Dr Samvel Azatyan Manager Medicines Regulatory Support Programme

1. WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies 16-20 November 2009, WHO HQ, Geneva, Switzerland Medicines Regulatory Overview Dr Samvel Azatyan Manager Medicines Regulatory Support Programme Quality Assurance and Safety: MedicinesEssential Medicines and Pharmaceutical PoliciesWorld Health OrganizationE-mail: azatyans@who.int

2. Medicines as an instrument of public health • Medicines regulation is the totality of all measures - legal, administrative and technical - which governments take to ensure the safety, efficacy and quality of medicines, as well as the relevance and accuracy of product information • Medicines are produced and sold primarily "for business" • Many pharmaceutical companies are shareholders companies; • Under law the shareholders companies are OBLIGED to earn profit for shareholders.

3. Main reasons for regulating medicines • As a rule, patients are not able to make independent judgement about of the QUALITY, SAFETY and EFFICACY • Even doctors and pharmacists have difficulties, unless specially trained! • “…. drugs are a public good and not simply just another commodity: first for their high social value, and then because consumers and prescribers are unable to assess their quality, safety and efficacy.” Dr G.H. Brundtland, Former Director General of WHO

4. Main reasons for regulating medicines Consequences of under-regulation (weak regulatory capacity) • irrational consumption and prescription; • substandard, counterfeit, harmful, useless drugs on the market. Consequences of over- or improper regulation • shortage of needed medicines or delayed access; • increased costs of medicines due to cost of regulatory system; • lack of regulatory flexibility.

5. Rationale for Government role • Public health and safety concerns have obligedgovernments to intervene in the activities of the pharmaceutical sector; • In this context, medicines regulation is a public policy that restricts private sector activitiesin order to attain social goals set by the State; • Medicines regulation is done through National Medicines Regulatory Authorities (NMRAs).

6. Medicines regulatory authority Medicines regulatory authority means a network (institution) that administers the full spectrum of drug regulatory activities, including at least the following functions: • Marketing authorization for new products and variation of existing authorizations; • Quality control laboratory testing; • Adverse drug reaction monitoring; • Provision of drug information and promotion of rational drug use; • Good Manufacturing Practice (GMP) inspections and licensing of manufacturers, wholesalers and other distribution channels; • Enforcement operations; • Monitoring of Drug Utilization.

7. Principles of medicines regulation Regulation should: • Have patient in its centre; • Be evidence based; • Be risk oriented; • Bring added value; • Respect interests of stakeholders and real possibilities; • Be transparent but respect confidentiality; • Be effective and flexible; • Be part of broader drug policy.

8. Principles of medicines regulation …also keep in mind, that: • Regulations must be attuned to available resources (financial, technical, human, etc.); • Provisions that are developed and successfully implemented in one country may not be equally successful in another country, due to their complexity and lack of adequate resources; • The public health implications of application of guidelines of greater technical complexity should be considered.

9. Regulation of innovator products and multisource (generic) products • For innovator products proof of QUALITY, SAFETY and EFFICACY is needed. • For multisource products QUALITY, safety and efficacy data is referred to the originator, providing only evidence of INTERCHANGEABILITY (bioequivalence, clinical testing, in certain cases dissolution data).

10. Data required for regulatory approval Innovative medicine Experimental data/ Literature Clinical data Generic medicine Multisource interchangeable Proof of interchangeability Preclinical data Pharmaceutical data Pharmaceutical data Administrative and summarizing data, including GMP

11. Differences in regulatory capacity 193 WHO Member States: For various reasons, many regulatory authorities do not have the full capacity to perform all regulatory functions.

12. Critical issues in regulation • Not all regulatory functions are performed due to chronic shortages of human and technical resources; • Different institutional arrangements exist for the regulation of medicines; Weak regulatory frameworks and lack of enforcement can lead to various bottlenecks limiting access to essential medicines.

13. Main challenges in regulation • Increasing complexity of regulatory work (new technologies, globalization of commerce, internationalization of product development); • Concerns among civil society regarding the increasing autonomy of management and decision-making in regulatory systems; • Greater interaction between regulators and regulated private sector in the development of standards and regulations; • Regulators are perceived as an additional burden to access to new therapies (!);

14. Main challenges in regulation • Increasing difficulty for regulators to make fare balance between potential risks involved with new medicines and increasing public expectations for the safety of medicines; • Greater access to information and demand for quality information; • Increasing number of borderline products with health claims; • The gaps among regulatory systems of WHO Member States are rather increasing than decreasing.

15. Strategies used to cope with increasing demands • Concentration on priority issues most relevant for public health (risk-benefit approach); • Co-operation with partners in order to increase regulatory capacity by elimination of duplicated activities • Facilitated by comparable standards and administrative requirements; • Increased effectiveness of internal operations • Quality systems, international benchmarking.

16. Performance of core regulatory functions Core functions • Country Level: • Country A • Country B • Country C • … Sub-regional or regional level:

17. Faster access to medicines through sharing of regulatory information • WHO is working with regulators to find out how best to build confidence in regulatory decisions taken by other regulators, including -- how to facilitate exchange of consolidated information about assessments and inspections.

18. Sharing of expertise vs. recognition of decision Acceptance of expertise is not equal to acceptance of decision • Acceptance of decision • is formal legal act, frequently requiring international treaties • may modify liabilities of involved parties and requires legal specification of acceptance and non-acceptance • Acceptance of expertise • is sovereign and complex regulatory decision of NRA based on scientific arguments and confidence • may be applied case to case • is followed by formal independent decision according to national legislation and mandate of national MRA

19. Sharing of expertise vs. recognition of decision • If trustful expertise is available, not to consider it may be unjustified waste of resources needed elsewhere • Accepting the expertise of other regulators is complex regulatory and scientific decision, depending on • legislation, mandate • capacities and competence available for given issue • scientific arguments related to benefit/risk for public health • priorities for protection of public health • Understanding to limitations of transfer of expertise and its proper management are needed when considering expertise of others.

20. New regulatory pathways Smaller or less resourced regulatory authorities often rely on the approvals or opinions issued by the well-resourced regulatory authorities • Concern - risks/benefits balance in developing countries may be in some cases different from those in developed countries.. • However, the consideration of the assessments done by well resourced MRAs is a much better option than no guidance at all, or poor quality assessment.

21. New regulatory pathways Examples of this type of initiatives include, but are not limited to: • WHO PQP - HIV/AIDS, TB, malaria, RH, paediatric therapy • US PEPFAR - HIV/AIDS • EU Article 58 – assessment of products for use outside the European Union • Canada's Access to Medicines Regime – assessment of products according to WHO Model List of Essential Medicines • Other - orphans, paediatric therapy

22. Employing internationally accepted guidelines adapted to suit local needs/circumstances Three types of the guidelines and other normative documents are available for regulators: • National; • Regional (e.g., EU, ASEAN, SADC, etc.); • International (WHO, ICH).

23. WHO guidelines are available on most of the technical requirements for generic products WHO is mandated to “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products” (Article 2, WHO Constitution); WHO major initiatives to improve medicines quality and to promote global regulatory mechanisms: • International nonproprietary names for pharmaceutical substances; • International Pharmacopoeia; • WHO GMP guidelines; • WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce.

24. WHO Medicines Regulatory Package • A collection of tools aimed at supporting the work and decision making processes of National Medicines Regulatory Authorities (NMRAs) • This package contains: • Tools on the establishment and organisation of NMRAs; • Tools on the definition of requirements and guidance for their implementation; • Guidance on performance of the regulatory functions of NMRAs; • Training materials for NMRAs.

25. WHO Medicines Regulatory Package

26. Content of medicines regulatory package • Pharmacy practice • Advertisement and drug promotion • Rational use • Disposal of pharmaceuticals • Risk management • Information technologies • Control of narcotics and psychotropic substances • International cooperation and harmonization • Pharmacopoeia • Medical device regulation • Intellectual property rights • Medicines regulation and policies • Regulatory inspection • Drug control laboratory • Good regulatory practices (GRP) • Non-clinical and clinical trials • Starting materials • Manufacturing • Marketing authorization and product registration • Importation • Storage and distribution • Pharmacovigilance • Post-marketing surveillance

27. WHO approaches for regulatory support • Developing evidence - assessments of regulatory systems worldwide (around 50 NMRAs assessed in all 6 regions); • Providing direct technical support (capacity building, tools and guidance) to regions and countries (with PQ and IVB); • Stimulating / initiating collaboration between regulators from various countries on various regulatory activities ("North-South" and "South-South"); • Facilitating the establishment of "Centres of excellence" for regulatory affairs; • Promoting harmonization.

28. Harmonization – what does it mean? In a broad sense harmonization means harmonization of technical requirements for medicines regulation, i.e., legislations, guidelines, procedures, etc. • These requirements relate to the quality, safety and efficacy of the medicinal products, • These requirements could differ in complexity, from one type of marketing authorization application to another.

29. What we do mean under Harmonization? • True harmonization goes further than just common documentation; • It requires effective communication and collaboration aimed at building capacity and trust (e.g., information sharing, recognition and joint working); • In combination, these activities can lead to similar or collaborative approaches to drug registration • Paving the way for mutual recognition and/or centralized registration (if desired) in the longer-term

30. What we do not mean under Harmonization? Harmonization does not need to mean a loss of national sovereignty / autonomy (and certainly not in the early stages) • Common documentation merely stipulates the requirements for registration • Better communication enables countries to chose which information they will use • Collaborative mechanisms, such as joint assessments or inspections, does not imply collaborative decision-making In all cases the registration decision itself stays firmly in the hands of sovereign nations

31. Why the harmonization is needed? Formation of effective networks between regulatory authorities nationally and internationally may: • Facilitate sharing of scarce resources; • Eliminate duplicating of activities. • Networking of institutions in developing and developed countries is an important element in building regulatory capacity and trust

32. Why the harmonization is needed? Harmonization of medicines regulation is a desirable goal for many reasons: • Companies have to generate only one data set for all regions, and consequently the amount of human and animal experimentation is reduced; • The cost of development of new drugs and their regulatory documentation is reduced, which ought to lead to lower price; • Common regulatory standards for evaluations and inspections facilitate regulatory communication and information sharing;

33. Why the harmonization is needed? • Local products are more likely to be acceptable for export to other countries; • Faster access to medicines of high public health value; • Increased competitiveness for individual countries' markets at the face of "big pharma"

34. Effective harmonization • Medicines regulation could not be effective, if all major aspects of regulation are not addressed; • In real life, some very important areas of drug regulation, such as post-marketing surveillance of quality and safety, receive relatively little attention. Harmonization would not be successful unless all major components of regulation are covered!

35. Existing harmonization initiatives International initiatives: • International Conference of Drug Regulatory Authorities (ICDRA), biennial convened by the WHO since 1980; • The International Conference on Harmonization (ICH)

36. Existing harmonization initiatives Regional initiatives of regulators involved in harmonization include (but are not limited to): • Association of South-East Asian Nations (ASEAN); • Andean Community; • Gulf Cooperation Council; • Mercosur • Southern African Development Community (SADC)

37. Points for consideration before initiating the harmonization: Political commitment • upgrading of the requirements vs downgrading.. • willingness of sub-regional secretariats and potential members countries to participate in harmonization process; • Commitment of participating countries to continue the harmonization process, to carry the financial burden of maintaining the secretariat, investing in developing technical capacity of the staff.

38. African Medicines Registration Harmonization Initiative (AMRHI) • Process started with the informal consultations in ICDRA Meeting, September 2008, Bern, Switzerland; • In response to the growing recognition of the potential benefits of harmonizing medicines registration in Africa, a WHO concept paper was developed to describe a proposed approach to supporting drug registration harmonization within and across African regional groupings. WHO Drug Information, Volume 22, Number 3, 2008

39. African Medicines Registration Harmonization Initiative (AMRHI) • Further discussions and orientation in the meeting in Johannesburg, South Africa, 24-26 February, organized jointly by BMGF, NEPAD, William J. Clinton Foundation and the WHO. The purpose of the meeting was: • to explore the possibilities of supporting medicine registration harmonization, as an initial first step to broader regulatory harmonization within African Regional Economic Communities and organizations, and • to initiate a strategic approach to develop project proposals for mobilizing the necessary financial and technical resources to support RECs undertaking medicine registration harmonization.

40. African Medicines Registration Harmonization Initiative (AMRHI) The main objectives of the meeting were: • To promote the public health benefits of improved regulatory harmonization (including standardization, communication and collaboration) with an initial focus on drug registration; • To mobilize and structure donor community support for drug registration harmonization within and across African Regional Economic Communities; • To engage with RECs and member state National Medicines Regulatory Authorities on the proposed approach, solicit their feedback and agree next steps.

41. African Medicines Registration Harmonization Initiative (AMRHI) • Donor partners, NEPAD and WHO confirmed their interest in supporting the RECs, including necessary actions to support national implementation, strengthen national regulatory agencies and promote inter-REC and continental exchange of information, coordination and technical consistency. • Their strategic approach is to invite summary project proposals from committed RECs and seek financial and technical support for the most sound and promising proposals among them.

42. African Medicines Registration Harmonization Initiative (AMRHI) next steps for further implementation of the project: • By 31st May 2009 RECs are invited to submit to WHO and NEPAD a summary project proposal in support of regional medicine registration harmonization. A draft format and a suggested scope and outline are available. NEPAD and WHO are willing to give limited technical support to the development of such regional proposals. • April-May 2009: Submission of summary project proposals; • June 2009: Review of proposals and feedback to RECs; • July-October 2009: Selected RECs to submit their full project proposals to NEPAD & WHO; • November-December 2009: Review of full project proposals by Project consortium and submission to interested Donors; • January-June 2010: Implementation of first approved projects.

43. Conclusions • Available tools for medicines regulation can be packaged for ease of reference and information exchange; • Procedures can be streamlined and processes can be improved (e.g., Fast Track or Priority Review for those products that address unmet public health care needs); • Expert knowledge can be pooled and resources directed to functions that can improve public health and facilitate access to essential medicines; • Sharing of information, collaboration and harmonization can help to make the best use of available resources, reduce workload and improve overall regulatory performance.

44. Thank you! www.who.int/medicines mrsmail@who.int