updated labelling standard for over-the- pathway for clearance. counter paracetamol (U.S. adopted name: ►►FDA HIV update bulletin, 19 September 2016. acetaminophen), which provides clearer instructions and stronger warnings to help reduce the potential for liver damage. This Labelling changes follows a safety review completed in 2015, which found that more than half of the Metformin: for patients with paracetamol-related cases of serious liver moderate kidney impairment European Union – The EMA has completed a review of the antidiabetic metformin and has concluded that the

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medicine can be given to patients with with dose and duration of exposure. type 2 diabetes that have moderately Therefore the lowest effective daily dose reduced kidney function (glomerular should be used and the need for treatment filtration rate of 30–59 ml/min). Reduced should be regularly reassessed. The doses should be considered for these recommendation is based on results of two patients according to the dosage clinical trials showing that the 60 mg-dose recommendations to be provided in is effective in some but not all patients. the updated product information. The ►►Drug Safety Update volume 10 issue 3, contraindication for patients with severely October 2016: 1. reduced kidney function (glomerular filtration rate less than 30 ml/min) will remain. Improved dosing instructions Previously, metformin had not been recommended in patients with impaired Levetiracetam oral solution kidney function because of the risk of European Union – Cases of accidental lactic acidosis. The review found that the overdoses with levetiracetam oral solution large patient population with moderately (Keppra®) have been reported in Europe, reduced kidney function can benefit from with the majority of cases occurring in the use of metformin. Product information children aged between 6 months and for metformin-containing medicines 11 years. Where the cause of the reported approved in the EU is being revised and overdosing could be determined, it was harmonized to reflect current scientific either due to the use of an inappropriate evidence and recommendations. syringe or the misunderstanding of the ►►EMA Press release, 14 October 2016. caregiver about how to measure the dose. The EMA has recommended new measures to ensure the safe use of

Etoricoxib: lower recommended dose; levetiracetam oral solution. Different United Kingdom – The marketing colours will be used for the outer authorization holder, in communication packaging and bottle labels of the different with MHRA, has informed health presentations. Prescribers should ensure professionals of a revised dosing that they prescribe the age-appropriate recommendation for etoricoxib (Arcoxia®) presentation of the medicine, indicating when used to treat rheumatoid arthritis or the dose in mg with a ml equivalence ankylosing spondylitis. The recommended based on the correct age of the patient. starting dose has been lowered to Pharmacists should ensure that the 60 mg daily, with the option to increase appropriate presentation is dispensed. to a maximum of 90 mg once daily if With every prescription, healthcare necessary. Once the patient is clinically professionals should advise the patient stabilised, down-titration to 60 mg once and/or caregiver on how to measure the daily may be appropriate. In the absence prescribed dose, reminding them to use of therapeutic benefit, other treatment only the syringe included in the package options should be considered. with each bottle and to discard the syringe The cardiovascular risk, and other once the bottle is empty. important risks of etoricoxib, may increase ►►EMA Press release, 14 October 2016.

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Unchanged recommendations derived and urine-derived medicinal products with respect to Zika virus. 15 September 2016. Urine- and plasma-derived medicines: safe regarding Zika ; European Union – The EMA has Non-compliance with good practices confirmed that there is no increased risk of contamination with the Zika virus Pharmaceutics International Inc., for patients who take plasma-derived U.S.: import stop to EU; medicines such as coagulation factors European Union – The EMA has or immunoglobulins, or urine-derived recommended that medicines medicines such as certain hormone-based manufactured by Pharmaceutics treatments or urokinase products. International Inc., United States, should A review of information showed that no longer be supplied in the EU. The the manufacturing processes used for only exception is sodium phenylbutyrate plasma-derived products, such as the (Ammonaps®), a medicine used to solvent/detergent method to inactivate treat urea cycle disorders which is viruses, liquid heat inactivation and virus considered to be critical for public health. filtration, inactivate or remove the Zika In countries where alternatives are virus from the finished product. Likewise, available Ammonaps® will be recalled. manufacturing processes for urine-derived Certain other medicines supplied by products contain complementary steps Pharmaceutics International Inc. are with inactivation/removal capacity for available from alternative registered enveloped viruses, which are considered manufacturing sites and will remain sufficient to ensure the Zika virus safety of available in the EU. these products. The EMA concluded that These precautionary measures follow no additional safety measures such as a review that was triggered by inspection screening, testing, deferral or exclusion of findings of continued non-compliance with certain donors are necessary. good manufacturing practice. ►►EMA Press release, 21 September 2016. ►►EMA Press release, 16 September 2016. å EMA/CHMP Biological Working Party (BWP). Report on viral safety of plasma-

Safety reviews started

Under review Concerns Reference Medicine: Certain Traces of cows’ milk proteins could affect ►►EMA. Article injectable methyl­ treatment of acute reactions in the small number 31 Referral prednisolone products of highly sensitive patients allergic to lactose. started. EMEA/ used to treat severe, The reaction to the medicine may be mistaken H/A-31/1449. 1 rapidly developing for a worsening of the original condition, leading December 2016. (acute) allergic reactions to additional doses of the medicine being given. Contract research Inspection findings of non-compliance with good ►►EMA. Article 31 organization: Micro clinical practice at the study sites in Chennai Referral started. Therapeutic Research and Coimbatore, India 16 December Labs, India 2016.

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Regulatory news

Pre-market assessment Post-market surveillance

EMA publishes clinical reports Social media campaign on European Union – The EMA has started reporting of medicines side effects to give open access to clinical reports for United Kingdom, European Union – new medicines for human use authorized On 7–11 November 2016 the MHRA held in the EU on a new website, following the a social media campaign to promote adoption of a new policy after extensive reporting of suspected side effects as consultation with stakeholders. The part of an EU-wide awareness week. website will include the clinical reports Twenty-two EU Member States took part contained in applications for marketing in the combined cross-European social authorization submitted to the Agency media campaign organized under the on or after 1 January 2015, and in Strengthening Collaboration for Operating applications for extension or modification Pharmacovigilance in Europe (SCOPE) of an indication, or for line extension, Joint Action project, which aims to raise submitted on or after 1 July 2015. The awareness of national reporting systems data is intended to increase transparency, for suspected side effects in medicines. facilitate independent re-analysis and ►►UK Government Press release, 7 November support efficient medicine development. 2016. Data for two medicines were published initially, comprising over 100 clinical reports. EMA expects to offer access to EU project to strengthen market approximately 4500 clinical reports per surveillance for medical devices year. (1) Bratislava, Slovakia – At the 39th Data for two additional medicines meeting of the EU Competent Authorities followed one month later. (2) for Medical Devices (CAMD) held in Health Action International (HAI) has Bratislava in October 2016, the MHRA welcomed the move and has emphasized launched the Joint Action on Market its strong support for the principle that Surveillance of Medical Devices. Post- clinical trial data must be made publicly marketing surveillance is a crucial part of available to all. (3) health product regulation to make sure ►►(1) EMA Press release, 20 October 2016. that medical devices are acceptably safe (2) EMA Press release, 24 November 2016. and perform as intended. The project aims EMA. Online access to clinical data for to improve the coordination of surveillance medicinal products for human use. https:// activities by EU member states and to clinicaldata.ema.europa.eu. ensure adequate communications and cooperation. (3) HAI. Clinical Trial Data Transparency on ►►MHRA News story, 17 November 2016. Trial – EMA Under Pressure From Pharma Lawsuit. 1 December 2016.

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EU–U.S. collaboration on inspections of API manufacturers medicines for rare diseases worldwide, including information on European Union, United States of planning, policy and reports. The overall America – The EMA and the FDA have objective of the collaboration is to increase set up a new working group to share cooperation and mutual reliance between experiences and best regulatory practices participating organizations to make the in the development of medicines for rare best possible use of inspection resources. diseases. Global collaboration in this area ►►EMA News, 25 November 2016. is particularly important to ensure that the few studies that can be conducted in the small patient populations can benefit Mapping of global medicines all patients. The agencies will exchange regulatory initiatives information on topics such as the design European Union – The EMA has of clinical trials and the use of statistical published a comprehensive overview of analysis methods, the selection and global initiatives on medicine regulation. validation of trial endpoints, preclinical The mapping was carried out by EMA evidence to support development on behalf of the International Coalition of programmes, the design of post-marketing Medicines Regulatory Authorities (ICMRA). studies, and risk management strategies The aim of the mapping exercise was to for long-term safety issues. raise awareness of ongoing activities, The existing EMA/FDA “Cluster on provide a basis for strategic coordination orphan medicinal products” will continue and identify possible gaps. to focus on orphan designation and The report was presented at the exclusivity. 11th Summit of Heads of Medicines ►►EMA News, 26 September 2016. Regulatory Agencies and the annual ICMRA meeting held in Interlaken, Switzerland, on 11-13 October 2016. Japan joins international It includes wide-ranging activities collaboration on GMP inspections such as the harmonization work of the The ongoing international collaboration International Council for Harmonisation of on good manufacturing practice (GMP) Technical Requirements for Registration inspections of manufacturers of active of Pharmaceuticals for Human Use (ICH), pharmaceutical ingredients (API) is and identifies areas of particular strategic to be expanded to include Japan’s interest for ICMRA including generic Pharmaceutical and Medical Devices medicines, good manufacturing practice Agency (PMDA). inspections, exchange of confidential The collaboration started as a pilot in information, supply-chain integrity, crisis 2008 and was fully implemented in 2011. management, pharmacovigilance and It currently includes EMA, five regulatory information technology systems. authorities of EU Member States, the ►►EMA News, 13 October 2016. European Directorate of the Quality of EMA. Connecting the dots. Towards Medicines and Healthcare (EDQM) the global knowledge of the international U.S. FDA, the TGA of Australia, Health medicine regulatory landscape: mapping of Canada and WHO. The participating international initiatives. 2016. organizations share information on

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MHRA and Swissmedic sign under-reporting, meaning that the findings agreement should be interpreted with caution. Interlaken, Switzerland – The ►►EMA News, 14 October 2016. MHRA and Swissmedic have signed a EMA. Sales of veterinary antimicrobial Memorandum of Understanding (MoU). agents in 29 European countries in 2014. The agreement was signed on the Sixth ESVAC report. sidelines of the 11th Summit of the Heads of Medicines Regulatory Agencies in Interlaken, Switzerland. It focuses on Indian FDC ban reversed implementing a shared approach to India – The Delhi High Court has stayed complex challenges and on promoting a government ban on 344 fixed-dose each other’s regulatory frameworks, combination (FDC) medicines after more requirements and processes, as a basis than six months of hearing more than for information-sharing. 300 petitions filed by pharmaceutical ►►MHRA Press Release, 11 October 2016. companies. (1) Swissmedic Announcement, 11 October The ban, which affected analgesic and 2016. antibiotic combinations among others, had been announced in March 2016 in the interest of public health. (2) Use of medicines ►►(1) Reuters Money News, 1 December 2016. (2) Regulatory News. WHO Drug Report on sales of veterinary Information. 2016; 30 (2): 213. antibiotics in Europe European Union – The Sixth report on the sales of veterinary antibiotics in Under discussion Europe highlights a slight downward trend, suggesting that actions taken by European Union – The European EU member states to fight antimicrobial Medicines Agency (EMA) has published a resistance are making a difference. revised guideline on first-in-human clinical trials. The revision was based on a concept A total of 28 countries reported data to paper released for comment earlier in 2016 the European Surveillance of Veterinary and took into account the lessons learnt from Antimicrobial Consumption (ESVAC) the tragic incident which occurred during a for the year 2014. While a considerable clinical trial in Rennes, France, in January increase was noted in one European 2016. The revised guideline is open for country due to an improvement in data public consultation until 28 February 2017. collection systems, an overall decrease of ►►EMA Press release, 15 November 2016. 12% was found in 24 of the 25 countries that provided data for this four-year European Union – The European period. Other countries also changed Commission (EC) is seeking views and their reporting systems or identified feedback from stakeholders, to support the Commission in drafting its second report on the Paediatric Regulation after ten years of implementation.The consultation is open until 20 February 2017. ►►EMA News, 15 November 2016.Under d

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Approved

Obeticholic acid: for rare, chronic Class: Fixed-ratio combination of insulin liver disease glargine, a basal insulin analogue, and Product name: Ocaliva® lixisenatide, a glucagon-like peptide 1 Dosage form: Tablets (GLP-1) receptor agonist Class: Bile acid preparation; Approval: EMA ATC code: A05AA04 Use: In combination with metformin, Approval: EMA (orphan product; conditional treatment of diabetes mellitus in adults approval) when glycaemic control has not been Use: In combination with ursodeoxycholic provided by other treatments. acid (UDCA), treatment of primary biliary Benefits: Clinically relevant effect on cholangitis (also known as primary glycaemic control in patients with type-2 biliary cirrhosis) in patients who cannot diabetes when used with metformin. successfully be treated with UDCA alone. ►►EMA CHMP Summary of opinion, Benefits: Ability to delay development of 10 November 2016. liver fibrosis, cirrhosis liver transplant and death through reduction of alkaline

phosphatase and bilirubin levels in Lonoctocog alfa : for haemophilia A adults with primary biliary cholangitis. Product name: Afstyla® The efficacy remains to be formally Dosage form: Powder and solvent for solution demonstrated by means of post- for injection or infusion authorization follow-up. Class: Single-chain recombinant human Note: In the past, the only option for these factor VIII product; ATC code: B02BD02 patients has been a liver transplant. Approval: EMA CHMP recommendation ►►EMA Press release, 14 October 2016. Use: Treatment and prophylaxis of bleeding in patients with haemophilia A. Benefits: Ability to prevent and control

Insulin aspart : for diabetes mellitus bleeding when used on demand and Product name: Fiasp® when used for surgical procedures in Dosage form: Solution for injection adults and children with haemophilia Class: Fast-acting insulin analogue; A. Lonoctocog alfa has demonstrated a ATC code: A10AB05 higher affinity for von Willebrand factor Approval: EMA (VWF) than full-length recombinant Use: Treatment of diabetes mellitus in adults factor VIII. VWF stabilises factor VIII and Benefits: Ability to control blood glucose. protects it from degradation. Note: Fiasp® is an ultra-rapid-acting ►►EMA Summary of opinion, 10 November formulation of insulin aspart. 2016. ►►EMA CHMP Summary of opinion, 10 November 2016.

Etelcalcetide : for secondary hyperparathyroidism

Insulin glargine/lixisenatide: for Product name: Parsabiv® diabetes mellitus Dosage form: Solution for injection Product name: Suliqua® Class: Synthetic peptide, calcimimetic agent Dosage form: Solution for injection ATC code: H05BX04 Approval: EMA

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Approved

Use: Treatment of secondary Benefits: Improved survival. hyperparathyroidism in adults with chronic Safety information: Olaratumab has some kidney disease on haemodialysis therapy. serious risks including infusion-related Benefits: Ability to reduce abnormally reactions and embryo-foetal harm. elevated serum parathyroid hormone ►►EMA Press release, 16 September 2016. levels in patients with chronic kidney FDA News release, 19 October 2016. disease on haemodialysis therapy. ►►EMA Summary of opinion, 15 September

2016. Palbociclib: for breast cancer Product name: Ibrance® Dosage form: Hard capsules

Tenofovir alafenamide: for chronic Class: Inhibitor of cyclin-dependent kinases hepatitis B (CDK) 4 and 6; ATC code: L01XE33 Product name: Vemlidy® Approval: EMA Dosage form: Film-coated tablets Use: In combination with other medicines, Class: Nucleotide reverse transcriptase treatment of hormone receptor (HR)- inhibitor; ATC code: J05AF13 positive and human epidermal growth Approval: EMA factor receptor 2 (HER2)-negative locally Use: Treatment of chronic hepatitis B in advanced or metastatic breast cancer. adults and adolescents aged 12 years Benefits: Improved progression-free survival. and older. ►►EMA Press release, 16 September 2016. Benefits: Ability to achieve a sustained antiviral response in treatment-naive and

treatment-experienced patients. Eteplirsen: for Duchenne muscular Safety information: Lower impact on dystrophy renal safety and bone mineral density Product name: Exondys 51® compared to tenofovir disoproxil. Dosage form: Injection for intravenous use ►►EMA CHMP Summary of opinion, Class: Antisense oligonucleotide: 10 November 2016. ATC code: M09AX06 (temporary code) Approval: FDA (orphan medicinal product, fast track designation; accelerated

Olaratumab : for soft tissue sarcoma approval under a rare paediatric disease Product name: Lartruvo® priority review voucher) Dosage form: Concentrate for solution for Use: Treatment of patients with Duchenne infusion muscular dystrophy with a confirmed Class: Human IgG1 monoclonal antibody mutation of the dystrophin gene amenable and antagonist of platelet derived growth to exon 51 skipping. factor receptor-α (PDGFR-α) expressed Benefits: Dystrophin increase in skeletal on tumour and stromal cells; muscle (surrogate endpoint). ATC code: L01XC27 Notes: The FDA has required a study to Approval: EMA (orphan product, accelerated assess whether the product improves assessment; conditional marketing motor function. authorization): FDA (orphan drug; fast- ►►FDA News release, 19 September 2016. track designation, priority review, break- through therapy, accelerated assessment)

Use: In combination with doxorubicin, Baricitinib:: for rheumatoid arthritis treatment of adults with soft tissue Product name: Olumiant® sarcoma. Dosage form: Tablets

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Approved

Class: Selective and reversible inhibitor of Biosimilars Janus kinase (JAK) 1 and 2; ATC code: L04AA37 Insulin glargine Approval: EMA Product name: Lusduna® Use: Treatment of active rheumatoid arthritis Reference product: Lantus® in adults who cannot be treated with other Approval: EMA disease-modifying anti-rheumatic drugs. Use: Treatment of diabetes mellitus Benefits: Reduces the symptoms of ►►EMA/CHMP Summary of opinion, rheumatoid arthritis 10 November 2016. EMA Press release, 16 Dec 2016.

Naloxone nasal spray : for opioid Teriparatide overdose Product name: Movymia® Product name: Narcan® Reference product: Forsteo® Dosage form: Nasal spray Approval: EMA Class: Antidote; ATC code: V03AB15 Use: Treatment of osteoporosis Approval: Health Canada (expedited review) ►►EMA/CHMP Summary of opinion, Use: Emergency treatment of opioid 10 November 2016. overdose (non-prescription use) Notes: Since early 2016, naloxone is available without a prescription in Canada Product name: Terrosa® for emergency treatment of opioid Reference product: Forsteo® overdose. A temporary import permit for a Approval: EMA U.S. FDA-approved product was granted Use: Treatment of osteoporosis in July 2016. ►►EMA/CHMP Summary of opinion, ►►Government of Canada News release, 10 November 2016. 3 October 2016.

Rituximab

Edotreotide: for diagnosis of gastro- Product name: Truxima® entero-pancreatic neuroendocrine Reference product: Mabthera® tumours; Approval: EMA Product name: SomaKit TOC® Use: treatment of non-Hodgkin’s lymphoma, Dosage form: Kit for radiopharmaceutical chronic lymphocytic leukaemia, preparation rheumatoid arthritis, granulomatosis with Class: Diagnostic radiopharmaceutical for polyangiitis and microscopic polyangiitis. tumour detection; ATC code: V09IX09 ►►EMA Summary of opinion, 15 December Approval: EMA (orphan product) 2016. Use: After radiolabelling with gallium (68Ga) chloride solution, for Positron Emission Tomography (PET) imaging of Adalimumab-atto somatostatin receptor overexpression Product name: Amjevita® in adult patients with well-differentiated Reference product: Adalimumab (Humira®) gastro-entero-pancreatic neuroendocrine Approval: FDA (biosimilar, not tumours. interchangeable with Humira®) Benefits: Ability to localize primary tumours Use: Treatment of multiple inflammatory and their metastases. diseases in adult patients. ►►EMA Summary of opinion, 13 October 2016.

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Approved

Safety information: Boxed Warning about Newly approved use: Treatment of adult an increased risk of serious infections, patients with relapsed or refractory lymphoma and other malignancies, classical Hodgkin lymphoma after including some fatal ones, in children autologous stem cell transplant and and adolescent patients treated with treatment with brentuximab vedotin. tumour necrosis factor blockers, including ►►EMA/CHMP Summary of opinion, adalimumab products. 13 October 2016. ►►FDA News release, 23 September 2016.

Canakinumab : for rare and serious

Extension of indications auto-inflammatory diseases ; Product name: Ilaris®

Empagliflozin: to reduce Approval: FDA cardiovascular risk in diabetes Newly approved use: Treatment of Tumour Product name: Jardiance® Necrosis Factor Receptor Associated Approval: FDA Periodic Syndrome (TRAPS); Newly approved use: To reduce the risk of Hyperimmunoglobulin D Syndrome cardiovascular death in adults with type 2 (HIDS)/Mevalonate Kinase Deficiency diabetes. (MKD); and Familial Mediterranean Fever Notes: Empagliflozin is not intended for (FMF) in adults and children. patients with type 1 diabetes or for the Note: Canakinumab was previously FDA- treatment of diabetic ketoacidosis. It is approved for another periodic fever contraindicated in patients with a history syndrome called Cryopyrin-Associated of serious hypersensitivity reactions to the Periodic Syndromes (CAPS) and for medicine, severe renal impairment, end- active systemic juvenile idiopathic stage renal disease, or those on dialysis. arthritis. ►►FDA News release, 2 December 2016. ►►FDA News release, 23 September 2016. å

Maraviroc : for use in children Product name: Selzentry® Approval: FDA Newly approved use: For the treatment of CCR5-tropic human immunodeficiency virus type 1 (HIV 1) infection in patients 2 years of age and older weighing at least 10 kg. Note: Maraviroc is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. ►►What’s New at FDA in HIV/AIDS. Bulletin, 7 November 2016.

Nivolumab: for Hodgkins lymphoma Product name: Opdivo® Approval: EMA

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Publications and events

Research and ethics Access to medicines

Revised CIOMS ethical guidelines UN High Level Panel report on Geneva – The Council for International access to health technologies Organizations of Medical Sciences New York – The United Nations High (CIOMS) has released its revised Level Panel on access to medicines has International Ethical Guidelines for Health- published a groundbreaking new report, Related Research Involving Humans stating that the world must take bold (1). The Guidelines were written in close new approaches to health technology collaboration with WHO. They aim to innovation and ensuring access so that indicate how the ethical principles for all people can benefit from the medical research involving humans – as set forth advances that have dramatically improved in the Declaration of Helsinki – can be the lives of millions around the world in the effectively implemented, particularly in last century. low- and middle-income countries. The Panel suggested that initially The scope of the Guidelines has been governments should begin negotiating a broadened to include research on health- code of principles for biomedical research related data. The revised Guidelines place and development (R&D) and report more emphasis on the scientific and social annually on their progress, in preparation value of research to ensure that important for negotiating a binding convention that unsolved questions are addressed, and on de-links the costs of R&D from end prices. the context in which research is conducted. The Panel noted with grave concern They recognize that low resource settings reports of governments being subjected may exist in high- and middle-income to undue political and economic pressure countries. They further call for governance to forgo the use of the flexibilities provided systems to protect the interests of in the World Trade Organization (WTO) individuals in a world where informed Agreement on Trade-Related Aspects of consent is proving inappropriate for the Intellectual Property Rights (TRIPS), and growing number of health-related studies. felt strongly that this was undermining A commentary on the revised Guidelines their efforts to meet their human rights has been published in JAMA (2). and public health obligations. The Panel ►►(1) CIOMS. International Ethical Guidelines views transparency as a core component for Health-Related Research Involving of accountability frameworks to hold all Humans. Geneva, 2016 (subject to copy- stakeholders responsible for the impact of editing). their actions on innovation and access. (2) van Delden JJM, van der Graaf R. The High Level Panel was established Revised CIOMS International Ethical by the United Nations Secretary-General Guidelines for Health-Related Research Involving Humans. JAMA. Published to propose solutions for addressing the online December 6, 2016. doi:10.1001/ incoherences between international jama.2016.18977. human rights, trade, intellectual property

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rights and public health objectives. Trade Organisation’s Agreement on Humanitarian organizations have Trade-related Aspects of Intellectual welcomed the report, urging governments Property Rights (TRIPS), which provide and the international community to governments with options that allow implement its recommendations. for the protection of public health, are ►►Announcement. United Nations Secretary- under continual threat from the TRIPS- General’s High Level Panel on Access to plus obligations included in bilateral and Medicines. 14 September 2016. regional trade agreements. Report of the United Nations Secretary- • Assuring the quality and safety General’s High Level Panel on Access of medicines. The Commission’s to Medicines. Promoting innovation and recommendations build on existing access to health technologies. September 2016. procurement strategies for certain donor- funded medicines and on emerging trends towards regulatory collaboration Report of the Lancet Commission and electronic communications. They call on Essential Medicines for the use of an international standard London – The Lancet Commission on regulatory dossier with a harmonized Essential Medicines has presented its content and format, and for a moving report. The Commission was established focus of WHO Prequalification on new in late 2014 to take stock of progress essential medicines. Recommendations and challenges in providing access to are also made on good practices affordable and quality-assured essential in procurement and regulation, medicines for all. Thirty years after the with concrete targets and a public first international conference on essential accountability mechanism for the medicines policies, held in 1985 in Nairobi, performance of regulatory authorities. the report provides recommendations to • Promoting the appropriate use of implement effective essential medicines essential medicines. The Commission’s policies in five crucial areas. recommendations focus on strategies • Paying for a basket of essential that enable collaboration among medicines: An estimated US$ 13–25 per patients, health-care providers, insurers, person per year is required to finance supply chain managers, and others – a basic package of 201 essential including the pharmaceutical industry medicines. Yet in 2010, the majority – to incentivize and support quality of low-income countries and 13 of 47 medicines use. The authors say that a middle-income countries spent less than key driver of inappropriate medicines US$ 13 per capita on pharmaceuticals. use is pharmaceutical promotion, which • Making essential medicines affordable. should be controlled and monitored by National and global policies – such as robust regulatory authorities. promoting the use of generic medicines, • Global research and development price transparency and pooled (R&D) framework. The Commission procurement – can support sustainable recommends that the costs of R&D access to essential medicines if they should be delinked from the price are implemented effectively. Related of medicines and funded up-front to this, the Commission warns that from a Global Research Fund. flexibilities included in the World Following the success of patent

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pools for antiretrovirals and other another 420. Seven companies have medicines categories the report calls published new or expanded pledges since for the creation of a general essential 2014 to waive or abandon patent rights medicines patent pool, to licence for certain products in certain regions, patents to other companies in order to and new commitments are pointing the create a competitive generics market. way to broader use of voluntary licensing The Commission calls for strong in the future. However, middle-income government and international countries outside of sub-Saharan Africa leadership to effectively implement are more likely to be left out of licensing essential medicines policies and create agreements. Also, companies apply for accountability, and proposes a set of marketing authorization in only 25% of 24 indicators to measure progress. the countries that the Index identifies as The work of the Commission was highest priority. funded by the Bill & Melinda Gates The Index is published every two years Foundation, WHO, the University Medical by the Access to Medicine Foundation, Centre Groningen, Boston University, an independent non-profit organisation and by academic institutions and funded by the UK Government (UK AID), other organizations that allowed their the Dutch Ministry of Foreign Affairs and staff to devote time to the work of the the Bill & Melinda Gates Foundation. Commission. ►►Access to Medicine Foundation News, ►►Press release, 7 November 2016. 14 November 2016. Wirtz VJ, Hogerzeil HV, Gray AL, et al. Access to Medicine Index 2016. Essential medicines for universal health www.accesstomedicineindex.org coverage. Lancet 2016; published online Nov 7. http://dx.doi.org/10.1016/S0140- 6736(16)31599-9 High price of hepatitis C treatment Geneva – A new WHO report shows Access to Medicine Index 2016 that over one million people in low- and Amsterdam – The Access to Medicine middle-income countries have been Foundation has published its 2016 Access treated with the new direct-acting antiviral to Medicine Index. medicines for hepatitis C since their The Index ranks 20 of the world’s largest introduction two years ago, despite the pharmaceutical companies on their efforts very high cost of these products. The to improve access to medicine in low- and report includes information on access, middle-income countries, identifies best prices, patents and registration of hepatitis practices and highlights progress and C medicines, supporting country efforts to remaining gaps. The findings show that increase access to these medicines. the pharmaceutical industry is extremely Among middle-income countries, the diverse. GSK leads the ranking for the prices of hepatitis C medicines vary fifth time, followed by Johnson & Johnson, greatly. For example, a three-month Novartis and Merck KGaA. treatment with sofosbuvir and daclatasvir Pharmaceutical companies have 850 costs from US$ 9 400 in Brazil to products on the market for the 51 most US$ 79 900 in Romania. The report shows burdensome diseases in low- and middle- how political will, civil society advocacy income countries, and are developing and pricing negotiations are helping to

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make treatment accessible for people Updated paediatric ARV formulary who need it. Nevertheless, the high prices and list of hepatitis C treatments remain a major The Inter-Agency Task Team (IATT) on the barrier to their access. WHO is working Prevention and Treatment of HIV Infection on new pricing models for these and other in Pregnant Women, Mothers and expensive medicines in order to increase Children has published the 2016 update access to all essential medicines in all to the IATT Paediatric ARV Formulary and countries. Limited-Use List. This edition reflects the ►►WHO News release, 27 October 2016. 2016 WHO Consolidated Guidelines and WHO. Global Report on Access to Hepatitis takes account of changes in the markets. C Treatment: Focus on Overcoming The formulary serves as guidance for Barriers. Geneva, World Health treatment programmes, procurement Organization: 2016. agencies, funders and manufacturers to select optimal dosage forms for children. ►►WHO/IATT/UNICEF. Policy brief. IATT Medicines patent and licences paediatric ARV formulary and limited-use database upgraded list: 2016 update. Geneva – The Medicines Patent Pool (MPP) has upgraded its patent database to include patent and licensing data Quality of medicines for HIV, hepatitis C and tuberculosis medicines. The Medicines Patents & Sample testing survey on Licences Database (MedsPaL) includes medicines for women and children data covering 4 000 national patent Geneva – WHO has published a report applications in more than 100 low- and of a quality testing survey of selected middle-income countries (LMICs). medicines from the list of 13 life-saving MedsPaL offers searchable information commodities as identified by the UN on 35 patented medicines and more Commission on Life-Saving Commodities than 100 pharmaceutical formulations for Women and Children (UNCoLSC) (1). for the treatment of HIV, hepatitis C The survey was organized by the WHO and tuberculosis included in WHO Prequalification Team in cooperation guidelines or in its Essential Medicines with the national medicines regulatory List. The information is regularly updated authorities and Ministries of Health of through automatic data feeds from the Burkina Faso, Kenya, Madagascar, Nepal, European Patent Office’s public database Nigeria, Tajikistan, Tanzania, Uganda, Espacenet, online searches, expert Viet Nam and Zimbabwe. A total of 204 analysis and collaboration with national samples were collected and tested, patent offices. of which 157 (77%) complied with the ►►MPP Press release, 5 October 2016. specifications set for the survey. Eleven The Medicines Patents & Licences samples of WHO-prequalified medicines Database is available at: www.medspal.org were included in the survey, and all complied with specifications. A summary of the findings was published in an earlier issue of this journal (2).

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The survey provides a snapshot of Antimicrobial resistance the quality of the sampled products and their availability in selected countries. Landmark UN declaration on The results enable WHO to confirm to antimicrobial resistance which extent compliant testing results New York – For the first time, Heads of are supported by compliance with good State have committed to taking a broad, manufacturing practice and proper coordinated approach to address the regulatory documentation. root causes of antimicrobial resistance ►► (1) WHO. Survey of the quality of medicines across multiple sectors, especially human identified by the United Nations Commission health, animal health and agriculture. The on Life-Saving Commodities for Women and pledge was made at a high-level meeting Children. 2016. on antimicrobial resistance convened (2) Quality and availability of selected by the President of the 71st session of life-saving reproductive health medicines the UN General Assembly. Countries in developing countries. WHO Drug Information 2015;29(3):324-333. reaffirmed their commitment to develop national action plans based on the “Global Action Plan on Antimicrobial Fighting poor-quality medicines in Resistance” developed in 2015 by WHO in low- and middle-income countries coordination with the Food and Agriculture An article in the Journal of Pharmaceutical Organization of the United Nations (FAO) Policy and Practice highlights the divide and the World Organisation for Animal in pharmaceutical quality between the Health (OIE). They pledged to strengthen North and the South. The authors warn the regulation of antimicrobials, improve that despite an increasing awareness knowledge and awareness, promote of the problem and the launch of some best practices, and foster innovative positive initiatives the issue continues approaches using alternatives to to expose patients in low- and middle- antimicrobials and new technologies for income countries to the risk of receiving diagnosis and vaccines. (1) poor-quality medicines. They call for This is only the fourth time a health more advocacy to achieve universal issue has been taken up by the UN access to quality-assured medicines and General Assembly. The other issues were emphasize that this advocacy should be HIV, non-communicable diseases and based on evidence from research and Ebola. In her opening speech, the WHO monitoring programmes, should target all Director-General stressed that actions are stakeholders – regulators, international urgently needed, and that a global crisis of organizations, journalists, purchasers, this magnitude demands attention at the prescribers, programme managers, policy highest political level. The declaration was makers, public health actors and patients spearheaded by a campaign led by health – and should be grounded in a common officials from the United Kingdom(2) understanding of the technical concepts. ►►(1) Office of the President of the UN General ►►Ravinetto R, Vandenbergh D, Macé C. et al. Assembly (OPGA)/WHO/FAO/OIE Joint Fighting poor-quality medicines in low- and news release, 21 September 2016. middle-income countries: the importance (2) United Kingdom Department of Health. of advocacy and pedagogy. Journal of News story. 21 September 2016. Pharmaceutical Policy and Practice. 2016;9:36. doi: 10.1186/s40545-016-0088-0.

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The economic threat of drug- South Korea, Australia and Canada – resistant infections were listed at the time of writing. (1) New York – The World Bank has released There is a pressing need to improve a new research report showing that by the use of medicines to maximize 2050, drug-resistant infections could their effectiveness and minimize their cause global economic damage similar harms. This can be best achieved by to that of the 2008 financial crisis. The expanding knowledge and expertise of impact of antimicrobial resistance would clinical pharmacology and therapeutics reduce annual global gross domestic around the world. The mentoring centres product (GDP), pushing up to 28 million will support, mentor or train future people into poverty by 2050. At the global generations with skills to undertake level the volume of real exports would research and teaching in this area and shrink, healthcare costs could increase to serve on governmental organizations by more than US$ 1 trillion per year, and involved in medicines regulation and economic losses could amount to an health technology assessment. The estimated US$ 100 trillion by 2050. pilot programme is consistent with WHO The report recommends a number of initiatives such as the Essential Medicines solutions to address the crisis. It highlights List, and is in line with the joint IUPHAR/ the need to strengthen investments in WHO publication Clinical Pharmacology in public and veterinary health systems Health Care, Teaching and Research (2). and overall preparedness to tackle ►►(1) IUPHAR Clinical Divisions. Mentoring infectious diseases, with surveillance Centres [website]. for antimicrobial resistance as an (2) WHO, IUPHAR, CIOMS. Clinical integral component. It strongly supports Pharmacology in Health Care, Teaching and implementation and adequate financing Research. Geneva: Council for International of the WHO Action plan on Antimicrobial Organizations of Medical Sciences, 2012. Resistance, which was endorsed in 2015. ►►World Bank Press release, 19 September 2016. Disease updates

Tuberculosis: WHO global report Clinical use of medicines Geneva, Washington – WHO has published its 2016 Global tuberculosis Mentoring programme report. The report highlights the Basle – The Clinical Division of inequalities among countries with respect International Union of Basic and Clinical to access to medical products to fight Pharmacology (IUPHAR) has initiated tuberculosis, and signals the need for a pilot programme to establish a list of bold political commitment and increased “mentor departments” who are willing funding. to provide advice in the area of clinical In low- and middle-income countries, pharmacology, ranging from simple most of which continue to rely heavily on communication through to collaborative international donations, investments to research and researcher exchange. Five curb the tuberculosis epidemic are almost centres – located in Scotland, Spain, US$ 2 billion short of the US$ 8.3 billion needed in 2016. In addition, WHO

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estimates that at least US$ 1 billion Plan implementation to eliminate measles per year is needed to accelerate in four of six WHO regions by 2015 has the development of new vaccines, been missed. The Democratic Republic diagnostics, and medicines. of the Congo, Ethiopia, India, Indonesia, In 2015, there were an estimated Nigeria and Pakistan accounted for half of 10.4 million new tuberculosis cases the unvaccinated infants and 75% of the worldwide. Six countries accounted for measles deaths in 2015. Large outbreaks 60% of the total burden. India has the were reported in Egypt, Ethiopia, most cases, followed by Indonesia, China, Germany, Kyrgyzstan and Mongolia, and Nigeria, Pakistan and South Africa. An outbreaks were also reported in Nigeria, estimated 1.8 million people died from Somalia and South Sudan. In Germany tuberculosis in 2015, of whom 0.4 million and Mongolia older persons were affected, were co-infected with HIV. Although highlighting the need to vaccinate global deaths from tuberculosis fell by adolescents and young adults who have 22% between 2000 and 2015 the disease no protection against measles. was among the top 10 causes of death ►►CDC/GAVI/UNICEF/WHO Joint news worldwide in 2015, responsible for more release, 10 November 2016. deaths than HIV and malaria. Gaps in Patel MK, Gacic-Dobo M, Strebel PM, et diagnosis and reporting remain major al. Progress Toward Regional Measles challenges. An estimated 480 000 people Elimination — Worldwide, 2000–2015. WHO Weekly Epidemiological Record, contracted multidrug-resistant tuberculosis 11 November 2016; 91(46): 525–35 in 2015, with India, China, and the and Russian Federation together accounting MMWR Morb Mortal Wkly Rep for nearly half of all cases. 2016;65:1228–1233. DOI: http://dx.doi. ►►WHO News release, 13 October 2016. org/10.15585/mmwr.mm6544a6.

Measles: immunization gap persists Malaria: funding secured for New York/Atlanta/Geneva – New vaccine pilots data show that despite a 79% worldwide Geneva – Funding has been secured decrease in measles deaths between for the initial phase of pilot projects to roll 2000 and 2015, the disease remains one out the world’s first malaria vaccine in of the leading causes of death among in sub-Saharan Africa. Vaccinations are young children globally with an estimated due to begin in 2018.The Global Fund 134 000 children having died from it in to Fight AIDS, Tuberculosis and Malaria 2015. has approved US$ 15 million covering Mass measles vaccination campaigns the first phase of the pilot. Earlier in 2016, and a global increase in routine measles Gavi, the Vaccine Alliance had committed vaccination coverage saved an estimated up to US$ 27.5 million and UNITAID had 20.3 million young lives between 2000 and pledged US$ 9.6 million. 2015, according to UNICEF, WHO, Gavi, The vaccine, known as RTS,S, the Vaccine Alliance, and the Centers for provides partial protection against Disease Control and Prevention (CDC). P. falciparum malaria in young children. But progress has been uneven, and It was developed through a partnership the target of the Global Vaccine Action between GlaxoSmithKline and the PATH

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Malaria Vaccine Initiative (MVI), with WHO matters support from the Bill & Melinda Gates Foundation and from a network of African Model prequalification dossier research centres. In July 2015 the EMA Geneva – The WHO Prequalification issued a positive scientific opinion of the Team – medicines (PQTm) has published RTS,S vaccine, and in October 2015, a model dossier on its website, illustrating two independent WHO advisory groups how data should be submitted to WHO recommended its pilot implementation in for prequalification. The model dossier 3–5 settings in sub-Saharan Africa. is intended to serve as a training tool for The RTS,S vaccine is proposed as a regulators, as guidance for applicants, tool to complement the current WHO- and as an example case for organizations recommended malaria interventions. involved in harmonizing regulatory ►►WHO News release, 17 November 2016. requirements. WHO requires that dossiers for generic medicines are submitted in the

Zika: end of public health emergency; Common Technical Document (CTD) The fifth meeting of the Emergency format of the International Council for Committee (EC) on Zika and microcephaly Harmonisation of Technical Requirements was convened by the Director-General for Pharmaceuticals for Human Use (ICH). under the International Health Regulations The model dossier includes the completed (IHR 2005) on 18 November 2016. quality templates and the corresponding Research has now demonstrated the data expected in CTD Module 3, with link between Zika virus infection and proprietary information redacted. microcephaly, making it necessary to ►►PQ update, 14 September 2016. develop a robust longer-term mechanism Feedback is encouraged and should be sent to manage the global response. to: Dr. M. Stahl, Group Leader Medicines The EC felt that, while Zika virus and Assessments, WHO Prequalification Team – associated consequences remain a Medicines; [email protected]. significant public health challenge, they no longer represent a Public Health Emergency of International Concern New medicines invited for (PHEIC). The EC recommended that a prequalification sustained programme of work should be Geneva – WHO has published new established with dedicated resources invitations for Expression of Interest to address the long-term nature of the for prequalification (EOI). The 14th EOI disease and its associated consequences, for anti-TB medicines newly includes and agreed to the proposed WHO Zika isoniazid/rifapentine 150mg/150mg transition plan. Based on this advice, dispersible tablets and 300mg/300mg the Director-General declared the coated tablets or capsules, as well as end of the PHEIC and reissued the gatifloxacin 200mg tablets and 400 mg Temporary Recommendations, which scored tablets. The 11th EOI for active will be incorporated into the longer-term pharmaceutical ingredients newly includes response mechanism. gatifloxacin. ►►WHO Statement, 18 November 2016. ►►PQ Updates, 6 October and 7 October 2016.

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Seminar for laboratories held in The new arrangement is modelled China on the practice of national regulatory Shenzhen – The 5th WHO Interregional authorities around the world, which Seminar for Quality Control Laboratories charge application fees for evaluation and involved in WHO Prequalification was held registration services. It will be launched in in Shenzhen, Guangdong Province, China January 2017 for vaccines and medicines in October 2016. It is the first time that and in early 2018 for diagnostics. this seminar was held in China. More than WHO began to charge prequalification 60 laboratory directors from 42 countries fees in 1999 for vaccines, in 2008 for and representatives from 26 provincial diagnostics, and in 2013 for medicines. drug testing institutions of China Before fees were introduced, the sole participated in the technical discussions. donor for vaccines prequalification was ►►China Food and Drug Administration UNICEF, and medicines prequalification (CFDA) News, 26 October 2016. was funded by two donors, the Bill & Melinda Gates Foundation and UNITAID. The new fee model is expected to “Green” procurement of health generate revenues of about US$ 20 million commodities annually, which will cover about half of the Geneva - WHO has joined other programme’s operating costs. international agencies in signing a ►►PQ update, 30 September 2016. Statement of Intent to align and “green” WHO Prequalification Financing Model – the procurement of health commodities, Questions and Answers [website]. in an effort to protect the environment and contribute to sustainable development. WHO and the other signatories – including GAVI, UNDP, UNICEF, the Global Fund, UNITAID, UNFPA and UNOPS – procure an estimated Upcoming events US$ 3 billion in health commodities each year. They have agreed to reflect 2017 joint UNICEF-UNFPA-WHO their common commitment in their manufacturers meeting standard engagement with suppliers and The 2017 joint UNICEF-UNFPA-WHO manufacturers. They will also include it in manufacturers meeting will take place in their institutional strategies and policies. the week of 3 April 2017 in Copenhagen, ►►WHO News release, 7 December 2016. Denmark. The manufacturers meeting provides information for suppliers of medical products for use by UN agencies New prequalification fee structure and other international organizations. Geneva – WHO, industry groups and ►►WHO Prequalification update, 30 September key partners have agreed on a new fee 2016. å structure that aims to support financial predictability, sustainability and expansion of prequalification services including the setting and public disclosure of quantitative performance targets.

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ATC/DDD classification

The Anatomical Therapeutic Chemical (ATC) classification system and the Defined Daily Dose (DDD) as a measuring unit are tools for exchanging and comparing data on drug use at international, national or local levels. The ATC/DDD system has become the gold standard for international drug utilization research. It is maintained by the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway. Visit www.whocc.no/ for more information.

ATC/DDD classification (temporary)

The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in October 2016. Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 February 2017. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2018 version of the ATC/DDD Index.

New ATC 5th level codes ATC level name/INN ATC code benralizumab R03DX10 binimetinib L01XE41 brigatinib L01XE43 cerliponase alfa A16AB17 dupilumab D11AH05 eteplirsen M09AX06 etirinotecan pegol L01XX56 hydromorphone and naloxone N02AA53 idursulfase beta A16AB16 insulin glargine and lixisenatide A10AE54 Lavandulae aetheroleum N05BX05 lutetium (177Lu) oxodotreotide V10XX04 mepyramine theophyllinacetate R03DA12 migalastat A16AX14 netarsudil S01EX05 niraparib L01XX54 obiltoxaximab J06BB22 olaratumab L01XC27 opicapone N04BX04 ozenoxacin D06AX14 padeliporfin L01XD07 pegteograstim L03AA17 plitidepsin L01XX57 Continued

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Temporary

New ATC 5th level codes (continued) ATC level name/INN ATC code ramipril, amlodipine and hydrochlorothiazide C09BX03 rebamipide A02BX14 ribociclib L01XE42 romosozumab M05BX06 rosuvastatin, amlodipine and perindopril C10BX14 rosuvastatin, perindopril and indapamide C10BX13 rucaparib L01XX55 semaglutide A10BJ06 sodium zirconium cyclosilicate V03AE10 sofosbuvir and velpatasvir J05AX691) suvorexant N05CM19 tetracaine, combinations N01BA53 velmanase alfa A16AB15 zoster, purified antigen J07BK03 1) Temporary code in J05AX69 will be changed to J05AP55 in connection with the implementation of the proposed new ATC 4th level Antivirals for treatment of HCV infections in 2018.

New ATC level codes (other than 5th levels) ATC level name/INN ATC code Antivirals for treatment of HCV infections J05AP

Change of ATC codes ATC level name/INN Previous ATC New ATC argipressin H01BA06 H01BA011) asunaprevir J05AE15 J05AP06 benzydamine A01AD02 R02AX032) boceprevir J05AE12 J05AP03 ceftriaxone, combinations J01DD54 J01DD633) daclatasvir J05AX14 J05AP07 dasabuvir J05AX16 J05AP09 dasabuvir, ombitasvir, paritaprevir and ritonavir J05AX66 J05AP52 elbasvir and grazoprevir J05AX68 J05AP54 faldaprevir J05AE13 J05AP04 ombitasvir, paritaprevir and ritonavir J05AX67 J05AP53 ribavirin J05AB04 J05AP01 simeprevir J05AE14 J05AP05 sofosbuvir J05AX15 J05AP08 sofosbuvir and ledipasvir J05AX65 J05AP51 sofosbuvir and velpatasvir J05AX694) J05AP55 telaprevir J05AE11 J05AP02 1) Altered ATC level name to vasopressin (argipressin) 2) Split of code. Alteration of ATC code includes only benzydamine lozenges 3) Split of code. Combinations of ceftriaxone and other substances remain in J01DD54 while combinations of ceftriaxone and beta-lactamase inhibitors are moved to J01DD63 4) Temporary new code in J05AX69 will be changed to J05AP55 in connection with the implementation of the proposed new ATC 4th level Antivirals for treatment of HCV infections in 2018 (see temporary list –“New ATC level codes (other than 5th levels)”

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Temporary

Change of ATC level names

Previous New ATC code amoxicillin and enzyme inhibitor amoxicillin and beta-lactamase inhibitor J01CR02 ampicillin and enzyme inhibitor ampicillin and beta-lactamase inhibitor J01CR01 Bile acid preparations Bile acids and derivatives A05AA cefoperazone, combinations cefoperazone and beta-lactamase J01DD62 inhibitor cefotaxime, combinations cefotaxime and beta-lactamase inhibitor J01DD51 ceftazidime, combinations ceftazidime and beta-lactamase inhibitor J01DD52 ceftolozane and enzyme inhibitor ceftolozane and beta-lactamase inhibitor J01DI54 imipenem and enzyme inhibitor imipenem and cilastatin J01DH51 piperacillin and enzyme inhibitor piperacillin and beta-lactamase inhibitor J01CR05 ticarcillin and enzyme inhibitor ticarcillin and beta-lactamase inhibitor J01CR03

New DDDs ATC level name/INN DDD unit Adm.R* ATC code rebamipide 0.3 g O A02BX14 voglibose 0.6 mg O A10BF03 migalastat 61.5 mg O A16AX14 vorapaxar 2.08 mg O B01AC26 selexipag 1.8 mg O B01AC27 ferric proteinsuccinylate 80 mg O Fe3+ B03AB09 fimasartan 60 mg O C09CA10 ceftazidime and beta-lactamase 6 g2) P J01DD52 inhibitor1) pegteograstim 0.3 mg P L03AA17 opicapone 50 mg O N04BX04 pitolisant 18 mg O N07XX11 reslizumab 7.5 mg P R03DX08 doxylamine 25 mg O R06AA09 1) Previous level name, ceftazidime, combinations 2) Refers to ceftazidime

Changes of DDDs ATC level name/INN Previous DDD New DDD ATC code DDD Unit Adm.R.* DDD Unit Adm.R.* daclizumab 0.35 g1) P 5 mg P L04AC01 * Administration Route: O=oral; P=parenteral 1) Course dose

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ATC/DDD classification (final)

The following ATC codes, DDDs and alterations were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in March 2016. These are considered as final and will be included in theJanuary 2017 version of the ATC/DDD Index.

New ATC 5th level codes Please note that the list does not include new ATC codes established as a result of ATC alterations. ATC level name/INN ATC code atorvastatin, acetylsalicylic acid and perindopril C10BX12 baricitinib L04AA37 bentazepam N05BA24 Betulae cortex D03AX13 bezlotoxumab J06BB21 burosumab M05BX05 cinitapride A03FA08 fluciclovine (18F) V09IX12 fluoroestradiol 18( F) V09IX11 formoterol and glycopyrronium bromide R03AL07 hydroquinidine C01BA13 methacetin (13C) V04CE03 midostaurin L01XE39 naloxone A06AH04 ocrelizumab L04AA36 olmutinib L01XE40 patiromer calcium V03AE09 piketoprofen M02AA28 pimavanserin N05AX17 rolapitant A04AD14 sarilumab L04AC14 solithromycin J01FA16 tenofovir alafenamide J05AF13 tramadol and other non-opioid analgesics N02AJ15 uridine triacetate A16AX13 venetoclax L01XX52 vosaroxin L01XX53

New DDDs ATC level name/INN DDD unit Adm.R* ATC code bentazepam 75 mg O N05BA24 brivaracetam 0.1 g O,P N03AX23 ceftolozane and enzyme inhibitor1) 3 g2) P J01DI54 dalbavancin 1.5 g3) P J01XA04 doxofylline 0.8 g O,P R03DA11 Continued

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New DDDs (continued) ATC level name/INN DDD unit Adm.R* ATC code evolocumab 10 mg P C10AX13 ibuprofen 1.2 g P M01AE01 idebenone 0.9 g O N06BX13 isavuconazole 0.2 g O,P J02AC05 mepolizumab 3.6 mg P R03DX094) posaconazole 0.3 g P J02AC04 sebelipase alfa 5 mg P A16AB14 tiopronin 0.8 g O G04BX165)

* Administration Route: O=oral; P=parenteral 1) ATC level name will be changed to ceftolozane and beta-lactamase inhibitor in the 2018 ATC/DDD index. See temporary list 2) Refers to ceftolozane 3) Course dose 4) ATC code changed from L04AC06, new code valid from January 2017 5) ATC code changed from R05CB12, new code valid from January 2017

Changes of DDDs ATC level name/INN Previous DDD New DDD ATC code DDD Unit Adm.R.* DDD Unit Adm.R.* posaconazole 0.8 g O 0.3 g O J02AC04 thioctic acid 0.2 g O,P 0.6 g O,P A16AX01 * Administration Route: O=oral; P=parenteral

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