1. Regulatory issues, including ICDRA IPC Meeting, 16-17 December 2014. Washington D.C., United States Dr Lembit Rägo Head Regulation of Medicines and other Health Technologies Essential Medicines and Health Products World Health Organization Geneva, Switzerland E-mail: ragol@who.int

2. 2 |2 | Content Restructuring in WHO – one single unit for all health product streams with four specific activity oriented teams Major landmarks in Global regulatory scenery Regulators and emergency response WHA resolutions and ICDRA Concluding remarks Disclaimer. The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and not necessarily those of the World Health Organization

3. 3 |3 | Essential Medicines and Health Products [EMP] Policy, Access and Use [PAU] Regulation of Medicines and other Health Technologies [RHT] Technologies Standards and Norms [TSN] Regulatory Systems Strengthening [RSS] Prequalification Team [PQT] Safety and Vigilance [SAV] Public Health, Innovation and Intellectual Property [PHI] New structure of Department of Essential Medicines & Health Products. RHT unit covers medicines, biologicals including vaccines and blood products, and medical devices with focus on in vitro diagnostics More at: http://www.who.int/medicines/en/

4. 4 |4 | WHO Ebola pages health products part

5. 5 |5 | Globalization and diseases Emergencies involving emerging diseases (SARS, MERS, H1N1…, Ebola) is a Global issue. No geographic area is immune – reduced flying times/better connections brings it to all of us When crisis is over – could WHO convene a group to look at the lessons from not only Ebola, but also other recent experiences, to see what WHO did and did not do well, what affected NRAs did and did not do well, and what non-immediately affected NRAs did and did not do well …

6. 6 |6 | How to better respond to challenges like Ebola? Good news – good cooperation between concerned regulators and WHO (US FDA, EMA, Swissmedic, HC, African regulators from affected countries – AVAREF etc.) The issue of clinical data confidentiality and study plan confidentiality in light of an epidemic. Companies have been open, the agencies still reluctant …Need for WHO guidance on planning, executing, and transparency of clinical trials/data in epidemic situations as a guide to expected behavior by member states and companies in epidemic situations? “Emergency listings/approvals” to allow use in the affected countries. Likely real “learning” about these products will come outside the clinical trials environment. But who’s responsible for that and who is assuring that the necessary structures are there?

7. 7 |7 |  WHO is mandated to “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products” (Article 2, WHO Constitution); the work is at large focusing on specific topics not address by other parties and complimentary to other standard setting initiatives  WHO Expert Committee on Specifications for Pharmaceutical Preparations  WHO International Working Group on International Nonproprietary Names (also for biologicals)  WHO Expert Committee on Biological Standardization …  Joint FAO/WHO Expert Committee on Food Additives Standards and WHO

8. 8 |8 | WHO global standards and norms – what are they? http://www.who.int/biologicals/biotherapeutics/en/ Global written standards Global measurement standards standards INNs Measurement standards: tools for product development, licensing and lot release A single name for a substance for use globally (more than 8000 names assigned)

9. 9 |9 | WHO global standards - current portfolio Pharmaceutical Preparations approximately 75 written standards approximately 240 International Chemical Reference Substances a total of 700 specifications and test requirements in the International Pharmacopeia Biologicals approximately 70 written standards approximately 300 international Biological Reference Substances

10. 10 | 2010201120122013 Development of written standards for biologicals ECBS 2010 - 2014 Cell substrates (TRS 978) YFV (TRS 978) Hep B (TRS 978) Vaccine lot release (TRS 978) Dengue (TRS 979) BCG (TRS 979) aP (TRS 979) OPV (TRS 980) D, T + Combos (TRS 980) Malaria (TRS 980) JE LA (TRS 980) Nonclinical evaluation of adjuvanted vaccines (new) Biologicals derived by rDNA tech (revised) Typhoid conjugate vaccines (new) Strategic plan for blood and blood products (revised) IPV (revision of TRS 926) Manufacturing Changes (new) Regulatory Risk Assessment (new) 2014

11. 11 | http://www.who.int/biologicals/biotherapeutics/similar_biotherapeutic_products/en/

12. 12 | Collaboration in making regulatory guidelines: Good Review Practices Proposal from APEC to WHO/ECSPP and WHO/ECBS to develop a Guideline on GRevP Such a guideline would be the first of its kind globally, addressing an important gap ECSPP/ECBS agreed to collaborate with APEC to develop draft GRevP guidelines Global consultation process completed in 2014, and guideline adopted by WHO ECSPP

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14. 14 | https://extranet.who.int/sree/Reports?op=vs&path=/WHO_HQ_Reports/G4/PROD/EXT/Design%201.1 http://apps.who.int/prequal/trainingresources/training_EMP_table.htm http://apps.who.int/prequal/trainingresources/training_EMP_table_2.htm http://www.who.int/medicines/training/qsm_training/en/

15. 15 | Increased Collaboration: WHO Prequalification inspections' group has increased steadily International Collaboration Share the workload and promote avoiding duplicative inspections. Facilitation of harmonization through joint inspections and sharing of outcomes. Capacity building of NMRAs inspectors. Facilitating use of WHO-PQ inspection results in national regulatory environment for information and decision making. Mainly EU Inspectorates EAC NMRAs Joint Inspections PICS Inspectorates Independent Experts Co- inspectors Host country inspectorates Recipient country NMRAs Observers USFDA, EMA, TGA, WHO EU NCAs (UK, FR, IT, GER, IR) EDQM International API inspection Collaboration Teleconferences Joint investigations Coordinated actions, press releases Collaboration in handling GMP related crises

16. 16 | AVAREF-African Vaccine Regulatory Forum An informal network approach to regulation of clinical trials in Africa National Regulatory Authority Ethics Committees Representation: 19 countries target for CT of HIV, Malaria, TB, meningitis vaccines Scope Regulation of medicines Regulation of vaccines Regulation of clinical trials Support from USFDA, Health Canada, European regulators New vaccines in clinical development presented by sponsors/Vaccine developers Recognized and supported by donors as an efficient platform Informal structure allows rapid and dynamic response as per needs identified Currently working on formalization process

17. 17 | World Health Assembly 2014 resolution WHA67.21 on biotherapeutic products

18. 18 | http://apps.who.int/gb/e/e_wha67.html WHA67.21 Urges Member States: (1) to develop or strengthen, as appropriate, national regulatory assessment and authorization frameworks, with a view to meeting the public health needs for biotherapeutic products, including similar biotherapeutic products; (2) to develop the necessary scientific expertise to facilitate development of solid, scientifically-based regulatory frameworks that promote access to products that are affordable, safe, efficacious and of quality, taking note of the relevant WHO guidelines that may be adapted to the national context and capacity; (3) to work to ensure that the introduction of new national regulations, where appropriate, does not constitute a barrier to access to quality, safe, efficacious and affordable biotherapeutic products, including similar biotherapeutic products;

19. 19 | WHA67.21 REQUESTS the Director-General of WHO: (1) to support Member States in strengthening their capacity in the area of the health regulation of biotherapeutic products, including similar biotherapeutic products; (2) to support, as appropriate, the development of national regulatory frameworks that promote access to quality, safe, efficacious and affordable biotherapeutic products, including similar biotherapeutic products; (3) to encourage and promote cooperation and exchange of information, as appropriate, among Member States in relation to biotherapeutic products, including similar biotherapeutic products; (4) to convene the WHO Expert Committee on Biological Standardization to update the 2009 guidelines, taking into account the technological advances for the characterization of biotherapeutic products and considering national regulatory needs and capacities

20. 20 | Where we are with medicines regulatory systems today? WHO has developed a comprehensive Assessment Tool for National Regulatory Authorities with objectives: 1. To identify gaps and help to develop institutional development plans 2. In conjunction with vaccines prequalification: as a pre- condition of prequalification The attached publication from 2010 is a good example of this work and available also on web site. Note. Each study published is out of date in certain details and progress has been made since assessments in several countries

21. 21 | Regulatory system strengthening for medical products WHA67.20

22. 22 | WHA67.20 Urges Member States, among others: 1) to strengthen national regulatory systems, including – as appropriate and voluntarily – by: (a) undergoing self-evaluations, including with WHO support, to identify the strengths and opportunities for improvement in regulatory system functions, as a first step towards formulating plans for regulatory system strengthening, including through WHO-coordinated institutional development plans; … (e) developing needed competencies as an integral part of, although not limited to, the health workforce, and encouraging the development of the regulatory field as a profession; (f) facilitating the use of relevant guidance and science-based outputs of WHO expert committees and good regulatory practices at the national, regional and international levels; … (2) to engage in global, regional and subregional networks of national regulatory authorities, as appropriate, recognizing the importance of collaboration to pool regulatory capacities to promote greater access to quality, safe, efficacious and affordable medical products; (3) to promote international cooperation, as appropriate, for collaboration and information sharing, including through electronic platforms; … (10) to identify the need to strengthen regulatory system capacity, collaboration and cooperation in the technically complex areas where substantial gaps may still exist, such as the regulation of biotherapeutic products, blood products, and in vitro diagnostics;

23. 23 | WHA67.20 REQUESTS the Director-General of WHO, among others: (1) to continue to support Member States upon their request in the area of regulatory system strengthening, including, as appropriate, by continuing to: (a) evaluate national regulatory systems; … (e) provide technical support to national regulatory authorities and governments; (2) to continue to develop appropriate norms, standards and guidelines, including taking into account national, regional and international needs and initiatives, in accordance with WHO principles; … (5) to promote the greater participation of Member States in existing international and regional initiatives for collaboration and cooperation in accordance with WHO principles and guidelines; … (10) to increase support and guidance for strengthening the capacity to regulate increasingly complex biological products with the focus on biotherapeutic products, blood products and associated in vitro diagnostics, and, where appropriate, on new medicines for human use based on gene therapy, somatic-cell therapy and tissue engineering;

24. 24 | Harmonization and convergence of regulatory requirements: creating basis for regulatory cooperation Objective of drug regulation: TO IMPROVE AND PROMOTE PUBLIC HEALTH Harmonization/convergence is aimed to diminish duplicative efforts, creates "common language", can facilitate cooperation and access to medicines In case of harmonization/convergence of regulations the main objective should be: –MEASURABLE PUBLIC HEALTH GAINS There may be other gains, but these should be in the centre

25. 25 | Harmonization and convergence initiatives Inter-regional, regional and sub-regional – ICH, IPRF, APEC, Pan American Network for Drug Regulatory Harmonization (PANDRH), ASEAN, SADC, EAC (part of AMRHI), Gulf Cooperation Council, IGDRP etc. Not harmonized! – Good Harmonization Practice (GHP) needed? –Different organization – with or without strong secretariat –Different involvement of industries and other parties –Different in terms of implementation – some focused on implementation, others rather focused on convergence of regulatory thinking and eduction –Different focus technical areas/products –…

26. 26 | Key elements of success (1) Enabling environment and foundation –Good Governance principles implemented –Modern legal systems allowing certain flexibilities Political will and shared common vision Similar socioeconomic development of participating countries Participants functional regulatory authorities with necessary capacity and resources available

27. 27 | Key elements of success (2) Willingness to invest into harmonization and convergence Effective governance and secretariat Willingness to cooperate and compromise Commitment for implementation and updating/revision Commitment for applying Good Regulatory/Review Practice principles when implementing …

28. 28 | Timely access to better (hopefully) medicines ladder. Where the cooperation and reliance on work done by other regulators fits in? Good Decision Making Practices Good Review Practices based on CTD, alignment and effective cooperation and worksharing Harmonization and convergence of technical requirements in conjunction with harmonized training principles and model core curricula for regulators Applicable modern laws and enabling legal system General Good Governance in Public Sector, including transparency and accountability

29. 29 | Regulatory co-operatio n In nowadays complex and interlinked World with rapidly advancing science not a single regulator can operate in isolation, or cope with all the work to be done –Regulators have ONE common thing across small and big – all complain about lack of resources Cooperation can be passive/receiving and active/contributing Cooperation can be institutionalized and legally mandated or voluntary Whatever the option/s cooperation enables saving resources and making more QUALITY DECISIONS

30. 30 | Experiences of success EU experiences – few regulators from 28 MS take the active lead but all benefit (harmonization and legal framework major enabling factor) EAC and ZaZiBoNa in Africa Joint reviews of clinical trial applications/products across borders –AVAREF –Medicines Prequalification Programme jointly with EAC regulators Promoting international harmonized standards and good review by staff exchange –Medicines prequalification has a 3 months rotational fellow position for quality assessors has lead to local subregional activities of cooperation; SA 1 st API rotation, Inspectors rotation - China

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32. 32 | Collaboration and cooperation in ICDRA 14 th ICDRA recommendations in 2010 for Medicines Regulatory Authorities in Singapore:  Take account of one another’s work with a view to improving the efficiency of the global regulatory system.  Commit resources to form cooperative networks based on uniformity of standards and inspection systems.  Engage with regional and international initiatives promoting harmonization, information sharing and use of data generated by other regulators as a tool for improving timely access to medicines and medical products.

33. 33 | Collaboration is a necessity, not nicessety. Next ICDRA will be hosted by an African country in 2016! http://www.anvisa.gov.br/hotsite/icdra/index.html#

34. 34 | http://www.who.int/medicines/areas/quality_safety/ regulation_legislation/icdra/en/

35. 35 | 16th ICDRA sessions

36. 36 | Plenary 4 Strengthening regulatory systems for medical products Recognize that effective regulatory systems are an essential component of health system strengthening that contribute to better public health outcomes; that regulators are an essential part of the health workforce; and that inefficient regulatory systems themselves can be a barrier to access safe, effective and quality medical products. Strengthen WHO’s role in strengthening regulatory systems for medical products from a public health perspective, and in supporting national drug regulatory authorities and relevant regional bodies in this area, and in particular in developing countries. Support the development and strengthening of national regulatory systems through the assessment of regulatory functions and system performance with WHO support, and the development and implementation of institutional development plans that will protect and promote health at the national level, and will pool and leverage regulatory capacity regionally and globally to promote access to quality, safe and efficacious and affordable medical products

37. 37 | Concluding remarks