WHO Drug Information Vol. 30, No. 2, 2016

WHO Drug Information Contents

ICDRA 208 Non-compliance with good practices Alkem Bioequivalence Centre, India; Semler 173 International Conference of Drug Regulatory Research Center Pvt Ltd, India ; Anuh Authorities (ICDRA) comes to Africa Pharma API manufacturing site, India 209 Falsified product alert Injectable carmustine Quality testing of vaccines 176 Hands-on training on a standardized protocol to test saccharide content of priority vaccines Regulatory news 210 Pre-market assessment EMA offers routine parallel scientific Medicines shortages advice; EMA guidance on patient-reported 180 Global approaches to addressing shortages of outcomes for anticancer medicines; Ten essential medicines in health systems years of EMA’s small and medium enterprise initiative; Access to advanced therapies 211 Access to investigational products Concept paper for discussion FDA simplifies request process for 186 A stepwise approach for pharmaceutical compassionate use products companies in developing countries to attain 211 Information-sharing WHO GMP standards Guide to key EMA information on human medicines 212 Post-marketing control Safety news EMA adopts rules for public hearings on 199 Safety warnings selected safety reviews; FDA revises rule

Loperamide : Serious heart problems with high doses; Saxagliptin, alogliptin : heart on reporting of veterinary antimicrobial

failure; Fluconazole : risk of miscarriage; Imatinib, dasatinib, nilotinib, sales; Update on Japan’s data network on

bosutinib, ponatinib: hepatitis B reactivation ; Trametinib : gastrointestinal perforation and colitis; Aflibercept : adverse drug reaction in children

osteonecrosis of the jaw; Idelalisib : infections and other serious adverse events; Thalidomide : viral reactivation and pulmonary hypertension; Pomalidomide : hepatitis B 213 Law enforcement

reactivation; Olanzapine : rare but serious skin reactions; Operation Pangea IX highlights the dangers of 203 Known risks buying medicines online

Metformin : expansion of use in kidney impairment; Aspirin-containing antacids : serious bleeding; Oral 213 Rational medicines use

ketoconazole : use only for serious fungal infections ; Opioids : enhanced warnings; Aripiprazole : impulse control disorders; India bans over 300 fixed-dose combinations 204 Restrictions 214 Under discussion

Fluoroquinolones : restricted use in certain uncomplicated infections; 205 Withdrawals from the market Approved

Meprobamate : last marketing authorization cancelled in U.K.; Fusafungin-containing sprays : rare but serious allergic 215 Obeticholic acid : for primary biliary cholangitis; Defibrotide sodium : for rare complication in stem cell transplants;

reactions; Veterinary drug carbadox : to be removed from the U.S. market; Sofosbuvir/velpatasvir : for hepatitis C virus infection; Pandemic influenza

205 Unchanged recommendations (H5N1) vaccine (live attenuated); Venetoclax :

Recombinant factor VIII products : no difference in risk of antibody for chronic lymphocytic leukaemia; Daclizumab : for relapsing multiple sclerosis; Ixekizumab : for psoriasis; Opicapone : for Parkinson’s

formation; Meningococcal vaccine : no new safety concerns; Inhaled disease; Pimavanserin : for symptoms associated with Parkinson’s disease; Buprenorphine implant : in opioid dependence;

corticosteroids for COPD Reslizumab : for severe asthma; Obiltoxaximab : for inhalational anthrax; Atezolizumab : for bladder cancer;

207 Medicines safety reviews started Migalastat : for Fabry disease; New gene therapy for ADA-SCID Canagliflozin; Escherichia coli bacteria 218 EMA Article 58 positive opinion

; Ticagrelor; Vancomycin-containing Chlorhexidine digluconate : to prevent umbilical infection in newborn infants; products; Fluconazole; Direct- 219 Biosimilars acting antivirals for hepatitis C Infliximab ; Idelalisib; Sumatriptan ; Gadolinium- 219 Brand name change

containing contrast agents Vortioxetine : brand name changed to avoid confusion; 219 Extensions of indications

Crizotinib : for certain rare, advanced non-small cell lung cancers; Obinutuzumab : for follicular lymphoma;

Continued

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Continued

220 Diagnostics 226 Controlled substances 18 Investigational Zika test; Fluciclovine ( F): to detect prostate cancer recurrence; A public health approach to the world drug 68 Gallium ( Ga) dotatate : to detect rare neuroendocrine tumours; problem 220 Veterinary drug 226 WHO matters

Pegbovigrastim : to reduce the incidence of mastitis; Sixty-ninth World Health Assembly : setting the course for global public

health; New WHO medicines quality guidelines published; WHO announces Phase 7 of Publications and events its external assessment scheme for quality 221 Access to medicines control laboratories; Primaquine invited for WHO submission to the UN High-Level Panel prequalification; Prequalification of vector ; Regulatory approaches to make medicines control products more affordable; UNITAID discussion 229 Upcoming events paper on affordability of essential medicines 17th ICDRA ; Intellectual property and local medicines production ; GlaxoSmithKline announces new approach to patents; Study shows Consultation documents hepatitis C medicines prices are globally 230 The International Pharmacopoeia unaffordable; DNDi and pharmaceutical 230 Revision of Chapter 2.6, Non-aqueous titration company to test new hepatitis C medicine; Medicines patent pool and TB Alliance to collaborate ATC/DDD classification 223 Disease updates 234 ATC/DDD classification (temporary)

HIV and hepatitis C co-infection ; Diabetes : global action 236 ATC/DDD classification (final)

needed; Depression and anxiety : the investment case; Multidrug-resistant

tuberculosis : WHO recommends shorter regimen; Malaria : push for further progress ; Zika : WHO identifies research and development priorities; Ebola : no longer a public health emergency; 226 Vaccination International Nonproprietary Recent gains and remaining gaps Names (INN) 241 Proposed INN: List 115

Abbreviations and web sites

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 (available at www.who.int/medicines/publications/druginformation) has direct clickable hyperlinks to the documents and web pages referenced.

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ICDRA

International Conference of Drug Regulatory Authorities (ICDRA) comes to Africa

Established in 1980 as a platform to develop international consensus, the WHO-convened ICDRA conference has become the place of choice for regulators from WHO Member States to meet and discuss strategies to harmonize regulation and improve the safety, efficacy and quality of medicines. The 17th ICDRA, to be held in November 2016, will be the first to take place in sub-Saharan Africa.

ICDRA – a forum for regulatory authorities vaccines, biomedicines and herbal The International Conference of Drug products. The ICDRA programme is Regulatory Authorities (ICDRA) provides developed by a planning committee of medical products regulators of WHO representatives from medicines regulatory Member States with a forum to meet and authorities. While the pre-ICDRA event discuss ways to strengthen collaboration. is open to all interested stakeholders, It is co-organized every two years by participation at the actual conference is WHO and the regulatory authority of the restricted to representatives of medicines host country. regulatory authorities. Recommendations The ICDRA conferences have been are agreed at each ICDRA for action guiding regulatory authorities, WHO and among agencies, WHO and related interested stakeholders in determining institutions and are documented on the priorities for action in national and WHO web site (1). international regulation of medicines,

International Conference of Drug Regulatory Authorities (ICDRA) The 17th ICDRA will take place in Cape Town, South Africa on 27 November – 2 December 2016

Register now: www.icdra.co.za Closing date for registrations: 31 August 2016

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Bringing regulators together WHO concept paper was then developed From their inception, the ICDRA to describe a proposed approach to conferences have been instrumental supporting harmonization of medicines in bringing regulators together to move registration within and across African towards international harmonization regional economic communities (2). (Box 1). Regulatory harmonization was Further discussions and a call for pioneered in Europe some forty years ago, proposals followed in 2009. The first eventually leading to the establishment project started in the East African of the International Conference for Community (EAC) in 2011; active projects Harmonisation of Technical Requirements are meanwhile ongoing in several regions. for Pharmaceuticals for Human Use One aim of the African Medicines (ICH, recently renamed International Regulatory Harmonisation Programme Council on Harmonization)1. Regulatory (AMRH) is to establish – in partnership harmonization then took hold in other with the African Union Commission and parts of the world, with active initiatives WHO – the African Medicines Agency, ongoing within the Pan American Network which will operate under the authority of for Drug Regulatory Harmonization AMRH. During a meeting in Luanda in (PANDRH), the Asia-Pacific Economic 2014, African Health Ministers endorsed Cooperation (APEC), the Association of this proposal (3). the Southeast Asian Nations (ASEAN), the Given this impressive momentum, it is Gulf Cooperation Council (GCC) and more fitting that in 2016 the ICDRA conference recently also in Africa. should come to Africa. The 17th ICDRA will be hosted by the South African Focus on Africa medicines regulatory authority in Cape The potential benefits of harmonizing Town on 29 November – 2 December medicines registration in Africa were 2016. The theme of the event is “Patients recognized at the 13th ICDRA in 2008. A are waiting: How regulators collectively make a difference”. In keeping with 1 www.ich.org

Box 1: ICDRAs around the world

Action plans on First informal harmonization consultations on between Europe, harmonizing medicines Japan and the U.S. regulation in Africa

1990: ICH conceived

1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th 14th 15th 16th 17th ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA ICDRA 1980 1982 1984 1986 1989 1991 1994 1996 1999 2002 2004 2006 2008 2010 2012 2014 2016

Anna­ Rome Saltsjö­ Tokyo Paris Ottawa Noord­ Manama Berlin Hong Madrid Seoul Berne Singa­ Tallinn Rio de Cape polis (Italy) baden (Japan) (France) (Canada) wijker­ (Bahrain) (Ger­ Kong (Spain) (Republic (Switzer­ pore (Estonia) Janeiro Town (United (Sweden) – first hout – first many) (China) of Korea) land) (Singa­ (Brazil) (South States of in Asia (Nether­ in an pore) – first in Africa) America) lands) Arabic South – first in country America Africa

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Box 2: 17th ICDRA and Pre-ICDRA programme (P = Plenary; W = Workshop)

Pre-ICDRA (open): 27–28 November 2016 ICDRA (Regulators only): 29 November-2 December 2016 P–1: African Medicines Regulatory P–1: Opening Ceremony Harmonization Initiative P–2: Update on 16th ICDRA recommendations: P–2: Collaboration and harmonization in the field Global context, local actions of medical devices P–3: Strengthening of Regulatory Systems: Follow-up on WHA Resolution 67.20 W–1: EAC/MRH – what has been achieved so P–4: Regulatory preparedness for public health far? emergencies: Lessons learned from Ebola W–2: Global Regulatory Model for Medical W–A: Similar biotherapeutic products Devices – where to start? W–B: Model regulatory framework for medical devices: W–3: Reducing inspections burden pre-requisites for successful implementation W–4: Enablers for regulatory cooperation and including reliance sustainability W–C: Pharmacovigilance/Safety monitoring W–D: Blood products – old and new challenges W–5: Stakeholders collaboration in emergency P–5: Good regulatory practices situations: learning from Ebola, Zika and P–6: Strengthening supply chain integrity the R&D Blueprint W–E: Regulatory challenges of medical products for W–6: Shortages of medicines: what regulators maternal & child health can do to help W–F: Progress in fighting substandard/spurious/falsified/ W–7: Regulatory cooperation for new treatments: falsely labelled/counterfeit medicines stakeholders’ views W–G: Update on vaccines regulation W–8: Promise of more effective regulatory W–H: Safety of herbal medicines: present challenges and system through cooperation; reality or opportunities myth: what has been achieved today? P–7: Global scenery of regulatory convergence W–9: Work sharing initiatives: linking opportunities W–I: Regulators’ response to shortages of supplies W–10: Good reliance practices W–J: Regulators’ role in addressing antimicrobial P–3: Partnerships – how to effectively resistance cooperate? P–8: Closing the motto of “Strengthening regulatory collaboration and good regulatory systems through convergence, reliance practices in the interest of public health. and networks” the 17th ICDRA offers a rich programme of topics for discussion References (Box 2). 1 WHO Essential medicines and health More than ever, regulatory convergence products. International Conference of Drug and cooperation are needed to ensure that Regulatory Authorities (web page). www. patients around the world, including those who.int/medicines/areas/quality_safety/ regulation_legislation/icdra/en/ in the resource-constrained environments 2 African Medicines Regulatory of many African countries, have access Harmonization Initiative (AMRHI): a WHO to quality medical products at affordable concept paper. WHO Drug Information, prices. By facilitating discussions among Volume 22, Number 3, 2008. regulators in an atmosphere of trust and 3 African Medicines Agency: Setting professional commitment, the 17th ICDRA Milestones towards its Establishment. will be instrumental in bringing about 1st African Ministers of Health meeting progress in this ambitious agenda. It is jointly convened by the AUC and WHO, an opportunity not to be missed by any Luanda, Angola, 14-17/04/2014. regulatory authority wishing to contribute (See page 229 under “Upcoming events” for to global regulatory convergence, effective practical information) å

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Quality testing of vaccines

Hands-on training on a standardized protocol to test saccharide content of priority vaccines

To facilitate access to good-quality vaccines, the WHO Prequalification Team (PQT) promotes standardized testing protocols that can be used to test vaccines produced by different manufacturers. A harmonized test method has been identified to determine polyribosyl-ribitol-phosphate (PRP) content in liquid vaccine combinations containing a whole-cell pertussis component. The use of this method saves significant time and resources at quality control laboratories. Hands-on training courses for quality control laboratory technicians from 13 countries have been organized, enabling them to implement this protocol at their institutions.

Introduction type b is polyribosyl-ribitol-phosphate Diphtheria, tetanus, whole-cell pertussis (PRP), a saccharide. Total and free (DTwP)-based pentavalent vaccine (liquid (unconjugated) saccharide content is presentation) is a globally important the single critical parameter indicative of vaccine. This combination “five-in-one” Hib conjugate vaccine quality. However, vaccine protects children from diphtheria, quantitative determination of PRP in pertussis (whooping cough), tetanus, different liquid formulations is challenging hepatitis B and Haemophilus influenzae for laboratories and manufacturers type b (Hib), which causes pneumonia and because differences in Hib carrier meningitis. It is less traumatic for infants protein, antigen combinations, adjuvant, to receive and easier for programmes to preservatives and other excipients administer than previous formulations. interfere with the testing. Specific In recent years, global demand for this methodologies need to be established vaccine has increased rapidly (1). The and validated for each individual product, WHO Prequalification Team (PQT) which is time-consuming. Laboratories that prequalifies this type of vaccine for use in test Hib vaccines on behalf of WHO PQT national immunization programmes (2). during the prequalification process usually The active ingredient of a Hib vaccine use their own testing methods, since that prevents infection by H. influenzae applying the manufacturer’s methodology

The content of this article was contributed by Dr Ute Rosskopf of the WHO Prequalification Team. The study to identify a harmonized assay was organized in the framework of the WHO Vaccines Prequalification Programme, with funding from the United States Agency for International Development (USAID). WHO thanks Dr Christina von Hunolstein, Bacterial Vaccine Unit, National Centre for Immunobiologicals Research and Evaluation (CRIVIB), Istituto Superiore di Sanità (ISS), Italy, and Dr Barbara Bolgiano, Division of Bacteriology, National Institute of Biological Standards and Control (NIBSC), United Kingdom, for performing the tests in the study and co-organizing the subsequent hands-on training courses. WHO is grateful to the following manufacturers for their donations of vaccine samples (in alphabetical order): Berna Biotech Korea Corp., Yeonsu-gu, Incheon, Republic of Korea; Biological E. Limited, Hyderabad, India; Novartis Vaccines and Diagnostics S.r.I., Siena, Italy; Serum Institute of India Limited, Hadapsar, Pune, India. The preparation of a pentavalent vaccine exclusively for the purpose of this study was much appreciated.

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would take even more time and would To verify the method further, another represent an additional challenge. study was subsequently conducted in collaboration with the Biological A harmonized assay Standardisation Programme of the During evaluation of a new product for European Directorate for the Quality of prequalification, a WHO-contracted Medicines & HealthCare (EDQM) and the laboratory obtained non-compliant EU Commission, with participation of five results when testing the PRP content manufacturers and five national control of the Hib component of a pentavalent laboratories. Publication of the results is vaccine lot. A group of experts convened under way. by WHO concluded that the non- compliance was due to differences Hands-on training courses in testing methodologies rather than a deficiency in the product itself. The Testing of Hib-combination vaccines experts recommended that WHO focus To support countries in quality assurance on standardization of a test protocol to for Hib-containing liquid combination assess PRP in liquid vaccine preparations. vaccines, a hands-on training course was In 2013 WHO PQT initiated a small designed to enable correct implementation project to identify a protocol to reliably of the assay identified in the study.The determine the total and free PRP content trainees perform sample preparation and of the Hib conjugate component of liquid other critical steps for the chromatographic vaccine presentations (3). Two laboratories runs, and calculate their own test results were requested to test samples of using a dedicated Excel spreadsheet. five selected vaccines according to Test outcomes, real-life experiences and their own test protocols, using two challenges in using the test protocol are different reference standards. The data discussed extensively. demonstrated that one of the protocols During 2014 and 2015 four one-week was successful in providing accurate courses were co-organized by WHO and measurements of total and unconjugated the Bacterial Vaccine Unit of the Istituto PRP in complex matrices of immunogens, Superiore di Sanità (ISS) in Rome, Italy. adjuvants and excipients (Box 1). A total of 20 participants were trained, The test protocol identified in the including four from India, three from study gives laboratories an efficient the Republic of Korea, two each from means of determining Hib component in Cuba and Indonesia and one each from liquid vaccine presentations produced Bangladesh, Brazil, Canada, China, Iran, by different manufacturers. Additional Mexico, Poland, South Africa and Thailand. investigations showed that the test A fifth course will take place in June 2016 protocol is applicable to all WHO- at the national control laboratory in China. prequalified vaccine combinations Feedback from course participants has containing a whole-cell pertussis been extremely positive. Suggestions component (5) – which is used in most were made for WHO to offer similar developing countries consistent with WHO training on other glycoconjugated or recommendations (6) – using either of the polysaccharide vaccines, as well as two reference standards. additional theoretical training on issues such as validation of High Performance

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Box 1: Identification of a harmonized assay Study aim: To compare total and free polyribosyl-ribitol-phosphate (PRP) content of the H. influenzae type b conjugate component of liquid vaccine presentations as determined at two independent laboratories with the values obtained by the manufacturer at lot release. Materials and methods: High-performance anion exchange chromatography pulsed amperometric detection (HPAEC-PAD) (4) was performed at two laboratories using their own HPAEC-PAD protocols and validity criteria. Vaccine sample panel (the order does not reflect the sample numbers in the Figures below): • DTPwHepB-Hib: Hib-TT, Thiomersal (0.01 %), Al phosphate • DTPwHepB-Hib: Hib-TT, Thiomersal (0.005 %), Al phosphate • DTPwHepB-Hib: Hib-CRM, Al phosphate • DTPw-Hib: Hib-CRM, Thiomersal, Al phosphate • DTPwHepB-Hib: Thiomersal, Al phosphate, sub-potent Hib-TT component (low total PRP content and high free PRP content) prepared for the purpose of the study. Reference standards (RS): • Ribitol RS (Fluka, lot number BCBJ6567V). • WHO PRP 1st International Standard (code no. 02/208). Analytical conditions: Samples were analyzed as described in the laboratories’ HPAEC-PAD test protocols. A Dionex DX-500 chromatography system equipped with a CarboPac MA1 analytical column was used in combination with a CarboPac MA1 guard column. PRP was hydrolyzed with 0.3 M HCl for 2 hours at 100°C. Samples were pre-treated to determine free PRP content, using C4 SPE cartridges (Laboratory 1) or 30 or 100 kDa pore size Microcon ultrafiltration membranes (Laboratory 2). Two independent runs were performed to determine total and free PRP content. Results: Figures 1 and 2 show the total and free PRP content determined by the manufacturer at lot release (Mf) and the geometrical means of the two values obtained at each of the two laboratories (Lab1, Lab2). Figure 1: Total PRP content (µg per single human dose) WHO RS; manufacturer in-house RS; Ribitol RS; ..... Specification

Sample 1 Sample 2 Sample 3 Sample 4 Sample 5

Figure 2: Free PRP content (percentage per single human dose) WHO RS; manufacturer in-house RS; Ribitol RS; ..... Specification

Sample 1 Sample 2 Sample 3 Sample 4 Sample 5

Conclusions • Both laboratories identified the sub-potent vaccine (Sample 5). • The two reference standards gave similar results at both laboratories. • The test protocol of Laboratory 1 showed better agreement with the manufacturers’ data for the free PRP content than the test protocol of Laboratory 2.

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Anion Exchange Chromatography with testing outcomes. This will benefit the Pulsed Amperometric Detection (HPAEC- prequalification process and thereby PAD) analysis, statistical analysis, creation help to ensure a sustainable supply of validity criteria and qualification of of good quality vaccines to national chromatographic equipment. immunization programmes. Considering that immunization is one of the most Testing of meningococcal vaccines cost-effective public health interventions Course participants had expressed (8), the value for WHO Member States is interest in trainings on meningococcal significant. vaccines, which – like Hib combination vaccines – are on the priority list for WHO References prequalification(7) . In February 2016 WHO 1 UNICEF Supply Division. Pentavalent and the Division of Bacteriology of the U.K. vaccine (DTwP-HepB-Hib): Market & Supply National Institute of Biological Standards Update. July 2015. and Control (NIBSC) organized a two- 2 WHO. Procedure for assessing the week course on the use of HPAEC-PAD acceptability, in principle, of vaccines for purchase by United Nations agencies. for the quantitative determination of the Annex 6. In: WHO Technical Report Series saccharide content of the meningococcal 978. Geneva: World Health Organization, serotypes A, C, W and Y. Participants from 2010. the national control laboratories of Brazil, 3 Study report: Quantitative determination China, Cuba, India, Indonesia and South of the saccharide and unconjugated Africa attended the training. saccharide content of Haemophilus influenzaetype b conjugate component Conclusions in liquid vaccine presentations. Available at: www.who.int/immunization_standards/ The harmonized assay for testing of vaccine_quality/Study_Report_Vaccines_ saccharide content in liquid combination May2014.pdf vaccine preparations enables national 4 Bardotti A et al. Quantitative determination quality control laboratories and of saccharide in Haemophilus influenzae manufacturers to reduce the time spent on type b glycoconjugate vaccines, alone developing and transferring test methods. and in combination with DPT, by use There are currently eight liquid Hib of high-performance anion-exchange chromatography with pulsed amperometric combination vaccines with a whole detection. Vaccine 2000;(18):1982‒93. cell pertussis component on the WHO 5 WHO. WHO prequalified vaccines_List of prequalification list(5) , originating from Italy, prequalified vaccines [web page]. Available the Republic of Korea, India and Indonesia. at: https://extranet.who.int/gavi/PQ_Web/ Technicians from these and ten additional 6 WHO. Pertussis vaccines: WHO position countries participated in hands-on training paper. Weekly epidemiological record. 40, courses on the use of the harmonized test 2010, 85, 385–400. protocol. Training on HPAEC-PAD testing of 7 WHO Immunization. Priority setting for meningococcal vaccines has also started. WHO vaccine prequalification [web page]. Further courses will follow. Available at: www.who.int/immunization_ standards/vaccine_quality/pq_priorities/en/. Successful implementation of the harmonized assay, based on proper 8 WHO, UNICEF, World Bank. State of the world’s vaccines and immunization. Third validation, will enable quality control Edition. Geneva: World Health Organization, laboratories to obtain accurate and reliable 2009. å

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Medicines shortages

Global approaches to addressing shortages of essential medicines in health systems

Shortages of essential drugs are becoming increasingly frequent globally, burdening health systems with additional costs and posing risks to the health of patients who fail to receive the medicines they need. The problem has received increasing attention in recent years. Building on the outcomes of previous discussions, participants at a WHO-convened technical consultation reviewed the factors contributing to medicines shortages and discussed approaches that could be effective to prevent and manage them at the global scale.

Background global scale (3). The discussions built Shortages of essential medicines have on the findings and recommendations of been reported from high-, middle- and an earlier summit meeting convened by low-income countries. They are expensive International Pharmaceutical Federation for health systems to manage, causing (FIP) in 2013 (4). additional costs for replacement of medicines and absorbing significant Types of medicines affected staff time (Box 1). Medicines shortages Available data indicate that products in pose risks for patient health as a result short supply include many commonly used of non-treatment, under-treatment and medicines such as antibiotics, cancer possible medication errors from attempts medicines, cardiovascular medicines and to substitute missing medicines. anaesthetics. Many of them are off-patent While medicines shortages are products and are difficult to formulate not a new phenomenon, they have or have a tightly defined shelf life. This been increasing in recent years (1, 2), combines with characteristics at the levels prompting international concern about of manufacturers, buyers and supply long-term supply of key medicines. chains as described below. A technical consultation was hosted by As a first step in defining a global list of WHO in December 2015 to discuss the essential medicines at risk of shortages bottlenecks and reasons for shortages, a preliminary analysis was presented consider existing solutions and identify at the meeting, comparing the WHO approaches that could be effective at the Essential Medicines List (EML) with four

This article is based on the meeting report of a technical consultation on preventing and managing global stock outs of medicines, convened by the WHO Department of Essential Medicines and Health Products and coordinated by Lisa Hedman. The technical consultation received financial and technical support from the International Pharmaceutical Federation (FIP).

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current public databases of medicines exchange of stock through the grey in short supply. Adrenaline (epinephrine) market, posing risks for drug quality. and atropine sulfate were listed in all the With increasing international funding for databases reviewed, and many antibiotics treatment of priority diseases there has – especially the cephalosporins – were been an increased demand for certain listed in three out of the four databases. medicines in low- and middle-income A well-studied example of an affected countries that have not historically been antibiotic is benzathine penicillin, which large buyers in the global markets. has been in chronic short supply for Significant demand changes can occur in several years with global implications (5). this global marketplace, for example due Another example is insulin, which can to changing treatment guidelines. In case be accessed reliably by only half of the of a shortage, local attempts at solutions 100 million people around the world who sometimes merely transfer a shortage need it (6). Children’s medicines are also from one country to another. often affected by shortages, representing A host of factors challenge the a separate and important issue. successful procurement of medicines from global markets. Commonly reported Factors contributing to shortages problems include fragmented demand, A range of causes and contributing factors rigid rules on tenders, rigid shelf life combine to create situations where the requirements, overly customized demand for a medicine is not met by specifications and payment issues. All adequate supply. this can lead to manufacturers refusing to participate in tenders, or holding orders Demand side until they combine to full batch quantities Unexpected demand changes or to be able to supply from fresh production. fluctuations can lead to medicines At the supply chain level, unreliable shortages, and the risk increases with the data from peripheral facilities continue use of just-in-time inventory control where to be a major problem in most low- and facilities sometime hold no or insufficient middle income countries, hindering buffer stock. Uncertain availability can coordinated stock management and in turn lead to “hoarding” and to informal effective forecasting.

Box 1: Medicines shortages: a widespread and persistent problem • In the U.S., new drug shortages rose from 70 in 2006 to a high of 267 in 2011. The total number of new and ongoing shortages crossed the 450 mark in 2012 (1). In an example cited by FIP, shortages cost U.S. hospitals US$ 416 million, i.e. US$ 200 million to purchase more expensive alternatives and US$216 million in labour costs . • In a large European survey, 21% of hospital pharmacists reported experiencing a shortage of medicines every day, a further 45% every week. One in five pharmacists felt that they could not manage the shortage all or most of the time, suggesting that medicines shortages cause patients to suffer disruption to their treatment. (2) • Fewer data are available from low- and middle-income countries. However, the experiences reported at the meeting by national and international actors suggest that there are significant challenges in ensuring access to needed medicines.

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Payment systems can cause problems or frequently changing regulatory in both high-income and low-income requirements make market entry in many countries. Limited health budgets are target countries costly and unpredictable. creating downward pressure on prices, These challenges contribute to quality- threatening manufacturers’ ability to assured finished products of certain maintain quality manufacturing. However, essential medicines being scarce on the sudden changes in payment structures global pharmaceutical market. or perverse incentives to use expensive products seem to cause as much trouble Meeting recommendations as not having sufficient funds. Risk-based public health approach Supply side Noting that shortages of medicines directly For a viable market model, a supplier base impact the health of patients, the meeting of at least three different manufacturers participants emphasized that a patient- is generally considered desirable. For centred approach to managing medicines some needed products, particularly those shortages is required. Risk management which are less attractive from a marketing principles should be used to identify perspective, the manufacturing base is and prioritize measures to ensure the very limited. Mergers and acquisitions continued supply of the medicines that are have further reduced the number of most needed in public health systems. manufacturers that produce certain finished products. For instance, in the Effective stakeholder discussion U.S., the majority of the injectable generic Coordination, communication and products is supplied by only seven major transparency should be fundamental manufacturers (4). principles in all actions between Medicines shortages have been stakeholders at the national, regional and increasingly related to quality and raw global level. Civil society and professional material problems at the manufacturing associations should continue to play a role level. In the globalized pharmaceutical in preventing and managing global stock markets there is an increased competition outs. With their position in communities for active pharmaceutical ingredients and other forums, they frequently have (API). There has been a move towards access to information that would be useful API suppliers from emerging economies, in detecting, or responding to, medicines such as India and China, which have shortages. come to experience tensions in catering for local and international demands and Procurement quality standards. Yet these sources cover Understanding global and national a significant part of global API needs and demand, especially for vulnerable are not easy to replace at short notice. products, was recognized as important. Maintaining quality systems for The experience of market shaping by finished pharmaceutical products in line global organizations could be leveraged. with current, international standards It should be noted that existing strategies has become a complex and expensive have often been developed for medicines endeavour. Moreover, long timelines with single indications managed under to regulatory approval and diverse specialized treatment programmes – such

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as vaccines or antiretrovirals – and would medicines across different populations, likely fail for many of the medicines that including clinical trial patients, and across have indications across several categories phases of treatment. It was also proposed of general medicine. that criteria should be defined to prioritize Tender and procurement practices the use of medicines in short supply, should be critically reviewed to identify noting that this may be controversial. possible causes of shortages. While there Ideally, agreement on a management may not be a single perfect solution, approaches should be reached before it was recognized as necessary to shortages occur. consider the nature of each product, the available alternatives on the market as Pricing well as market demand in establishing A fair medicines price must be viable for tender conditions. Approaches that the supplier and affordable for the buyer. have improved the availability of certain Exceedingly high prices are making medicines in pooled procurement some patented medicines unaffordable mechanisms could be considered, such for health systems, and measures to as advanced purchase commitments ensure affordability have been much for priority drugs, engagement of discussed for example for antiretrovirals manufacturers, credit facilities that a decade ago, and more recently for promote consistency and predictability of cancer treatments and new medicines cash flows, and consolidation of product to treat tuberculosis and hepatitis C. specifications. Meeting participants felt that negotiation with the patent holder to reach a mutually Supply chain management acceptable agreement should be the first Participants agreed that the importance approach. If this fails, the flexibilities of the of promoting efficient and effective TRIPS agreement such as compulsory management throughout the supply chain licencing can be used; however this has cannot be overemphasized. significant costs and implications and IT systems that facilitate both upstream should be carefully considered. and downstream collection of information At the other end of the spectrum, the need additional support. Rapidly low prices of certain off-patent medicines advancing the use of standardized bar are contributing to medicines shortages. coding – for example using GS1 as a For example, methotrexate is crucial to common standard – was acknowledged the treatment of many oncological and as important and feasible. immunological conditions, yet it has been reported as in short supply repeatedly. Ethical medicines use Would an agreed global minimum price Ethical approach to management of help keep it on the market? How would shortages were discussed using examples such a price be set? Meeting participants from specialist areas of medicine, such agreed that more transparency about the as paediatric oncology, and national cost of production and the basis for pricing experiences for example in Canada. would be helpful to enable a constructive Suggested principles include evidence- dialogue between manufacturers and based clinical decisions, fair access to procurement groups.

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Regulation would support countries without an Drug regulators themselves have limited existing mechanism in establishing one. scope for action, since while they can keep a drug off the market, they cannot Global notification system require a company to make a product. A global reporting mechanism could Approaches to prevent and mitigate provide valuable insight into the supply interruptions, such as mandatory development of the global medicines notification by manufacturers of current market. Such a system could monitor a list or impending shortages, and expedited of medicines yet to be prioritized based inspections and reviews to incentivize on product and market characteristics. manufacturing of good quality needed Data contributed to a global reporting products, have been adopted for example mechanism would need to be from verified by the U.S. FDA (7). sources and must be validated. The value The value of good practices in of having public access to databases responding to shortages, and of as well as public reporting was clearly understanding the interaction and impact recognized. of regulatory decisions on availability of medicines, was recognized. Regulatory Way forward best practices should be collected, where The following priorities for WHO were possible harmonized, and provided as identified based on the meeting outcomes: guidance to others. 1. Develop a consolidated list of medicines that are in short supply and are critical for National reporting systems use in medicine (from the WHO essential Notification systems of medicines medicines list) or are at risk of short shortages exist in most high-income supply. countries but are not yet required in 2. Develop an approach to market shaping many low- and middle-income countries for these medicines in collaboration with (LMIC). However, existing databases have global partners. different definitions and approaches. For 3. Facilitate harmonization of definitions used example, a “shortage” may be reported in relation to shortages. when health facilities are unable to pay for 4. Consider development of a global medicines, which does not mean that the shortage notification system, resources product is unavailable on the market. In permitting. some databases the reason of shortage is 5. Facilitate development of global best given as “unknown” for almost half of the practices for regulatory authorities in reported stock-outs. relation to notification and management It was agreed that it would be essential of shortages, including data standards, to harmonize definitions of “stock outs” database management and regulatory/ and “shortages”, noting that work has legislative strategies to minimize impact of commenced on this in some groups, and shortages. to establish standards for reporting that 6. Work with partners such as global can be used for databases generally. industry representatives and professional Harmonization of reporting systems associations to develop good practice according to best practice would facilitate standards in managing shortages. collaboration between regulators and

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7. Work with global partners to develop References consolidated volume and consumption 1 American Hospital Association, American data for ’vulnerable’ medicines. Society of Anesthesiologists, American 8. Work with partners to develop appropriate Society of Clinical Oncology, American pricing strategies to ensure supply of Society of Hospital Pharmacists, Institute for Safe Medication Practices, The PEW ‘vulnerable’ medicines. Charitable Trusts. 2014 Drug Shortages 9. Continue to support countries, with Summit. 1 August 2014 [meeting report]. global partners, to improve supply chain 2 European Association of Hospital management, including up to date Pharmacists (EAHP). Medicines shortages guidance and policies. in European hospitals. The evidence and The issue of drug shortages was brought case for action. October 2014. to the attention of the WHO Executive 3 WHO. Technical consultation on preventing Board in January 2016 (8) and will be and managing global stock outs of discussed as a specific topic for the first medicines [meeting report]. Geneva, Switzerland, 8–9 December 2015. time at the World Health Assembly in May 4 International Federation of Pharmacists 2016. (FIP). 2013 Summit on Medicines Shortages [meeting report]. Conclusions 5 Wyber R, Taubert K, Marko S, Kaplan EL. Shortages of key medicines will likely Benzathine penicillin G for the management continue to be a problem. Meeting of RHD: concerns about quality and access, participants recognized that shortages and opportunities for intervention and of medicines and technologies are of improvement. Global Heart 2013:8;227– 234. DOI: http://dx.doi.org/10.1016/j. concern to all countries, and that a gheart.2013.08.011 coordinated, end-to-end approach across 6 Health Action International. Inequities and the health system is needed to mitigate Inefficiencies in the Global Insulin Market. their impact on public health. Global Fact Sheet 1. November 2015. institutional leadership will be required 7 U.S. FDA. Strategic Plan for Preventing to move forward on priority issues for and Mitigating Drug Shortages. October improving access to needed medicines in 2013. health systems. 8 WHO. Addressing the global shortages of medicines, and the safety and accessibility of children’s medication. Report by the Secretariat. EB138/41, 18 December 2016. å

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Concept paper for discussion

A stepwise approach for pharmaceutical companies in developing countries to attain WHO GMP standards

This concept paper aims to provide a risk-based, phased approach for development of a country-specific, achievable roadmap towards WHO GMP for the manufacture of finished pharmaceutical products in low- and middle- income countries. The concept paper is based on the experience of the United Nations Industrial Development Organization (UNIDO) in developing and implementing national level GMP roadmaps. It describes the concept, the tools that have been developed and the process utilised for implementation. It is proposed for discussion on how policy makers and regulators can mitigate risk to public health during transition of an industry to GMP compliance based on a risk-based, phased roadmap. Comments and suggestions on this paper are invited to facilitate further discussion. They should be sent to [email protected].

Introduction States only “about 20% are known to have well developed drug regulation” whereas Background “30% either have no drug regulation in Adherence to Good Manufacturing Practices place or а very limited capacity that hardly (GMP) is essential for consistent quality functions” (1). As a result, pharmaceutical assurance of medicinal products and is companies located in developing countries important for ensuring their consistent safety frequently feature operating environments and efficacy. However, due to the lack of and procedures that fall below standards financial, technical and human resource that should ultimately be acceptable. Due capacities, pharmaceutical manufacturers in to the lack of unified quality requirements, developing countries are often overwhelmed individual companies trying to improve their by the vast array of GMP requirements and manufacturing standards are struggling to therefore fail to operate in line with such remain competitive in the low-priced market internationally acceptable standards. The while many manufacturers are discouraged situation is fuelled by the fact that regulatory from making the necessary investments authorities in many developing countries that are required to upgrade. According to cannot meet the demands associated with WHO low- and middle-income countries internationally acceptable GMP standards. bear the greatest burden of substandard Of the more than 190 WHO Member products (2), whereby the rate of substandard

This document has been prepared by Kay Weyer, Ph.D., UNIDO Senior Pharmaceutical Manufacturing Expert (Consultant). It is largely based on the document listed as Reference 10 on page 196. This article is published in the interest of receiving feedback and initiating discussion. The views presented in this paper remain the sole responsibility of the authors. Publication of this material in WHO Drug Information does not necessarily mean endorsement of its content by WHO.

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products can even exceed 60% in particular application of the roadmap concept in countries for certain life-saving drugs such a developing country as evidenced by as anti-malarials (3). The use of substandard the implementation of the Kenya GMP medicines can lead to harmful and even Roadmap (6). lethal consequences including therapeutic This document should be read in failure, drug resistance or toxicity. conjunction with the respective WHO GMP Thus, there clearly exists an urgent need guidelines mentioned in Footnote 1. for improvement of existing manufacturing standards. However, there are significant Scope challenges to raising standards. A central This document focuses on WHO GMP requirement to address the multitude of requirements for the manufacture of issues is the establishment of a stepwise medicines in their finished dosage forms. technical pathway towards GMP compliance Although the concept was initially based on an assessment of the current developed for the manufacture of non-sterile situation within a country. dosage forms containing small molecular entities, the strategic approach presented Purpose in this paper can be applied to various GMP This concept paper explains UNIDO’s environments as long it is ensured that approach to developing a country-specific, internationally recognized GMP guidelines achievable roadmap towards internationally are utilized as reference standard and that acceptable GMP standards, such as those risks resulting from existing manufacturing issued by the World Health Organization practices are adequately mitigated during (WHO). The paper points out the need for a the progress of companies from existing risk-based, phased roadmap towards WHO practices to full compliance with GMP. GMP compliance and explains required steps and tools for its development. GMP roadmap concept The purpose of this document is to provide the technical aspects of developing a Need for a risk-based, phased approach stepwise, phased, and risk-based approach towards WHO GMP for pharmaceutical manufacturers to reach Observations from GMP inspections full WHO GMP compliance. This roadmap performed by WHO at manufacturers of shall set the path for the industry in individual medicinal products in developing countries countries to progress within a specified revealed a high number of deviations period of time to compliance with the from WHO GMP, including some critical internationally acceptable GMP standards deficiencies posing a potential risk of defined by WHO1. harm to patients (7). GMP compliance The document also highlights the assessments conducted recently by various benefits that such a GMP roadmap UNIDO as part of the GMP roadmap approach has for the pharmaceutical sector work resulted in the observation of similar in developing countries. Finally, this paper deficiencies, underlining the urgent need provides an example of the successful for improvement of existing manufacturing 1 The GMP standard referred to in this document standards. For the majority of pharmaceutical is as outlined in (4). Updated WHO GMP manufacturers in developing countries the guidelines are published in the WHO Technical gap between WHO GMP requirements Report Series (TRS). The most recent version is and current manufacturing practices is TRS 986, Annex 2 (5).

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substantial. Therefore, the transition from with WHO GMP. Thereby it has to be current manufacturing practices to full ensured that the sample of pharmaceutical compliance with WHO GMP standards is a manufacturers selected for the baseline time-consuming process which cannot be assessment is representative of the various achieved overnight. In order for the upgrading levels of compliance with WHO GMP within a approach to be realistic and achievable, country. a stepwise, phased pathway with clearly WHO GMP is a highly suitable GMP defined milestones and targets at the end of reference standard as it is based on each phase should be developed, guiding the unified principles and practices agreed by pharmaceutical sector from the status quo to the world’s leading regulatory agencies the targeted WHO GMP compliance. and hence receives wide international While developing such an approach, it acceptance. Besides, many pharmaceutical is essential to identify those areas of WHO manufacturers in developing countries strive GMP where companies are least compliant. to achieve compliance with WHO GMP as These areas pose the biggest threat to the part of the requirements for having their quality, safety and efficacy of the medicinal products prequalified by WHO. products manufactured and therefore have It is essential that this baseline assessment to be addressed with priority in order to avoid is well prepared and conducted thoroughly, exposing patients to preventable risks. as its results provide the basis for the specific In summary, this highlights that to ensure design of the GMP roadmap. Therefore, an achievable and hence realistic pathway unified tools have to be developed and towards full WHO GMP compliance the applied equally to all pharmaceutical roadmap approach has to be manufacturers participating in the baseline • risk-based, focusing first on those areas assessment in order to ensure transparency of WHO GMP with which least compliance and consistency of obtained results. These exists and which are hence posing the tools include 1) the definition of key elements highest risk to the quality, safety and and focus areas during assessments; efficacy of medicines manufactured; and 2) preparation of an assessment schedule • structured in phases allowing a stepwise to be applied to all companies; and 3) the transition to full WHO GMP compliance definition of rating of observations. with clearly defined targets at the end of WHO GMP can be divided into 17 key each phase. areas which are called “key quality elements”, listed below. Steps for a risk-based, phased approach 1. Pharmaceutical Quality System towards WHO GMP compliance in a 2. Utilities impacting Good Manufacturing specific country Practices (GMP) 3. Sanitation and hygiene Step 1: Baseline assessment of existing 4. Qualification and validation manufacturing practices 5. Complaints The baseline assessment is the starting 6. Product recalls point for the development process leading 7. Contract production, analysis and other to a GMP roadmap. During the baseline activities assessment field studies are performed on 8. Self-inspection, quality audits and a sample of pharmaceutical manufacturers suppliers’ audits and approval which have not yet achieved full compliance 9. Personnel

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10. Training the pharmaceutical sector in a given 11. Personal hygiene country. Rather, a tool is required to 12. Premises compare individual companies in terms of 13. Equipment their compliance with WHO GMP and to 14. Materials identify those key quality elements where 15. Documentation highest and lowest compliance rates are 16. Good practices in production observed. Therefore, a rating scheme has 17. Good practices in quality control been developed that enables aggregation For each of these key quality elements the of individual observations related to a assessment focus has to be defined. Based specific key quality element so as to reflect on the defined key quality elements and its composite compliance with WHO GMP focus areas, an assessment schedule is requirements. The rating scheme comprises prepared which is uniformly applied to all the following three levels: companies. In order to allow for a thorough • Compliance of a key quality element with assessment while at the same time avoiding WHO GMP is rated “acceptable” if no or too lengthy a time period for the field study, it only “other” (i.e. “minor”) deficiencies have is recommended that the assessment of each been observed in areas related to this company takes two full days. Deficiencies specific key quality element. of individual companies observed during • Compliance of a key quality element with the assessment are rated using a standard WHO GMP is rated “requires improvement” rating scheme of “critical”, “major”, “other”, as (short: “improve”) if only few “major” outlined for example in the compilation of EU deficiencies (n ≤ 5) were observed in areas “Community Procedures on Inspections and related to this specific key quality element. Exchange of Information” (8). • Compliance of a key quality element with WHO GMP is rated “inadequate” if at Step 2: Evaluation of assessment results least one “critical” and/or a considerable and identification of common main number (n > 5) of “major” deficiencies are technical challenges observed in the respective area or if the In order to evaluate the level of compliance entire key quality element is not available with WHO GMP and to identify the main at a company. technical challenges across the range of This rating key makes it possible to compare pharmaceutical companies within individual company performances and to identify those countries, two tools have been developed: key quality elements for which highest and 1. Identification of key quality elements lowest compliance has been observed. In affected by highest and lowest compliance this way the main technical challenges for with WHO GMP; and compliance can be identified. The rating 2. Risk categorization of companies based on key is a useful tool to evaluate particular their compliance with WHO GMP. weaknesses in compliance of pharmaceutical Tool 1: Identification of key quality manufacturers within a country. elements affected by highest and lowest The described evaluation tool can also compliance with WHO GMP be used for trending of GMP compliance Using the plain ratings of individual of companies and for monitoring their observations made during each company development towards full WHO GMP assessment would not be suitable to compliance throughout the implementation of identify common main challenges across the roadmap.

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Tool 2: Risk categorization of companies “B” and “C”, with a rating of “C” representing based on their compliance with WHO GMP a high- risk company and a rating of “A” GMP compliance can be understood as the indicating a low risk company. result of compliant structural and compliant In order to increase the transparency organizational measures. In this paper the and objectivity of the scores given for the term “site” applies to the physical entity of compliance of site and QMS with WHO GMP, mainly premises, utilities and equipment indicator criteria have been defined which are used for pharmaceutical manufacturing. The presented in Annex 1. term “quality management system (QMS)” is This risk categorization is a suitable applied for all documentation systems and tool for benchmarking GMP compliance procedures used by a company to ensure of companies and can also be used in GMP compliance. The interconnection conjunction with “Tool 1” to monitor the between site, QMS and GMP is illustrated in companies’ progress in the upgrading Figure 1. process towards full WHO GMP compliance. The risk classification uses a matrix to Additionally, the tools presented above categorize companies based on the two can be utilized by individual pharmaceutical risk-indicating factors for GMP compliance: manufacturers in the context of a gap 1) Compliance of site with WHO GMP analysis and in order to prioritize and standards; and 2) Compliance of quality streamline corrective and preventive actions management system with WHO GMP (CAPA). standards. A score of “1”, “2” or “3” is assigned to Step 3: Design of a GMP roadmap based both the site and the quality management on evaluation results system to describe their respective degree Based on the evaluation outcomes a of compliance with WHO GMP. A score risk-based, phased GMP roadmap can of “3” represents high compliance-related be designed. Tool 1 identifies the key risk whereas a score of “1” indicates low quality elements for which the most compliance-related risk. severe deficiencies versus WHO GMP A matrix is used for combining these two exist and hence identifies the main scores in order to generate an estimate of the technical challenges for the sector within overall compliance-related risk associated the country which need to be addressed with a pharmaceutical manufacturer with highest priority. Tool 2 allows one to (Table 1). The resulting risk ratings are “A”, determine whether the main reason for

Figure 1: Interconnection between Site, QMS and GMP

Good manufacturing practice (GMP)

Site Quality Physical entity management mainly: system ▪▪Premises (QMS): ▪▪Utilities ▪▪Systems ▪▪Equipment ▪▪Procedures

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Table 1: Risk matrix for the categorization of companies based on their GMP compliance Quality Management System (QMS) 3 – No QMS in 2 – Requirements 1 – A systematic place are implemented approach in line sporadically only; a with WHO GMP systematic approach in place and to GMP is not in place implemented 1 – Site is in general compliant with WHO GMP C B A 2 – Site shows significant Site deficiencies versus WHO GMP, but C B B production safety is not impaired 3 – Site unsuitable for pharmaceutical manufacturing C C C → production safety impaired A: Existing approach towards pharmaceutical manufacturing in general in line with WHO GMP requirements → low-risk company B: Existing approach towards pharmaceutical manufacturing not in line with WHO GMP but reduced risk with regard to production safety → medium-risk company C: Existing approach towards pharmaceutical manufacturing not in line with WHO GMP and high risk with regard to production safety → high-risk company low compliance with WHO GMP is caused the outcome of the evaluation it might be by site- or QMS-related aspects of GMP, advisable to further divide the main phases which helps to streamline the upgrading into sub-phases. The content of those (sub-) approach. Furthermore, this tool allows one phases will be primarily defined by the to characterize the currently predominating outcome of the compliance assessment of level of compliance-related risk associated the key quality elements, with the first phase with pharmaceutical manufacturers within focusing particularly on those elements a country, and provides guidance in that show the most severe deviations from determining the number of phases needed WHO GMP. Whether the first phase will put to achieve full compliance with WHO GMP. emphasis on site- or QMS-related GMP If the predominantly existing compliance- aspects will depend on the outcome of the related risk of the pharmaceutical companies company risk assessment to the extent in a country is rated as class “C” (i.e. that a distinct trend of compliance-related predominance of high risk companies with risk distribution between the two aspects is inadequate manufacturing standards and revealed. procedures impairing production safety) As the individual phases of the GMP at least 2 main phases will be needed to roadmap are defined according to the gradually improve from the existing level severity of deficiencies versus WHO GMP to full WHO GMP compliance: Phase I and the compliance-related risk observed at from level “C” to “B” will primarily focus on pharmaceutical manufacturers, the evaluation reducing the risk to production safety, Phase results are instrumental in realizing a II from level “B” to “A” will aim to achieve full stepwise, risk-based approach towards compliance with WHO GMP. In this context, achievement of full WHO GMP compliance. it is well acknowledged that depending on

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Benefits of a risk-based, phased roadmap allowing existing companies to improve towards WHO GMP gradually until they are in line with WHO A risk-based, phased approach towards GMP requirements and ensuring that new WHO GMP compliance has many benefits companies comply with WHO GMP before for the pharmaceutical sector of developing their licensing. countries, including the following. • The development of a risk-based, phased Outlook on aligning the approach with roadmap results in an achievable and other stakeholders’ activities scientifically sound pathway towards The risk-based, phased roadmap towards internationally acceptable GMP standards, WHO GMP has to be anchored as a key which will eventually lead to a significant component in a holistic approach for reduction of substandard medicines. the development of the pharmaceutical • A step-wise transition of pharmaceutical manufacturing industry. In addition to a manufacturing practices towards a unified, GMP roadmap many other components internationally acceptable quality standard essential for the industrial development of the following clearly defined requirements, pharmaceutical sector in developing countries activities and milestones ensures the have to be taken into consideration. Those presence of a level playing field throughout components, which include strengthening of the phases of the roadmap. the regulatory functions, access to affordable • The risk-based, phased roadmap ensures finance, development of incentive schemes, that all stakeholders have the same development of necessary human resources understanding of GMP throughout each of and securing distribution chains have to be the transition phases, addressed to enable sustainable high quality ––demystifying requirements of WHO local production to be achieved through the GMP and hence leading to an increased GMP roadmap approach. willingness to implement WHO GMP by While the roadmap approach presented the industry, and by UNIDO in this concept paper focuses ––increasing transparency during licensing on improving the quality of pharmaceutical procedures and regulatory GMP manufacturing, other stakeholders, especially inspections and hence strengthening the Essential Medicines Department of regulatory authorities. WHO, are working on a risk assessment A well-defined risk-based, phased roadmap regarding the suitability of products for will enable: manufacture in companies according • already existing companies to perform a to their respective levels of compliance gap analysis between their current GMP to WHO GMP. Both organizations have compliance and WHO GMP requirements acknowledged the complementarities of and to follow a stepwise approach towards the respective methodologies and have WHO GMP compliance; indicated willingness to incorporate them • new start-up companies to assure that all into a joint approach correlating the phases necessary elements and systems are taken of the roadmap and the risk classification of into consideration and are in place before pharmaceutical manufacturers with product the actual launch of the company; and manufacturing requirements. • the regulatory authority to review licensing criteria for new and existing facilities,

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A practical example of successful of manufacturers in the country. The scope development of a risk-based, of the baseline assessment was limited to phased roadmap to WHO GMP the manufacture of small molecule, non- compliance sterile medicinal products. The results shown The approach outlined above has been below are anonymized and the sequence of used to develop GMP roadmaps for Kenya the companies assessed is randomized, not and Ghana delineating the pathway from allowing participants to be traced. existing GMP compliance to full WHO GMP Using evaluation tool 1 the compliance compliance. Country-specific roadmaps were of participating companies with key quality devised taking into consideration the main elements of WHO GMP was assessed. technical challenges faced by manufacturers The results of this assessment, as shown of medicinal products. in Figure 2, indicate that the companies’ The development of the Kenya GMP compliance with WHO GMP was not rated Roadmap (6) is described here as a practical acceptable for the majority of key quality example for the successful development of a elements. risk-based, phased GMP roadmap using the Figure 2 also shows that seven key quality aforementioned approach. elements were associated with the lowest The baseline assessment of existing possible compliance rating (i.e. inadequate) manufacturing practices was performed in more than half of the participating at seven pharmaceutical companies that, companies. The elements listed below should while all falling short of full WHO GMP be addressed with priority as they pose compliance, represented the different levels

Figure 2: Compliance of participating companies with key quality elements of GMP

Key quality element: Utilities impacting GMP* Premises* Material handling* Good practices in quality control* Quality assurance** Sanitation and hygiene Qualification and validation Personal hygiene Complaints Product recalls Equipment Documentation Good practices in production Self-inspection and quality audits** Training Contract production and analysis** Personnel 0 1 2 3 4 5 6 7 Number of companies ■Acceptable ■Improve ■Inadequate □Not applicable * Key quality elements written in red indicate those for which the highest number of companies showed least compliance. ** As the assessment had been performed before TRS 986, Annex 2 (5) became official, terms used for the key quality elements were based on TRS 961, Annex 3 (9), e.g. the term “Quality assurance” was used instead of “Pharmaceutical quality system”.

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the most severe risk to quality, safety and from “2” to “3”. This result underlines that the efficacy of the manufactured products: selection of companies was suitable for the • Quality assurance assessment, as the selection criteria were • Utilities impacting Good Manufacturing to include companies representing different Practices (GMP) levels of GMP compliance (risk scores • Sanitation and hygiene between “1” and “3”) while having not yet • Qualification and validation achieved full compliance with WHO GMP (no • Premises company with an overall GMP rating of “A”). • Material handling The risk assessment reveals that in general • Good practices in quality control the scores for the site were higher than those related to the QMS. The usually higher Evaluation tool 2 was used to categorize risk associated with site was for almost all participating companies regarding their companies the main cause for downgrading compliance with WHO GMP based on two the overall GMP compliance rating. This risk-indicating factors, namely: clearly indicates that particular guidance is • Compliance of site with WHO GMP needed regarding site-related GMP aspects standards and design requirements. • Compliance of quality management The following conclusions can be systems with WHO GMP standards drawn from the assessment performed at The results are displayed in Table 2. pharmaceutical companies in Kenya and needed to be reflected in the design of the Table 2: Results of the risk categorization of roadmap to WHO GMP compliance: companies based on their compliance with • Site-related GMP aspects need to be WHO GMP prioritized for improvement. Company name Risk Risk Overall • Immediate measures are also required to score score GMP reduce product-related risks caused by Site QMS rating inadequacies of the QMS, with a special Company 1 2 1 B focus on those key quality elements with Company 2 2 2 B the lowest observed compliance ratings. Company 3 3 2 C Taking into account the evaluation results, a Company 4 3 2 C risk-based, two-phased approach has been Company 5 3 2 C designed for the Kenya GMP Roadmap as Company 6 3 2 C shown in Figure 3. Company 7 3 3 C Phase I focuses on the mitigation of risks impairing production safety by The risk assessment shows that out of establishment of WHO GMP compliant sites the seven companies assessed only and improvement of those QMS elements two achieved an overall GMP rating of for which the majority of companies showed “B” (medium risk company) whereas the the most severe deficiencies versus WHO remaining companies received an overall GMP (“QMS 1”). Using the results of the GMP rating of “C” (high risk company). The risk assessment, the majority of companies risk scores for compliance of the QMS with initially rated as “C” should reach a “B” rating WHO GMP requirements ranged from “1” at the end of Phase I as their sites (being a to “3”, the risk scores for compliance of the main contributory factor for their low GMP site with WHO GMP requirements ranged compliance rating) should then be in line with

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WHO GMP requirements. Besides, those and milestones for improvement of site- key quality elements for which the majority of related and QMS-related GMP aspects. The companies showed least compliance will be structure of the Kenya GMP Roadmap is in line with WHO GMP requirements at the provided in Annex 2. end of Phase I, enabling companies to have The roadmap has been complemented with at least a sporadic implementation of QMS in an implementation plan embracing all facets place. required for successful implementation of the During Phase II the main focus will be on Kenyan roadmap towards compliance with establishing a comprehensive, WHO GMP WHO GMP requirements including definition compliant quality management system of near- and mid-term requirements. The (“QMS 2”) so that ultimately both structural roadmap and implementation plan were (“site”) and organizational (“QMS”) measures agreed and endorsed by key stakeholders for GMP compliance will be in line with including representatives from industry WHO GMP. As the definition of the individual and government (both policy-makers and phases of the GMP roadmap is based on regulators) during meetings in 2013 and 2014 both the severity of deficiencies versus and are part of the implementation of the WHO GMP and the compliance-related Kenyan Pharmaceutical Sector Development risk observed at Kenyan pharmaceutical Strategy. manufacturers, a stepwise, risk-based The targeted timeline for implementation approach has been realized for the Kenyan of the Kenya GMP Roadmap, as agreed roadmap towards achievement of full amongst all stakeholders, is five years, WHO GMP compliance. This technical whereby the first phase is targeted to take roadmap provides for each of its phases no longer than three years; and the second a detailed breakdown of required actions phase is targeted to be completed within two

Figure 3: Risk-based, phased approach of the Kenyan roadmap towards achievement of full WHO GMP compliance

Overall GMP Phase focus and targeted outcomes Phase compliance rating number Site and Quality Management Systems in line with A WHO GMP requirements ▲ Improvement and implementation of those QMS ── Phase II with identified lower risk (QMS 2) ▲ Site generally in line with WHO GMP requirements / B QMS 1 in line with WHO GMP requirements ▲ Improvement and implementation of those QMS for which majority of companies showed least compliance (QMS 1) ── Phase I Construction / modification of sites as per WHO GMP requirements ▲ Site and Quality Management Systems not in line C with WHO GMP requirements

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years. The time allocated to Phase I is longer References due to the need for modification of existing 1 WHO. Untitled document. Available at: http:// sites or construction of new sites during this www.who.int/medicines/services/counterfeit/ phase. faqs/QACounterfeit-October2009.pdf. In line with the implementation plan for 2 WHO. Substandard, spurious, falsely the roadmap all Kenyan manufacturers labelled, falsified and counterfeit (SSFFC) medical products. Fact sheet. Updated of finished pharmaceutical products were January 2016. assessed by internationally experienced GMP 3 WHO. Survey of the quality of selected inspectors in conjunction with inspectors from antimalarial medicines circulating in six the Pharmacy and Poisons Board in 2015. countries of sub-Saharan Africa. Geneva: The outcome of the gap analysis project World Health Organization, 2011. confirmed observations, conclusions and 4 WHO. Quality assurance of prioritizations made based on the baseline pharmaceuticals: a compendium of assessment for the development of the GMP guidelines and related materials. Volume Roadmap and hence verified the adequacy 2, Good manufacturing practices and inspection. 2nd updated edition. Geneva: of the approach and the aforementioned World Health Organization, 2007. tools used for the development of the GMP 5 WHO. WHO good manufacturing practices roadmap. for pharmaceutical products: main principles. Annex 2. In: WHO Technical Conclusion Report Series, No. 986. Geneva: World This document summarizes a methodology Health Organization, 2014. to develop a pathway for pharmaceutical 6 United Nations Industrial Development manufacturers in developing countries to Organization (UNIDO), Republic of Kenya. move towards WHO GMP standards. In order Kenya GMP Roadmap Concept. A Stepwise Approach for the Pharmaceutical Industry to to be manageable and scientifically sound, Attain WHO GMP Standards. [On line] 2014. the GMP roadmap should be risk-based and 7 Thrussell I. Examples of critical and major structured into phases. The concept has been observations from GMP inspections of successfully applied in Kenya and Ghana Manufacturing, QC and Contract Research where country-specific GMP roadmaps Organisations. Presented at the UNICEF have been developed in consultation Pharmaceutical Supplier Meeting 2012 on with key domestic stakeholders including 26 September 2012. the pharmaceutical industry, regulators 8 EMA. Compilation of Community and relevant governmental departments. Procedures on Inspections and Exchange of Information (EMA/572454/2014 Rev 17). Assessments of all Kenyan manufacturers [Online] 3 October 2014. . of finished pharmaceutical products by 9 WHO good manufacturing practices for internationally experienced GMP inspectors pharmaceutical products: main principles. in conjunction with inspectors from the Annex 3. In: WHO Technical Report Pharmacy and Poisons Board confirmed the Series, No. 961. Geneva: World Health observations, conclusions and prioritizations Organization, 2011. made based on the baseline assessment 10 United Nations Industrial Development for the development of the Kenya GMP Organization. White Paper on UNIDO’s GMP Roadmap Concept. Design of a Roadmap and hence verified adequacy of the Stepwise Approach for the Pharmaceutical approach and the tools used for development Industry in Developing Countries to Comply of the GMP roadmap. with WHO GMP.

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The Kenyan roadmap towards achievement of full WHO GMP compliance Source: (6) Annex 1: Indicator rating system Indicator criteria have been defined in order to increase transparency when rating the compliance risks associated with “Site” and “Quality Management System” (“QMS”) of the companies assessed. A score of “3” represents a high compliance risk, whereas a score of “1” represents a low compliance risk. Indicators for score criteria for site Prerequisite Rating 1 2 3 Premises Premises are designed to be Premises show significant deficiencies Premises are unsuitable for suitable for pharmaceutical from WHO GMP but do not impair pharmaceutical manufacturing manufacturing production safety → Production safety impaired

Utility Utilities which have direct Utilities which have direct product Utilities which have direct product contact (e.g. water, contact (e.g. water, air handling, product contact (e.g. water, air air handling, compressed compressed dried air) are in place as handling, compressed dried dried air) are in place as required but not fully compliant with air) are not available although required, suitable and effective/ WHO GMP required, or available utilities functioning are unsuitable Equipment Equipment for all manufacturing Equipment for at least critical Equipment for critical steps and quality controls manufacturing steps and quality manufacturing steps and are suitable to perform the controls are in place and suitable to quality controls are not operation and functioning perform the operation and functioning available or not functioning When assigning the overall site rating, the rating (1, 2 or 3) which best reflects the various individual ratings that were assigned to the site attributes should be chosen. Indicators for score criteria for QMS Prerequisite Rating 1 2 3 GMP A systematic holistic approach No systematic approach towards No GMP documentation is in documenta­ towards GMP documentation is a documentation system is in place; procedures are totally tion and in place; procedures performed place; sporadic implementation of inadequate procedures are adequate and based on a GMP requirements; procedures documented system performed are not always based on a documented system Calibration/ A systematic approach Checks for performance of critical No calibration, qualification, qualifica­tion/ based on master documents, equipment, instruments and methods validation are performed validation schedules, protocols and done but not to an extent required reports is in place and/or not based on a systematic approach Preventive Comprehensive preventive Preventive maintenance for No preventive maintenance is main­tenance maintenance procedures based critical systems is performed but performed. on a systematic approach are no systematic approach including in place. schedules, protocols, reports/logs is in place Sanitation Cleaning is adequate; a No signs of inadequate cleaning are Evidence of widespread systematic approach to cleaning observed, but no systematic approach accumulation of residues/ consisting of validation, cleaning to cleaning including cleaning extraneous matter exists; schedules, logs is in place validation, schedules, logs is in place evidence of gross infestation is observed Material Documented procedures for Testing of materials/products is No testing of materials/products handling all types of material handling performed but not to the extent is performed. Procedures for are in place in line with required by pharmacopoeia and receipt, sampling, storage, pharmacopoeia/ international international guidelines. Procedures manufacturing and distribution guidelines for receipt, sampling, storage, are inadequate; no GMP manufacturing and distribution are documentation is in place defined but documentation is not in place for all operations Continued

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Indicators for score criteria for QMS (continued) Prerequisite Rating 1 2 3 Personnel/ Personnel has the right Personnel has the right qualification Personnel does not have the training qualification, experience and and knowledge to perform duties right qualification, knowledge knowledge to perform duties assigned, but no training program is and experience to perform the assigned, training program is in place duties assigned in place When assigning the overall QMS rating, the rating (1, 2 or 3) which best reflects the various individual ratings that were assigned to the QMS attributes should be chosen.

Annex 2: Exemplary structure of the Kenya GMP Roadmap Start: Site and quality management systems not in compliance with WHO GMP requirements Section 1.1: Phase I, Site Phase/Ref. No. Key quality element Actions for implementation Milestones 1.1.1 Premises Define scope of premises by taking into account: Scope of the ▪▪ Environment in which the premises are built premises defined ▪▪ Targeted product classes (e.g. if toxic, ... sensitizing, mutagenic, beta-lactams, sensitive to light, temperature and/or humidity) ▪▪ Targeted production capacity ▪▪ ...... End of section: Phase I, Site Site compliant with WHO GMP, but quality management systems (QMS) not in line with WHO GMP Section 1.2: Phase I, QMS Phase/Ref. No. Key quality element Actions for implementation Milestones 1.2.1 Quality assurance Development of an organizational structure Authorized (organogram) within the company outlining organizational charts hierarchy, functional levels and reporting lines. The in place organizational structure has to ensure a separation ... of quality assurance/control from production...... End of section: Phase I, QMS Note: During the improvement of site and QMS at already existing pharmaceutical manufacturers towards WHO GMP, activities outlined in Sections 1.1 and 1.2 should be conducted concurrently.

Site and QMS identified as main technical challenges in Kenya compliant with WHO GMP Section 2: Phase II Phase/Ref. No Key quality element Actions for implementation Milestones 2.1 Complaints Development and implementation of a Documented documented system regarding handling, system for handling, investigation, corrective and preventive actions of investigation, complaints containing: corrective and ▪▪ Responsible person(s) and responsibilities preventive actions of ▪▪ Procedures to be followed for handling, complaints in place investigation, corrective and preventive actions and implemented of complaints including timelines ... ▪▪ …...... End of section: Phase II Completion: Site and QMS in compliance with WHO GMP å

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Safety news

Safety warnings Saxagliptin, alogliptin: heart failure United States of America – An Loperamide: Serious heart FDA safety review has found that problems with high doses type 2 diabetes medicines containing United States of America – The saxagliptin (Onglyza®, Kombiglyze®) FDA has warned that higher than and alogliptin (Nesina®, Kazano®, recommended doses of the anti-diarrhoea Oseni®) may increase the risk of heart medicine loperamide (Imodium® and failure, particularly in patients who associated names), including through already have heart or kidney disease. abuse or misuse, can cause serious New warnings have been added to the and potentially fatal heart problems. The product information for these medicines. maximum FDA-approved doses for adults Health care professionals should consider are 8 mg per day for over-the-counter discontinuing saxagliptin- or alogliptin- use and 16 mg per day for prescription containing medicines in patients who use The risk may be increased when develop heart failure, and should monitor high doses of loperamide are taken with their diabetes control to see whether other medicines that inhibit CYP3A4, CYP2C8, antidiabetic medicines are required. (1) and/or P-glycoprotein. The EU product information for Health professionals should make saxagliptin-containing medicines states their patients aware of this risk and that caution is warranted in patients should instruct them to seek medical with risk factors such as a history of attention immediately if they experience heart failure or moderate to severe renal symptoms of heart problems. Loperamide impairment. It also states that patients toxicity should be suspected in case of should be advised of the characteristic unexplained QT interval prolongation, symptoms of heart failure and to report torsades de pointes or other ventricular such symptoms immediately to their health arrhythmias, syncope and cardiac arrest. care professionals. For alogliptin the EU In such cases loperamide should promptly product information includes a warning be discontinued and necessary therapy that experience of alogliptin use in clinical started. For some cases of torsades trials in patients with moderate to severe de pointes in which drug treatment congestive heart failure is limited and is ineffective, electrical pacing or caution is warranted in these patients. (2) cardioversion may be required. ►►(1) FDA Drug safety communication, 5 April ►►FDA Drug safety communication, 7 June 2016. 2016. (2) EMA Product information for Vipidia®. Annex 1: Summary of product characteristics, last updated 3 February 2015.

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Fluconazole: risk of miscarriage Imatinib, dasatinib, nilotinib, United States of America – The FDA bosutinib, ponatinib: hepatitis B is evaluating the results of a Danish reactivation study that point to a possible increased European Union, Canada – New risk of miscarriage with the use of oral wording has been included in product fluconazole (Diflucan® and generics), an information for products containing BCR- antifungal medicine used to treat yeast ABL tyrosine kinase inhibitors (including infections. The Agency is also reviewing imatinib, dasatinib, nilotinib, bosutinib additional data. Guidelines issued by and ponatinib) to warn about the risk of the U.S. Centers for Disease Control hepatitis B reactivation in patients who and Prevention (CDC) recommend only are chronic carriers of this virus. Some topical – not oral – antifungal products reported cases have resulted in acute in pregnant women, even in case of hepatic failure or fulminant hepatitis persisting or recurring infections that leading to liver transplantation or a fatal necessitate prolonged treatment. The outcome. current FDA product information states BCR-ABL tyrosine kinase inhibitors that data available from human studies are approved in the EU to treat certain suggest no increased risk in pregnant forms of leukaemia, lymphoma and other women exposed to a single 150 mg dose conditions. Patients should be tested for of oral fluconazole. However, high doses hepatitis B virus infection before treatment (400-800 mg/day) taken repeatedly have with a BCR-ABL tyrosine kinase inhibitor resulted in reports of abnormalities at is initiated. Patients carrying the hepatitis birth. In the Danish study, most of the B virus who need treatment should be oral fluconazole use appeared to be closely monitored during treatment and for one or two doses of 150 mg. Until the several months thereafter. review is complete, the FDA advises ►►EMA. Extracts from PRAC cautious prescribing of oral fluconazole in recommendations on signals. 25 February pregnancy. (1) 2016. The prescribing information for Health Canada Advisory, 4 May 2016. fluconazole-containing medicines in MHRA Drug Safety Update vol 9 issue 10, the EU cautions against use during May 2016: 1. pregnancy. This is based on reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, Trametinib: gastrointestinal giant anterior fontanelle, femoral bowing perforation and colitis and radio-humeral synostosis) in infants United Kingdom – Following a review whose mothers received long-term of data on trametinib (Mekinist®) by treatment with high doses of fluconazole European regulators, the MHRA has for fungal infections. (2) advised health professionals to use this ►►(1) FDA Drug safety communication, 26 April medicine with caution in patients with risk 2016. factors for gastrointestinal perforation, (2) Diflucan® 150 mg capsules. Summary such as gastrointestinal metastases, of product information. Last updated on UK diverticulitis or concomitant use of electronic Medicines Compendium (eMC) on medicines that can cause gastrointestinal 6 November 2015. perforation. Patients should be advised

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to seek urgent medical attention if they Idelalisib: infections and other develop severe abdominal pain. serious adverse events Trametinib is authorized in Europe Following observations of serious adverse either as monotherapy or in combination events – mostly infections – in clinical with dabrafenib for the treatment of adult trials involving the cancer medicine patients with unresectable or metastatic idelalisib (Zydelig®) several regulatory melanoma with a BRAF V600 mutation. safety reviews have been initiated ►►MHRA Drug Safety Update Vol9 issue 8 (see page 208), and the following March 2016: 1. announcements have been made.

European Union – The EMA has Aflibercept: osteonecrosis of the recommended new interim safety jaw measures for idelalisib. All patients should United Kingdom – The MHRA has receive prophylaxis for Pneumocystis advised that a dental examination and jirovecii pneumonia during treatment and appropriate preventive dentistry should should be monitored for respiratory signs be considered before starting treatment and symptoms and for cytomegalovirus with the anti-cancer medicine aflibercept infection. Patients should be monitored (Zaltrap®). During treatment, patients for neutropenia. In case of moderate should maintain good oral hygiene; or severe neutropenia treatment receive routine dental check-ups, and may need to be interrupted. Idelalisib report any oral symptoms such as dental should not be started in patients with mobility, pain or swelling to their health an ongoing systemic infection, or in care provider. previously untreated patients with This follows reports of cases of chronic lymphocytic leukaemia (CLL) osteonecrosis of the jaw in patients whose cancer cells have certain genetic who have been treated with aflibercept. mutations. Ongoing first-line treatment Patients who have received prior or for CLL should only be continued if concurrent treatment with an intravenous the benefits outweigh the risks for the bisphosphonate may be at particular individual patient. (1) risk. In these patients, invasive dental procedures should be avoided where United States of America – The FDA possible. has reminded health professionals that Aflibercept is also the active ingredient idelalisib is not approved in the United in Eylea® intravitreal injection, which States for previously untreated CLL. (2) is authorized for treatment of macular degeneration. Osteonecrosis of the Canada – Health Canada has jaw has not been identified as a risk recommended that idelalisib should not associated with Eylea®. be used for first line treatment of CLL. The ►►MHRA Drug Safety Update Vol 9 issue 9 product monograph will be updated to April 2016: 6. reflect this new information.(3) ►►(1) EMA Press release, 18 March 2016. (2) FDA Drug alert, 14 March 2016. (3) Health Canada Advisory, 3 May 2016.

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Thalidomide: viral reactivation and Pomalidomide in combination with pulmonary hypertension dexamethasone is used to treat adult European Union – Product information patients with relapsed and refractory for the anti-myeloma medicine thalidomide multiple myeloma. Cases of hepatitis B is being updated to include warnings on reactivation, some of which progressed to the risk of viral reactivation and pulmonary hepatic failure, have been reported in less hypertension. Information for health than 1 of 1 000 patients treated, with most care professionals is scheduled to be reports occurring during the first treatment disseminated in late June 2016 cycle. Cases of viral reactivation, including ►►MHRA Drug Safety Update Vol 9 issue 10 some serious cases, have been reported May 2016 2. following treatment with thalidomide, particularly in patients previously infected with the herpes zoster or hepatitis B Olanzapine: rare but serious skin viruses. Recommendations to mitigate this reactions ; risk are similar to those for pomalidomide United States of America – The FDA (see below). has warned health professionals and the Cases of pulmonary hypertension, public that the antipsychotic medicine including some fatal cases, have also olanzapine (Zyprexa®, Zyprexa Zydis®, been reported following treatment with Zyprexa Relprevv®, Symbyax® and thalidomide. Patients should be evaluated generics) can cause a rare but serious for signs and symptoms of underlying and potentially fatal skin reaction known cardiopulmonary disease before and as Drug Reaction with Eosinophilia and during thalidomide therapy. Systemic Symptoms (DRESS). A new ►►EMA Opinions on safety variations/PSURs. warning has been added to the product EMA/76604/2016. 27 May 2016. information for all olanzapine-containing products. Olanzapine is used to treat Pomalidomide: hepatitis B schizophrenia and bipolar disorder. reactivation Prescribers should explain the signs and United Kingdom – A review of clinical symptoms of severe skin reactions to their studies and reported suspected patients and instruct them to seek medical adverse drug reactions by European care if they develop a fever with a rash medicines regulators has concluded that and swollen lymph glands, or swelling in pomalidomide (Imnovid®) can cause the face. Health professionals should stop hepatitis B reactivation. Hepatitis B virus treatment with olanzapine immediately if status should be established before DRESS is suspected. (1) starting treatment with pomalidomide. If a patient tests positive, consultation with a European Union – European medicines physician with expertise in the treatment regulatory authorities have reviewed of hepatitis B is recommended. Previously cases of DRESS in patients taking infected patients should be closely olanzapine. An update of the product monitored for signs and symptoms of information for olanzapine-containing active infection throughout pomalidomide medicines has been recommended to treatment. list DRESS as a possible side effect. The

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condition is very rare and will be listed in 48 hours after the procedure, and re-start the product information as occurring at an metformin if renal function is stable. unknown frequency. (2) ►►FDA Drug safety communication, 8 April ►►(1) FDA Drug safety communication, 10 May 2016. 2016. (2) EMA. New product information wording – Extracts from PRAC recommendations on Aspirin-containing antacids: signals. EMA/PRAC/259913/2016, 28 April serious bleeding 2016. United States of America – The FDA has warned consumers about the risk Known risks of serious bleeding when using over- the-counter aspirin-containing antacid Metformin: expansion of use in products. Despite existing warnings in the kidney impairment product information, reports continue to be United States of America – The FDA received of these serious adverse events. has reviewed available data and has The FDA plans to convene an advisory expanded the use of the anti-diabetic committee of external experts to advise on medicine metformin to patients with mild whether additional regulatory actions are renal impairment and certain patients with needed. moderate renal impairment. Metformin ►►FDA Drug safety communication, 6 June was previously contraindicated in the 2016. U.S. in all patients with renal impairment because of the risk of lactic acidosis. The FDA recommends that the Oral ketoconazole: use only for glomerular filtration rate-estimating serious fungal infections equation (eGFR), rather than the blood United States of America – The FDA creatinine concentration, should be used has reminded health care professionals to assess kidney function. Metformin not to prescribe oral dosage forms of is contraindicated in patients with an the antifungal medicine ketoconazole eGFR <30 mL/minute/1.73 m2, and is not (Nizoral® and other names) for skin and recommended in patients with an eGFR nail fungal infections. Since 2013 oral of 30-45 mL/minute/1.73 m2. The eGFR ketoconazole is no longer approved to should be monitored at least annually, treat these conditions as it carries a risk and more often in patients at increased of serious liver damage, adrenal gland risk of renal impairment. Metformin problems and harmful interactions with should be stopped if the eGFR falls below other medicines and has been linked 30 mL/minute/1.73 m2, and treatment to one patient death since the labelling discontinuation considered if it falls below change. Oral ketoconazole should be used 45 mL/minute/1.73 m2. only for serious fungal infections when no If an iodinated contrast imaging other effective therapy is available. Yet, a procedure is to be performed in certain 2015 safety review found that ketoconazole at-risk patients, health professionals should tablets continue to be prescribed for skin stop metformin, re-evaluate the eGFR and nail fungal infections. ►►FDA Drug safety communication, 19 May 2016.

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Opioids: enhanced warnings gambling should be monitored carefully. United States of America – The FDA Altered or increased sexual interest (in up has announced new class-wide warnings to 1 in 100 people) and weight gain are for immediate-release opioid pain also listed as side effects. medications related to risks of misuse, ►►(1) FDA Drug safety communication, 3 May abuse, addiction, overdose and death, 2016. (2) Health Canada Advisory, 2 November and a warning that chronic use of opioids 2015. during pregnancy can result in neonatal (3) EMA Product information for opioid withdrawal syndrome (NOWS), Abilify®. Annex 1: Summary of product which may be life-threatening for the infant characteristics, updated 23 May 2016. if not recognized and treated. New safety warnings have also been added to all prescription opioid Restrictions medications to inform prescribers and patients of additional risks related to Fluoroquinolones: restricted use in opioid use. Clearer information has been certain uncomplicated infections; included about the indications, dosage, United States of America – The FDA interactions with other medicines including has approved labelling changes for the risk of serotonin syndrome, and about fluoroquinolone antibacterial medicines the effects of opioids on the endocrine (moxifloxacin, ofloxacin, ciprofloxacin) system, including adrenal insufficiency to limit their use in sinusitis, bronchitis and androgen deficiency. and uncomplicated urinary infection. ►►FDA News release, 22 March 2016. In treating these conditions, systemic fluoroquinolones should be reserved for patients who do not have alternative Aripiprazole: impulse control treatment options. The reason for this disorders ; restriction is the risk of a number of United States of America – The FDA disabling and potentially permanent serious has approved changes to the product side effects that can occur together. information of the mental health drug The FDA had communicated aripiprazole (Abilify®, Abilify Maintena®, safety information about systemic Aristada®) to warn about compulsive or fluoroquinolone drugs in 2008 and 2013. uncontrollable urges to gamble, binge An FDA safety review has shown that eat, shop, and have sex reported with this systemically used fluoroquinolones are medicine. Patients should be informed of associated with adverse effects that can these risks and closely monitored. (1) involve the tendons, muscles, joints, This follows a similar risk communication nerves and central nervous system. issued by Health Canada in 2015 (2). Health care professionals should stop Product information approved in the systemic fluoroquinolone treatment EU (3) lists pathological gambling as a immediately if a patient reports serious side effect which can occur in patients who side effects and switch to a non- have no history of gambling, and advises fluoroquinolone antibacterial drug to that patients treated with this medicine complete the patient’s treatment course. who have a history of pathological ►►FDA Drug safety communication, 13 May 2016.

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Withdrawals from the market or manage this risk. The evidence of beneficial effects of fusafungine is weak. Meprobamate: last marketing Taking into account the mild and self- authorization cancelled in U.K. limiting nature of upper airway infections United Kingdom – Following a such as rhinopharyngitis, the benefits 2012 EU-wide review of the sedative of fusafungine were not considered to medicine meprobamate, the remaining outweigh the risks. In addition, it could not licence holder in the UK has ceased be ruled out that fusafungine may promote manufacturing and the licence will be antibiotic resistance. cancelled by the end of 2016. (1) ►►EMA Press release, 1 April 2016. In 2012 the EMA had recommended that marketing authorizations for oral medicines containing meprobamate Veterinary drug carbadox: to be should be suspended in the EU due removed from the U.S. market ; to serious side effects seen with the United States of America – The FDA medicine (2). The suspension was has taken steps towards rescinding its implemented gradually to avoid the risk of approval of the use of the veterinary severe withdrawal symptoms in patients drug carbadox to treat pigs, because stopping treatment abruptly. the drug may leave trace amounts of a ►►(1) MHRA Drug Safety Update vol 9 issue 9, carcinogenic residue. A preliminary risk April 2016: 8. characterization had indicated that there (2) EMA Press release, 20 January 2012. could be a potential risk to human health from ingesting pork, especially pork liver, derived from carbadox-treated pigs. Fusafungin-containing sprays: rare Carbadox was first approved in the but serious allergic reactions U.S. in the early 1970s to control swine European Union – The EMA’s dysentery and bacterial swine enteritis. Co-ordination Group for Mutual It has also been used to promote weight Recognition and Decentralised gain and feed efficiency. Procedures – Human (CMDh) has ►►FDA News release, 8 April 2016. endorsed a recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC) to revoke the Unchanged recommendations marketing authorizations for fusafungine- containing products in the EU. Recombinant factor VIII products: Fusafungine is an antibiotic and anti- no difference in risk of antibody inflammatory used in nose and mouth formation sprays to treat upper airway infections European Union – The EMA’s including common cold. The EMA’s Pharmacovigilance Risk Assessment Pharmacovigilance Risk Assessment Committee (PRAC) has published a Committee (PRAC) has found that summary report of a meta-analysis fusafungin-containing sprays can cause designed to assess the risk of inhibitors rare but serious, potentially life-threatening (antibodies) against individual allergic reactions, and no measures have recombinant factor VIII products been identified to sufficiently reduce developing in previously untreated

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patients with severe haemophilia A. the Australian Technical Advisory Group Specifically, the review concluded that on Immunisation has recommended the overall, the currently available evidence prophylactic use of paracetamol with does not confirm an increased risk every dose of Bexsero® administered to associated with Kogenate® Bayer/ children less than two years old. Helixate® NexGen, compared with other ►►TGA final update, 22 March 2016. products. The conclusions are consistent with those of a 2013 PRAC review of Kogenate® Bayer/Helixate® NexGen. Inhaled corticosteroids for COPD ►►EMA News, 13 May 2016. European Union – The EMA has reviewed the known risk of pneumonia with inhaled corticosteroids for chronic Meningococcal vaccine: no new obstructive pulmonary disease (COPD). safety concerns The review concluded that the benefits Australia – The TGA has been closely of these medicines continue to outweigh monitoring reports of adverse events their well-known risk of pneumonia, which following immunisation with Bexsero® occurs in 1–10 of 100 patients treated. meningococcal B vaccine, specifically No conclusive evidence was found of those relating to fever in infants and any differences in the risk of pneumonia children. Fever is a potential risk factor between products. for the development of a seizure. The No changes are recommended in the TGA’s monitoring activities have found use of inhaled corticosteroids to treat no new or unexpected safety issues. All COPD. Health professionals should the adverse events observed during the however be vigilant for signs and monitoring were identified in the pre- symptoms of pneumonia, which overlap market evaluation, and the numbers of with those of exacerbations of COPD. reports were within expectations. Health ►►EMA Press release, 29 April 2016. professionals have been reminded that

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Medicines safety reviews started

Product Use Concerns Reviewing authority reference Canagliflozin Treatment of Increase in amputations, ►►EMA reviews diabetes (Vokanamet®, type 2 diabetes mostly affecting toes, medicine canagliflozin. Invokana®) observed in an ongoing EMA/267042/2016, clinical trial. 15 April 2016. The scope of the EMA review FDA Drug safety may be extended to other communication, SGLT2 inhibitors at a later 18 May 2016. stage. TGA Safety advisory, 7 June 2016. Escherichia Treatment Effectiveness not adequately ►►EMA Article 31 referral coli bacteria of diseases demonstrated - Review started, cells and affecting the 1 April 2016. autolysate stomach and gut, (Symbioflor 2® including irritable and associated bowel syndrome names) Ticagrelor Prevention of Placed on New Zealand early ►►Medsafe Monitoring (Brilinta ®) blood clots in warning monitoring scheme communication, adult patients due to possible safety 1 March 2016. with acute concern regarding depression coronary and suicidality , suggested by syndromes reports in the WHO database. Vancomycin- Treatment of Need for review of the ►►EMA Article 31 referral containing serious infections benefit-risk balance and - Review started, products with Gram- consideration of updates 1 April 2016. positive bacteria to product information to resistant to other promote appropriate use in antibiotics the context of the fight against antimicrobial resistance. Fluconazole Treatment of Possible increased risk of ►►FDA Drug safety Diflucan® and yeast infections, miscarriage. The FDA advises communication, generics treatment of cautious use of fluconazole 26 April 2016. cryptococcal in pregnancy (see also page meningitis 200). Direct-acting Treatment Hepatitis B reactivation. ►►EMA Article 20 referral antivirals for of chronic In April 2016 the review was - Review started, hepatitis C hepatitis C extended to also evaluate the 18 March 2016. (Exviera®, infection risk of liver cancer. Harvoni®, In Japan, updates have been PMDA Summary of Olysio®, recommended to the product investigation results, Sovaldi® and information for hepatitis C 18 May 2016. Viekirax® direct-acting antivirals to include the risk of hepatitis B reactivation. Continued

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Safety reviews (continued) Product Use Concerns Reviewing authority reference Idelalisib Treatment of Serious adverse events, ►►EMA Press release, (Zydelig®) certain rare blood including deaths mostly due to 11 March 2016. cancers infections, in ongoing clinical FDA Drug alert, trials evaluating idelalisib in 14 March 2016. combination with other cancer medicines. Six clinical trials TGA monitoring have been stopped. Patients communication, treated with idelalisib should 16 March 2016. be carefully monitored for Health Canada signs of infections. Advisory, 17 March (See also page 201) 2016. Sumatriptan Treatment of Risk of serious burns and ►►FDA Drug safety iontophoretic migraine potential permanent scarring communication, transdermal 2 June 2016. system (Zecuity®) Gadolinium- Contrast agent in Risk of gadolinium deposition ►►EMA Article 31 referral containing MRI scans in brain tissue – Review started, contrast agents 18 March 2016

Non-compliance with good practices Semler Research Center Pvt Ltd, India Alkem Bioequivalence Centre, India Geneva – The WHO Prequalification European Union – The EMA has started Team (PQT) has issued a notice of a review of medicines for which studies concern about serious observations made have been conducted at the Alkem during an inspection of Semler Research Laboratories Ltd site in Taloja, Mumbai, Center’s JP Nagar site and Sakar India. This follows a good clinical practice Nagar clinical unit on 27–31 January (GCP) inspection of this site which raised 2015 and a follow-up inspection on concerns regarding study data used 2-5 December 2015, stating that some to support the marketing authorization of the observations are indicative of applications of some medicines in the manipulation of several studies over an EU. The inspection was carried out jointly extended period of time. Manufacturers by the German and Dutch authorities in of affected prequalified products have March 2015 in the context of a routine been asked to submit risk assessments evaluation of applications for nationally with proposed corrective and preventive authorized medicines. The EMA will actions within 30 days (1). now determine which medicines are concerned and will review the available United States of America – The FDA data to determine whether any action is has notified pharmaceutical companies necessary to protect public health. that clinical and bioanalytical studies ►►EMA Article 31 referral - Review started, conducted by Semler Research Center Pvt 1 April 2016. Ltd in Bangalore, India, are unacceptable

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and need to be repeated. The notification specific risk posed by an individual FPP was made as a result of an FDA batch and the need to maintain continuity inspection of Semler’s bioanalytical facility of supply. on 29 September–9 October 2015, which ►►(1) WHO/PQT: medicines press release, found significant instances of misconduct 20 April 2016. including the substitution and manipulation (2) GMP certificates and non-compliance of study subject samples. (2) reports issued by medicines regulatory authorities in the European Economic Area (EEA) are publicly available at: http:// European Union – The EMA has started eudragmdp.ema.europa.eu/inspections/ a review of medicines for which studies gmpc/index.do have been conducted at Semler Research Centre Private Ltd, as the findings from the FDA and WHO inspections call into Falsified product alert question the reliability of data generated at Semler, including data used to support Injectable carmustine marketing authorization applications in the United States of America – The FDA has EU. (3) warned health professionals that a falsified ►►(1) WHO Notice of Concern, 12 April 2016. version of the FDA-approved cancer drug (2) FDA Notification to pharmaceutical carmustine for injection 100 mg (BiCNU®) companies, 20 April 2016. has been detected in some countries (3) EMA. Semler – Article 31 review started. outside the U.S. The authentic product is 29 April 2016. approved in the U.S. to treat different types of brain cancer, multiple myeloma, and lymphoma (Hodgkin’s and non-Hodgkin’s). Anuh Pharma API manufacturing The genuine product is manufactured by site, India Emcure Pharmaceuticals Ltd. Geneva – The WHO Prequalification team The product is available as a vial has temporarily de-listed two prequalified of BiCNU® and dehydrated alcohol active pharmaceutical ingredients (API) co-packaged together. The best way to manufactured by Anuh Pharma Ltd at its distinguish the genuine from the falsified facility in Boisar, India (1). This follows a product is to look at the BiCNU® vial statement of non-compliance with good inside the packaging. The authentic manufacturing practice (GMP) issued by product has a blue flip top while the the French medicines regulatory authority falsified product has a grey flip top. The (2). Anuh Pharma has requested WHO National Drug Code (NDC) number on to conduct an inspection to verify GMP the authentic product vial should end with compliance at the site. -31, not -41. Photographs of an authentic WHO has advised finished product and a falsified product, and a list of lot manufacturers to undertake a risk analysis numbers, batch vial, manufacturing dates, of API batches already purchased, and and expiration dates found on falsified to halt sourcing of further batches of products, are available on the FDA web pyrazinamide from Anuh Pharma until they site. are reinstated on the WHO prequalification ►►FDA Drug alert, 12 May 2016. list. National regulatory agencies and TGA Safety advisory, 23 May 2016. å procurers should consider both the

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Regulatory news

Pre-market assessment EMA guidance on patient-reported outcomes for anticancer medicines EMA offers routine parallel European Union – The EMA has scientific advice published new guidance on how patient- European Union – The EMA has reported outcome data should be published a report on its pilot on parallel integrated in oncology clinical trials. scientific advice allowing pharmaceutical Patient-reported outcomes include any companies to receive simultaneous data directly reported by a patient based feedback on their development plans for on his or her perception of a disease and new medicines from both regulators and its treatment. They provide information health-technology-assessment (HTA) on a patient’s quality of life, symptoms, bodies. A total of 63 parallel scientific treatment adherence or satisfaction with advice procedures were completed from care. The guidance acknowledges the July 2010 to December 2015. importance of bringing the perspective Parallel scientific advice helps to ensure of patients to the assessment of benefits that clinical trials are designed to generate and risks of cancer medicines. Patient- the evidence needed for both regulatory reported outcomes and health-related and health technology assessment. quality of life measures complement the Assessment of both the benefit-risk range of traditional indicators of efficacy of balance and the added value of a new an oncology medicine and can reflect both medicine at the same time can reduce positive and negative patient experiences. delays between its marketing authorization ►►EMA News, 22 April 2016. and decisions on reimbursement. The procedure is routinely offered by EMA since the end of the pilot. A best Ten years of EMA’s small and practice guide has also been published. (1) medium enterprise initiative A report by the EMA and the European European Union – Ten years after the network for Health Technology EMA’s small and medium enterprise Assessment (EUnetHTA) highlights the (SME) regulation came into force, the key achievements of work done in 2012– Agency has published a report that 2015 and future collaborative approaches highlights the importance of SMEs in for collection of robust post-authorization pharmaceutical innovation and trends data, rapid EUnetHTA relative observed in the past ten years. effectiveness assessments and joint SME applications account for discussions on the therapeutic indications approximately 10–15% of all marketing of medicines. (2) authorization applications for new ►►(1) EMA Press release, 31 March 2016. medicines. Of the medicines developed (2) EMA Press release, 14 April 2016. by SMEs and approved in the past ten years, more than half contained a new active substance, and 42% were for

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orphan medicines. SMEs are increasingly Access to investigational products making use of scientific advice during product development, including the FDA simplifies request process for parallel scientific advice with health- compassionate use products technology-assessment bodies that deal United States of America – The FDA with reimbursement decisions. has put into place a streamlined process By the end of 2015, 1619 companies for doctors to request expanded access, from across the EU were listed in a public also called “compassionate use”, to register maintained by EMA to enable investigational drugs and biologics for networking and increase transparency. their patients. A simplified application form ►►EMA News, 11 May 2016. (Form FDA 3926) has been released, together with step-by-step instructions on how to complete it. In addition, the FDA Access to advanced therapies has provided two guidance documents European Union – The EMA has with explanations about expanded published a report from a multi- access and how to request it, and stakeholder expert meeting held in May about how patients may be charged for 2016 to explore possible ways to foster investigational products. the development and authorization of ►►FDA News release, 2 June 2016. advanced therapy medicinal products in Europe. Advanced therapies comprise gene Information-sharing therapies, tissue-engineered products and somatic cell therapies. These medicines Guide to key EMA information on could open up new treatment options human medicines for a wide range of conditions, including European Union – The EMA has some where conventional approaches are released a new guide (1) that describes inadequate. However, since EU legislation the different types of information published on ATMPs entered into force in 2008, only by the Agency on human medicines during five such products have been authorized. of their life span, from early development The meeting report summarizes the ideas through initial evaluation, adoption of and solutions proposed on the subject positive or negative opinions, to post- by a wide range of stakeholders. The authorization changes and safety reviews. proposals are under discussion by EMA, Some best practice guidance for its committees and national regulatory marketing authorization holders, authorities with a view to determine applicants and third parties is provided in concrete actions over the next few the guide to ensure accurate and timely months. communication. This is especially relevant ►►EMA Press release, 3 June 2016. for information which might be sensitive or which may generate significant public interest. The guide includes an easy-reference annex with tables listing the document types produced by the Agency at different stages of a medicine’s life cycle, times

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of publication and links to the relevant FDA revises rule on reporting of EMA web pages. An online version of this veterinary antimicrobial sales overview is also available (2). United States of America – The FDA ►►EMA News, 20 May 2016. has finalized a revised rule on the annual (1) Guide to information on human reporting requirements of sales and medicines evaluated by EMA. What distribution of all antimicrobials for use in the Agency publishes and when. animals intended for human consumption EMA/515416/2015. 10 May 2016. or food-producing animals. In addition to (2) EMA. What we publish on medicines and overall estimates of antimicrobials sales, when [web page]. companies are now required to provide estimates broken down by major food- producing species (cattle, swine, chickens Post-marketing control and turkeys) . The new sales data will help the FDA to EMA adopts rules for public target its efforts to ensure judicious use of hearings on selected safety reviews medically important antimicrobials. European Union – The EMA has ►►FDA News release, 10 May 2016. adopted the final rules of procedure for public hearings to be held by its Pharmacovigilance Risk Assessment Update on Japan’s data network on Committee (PRAC). The process and adverse drug reaction in children procedures will be tested in a dry run in Japan – The Ministry of Health, Labour July 2016. and Welfare (MHLW) has provided Public hearings are a new tool for EMA an update on the “Children and to listen to the views and experiences Pharmaceuticals” Data Collecting Network of citizens regarding the supervision of Development Project in Japan. This medicines. Their legal basis is Article 107j project was conceived in 2012 to support of Directive 2001/83/EC. safer use of medicines for children. A Public hearings could take place as consolidated data collecting system has early as the fourth quarter of 2016, as been put into place by the National Center soon as a relevant topic is identified. for Child Health and Development, making They will be held on a case-by-case use of networks such as the Japanese basis in situations where the PRAC Association of Children’s Hospitals and determines that the views of the public related institutions. As of 29 February would bring added value to its review. 2016, approximately 140 000 adverse They will complement existing channels drug reaction reports have been received of stakeholder engagement during the from four children’s hospitals and early stage of a safety review, enabling 33 clinics. Ultimately, the system is to be the PRAC to consider different risk implemented in 11 children’s hospitals and minimization options in a wider public approximately 35 clinics. Further system health context. development is under consideration. ►►EMA Press release, 15 April 2015. ►►“Children and Pharmaceuticals” Data Collecting Network Development Project. Pharmaceuticals and Medical Devices Safety Information No. 331, March 2016:4-6.

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Law enforcement Concerns about unapproved fixed- dose combinations in India have been Operation Pangea IX highlights the supported by the findings published in dangers of buying medicines online a 2012 research report (2). The legal Lyon, France – Regulatory authorities conundrum is that until 1988, FDCs were of 103 countries participated in the not considered as new drugs in India International Operation Pangea IX, which and therefore needed no approval. Even took place from 30 May to 7 June 2016 after 1988, manufacturing licences for as part of the Ninth Annual International thousands of FDC products were still Internet Week of Action. Coordinated issued legally by state controllers until by INTERPOL, Operation Pangea is an 2002, when prior approval of the FDC annual global cooperative effort aiming to by the central drug controller became combat the unlawful sale and distribution mandatory. While the state governments of illegal prescription medicines and can prohibit manufacture of drugs only medical devices on the Internet. This if these are found to be falsified or if the year’s operation was the largest of manufacturer has violated any rules, the its kind so far. It led to the seizure of Central Government can ban drugs for 170 340 shipments containing a total of reasons of public health. (3) 12.2 million potentially dangerous illicit Public health supporters have welcomed medicines worth more than 53 million the move, while manufacturers feel that US$, as well as the suspension of 4 932 they are unjustly punished when they have websites selling illicit pharmaceuticals. not contravened any laws. Nine years ►►INTERPOL News, 9 June 2016. earlier, a similar government attempt could not be executed as the order was challenged in the Madras High Court. Rational medicines use Commentators doubt that the ban can be implemented effectively. (4) India bans over 300 fixed-dose ►►(1) The Gazette of India. No. 608, 10 March combinations 2016. India – The Ministry of Health has banned (2) McGettigan P et al. Use of Fixed Dose 344 fixed-dose combinations contained Combination (FDC) Drugs in India: Central in 1 600 brands worth 37 billion Indian Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Rupees (approximately 550 million US$) Drugs (NSAIDs), Metformin, or Psychotropic following recommendations of an expert Drugs. PLOS Medicine. Published online, 12 committee formed to examine their safety May 2015. http://dx.doi.org/10.1371/journal. and efficacy. The banned FDCs include pmed.1001826 cough syrup solutions, analgesic and (3) Talwar P. Irrational FDCs in India. E-drug antibiotic combinations and others, many post, 29 Jan 2015. of which are sold over the counter. (1) (4) Dabade G. Healing fast, killing slowly. Deccan Herald, 27 March 2016.

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Under discussion

European Union – A European expert United States of America – The FDA group has proposed further restrictions of has issued draft guidance on evaluating the use of the last-resort antibiotic colistin in the abuse deterrence of generic solid oral animals. The updated advice was provided opioid products. This follows the agency’s following the discovery of a new mechanism final guidance for brand name opioids, which of resistance in bacteria to colistin with was issued in April 2015 as the first step to potential for rapid spread. The comment provide a framework for what studies were period ended on 26 June 2016. needed to evaluate a product’s ability to ►►EMA Press release, 26 May 2016. deter abuse. The period for public comment is 60 days. European Union – The EMA has started a ►►FDA News release, 22 March 2016. review of the guidelines on the safety of first- in-human clinical trials in cooperation with United States of America – The FDA has the European Commission and EU Member issued three new draft guidance texts related States. The review follows a tragic incident to compounding of human medicines, which occurred during a Phase I clinical trial describing the Agency’s proposed policies in France in January 2016, leading to the and application of the prescription death of one participant and hospitalization requirement in section 503A of the Food, of five others. An agreed concept paper is Drug, and Cosmetic Act and the definition of expected by July 2016. the term “facility” in section 503B of the Act. ►►EMA Press release, 27 May 2016. The period for public comment is 90 days. ►►FDA Statement, 15 April 2016. Canada – The Government of Canada is moving forward with mandatory reporting European Union – The EMA has released of medicines shortages. Prequalified a draft reflection paper that outlines a contractors have been invited to submit framework for the extrapolation of clinical proposals to develop and maintain an trial data from adults to children to support independent website for reporting of the authorization of new medicines for shortages. children. The paper was published ahead of ►►Government of Canada. News release, a workshop held on the topic with experts 19 May 2016 and stakeholders in May 2016. The next version of the reflection paper is expected to Australia – The Advisory Committee on be released for public consultation by end of Medicines Scheduling met on 15 March July 2016. 2016 to consider the large number of ►►EMA News, 4 April 2016. submissions received on the proposed up-scheduling of all over-the-counter Canada – Health Canada has announced codeine products to become prescription- a proposed regulatory amendment to allow only medicines. A TGA-commissioned access to diacetylmorphine in chronic independent review of low dose codeine- relapsing opioid dependence under its containing products is also being considered. Special Access Programme (SAP) . The A final decision is expected after June 2016. period for public comment is 30 days. ►►TGA News, 24 March 2016. ►►Government of Canada. News release, 13 May 2016.

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Approved

Obeticholic acid: for primary biliary Sofosbuvir/velpatasvir: for hepatitis C cholangitis virus infection Product name: Ocaliva® Product name: Epclusa® Dosage form: Tablets Dosage form: Film-coated tablets Class: Bile acid preparation; Class: Fixed-dose combination of two ATC code: A05AA04 direct-acting antivirals: an NS5B inhibitor Approval: FDA (fast-track and orphan drug (sofosbuvir, ATC code J05AX15) and a designations; accelerated approval) novel NS5A inhibitor (velpatasvir). Use: Treatment of primary biliary cholangitis Approval: EMA recommendation in combination with ursodeoxycholic acid Use: Treatment of chronic hepatitis C virus (UDCA) in adults with an inadequate infection in adults response to UDCA, or as a single therapy Benefits: When used with or without in adults unable to tolerate UDCA. ribavirin, very high efficacy against all Benefits: Reduction in alkaline phosphatase HCV genotypes including in patients with (ALP) level as a surrogate endpoint to decompensated cirrhosis. predict clinical benefit. A confirmatory trial Note: The EMA has also recommended is ongoing to demonstrate improvement another hepatitis C fixed-dose in survival and slower progression to combination product, elbasvir and cirrhosis. grazoprevir (Zepatier®) for approval. This ►►FDA News release, 31 May 2016. product was approved by the U.S. FDA in January 2016. ►►EMA Press release, 27 May 2016.

Defibrotide sodium: for rare complication in stem cell transplants Product name: Defitelio® Pandemic influenza (H5N1) vaccine Dosage form: Injection for intravenous use (live attenuated) Class: Antithrombotic agent; Product name: Pandemic influenza vaccine ATC code: B01AX01 H5N1 MedImmune Approval: FDA (orphan drug designation, Dosage form: Nasal spray (suspension) priority review) Class: Influenza vaccine;ATC code: J07BB03 Use: Treatment of adult and paediatric Approval: EMA recommendation patients with hepatic veno-occlusive Use: Prophylaxis of influenza in an officially disease, also known as sinusoidal declared pandemic situation in children obstruction syndrome, with renal and adolescents from 12 months to or pulmonary dysfunction following less than 18 years of age. The vaccine haematopoietic stem cell transplantation. should be used in accordance with official Benefits: First FDA-approved treatment for guidance. this rare, potentially fatal complication in Benefits: Ability to achieve an immune patients who receive chemotherapy and memory response for H5N1 starting as haematopoietic stem cell transplantation. early as 4 weeks after vaccination and Safety information: Risk of bleeding and lasting for at least 4–5 years. allergic reactions. The product should ►►EMA/CHMP Summary of opinion, 1 April not be used in patients with bleeding 2016. complications or those receiving systemic anticoagulant or fibrinolytic therapy. ►►FDA News release, 30 March 2016.

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Approved

Venetoclax : for chronic lymphocytic Ixekizumab: for psoriasis leukaemia Product name: Taltz® Product name: Venclexta® Dosage form: Injection Dosage form: Tablet for oral use Class: Humanized monoclonal antibody Class: BCL-2 inhibitor; binding to interleukin (IL)-17A; ATC code (temporary): L01XX52 ATC code: L04AC13 Approval: FDA (breakthrough therapy Approval: FDA designation, priority review, accelerated Use: Treatment of psoriasis in patients who approval; orphan drug designation) are candidates for systemic therapy, Use: Treatment of patients with chronic phototherapy or both. lymphocytic leukaemia (CLL) with a 17p Benefits: Inhibition of the inflammatory deletion who have received at least one response that plays a role in the prior therapy. development of plaque psoriasis. Benefits: Additional treatment option Safety information: Serious allergic reactions targeting a protein which supports cancer and development or worsening of cell growth and is often overexpressed in inflammatory bowel disease have been CLL patients. reported. Safety information: Serious complications ►►FDA News release, 22 March 2016. can include pneumonia, neutropenia with fever, fever, autoimmune haemolytic

anaemia, anaemia and metabolic Opicapone: for Parkinson’s disease abnormalities known as tumour lysis Product name: Ongentys® syndrome. Live attenuated vaccines Dosage form: Hard capsules should not be given to patients taking Class: Peripheral, selective and reversible venetoclax. COMT inhibitor ►►FDA News release, 11 April 2016. Approval: EMA recommendation Use: Adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors

Daclizumab: for relapsing multiple (DDCIs) in adult patients with Parkinson’s sclerosis disease and end-of-dose motor Product name: Zinbryta® fluctuations who cannot be stabilized on Dosage form: Solution for injection those combinations. Class: Humanised IgG1 monoclonal Benefits: Ability to decrease off-time (time antibody, ATC code: L04AC01 when patients are severely restricted by Approval: EMA recommendation, FDA their symptoms) and to increase on-time Use: Treatment of adult patients with without troublesome dyskinesia. relapsing forms of multiple sclerosis ►►EMA/CHMP Summary of opinion, 28 April Benefits: Ability to reduce the relapse rate 2016. as well as the risk of 24-week confirmed disability progression.

Safety information: The most common side Pimavanserin : for symptoms effects include elevations of liver enzymes associated with Parkinson’s disease and hepatic injury, cutaneous events, Product name: Nuplazid® infections, gastrointestinal disorders and Dosage form: Tablets depression. Class: Atypical antipsychotic drug; ►►EMA/CHMP Summary of opinion, 28 April ATC code (temporary): N05AX17 2016. Approval: FDA (breakthrough therapy, FDA News release, 27 May 2016. priority review) Use: Treatment of hallucinations and delusions associated with psychosis

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Approved

experienced by some people with Benefits: Fewer asthma attacks, longer time Parkinson’s disease to first attack and improved lung function Benefits: First FDA-approved medicine to compared with placebo treat these symptoms associated with Safety information: Risk of serious Parkinson’s disease. hypersensitivity reactions. Safety information: As all medicines in ►►FDA News release, 23 March 2016. this class, the product carries a Boxed Warning about an increased risk of

death in older people with dementia- Obiltoxaximab: for inhalational related psychosis. No drug in this class is anthrax approved to treat patients with dementia- Product name: Anthim® related psychosis. Dosage form: Injection for intravenous use ►►FDA News release, 29 April 2016. Class: Monoclonal antibody Approval: FDA Use: Treatment of inhalational anthrax in

Buprenorphine implant: in opioid combination with appropriate antibacterial dependence drugs. Product name: Probuphine® Benefits: Neutralization of toxins produced Dosage form: Six-month implant by Bacillus anthracis; increased survival Class: Drug used in opioid dependence; rates compared with placebo, and – when ATC code: N07BC01 used in combination with antibacterials Approval: FDA – higher survival rates than with Use: Treatment of opioid use disorder as part antibacterial therapy alone. Anthrax is a of a complete treatment programme that potential bioterrorism threat. includes counselling and psychosocial Safety information: The product carries a support. Boxed Warning that the drug can cause Benefits: Improved patient convenience hypersensitivity reactions including compared with sublingual dosage forms anaphylaxis. Safety information: The product must be Note: The product was approved under prescribed and dispensed according the FDA’s Animal Rule, which allows to a Risk Evaluation and Mitigation efficacy findings from adequate and well- Strategy programme because of the risks controlled animal studies to support FDA of surgical complications, accidental approval when it is not feasible or ethical overdose, misuse and abuse if an implant to conduct efficacy trials in humans. comes out or protrudes from the skin. ►►FDA News release, 21 March 2016. ►►FDA News release, 26 May 2016.

Atezolizumab: for bladder cancer

Reslizumab: for severe asthma Product name: Tecentriq® Product name: Cinqair® Dosage form: injection for intravenous use Dosage form: Intravenous infusion for use Class: Programmed death-ligand 1 (PD-L1) every 4 weeks in a clinical setting inhibitor; first-in-class FDA-approved Class: Humanized interleukin-5 antagonist Approval: FDA (breakthrough therapy, monoclonal antibody; ATC code: R03DX08 priority review, accelerated approval) Approval: FDA Use: Treatment of patients with locally Use: In combination with other asthma advanced or metastatic urothelial medicines, for the maintenance treatment carcinoma whose disease has worsened of severe asthma not controlled with during or following platinum-containing conventional medicines in patients aged chemotherapy, or within 12 months 18 years and older. of receiving platinum-containing

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Approved

chemo­therapy either before or after have no matching donor for a stem cell surgical treatment. transplant. Benefits: Additional treatment option for Benefits: First authorized treatment for advanced or metastatic cases of this ADA-SCID in the EU. Other options common type of bladder cancer. include stem cell transplants, which can Safety information: Potential to cause be successful if there is a close match infection and severe immune-mediated between the patient and the donor, and side effects; potential to cause foetal compassionate use enzyme replacement harm. therapy, which may become less effective Note: The FDA has also approved a over time. diagnostic test to detect PD-L1 protein Note: ADA-SCID is an ultra-rare immune expression levels on patients’ tumour- disorder Children born with ADA-SCID infiltrating immune cells, helping to have virtually no immunity to fight determine which patients may benefit off everyday bacterial, fungal or viral most from treatment with atezolizumab. infections. ►►FDA News release, 18 May 2016. ►►EMA Press release, 1 April 2016.

Migalastat: for Fabry disease EMA Article 58 positive opinion Product name: Galafold® Dosage form: Hard capsules

Class: A pharmacological chaperone Chlorhexidine digluconate: to prevent

designed to selectively and reversibly umbilical infection in newborn infants; bind to certain mutant forms of the a-Gal Product name: Umbipro® A enzyme, resulting in restored enzyme Dosage form: Antiseptic gel activity. Class: Antiseptic agent; ATC code: D08AC02 Approval: EMA recommendation (orphan Approval: EMA Article 58 procedure, designation) providing a scientific opinion on the use of Use: Treatment of patients over 16 years a medicine outside the EU. with Fabry disease (alpha-galactosidose Use: To cleanse the umbilical cord stump A deficiency) with an amenable mutation. of newborn babies to prevent serious Benefits: More convenient treatment infection. option for this rare genetic disorder than Benefits: Studies found a 20%–38% intravenous enzyme replacement therapy. reduction in mortality in newborn infants ►►EMA Press release, 1 April 2016. delivered in community or primary care centres in resource-limited settings and a 24% to 75% reduction in umbilical cord New gene therapy for ADA-SCID infection where chlorhexidine was used. Product name: Strimvelis® Notes: WHO treatment guidelines Dosage form: Dispersion for infusion recommend chlorhexidine for umbilical Class: Gene therapy manufactured from cord care for home births in regions with a patient’s own immature CD34+ more than 30 deaths per 1 000 live births. bone marrow cells into which a normal It was identified by the United Nations adenosine deaminase enzyme gene has as one of 13 life-saving commodities been inserted. for women and children. The product Approval: EMA recommendation (orphan was developed by the manufacturer designation) in partnership with Save the Children Use: Treatment of patients with adenosine- in response to a call from the United deaminase-deficient severe combined Nations’ Commission on Life-Saving immunodeficiency (ADA-SCID), who Commodities for Women and Children,

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Approved

which is a part of the Every Woman, Brand name change Every Child (EWEC) movement. ►►EMA Press release, 29 April 2016. ►►Draft monographs enabling independent Vortioxetine: brand name changed to quality control testing of chlorhexidine avoid confusion; digluconate solution and chlorhexidine Product name: Trintellix® (formerly: digluconate topical solution have been Brintellix®) proposed for inclusion in The International INN: Vortioxetine Pharmacopoeia. They are available for Class: Antidepressant; serotonin reuptake public comment at www.who.int/medicines/ inhibitor (SSRI); ATC code: N06AX26 areas/quality_safety/quality_assurance/ Approval: FDA projects and will be reproduced in Issue 3 Note: The brand name was changed to (2016) of WHO Drug Information. avoid confusion with ticagrelor (Brilinta®), an antithrombotic agent. Trintellix® is expected to be available from June 2016. Biosimilars No other changes will be made to the product information or packaging, and the medicine is exactly the same. Infliximab ►►FDA Drug safety communication, 2 May Class: Immunosuppressant; ATC code: 2016. L04AB02 Use: Treatment of rheumatoid arthritis, ulcerative colitis, Crohn’s disease, Extensions of indications psoriatic arthritis, psoriasis and ankylosing spondylitis.

Benefits: Biosimilars can provide access to Crizotinib: for certain rare, advanced important treatment options for patients non-small cell lung cancers who need them. Product name: Xalkori® Approval: FDA (breakthrough therapy, 1. priority review; orphan drug designation) Active substance: Infliximab Newly approved use: Treatment of patients Product name: Flixabi® with advanced (metastatic) non-small Dosage form: Powder for concentrate for cell lung cancer whose tumours have solution for infusion an ROS-1 gene alteration (first FDA- Approval: EMA recommendation (biosimilar approved medicine for this indication). to Remicade®) ►►FDA News release, 11 March 2016. ►►EMA/CHMP Summary of opinion, 1 April 2016.

Obinutuzumab: for follicular

2. lymphoma; Active substance: Infliximab-dyyb Product name: Gazyvaro® Product name: Inflectra® Approval: EMA recommendation Dosage form: Intravenous injection Newly approved use: In combination with Approval: FDA (biosimilar to, but not bendamustine, treatment of follicular interchangeable with, Remicade®) lymphoma in patients previously treated Notes: Inflectra® is the second biosimilar to with chemotherapy. be approved in the United States, after ►►EMA Press release, 29 April 2016. filgrastim-sndz (Zarzio®). Inflectra® was authorized in the EU in 2013. ►►FDA News release, 5 April 2016.

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Approved

68 Diagnostics Gallium ( Ga) dotatate: to detect rare

neuroendocrine tumours; Product name: Netspot® Investigational Zika test Dosage form: Injection for intravenous use United States of America – The FDA Class: Diagnostic radiopharmaceutical has announced the availability of an Approval: FDA (orphan drug designation; investigational test to screen donated priority review) blood in areas with active mosquito-borne Use: To help locate somatostatin receptor- transmission of Zika virus. This follows FDA positive neuroendocrine tumours in adults guidance issued in February to reduce the and children. Findings may need to be risk of transfusion-transmitted Zika virus. confirmed by histopathology or other The FDA, the Office of the Assistant assessments. Secretary for Preparedness and Response/ Benefits: Useful method to locate Biomedical Advanced Research and neuroendocrine tumours, to inform Development Authority and the Centers for planning of therapy. Disease Control and Prevention are working ►►FDA News release, 1 June 2016. to assist manufacturers with development of Zika virus screening tests to help protect the United States’ supply of blood and blood Veterinary drug components during this outbreak. ►►FDA News release, 30 March 2016.

Pegbovigrastim: to reduce the

incidence of mastitis; 18 Fluciclovine ( F): to detect prostate United States of America, Canada – The cancer recurrence FDA and Health Canada have announced Product name: Axumin® the simultaneous approval of pegbovigrastim Dosage form: Injection injection (Imrestor®), an innovative Class: Radioactive diagnostic agent veterinary drug that restores immune Approval: FDA response and reduces and reduces the Use: For use in positron emission incidence of clinical mastitis of dairy cows tomography (PET) imaging in men with and replacement dairy heifers. suspected prostate cancer recurrence Clinical mastitis is the inflammation of based on elevated prostate specific the mammary gland and udder tissue. antigen (PSA) levels following prior Mastitis is a common disease in dairy treatment. Clinical correlation, which cattle. Pegbovigrastim is expected to may include histopathological evaluation reduce reliance on other drugs, including of the suspected recurrence site, is antimicrobials, to treat mastitis infections. recommended. Pegbovigrastim is the first simultaneously Benefits: Accurate imaging approach for reviewed and approved animal drug for use patients with suspected recurrent prostate in food-producing animals, and the fourth cancer when the PSA is at low levels. animal drug approved under the Canada– ►►FDA News release, 27 May 2016. United States Regulatory Cooperation Council (RCC). ►►Government of Canada. News release, 24 March 2016. FDA Center for Veterinary Medicine (CVM) update, 29 March 2016. å

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Publications and events

Access to medicines current debate on the cost of medicines. They propose five main ways how WHO submission to the UN High- regulators can make a contribution to Level Panel affordable health care: 1) Enable the rapid Geneva – WHO has made a submission approval of generics and biosimilars; to the UN Secretary-General’s High- 2) ensure that medicines comparable Level Panel on Access to Medicines to already approved ones continue to to recommend solutions to remedy the come on the market, thus increasing policy incoherence between the justifiable competition; 3) encourage clinical trials rights of inventors, international human that demonstrate safety and efficacy and rights law, trade rules and public health also provide data to guide reimbursement in the context of health technologies. The decisions; 4) facilitate the collection of submission presents WHO’s experience post-approval data that are important for and a number of ongoing WHO projects payers, for example data on outcomes to foster the development of priority health for patients; and 5) foster new models products, including the WHO/DNDi Global for research and development enabling Antibiotic R&D Partnership, and makes a companies to reduce the price of their number of suggestions for possible areas medicines. of action to the Panel. ►►EMA News, 12 May 2016. ►►WHO Submission to the UN SG High Level Eichler HG, Hurts H, Broich K, Rasi G. Drug Panel on Access to Medicines. 17th March Regulation and Pricing — Can Regulators 2016. Influence Affordability? N Engl J Med 2016; WHO Public health, innovation, intellectual 374:1807-9. DOI: 10.1056/NEJMp1601294. property and trade. UN Secretary-General’s High-Level Panel on Access to Medicines [web page]. UNITAID discussion paper on affordability of essential medicines Regulatory approaches to make Geneva – UNITAID has published a medicines more affordable discussion paper that assesses the European Union – In an article published affordability of medicines and biologicals in the New England Journal of Medicine, to treat hepatitis C, cancer and multi representatives of European regulatory drug-resistant tuberculosis and proposes authorities discuss possible regulatory options for making them more affordable interventions to facilitate continued access through price negotiations, voluntary to safe and effective medicines in health licensing, patent pooling, and use of systems at affordable prices. TRIPS flexibilities. The report emphasizes The authors argue that although the that the recent shifts in the WHO Essential pricing of medicines is clearly out of Medicines paradigm demand a bold their remit, regulators cannot ignore the approach to avoid unnecessary delays in

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making these medicines available to the and G20 countries. Additionally, GSK populations in need. intends to commit its future portfolio of ►►Ensuring that essential medicines are cancer treatments to patent pooling and also affordable medicines: challenges and will explore the concept with the Medicines options. Discussion paper. Geneva: WHO Patent Pool (MPP). GSK would be the (Acting as the host organization for the first company to licence cancer medicines Secretariat of UNITAID), 2016. to the patent pool. GSK will also work towards making information about its Intellectual property and local current and future patent portfolio freely medicines production available. (1) Geneva – A new WHO study on the The Union for Affordable Cancer role of intellectual property in medicines Treatment (UACT) has welcomed the production sets out strategies and options announcement, stating that it is “significant to facilitate local production in developing and encouraging” that GSK is seeking countries. Using practical examples and collaboration with the MPP, a public patent landscapes, the report describes health-driven licensing mechanism with a the options available to countries with proven track record. (2) a generic pharmaceutical industry to ►►(1) GSK Press release, 31 March 2016. design an intellectual property system (2) UACT Statement, 6 April 2016. that is favourable for local production and potentially for public health. The report contains detailed patent Study shows hepatitis C medicines information on atazanavir, raltegravir, prices are globally unaffordable imatinib, sitagliptin, pegylated interferon A comparative study of prices and alfa-2a, and human papillomavirus affordability of sofosbuvir and ledipasvir/ vaccine (Gardasil®). sofosbuvir across 30 countries has shown ►►WHO. The role of intellectual property in that current prices of these medicines are local production in developing countries variable and unaffordable globally. A fairer - Opportunities and challenges. Geneva, pricing framework is needed if countries World Health Organization: 2016. are to increase investment to minimize the burden of hepatitis C. ►►Iyengar S, Tay-Teo K, Vogler S, Beyer P, GlaxoSmithKline announces new Wiktor S, de Joncheere K, et al. Prices, approach to patents costs, and affordability of new medicines Ahead of the meeting of the UN High for hepatitis C in 30 countries: an economic analysis. PLoS Med 13(5): e1002032. Level Panel on Access to Medicines, doi:10.1371/journal.pmed.1002032. GlaxoSmithKline (GSK) has announced its new and more flexible approach to patents and intellectual property to increase DNDi and pharmaceutical company access to medicines. The company plans to test new hepatitis C medicine to use a graduated approach to filing Barcelona – The Drugs for Neglected and enforcing patents depending on a Diseases initiative (DNDi) and the country’s economic maturity, seeking Egyptian pharmaceutical company full patent protection only in high income Pharco Pharmaceuticals have signed countries, upper middle income countries agreements covering the clinical testing

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and scale-up of a hepatitis C treatment Disease updates regimen at a price of just under US$ 300. The announcement was made at the HIV and hepatitis C co-infection International Liver Congress 2016 Geneva – A WHO-commissioned study in Spain. The regimen consists of a has found that an estimated 2.3 million combination of ravidasvir – an NS5A people globally are co-infected with HIV inhibitor – and sofosbuvir. Phase III and hepatitis C virus (HCV). More than studies will be conducted in Malaysia and half of these are people who inject drugs. Thailand in patients with various levels HIV-infected people were found to be six of liver fibrosis, various genotypes of times more likely than HIV-uninfected hepatitis C virus, and with and without HIV people to have HCV infection. co-infection to compare the new regimen Globally, there are 37 million people with the combination of sofosbuvir and infected with HIV and around 115 million daclatasvir, a current standard of care. people with chronic HCV infection. The ►►DNDi Press release, 13 April 2016. study found that 27% of all HIV/HCV co-infections were in eastern Europe and central Asia, where injecting drug use is Medicines patent pool and TB driving the co-infection epidemic. The sub- Alliance to collaborate Saharan African region accounted for 19% New York and Geneva – The TB of all cases due to high burdens of HIV. Alliance and the Medicines Patent Pool This first global study of its kind was (MPP) have announced a Memorandum sponsored by WHO and conducted in of Understanding to encourage the collaboration with the London School development of new tuberculosis (TB) of Hygiene & Tropical Medicine and the regimens and ensure their availability in University of Bristol. It points to the need low-and middle-income countries. to improve HCV and HIV surveillance and The two organizations will work together integrated HIV/HCV services and to scale on licensing strategies for future up preventive interventions and access to tuberculosis drug regimens developed by HIV and HCV treatment. TB Alliance and promoting their uptake ►►WHO HIV News, 7 March 2016. in high burden countries. They will also Platt L, Easterbrook P, Gower E et al. collaborate on identifying promising future Prevalence and burden of HCV co-infection anti-tuberculosis compounds for licensing in people living with HIV: a global systematic opportunities and on improving access review and meta-analysis. The Lancet Infectious Diseases. Published Online: to correctly dosed, properly formulated 24 February 2016. DOI: http://dx.doi. anti-TB medicines for children. The parties org/10.1016/S1473-3099(15)00485-5. will share information with other public health organizations to develop market forecasts and intelligence. Diabetes: global action needed The agreement comes five months after Geneva – WHO has released its first UNITAID, the organization that funds the global report on diabetes, which reveals MPP, approved its expansion into the new that the number of people living with this areas of hepatitis C and tuberculosis. disease has almost quadrupled since ►►MPP Press release, 20 April 2016. 1980. In 2014 an estimated 422 million TB Alliance Press release, 18 April 2016. adults were living with diabetes, most

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of them living in developing countries. for a reduction by one third, in the next Diabetes caused 1.5 million deaths in 15 years, of the premature mortality from 2012, of which 43% occurred before the non-communicable diseases, including age of 70 years. Diabetes has far-reaching through promotion of mental health and health and socioeconomic impacts. well-being. Good management of diabetes includes ►►WHO, World Bank. Joint news release, use of a small set of generic medicines, 13 April 2016. interventions to promote healthy lifestyles, Chisholm D, Sweeny K, Sheehan P et al. patient education to facilitate self-care, Scaling-up treatment of depression and and regular screening for early detection anxiety: a global return on investment analysis. The Lancet Psychiatry. Published and treatment of complications. Insulin Online: 12 April 2016. DOI: http://dx.doi. and oral hypoglycaemic agents are org/10.1016/S2215-0366(16)30024-4. reported as available and affordable in only a minority of low-income countries. Global action is needed to halt the rise Multidrug-resistant tuberculosis: in diabetes and obesity, and to make WHO recommends shorter regimen affordable essential medicines available to Geneva –WHO has published new all people living with diabetes. recommendations to speed up the ►►WHO News release, 6 April 2016. detection and improve treatment WHO. Global report on diabetes. Geneva: outcomes for multidrug resistant World Health Organization; 2016. tuberculosis (MDR-TB) through use of a novel rapid diagnostic test and a shorter, cheaper treatment regimen. At Depression and anxiety: the less than US$ 1 000 per patient, the new investment case treatment regimen can be completed The results of a new WHO-led study show in 9–12 months, as opposed to 18–24 that investing in treatment for depression months for conventional regimens. and anxiety leads to fourfold returns in The shorter regimen is recommended terms of better health and ability to work. for patients diagnosed with uncomplicated Depression and anxiety disorders cost MDR-TB, for example those without the global economy US$ 1 trillion each resistance to fluoroquinolones and year. Between 1990 and 2013, the number injectable second-line drugs, and those of people suffering from depression and/ who have not yet been treated with or anxiety increased by nearly 50%, from second line drugs. A new diagnostic 416 million to 615 million or close to one test – called MTBDRsl – gives results on tenth of the world’s population. resistance to second-line drugs in just Governments spend on average 3% 24-48 hours, down from the 3 months of their health budgets on mental health, or longer required with other tests. This ranging from less than 1% in low-income new test has the potential to support countries to 5% in high-income countries. the appropriate use of the shortened Scaling up of mental health services treatment regimen and can thus help to is needed to achieve the Sustainable accelerate the global MDR-TB response. Development Goals target that calls ►►WHO News release, 12 May 2016.

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Malaria: push for further progress Zika: WHO identifies research and Geneva – A WHO report released on the development priorities occasion of World Malaria Day shows Geneva – International experts convened that the goal to eliminate malaria from by WHO have agreed on the research and at least 35 countries by 2030, adopted a development (R&D) priorities to protect year ago by the World Health Assembly, is pregnant women and their infants from ambitious but achievable. Many countries the consequences of Zika virus infection. are well on their way towards malaria Products to be prioritized include multiplex elimination, and malaria mortality rates tests for Zika and other flaviviruses such have declined by 60% globally since as dengue and chikungunya in addition the year 2000. However, nearly half of to more traditional tests, inactivated Zika the world’s population remain at risk of vaccines for women of childbearing age, malaria, and there is an urgent need for and innovative vector control tools that greater investment in high transmission reduce the mosquito population. settings, particularly in Africa. A number of such products are at With growing mosquito resistance to an early stage of development. WHO insecticides and parasite resistance to will propose target product profiles for antimalarials, new technologies need to vaccines and diagnostics for public be developed. As countries approach consultation. The R&D community has elimination, the ability to detect every responded vigorously to WHO’s call for infection also becomes increasingly applications under the WHO Emergency important. Further progress in the fight Use, Assessment and Listing (EUAL) against malaria will require strong procedure. A major advance compared leadership by governments of affected to the Ebola product R&D response of countries and an increase in global and 2014–2015 is the speed with which data domestic funding from currently $2.5 billion and experiences are being shared. to about $8.7 billion annually by 2030. (1) ►►WHO Note for the media, 9 March 2016.

Two UNITAID reports published ahead of 2016 World Malaria Day foresee a Ebola: no longer a public health rising demand for malaria diagnostics and emergency ; treatment through 2018, despite recent Geneva – The 9th meeting of the sharp declines in malaria prevalence International Health Regulations (IHR) worldwide. Over 400 million treatments Emergency Committee has stated that the and a vast scale-up in the market for Ebola situation in West Africa no longer malaria rapid diagnostic tests are needed constitutes a Public Health Emergency over the next three years to meet global of International Concern (PHEIC). The targets for eliminating malaria. (2) WHO Director-General has terminated ►►(1) WHO News release, 25 April 2016. the PHEIC in accordance with the International Health Regulations (2005) as (2) UNITAID Press release, 21 April 2016. well as the Temporary Recommendations UNITAID. Global Malaria Diagnostic and Artemisinin Treatment Commodities that she had issued in relation to this Demand Forecast: 2015-2018. event. The crucial need was emphasized UNITAID. Malaria Diagnostics Technology for continued international donor and and Market Landscape: 3rd Edition. technical support to prevent, detect

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and respond rapidly to any new Ebola Controlled substances outbreak in West Africa. (1) In early June WHO declared the end of A public health approach to the Ebola virus transmission in the Republic of world drug problem Guinea (2) and in Liberia (3), as 42 days New York – At the United Nations had passed from the second negative test General Assembly Special Session on the of the last person with confirmed infection. World Drug Problem held on 19-21 April ►►(1) WHO Statement, 29 March 2016. in New York, WHO highlighted the (2) WHO AFRO News release, 1st June 2016. public health dimensions of this issue. (3) WHO AFRO News release, 9 June 2016. Psychoactive drug use causes more than 400 000 deaths each year and contributes significantly to epidemics of HIV, viral Vaccination hepatitis and tuberculosis in all regions of the world. National drug policies often Recent gains and remaining gaps focus on law enforcement, with little Geneva – During World Immunization attention given to prevention, treatment Week 2016, held on 24-30 April, WHO has and harm reduction or access to controlled highlighted recent gains in immunization medicines. It is estimated that 83% of the coverage – with polio having eliminated in world’s population live in countries with one country, tetanus in three, and rubella low or non-existent access to controlled in one geographical region in 2015 – and medicines for the management of has outlined further steps that countries moderate to severe pain. (1) can take to meet global vaccination WHO’s role in promoting a public health- targets by 2020 as defined in the Global oriented approach to addressing the world Vaccine Action Plan. Immunization averts drug problem was also discussed by the 2–3 million deaths annually. However, WHO Executive Board and brought to the an additional 1.5 million deaths could be attention of the Sixty-ninth World Health averted if global vaccination coverage Assembly. (2) improves. ►►(1) WHO media centre. UNGASS 2016. Quality and use of data have been Special Session of the United Nations identified as factors that can help improve General Assembly on the World Drug vaccine coverage. In accordance with a Problem [web page]. 2015 World Health Assembly resolution (2) WHO Essential Medicines and Health Policies News, 1 March 2016. WHO has collected 1 600 vaccine price reports in what is today the largest international vaccine price database. WHO matters Prices paid for vaccines represent a large share of countries’ immunization Sixty-ninth World Health Assembly: budgets, and cost can represent a barrier setting the course for global public preventing countries from introducing new health vaccines. Geneva – Some 3 500 delegates from ►►WHO News release, 21 April 2016. WHO’s 194 Member States attended WHO. Global Vaccine Action Plan the Sixty-ninth World Health Assembly, 2011‑2020. held on 23–28 May 2016. In her opening WHO. V3P vaccine price database. speech, the WHO Director-General

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emphasized that universal health were adopted on good manufacturing coverage will be key to achieving practices for biologicals (following their health-related targets of the sustainable adoption by the Expert Committee on development agenda. Biological Standards a day earlier), good The Assembly took a number of trade and distribution practices for starting decisions related to medical products. It materials, and three other topics. adopted global health sector strategies ►►WHO Essential medicines and health on HIV, viral hepatitis and sexually products. WHO Expert Committee transmitted infections for the period on specifications for pharmaceutical 2016–2021, aiming to scale up treatment, preparations (Fiftieth report) [web page]. use of diagnostics and prevention measures in line with the targets laid down in the Sustainable Development Goals. WHO announces Phase 7 of its Delegates further agreed on a range of external assessment scheme for measures to ensure access to needed quality control laboratories medicines and vaccines, to address Geneva – WHO has announced global shortages (see also page 180), Phase 7 of its External Quality Assurance and to identify gaps in health research Assessment Scheme (EQAAS). The and development, especially for diseases Scheme was established by WHO in that disproportionately affect developing 2000 at the request of the Global Fund countries and attract little investment. as a mechanism to maximize health Resolutions were approved on the new benefits achieved on grant investments WHO health emergencies programme, the in pharmaceuticals and laboratory International Health Regulations, resilient supplies. The EQAAS has proven to be integrated health services, the Sustainable a major asset to WHO Member States. Development Goals, WHO’s engagement More than 60 laboratories across WHO’s with non-state actors, and a number of six regions have participated in past other issues. studies. Participation in comparative ►►WHO News release, 28 May 2016. external assessment studies is mandatory according to WHO’s good practices for pharmaceutical quality control laboratories New WHO medicines quality and for ISO 17025 accreditation. guidelines published The WHO EQAAS is at present the only Geneva – WHO has published the global, independent scheme to measure 50th meeting report of its Expert laboratories’ QC testing capabilities. Committee on Specifications for WHO is pleased to be able once more to Pharmaceutical Preparations. The ten offer preferential fees far below cost for annexed guidelines include five new participants from low- and middle-income texts on such important issues as good countries. For more information and data management practices, good expression of interest to participate, please pharmacopoeial practices, conducting contact WHO at [email protected]. medicines quality surveys, and provision ►►Information about EQAAS: by health professionals of children-specific WHO Essential medicines and health medicines that are not available as products. External quality assurance authorized products. Revised guidelines assessment scheme (EQAAS) [web page].

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Primaquine invited for development, evaluation and adoption of prequalification new vector control products and tools. Geneva – The WHO Prequalification PQT’s quality assurance processes, Team has published its 10th Invitation together with its close engagement with for Expression of Interest (EOI) for regulatory authorities globally, build prequalification of active pharmaceutical on WHO’s work to ensure that vector ingredients (API) and its 13th EOI for control products and pesticidal active antimalarial medicines. The two revised ingredients (for public health purposes) EOIs newly include primaquine API and are effective, safe, and meet stringent tablet formulations. quality and manufacturing standards. ►►10th Invitation to manufacturers of Active Key steps of the prequalification Pharmaceutical Ingredients (API) to submit process include assessment of product an Expression of Interest (EOI) for API dossiers, inspection of manufacturing evaluation to the WHO Prequalification sites, and supporting quality control Team: medicines. 27 April 2016. testing of products. Finally, products 13th Invitation to manufacturers of and manufacturing sites that meet antimalarial medicines to submit an Expression of Interest (EOI) for product prequalification requirements are added to evaluation to the WHO Prequalification (a) the WHO list of vector control products Team - Medicines (April 2016). or (b) the WHO list of manufacturing sites for public health pesticidal active ingredients, respectively. Prequalification of vector control Current vector control interventions face products serious challenges, including increasing Geneva – WHO has launched a new insecticide resistance, rapidly expanding temporary website for the prequalification arboviral diseases and the impact of of vector control products. Review climate change on vector distributions. functions for these products, previously To respond to these challenges, there is carried out by the Control of Neglected an urgent demand for innovative vector Tropical Diseases department, have been control products and the development of transferred to the WHO Prequalification new tools and approaches. Team (PQT). This reflects part of WHO’s ►►WHO Prequalification Team: vector control evolving approach to supporting the products (WHO PQ update, 7 June 2016).

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Upcoming events and harmonization of medical device regulation, good regulatory practices and 17th ICDRA global convergence of standards (see Registration is now open for the page 173 for more information). 17th International Conference of Drug Registration for the pre-ICDRA Regulatory Authorities (ICDRA), which will conference event is open to delegates be held at the International Convention from medicines regulatory authorities and Centre (ICC) in Cape Town, South Africa, other interested parties such as industry, on 29 November–2 December 2016. civil society, scientific institutions and non- A pre-ICDRA conference event titled governmental organizations. A registration “Patients are Waiting: How Regulators fee is applicable to delegates other than Collectively Make a Difference” will be medical products regulators. Registration convened on 27–28 November 2016 at for the 17th ICDRA is open exclusively the same venue. to delegates from medicines regulatory The 17th ICDRA will facilitate focused authorities and is free of charge. The discussions on medicines regulatory closing date for registrations is 31 August harmonization, strengthening of regulatory 2016. Early registration is encouraged. systems, regulatory preparedness around ►►17th ICDRA website, www.icdra.co.za å public health emergencies, collaboration

International Conference of Drug Regulatory Authorities (ICDRA) The 17th ICDRA will take place in Cape Town, South Africa on 27 November – 2 December 2016

Register now: www.icdra.co.za Closing date for registrations: 31 August 2016

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Consultation documents

To receive draft monographs by email please contact Mrs Wendy Bonny ([email protected]), stating that you wish to be added to the electronic mailing list.

The International Pharmacopoeia

Revision of Chapter 2.6, Non-aqueous titration

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.646, May 2016). The working document with line numbers and tracked changes is available for comment at www.who.int/medicines/areas/quality_safety/ quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

[Note from the Secretariat. As part of the activities to update The International Pharmacopoeia, mercury salts and other toxic reagents shall be replaced in order to reduce the risk to analysts and the environment. In the past, the addition of mercuric acetate has been necessary to permit the titration of halide salts of weak bases. These titrations can now be replaced by alternative procedures, notably the direct titration of the halide salts of weak bases with perchloric acid in anhydrous acetic acid or the titration of the halide salts of bases in alcoholic media with sodium hydroxide. As a first step in phasing out mercury-based methods, it is proposed to revise chapter 2.6. Non-aqueous titration. The monographs which currently prescribe the use of mercuric acetate for titrations will be gradually revised using the new recommended procedures Method A(i) and A(ii).] [Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.]

2.6. Non-aqueous titration Acids and bases have long been defined as substances that, when dissolved in water, furnish hydrogen and hydroxyl ions, respectively. This definition, introduced by Arrhenius, fails to recognize the fact that properties characteristic of acids or bases may also be developed in other solvents. A more generalized definition is that of Brönsted, who defined an acid as a proton donor, and a base as a proton acceptor. Even broader is the definition of Lewis, who defined an acid as any material that will accept an electron pair, a base as any material that will donate an electron pair, and neutralization as the formation of a coordination bond between an acid and a base. The apparent strength of an acid or base is determined by the extent of its reaction with a solvent. In aqueous solution all strong acids appear equally strong because they react with the + solvent to undergo almost complete conversion to hydronium ion (H3O ) and the acid anion. In a weakly protophilic solvent such as acetic acid, the extent of formation of the acetonium + ion (CH3COOH2 ) due to the addition of a proton provides a more sensitive differentiation of

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the strength of acids and shows that the order of decreasing strength for acids is perchloric, hydrobromic, sulfuric, hydrochloric and nitric. Acetic acid reacts incompletely with water to form hydronium ion and is therefore a weak acid. In contrast, it dissolves in a base such as ethylenediamine and reacts so completely with the solvent that it behaves as a strong acid. This so-called levelling effect is also observed for bases. In sulfuric acid almost all bases appear to be of the same strength. As the acid properties of the solvent decrease in the series sulfuric acid, acetic acid, phenol, water, pyridine and butylamine, bases dissolved in them become progressively weaker and the differences between bases are accentuated. In order of decreasing strength, strong bases of value for non-aqueous titrations are potassium methoxide, sodium methoxide, lithium methoxide and tetrabutylammonium hydroxide. Many water-insoluble compounds acquire enhanced acidic or basic properties when dissolved in organic solvents. Thus the choice of the appropriate medium and titrant permits the determination of a variety of such materials by non-aqueous titration . Further, depending upon which part of a compound is physiologically active, it is often possible to titrate that part by proper selection of solvent and titrant. The types of compounds, in a non-aqueous medium, that may be titrated as acids, by usually lithium methoxide or tetrabutyl ammonium hydroxide, include acid halides, acid anhydrides, carboxylic acids, amino acids, enols such as barbiturates and xanthines, imides, phenols, pyrroles and sulfonamides. The types of compounds, in a non- aqueous medium, that may be titrated as bases, by perchloric acid, include amines, nitrogen- containing heterocyclic compounds, quarternary ammonium compounds, alkali salts of organic acids, alkali salts of inorganic acids and some salts of amines. Many halide salts of weak bases and some quaternary ammonium compounds may be directly titrated in acetic anhydride using, preferably, potentiometric end-point detection or an indicator such as malachite green or crystal violet. In the titration of a basic compound amphiprotic solvents which have both protophilic and protogenic properties (e.g. acetic acid and the alcohols), which dissociate to a slight extent, are used as the medium. When acetic acid or acetic anhydride (halide salts of weak bases and quaternary ammonium compounds) is the medium, a volumetric solution of perchloric acid in glacial acetic acid may be used. When ethanol is used as the medium for halide salts of weak bases the titrant is a volumetric solution of sodium hydroxide. In the titration of an acidic compound a volumetric solution of lithium methoxide in a methanol-toluene solvent is often used. For many applications it is convenient to use a solution of tetrabutylammonium hydroxide in toluene; sodium methoxide, formerly in wide use, may often give rise to troublesome gelatinous precipitates. Because of interference by carbon dioxide, solvents for acidic compounds must be protected from excessive exposure to the atmosphere by a suitable cover or by an inert atmosphere during the titration. A blank determination should be carried out and the volume generally should not exceed 0.01 mL of a 0.1 mol/L titrant for each mL of solvent. The end-point may be determined visually by colour change or preferentially by potentiometry. If the calomel reference electrode is used it is advantageous to replace the aqueous potassium chloride solution in the salt bridge with lithium perchlorate/acetic acid TS for titrations in acidic solvents, or potassium chloride in methanol for titrations in basic solvents. It should be recognized that certain indicators in common use (crystal violet, for example) undergo a series of colour changes and, in establishing a non-aqueous titration method for a particular use, care should be taken to ensure that the colour change specified as the end-point of the titration

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corresponds to the maximum value of dE/dV (where E is the electromotive force and V the volume of titrant) in a potentiometric titration of the substance under consideration. When using titrants prepared with solvents that may have a relatively high coefficient of expansion, for example, glacial acetic acid, toluene, etc., care should be taken to compensate for differences in temperature that may exist between the time the titrant is used and that at which it was standardized.

Recommended procedures Method A (i) – for halide salts of organic bases Dissolve a quantity of the substance being examined to give an expected titration volume of between 70–90% of the burette volume, in 50 mL of dehydrated ethanol R and 5.0 mL of hydrochloric acid (0.01 mol/L) VS. Carry out a potentiometric titration using sodium hydroxide (0.1 mol/L) VS. Read the volume added between the two points of inflexion.

Method A (ii) – for bases, their salts and quaternary ammonium compounds Prepare a solution as specified in the monograph or dissolve the substance being examined in a suitable volume of medium (anhydrous acetic acid R1 or acetic anhydride R with or without the addition of formic acid R or dioxan R). The titration blank for the medium is to be established in a separate determination. When the end- point is determined visually by colour change, add 2–3 drops of crystal violet/acetic acid TS and titrate with perchloric acid of the specified concentration (mol/L) to the appropriate colour change of the indicator. When a different indicator is specified in the monograph this indicator should also be used for the neutralization of the medium and the standardization of the titrant. When the equivalence point is determined potentiometrically the indicator is omitted and neutralization of the medium and standardization of the titrant are also carried out potentiometrically. A glass electrode and a saturated calomel cell (containing potassium chloride (350 g/L) TS) as reference electrode are used. The junction between the calomel electrode and the titration liquid should have a reasonably low electrical resistance and there should be a minimum of transfer of liquid from one side to the other. Serious instability may result unless the connections between the potentiometer and the electrode system are in accordance with the manufacturer’s instructions.

When the temperature (t2) at which the titration is carried out differs from the

temperature (t1) at which the titrant was standardized, multiply the volume of the titrant

required by [1 + 0.001 (t1 – t2)] and calculate the result of the assay from the corrected volume.

Method B (for acids) The titrant, solvent and (in the case where the end-point is determined visually) the indicator to be used for each substance, are specified in the monograph. Protect the solution and titrant from carbon dioxide of the atmosphere throughout the determination. This may conveniently be done by replacing the air above the titration liquid with nitrogen.

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Dissolve the substance being examined in a suitable volume of the solvent previously neutralized to the indicator, warming and cooling if necessary, or prepare a solution as specified in the monograph. Titrate to the appropriate colour change of the indicator. Carry out a blank determination and make any necessary corrections. The titrant is standardized using the same solvent and indicator as specified for the substance. When the equivalence point is established potentiometrically the indicator is omitted and neutralization of the solution and standardization of the titrant are also carried out potentiometrically. A glass electrode and a saturated calomel reference electrode in which the aqueous potassium chloride (350 g/L) TS has been replaced by a saturated solution of potassium chloride R in methanol R are used. The junction between the calomel electrode and the titration liquid should have a reasonably low electrical resistance and there should be a minimum of transfer of the liquid from one side to the other. Serious instability may result unless the connections between the potentiometer and the electrode system are made in accordance with the manufacturer’s instruction.

***

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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 March 2016. Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 September 2016. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2017 version of the ATC/DDD Index.

New ATC 5th level codes 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 (18F) 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 Continued

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Temporary

New ATC 5th level codes (continued) ATC level name/INN ATC code 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 inhibitor 31) g P J01DI54 dalbavancin 1.52) g P J01XA04 doxofylline 0.8 g O,P R03DA11 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 R03DX093) posaconazole 0.3 g P J02AC04 sebelipase alfa 5 mg P A16AB14 tiopronin 0.8 g O G04BX164)

* Administration Route: O=oral; P=parenteral 1) Refers to ceftolozane 2) Course dose 3) ATC code changed from L04AC06, new code valid from January 2017 4) 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

WHO Collaborating Centre Oslo, May 2016

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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 October 2015. 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 aceneuramic acid M09AX05 alectinib L01XE36 alirocumab C10AX14 aminobenzoate potassium D11AX23 arterolane and piperaquine P01BX02 carvedilol and ivabradine C07FX06 cobimetinib L01XE38 daratumumab L01XC24 deoxycholic acid D11AX24 desfesoterodine G04BD13 edoxaban B01AF03 elbasvir and grazoprevir J05AX68 elotuzumab L01XC23 eluxadoline A07DA06 empegfilgrastim L03AA16 etelcalcetide H05BX04 ferric maltol B03AB10 fluoroethyl-L-tyrosine (18F) V09IX10 follitropin delta G03GA10 gallium (68Ga) endotreotide V09IX09 inotuzumab ozogamicin L01XC26 ixekizumab L04AC13 landiolol C07AB14 metoprolol and ivabradine C07FX05 metreleptin A16AA07 mogamulizumab L01XC25 osimertinib L01XE35 phenylephrine and ketorolac S01FB51 rociletinib L01XE37 safinamide N04BD03 salbutamol and beclometasone R03AK13 talimogene laherparepvec L01XX51 tiazotic acid C01EB23 tramadol and dexketoprofen N02AJ14 trientine A16AX12

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Final

New ATC level codes (other than 5th levels) ATC level name ATC code Beta blocking agents, other combinations C07FX Glucagon-like peptide-1 receptor (GLP-1) analogues A10BJ Opioids in combination with non-opioid analgesics N02AJ Sodium-glucose co-transporter 2 (SGLT2) inhibitors A10BK

Change of ATC codes ATC level name/INN Previous ATC code New ATC code albiglutide A10BX13 A10BJ04 canagliflozin A10BX11 A10BK02 dapagliflozin A10BX09 A10BK01 dulaglutide A10BX14 A10BJ05 empagliflozin A10BX12 A10BK03 exenatide A10BX04 A10BJ01 liraglutide A10BX07 A10BJ02 lixisenatide A10BX10 A10BJ03 mepolizumab L04AC06 R03DX09 methotrexate L01BA01 L04AX03 1) nonacog alfa B02BD09 B02BD04 2) tiopronin R05CB12 G04BX16 trenonacog alfa B02BD12 B02BD04 2)

1) Splitting of ATC code. Only the classification of pre-filled syringes of methotrexate for use in non-cancer indications is changed. These products will be moved to the existing ATC code for oral administered product of methotrexate. Parenteral preparations used for treatment of cancer will remain in L01BA01. 2) Existing ATC code B02BD04 coagulation factor IX

Change of ATC level names Previous New ATC code atenolol and other atenolol and nifedipine C07FB03 antihypertensives Beta blocking agents and Beta blocking agents, other combinations C07F other antihypertensives Beta blocking agents, Beta blocking agents and calcium channel C07FB selective, and other blockers antihypertensives bisoprolol and other bisoprolol and amlodipine C07FB07 antihypertensives nebivolol and other nevibolol and amlodipine C07FB12 antihypertensives oxycodone, combination oxycodone and naloxone N02AA55

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Final

Change of ATC code and/or ATC level name based on new ATC 4th levels established Previous ATC code and level name New ATC code and/or level name C07FA Beta blocking agents, Deleted non-selective, and other antihypertensives C07FX Beta blocking agents, other combinations C07FA05 propranolol and other C07FX01 propranolol and other antihypertensives combinations C07AA57 sotalol, combinations C07FX02 sotalol and acetylsalicylic acid C07AB52 metoprolol, combinations C07FX03 metoprolol and acetylsalicylic acid C07FB02 1) metoprolol and other C07FB02 metoprolol and felodipine 2) antihypertensives C07FB13 metoprolol and amlodipine C07AB57 bisoprolol, combinations C07FX04 bisoprolol and acetylsalicylic acid N02AJ Opioids in combination with non-opioid analgesics N02AA58 3) dihydrocodeine, combinations N02AJ01 4) dihydrocodeine and paracetamol N02BE51 3) paracetamol, combinations excl. psycholeptics N02AA58 3) dihydrocodeine, combinations N02AJ02 4) dihydrocodeine and N02BA51 3) acetylsalicylic acid, acetylsalicylic acid combinations excl. psycholeptics N02AA58 3) dihydrocodeine, combinations N02AJ03 4) dihydrocodeine and other non- opioid analgesics N02AA59 3) codeine, combinations excl. N02AJ06 4) codeine and paracetamol psycholeptics N02BE51 3) paracetamol, combinations excl. psycholeptics N02AA59 3) codeine, combinations excl. N02AJ07 4) codeine and acetylsalicylic acid psycholeptics N02BA51 3) acetylsalicylic acid, combinations excl. psycholeptics N02AA59 3) codeine, combinations excl. N02AJ08 4) codeine and ibuprofen psycholeptics M01AE51 3) ibuprofen, combinations N02AA59 3) codeine, combinations excl. N02AJ09 4) codeine and other non-opioid psycholeptics analgesics N02AX52 tramadol, combinations N02AJ13 tramadol and paracetamol N02AA55 3) oxycodone, combinations 5) N02AJ17 4) oxycodone and paracetamol paracetamol, combinations N02BE51 3) excl. psycholeptics Continued

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Final

Change of ATC code and/or ATC level name based on new ATC 4th levels established (continued) Previous ATC code and level name New ATC code and/or level name N02AA55 3) oxycodone, combinations 3) N02AJ18 4) oxycodone and acetylsalicylic N02BA51 3) acetylsalicylic acid, acid combinations excl. psycholeptics N02AA553) oxycodone, combinations 3) N02AJ19 4) oxycodone and ibuprofen 1) Splitting of ATC code in connection with alterations in C07FX 2) Existing ATC code 3) Splitting of ATC codes according to contents of the different fixed combinations of opioids and other analgesics. The ATC codes in N02AA, N02BA51, N02BE51 and M01AE51 will be maintained for other combinations. 4) Combinations with opioids and other analgesics currently classified in the following ATC codes N02AA55, N02AA58, N02AA59 will be moved to the new ATC 4th level N02AJ. All the existing combination codes will be kept in N02AA since there may be other combinations without analgesics available (e.g. oxycodone and naloxone will remain in N02AA55). The ATC classification of all low dose combinations products of codeine or dihydrocodeine (<20 mg dose) currently classified in N02B or M01A will be altered to the new ATC codes in N02AJ. 5) Combinations of oxycodone and naloxone will be maintained in N02AA55.

New DDDs ATC level name/INN DDD unit Adm.R* ATC code alirocumab 5.4 mg P C10AX14 apremilast 60 mg O L04AA32 ataluren 2.8 g O M09AX03 calcium acetate 6 g O V03AE07 cangrelor 50 mg P B01AC25 defibrotide 1.75 g P B01AX01 edoxaban 60 mg O B01AF03 elosulfase alfa 20 mg P A16AB12 ferric citrate 6 g O V03AE08 furazidin 0.3 g O J01XE03 iloperidone 18 mg O N05AX14 insulin degludec and liraglutide 40 U 1) P A10AE56 mifepristone, combinations 0.2 g 2) O G03XB51 naloxegol 25 mg O A06AH03 rifapentine 0.11 g O J04AB05 safinamide 75 mg O N04BD03 secukinumab 10 mg P L04AC10 tedizolid 0.2 g O,P J01XX11

* Administration Route: O=oral; P=parenteral 1) Refers to insulin degludec 2) Refers to mifepristone

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Final

Change of DDD ATC level name/INN Previous DDD New DDD ATC code DDD Unit Adm.R.* DDD Unit Adm.R.* ampicillin and enzyme inhibitor 2 g1) P 6 g1) P J01CR01 Blood coagulation factors 2) Deleted 2) B02BD mifepristone 0.6 g O 0.2 g O G03XB01 * Administration Route: O=oral; P=parenteral 1) Refers to ampicillin 2) DDDs for the various blood coagulation factors in all ATC 5th level codes in B02BD are deleted. No new DDDs will be established in B02BD Blood coagulation factors.

WHO Collaborating Centre Oslo, May 2016 å

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