Overview on Medicines Regulation: regulatory cooperation and harmonization in the focus Dr Samvel Azatyan Manager, Medicines Regulatory Support Programme Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies World Health Organization E-mail: azatyans@who.int

Why regulation of medicines is needed? What is special with medicines, compared to other goods / commodities? As a rule, patients are not able to make independent judgement about of the QUALITY, SAFETY and EFFICACY; Even health professionals have difficulties, unless they are specially trained; Medicines regulation is the totality of all measures - legal, administrative and technical - which governments undertake to ensure the quality, efficacy and safety of medicines, as well as the relevance and accuracy of the product information.

Why regulation of medicines is needed? Consequences of under-regulation due to the weak regulatory capacity irrational consumption and prescription; quality of medicines is not assured - substandard, counterfeit, harmful, useless medicines on the market. Consequences of over- or improper regulation shortage of needed medicines or delayed access; increased costs of medicines due to the cost of regulatory system.

Rationale for Government's role Governments are obliged to intervene in the activities of the pharmaceutical sector due to public health and safety concerns; In this context, medicines regulation is a public policy that restricts private sector activities in order to attain social goals identified by the State; Medicines regulation in the countries is performed through National Medicines Regulatory Authorities (NMRAs)

Medicines regulatory authority In a broad sense 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; GMP, GCP, GLP inspections; Licensing and post-license control of manufacturers, wholesalers and other distribution channels; Quality control laboratory testing; Adverse drug reaction monitoring; Provision of drug information and promotion of rational drug use; Enforcement operations; Monitoring of Drug Utilization, etc.

Main principles of medicines regulation – although, not always observed.. Medicines regulation should: Have patient in the focus; Be evidence and science based; Be risk based; Bring added value; Respect interests of stakeholders and real possibilities; Be transparent but respect confidentiality; Be effective and flexible; Be part of broader overall pharmaceutical policy of the country.

Main principles of medicines regulation – although, not always observed.. …But also keep in mind, that: Regulations must be attuned not to the wishes, but to available resources (technical, human, financial, etc.); Due to the complexity and resource constrains, the requirements developed and successfully implemented in one country may not be equally successful in another country; … Attempts to apply more sophisticated requirements may have (at least, in short term) serious public health implications.

Differences in regulatory capacity globally 193 WHO Member States: The reality is that many regulatory authorities don't have the full capacity to perform all regulatory functions, due to chronic shortages of human, technical, financial and other resources

Differences in regulatory capacity in African Region 46 WHO Member States: Source: WHO/AFRO/EDP/04.5: Availability of Drug Regulatory and Quality Assurance Elements in Member States of the WHO African Region, 2004, Brazzaville.

Assessments of medicines regulatory systems in 26 sub-Saharan African countries Guidelines and assessment procedures are not up to international standards and are often of an administrative rather than technical nature; Wide-ranging exemption clauses not justified by a risk assessment, for example for public sector imports or donations; Scarce resources severely limited technical assessment of dossiers; In spite of resource constraints few countries relied on decisions made by other regulators (such as stringent NMRAs or by the WHO Prequalification Programme); Regulatory decisions by other competent authorities were not widely recognized.

Critical issues in regulation of medicines Chronic shortages of resources; Different institutional arrangements existing for the regulation of medicines in different settings; Expertise and capacity existing in different NMRAs are different too.. Even well-resourced regulatory authorities are not anymore able and willing to carry the burden alone.. There is a clear need for a new approaches in the medicines regulation.

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.

"Innovative" approaches to cope with increasing demands and limited resources Avoid doing things that do not give added value; Concentrate on things that do give added value; Pragmatically and focus on priority issues, which are most relevant for public health (risk-benefit approach); Increase effectiveness of internal operations; Co-operate with partners in order to eliminate duplicated activities; Share your work with others – do what you can do better and let others to do what they can do better

Prioritization of the regulatory activities Many NMRAs with limited resources may limit their scope of activities to performance of those "core" regulatory functions, which could potentially bring maximum added value to the public health; Other regulatory functions could be more and more shared with the colleagues in other NMRAs (especially in the frameworks of existing RECs) and relying on the opinions made and decisions taken by other regulators; This will allow WHO and other partners to prioritize the support efforts and to introduce a system for accreditation (or prequalification) of NMRAs for performance of specific regulatory functions, in accordance with specific international standards.

More specific "innovative" (or heretic..) approach Introduction of the concept of "levelling" for the pharmaceutical products (essential medicines), according to the "quality-related risk", into: Low risk products Medium risk products High risk products This will create incentives and motivation for the development, in case if NMRA wishes to "jump" a level up, e.g., from regulation of low risk products to medium risk products.

What MRS is doing to support regulators 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 (from "North → South" to "South ↔ South"); Facilitating the establishment of "Centres of excellence" for regulatory affairs; Promoting harmonization.

Collaboration with other Programmes and Units within EMP and outside HSS/EMP QSM (PQ, Safety) QSM (Quality Assurance) QSM (Blood products) MAR (GGM) FCH/IVB QSS (Regulatory pathways) Disease-oriented programmes HTM/GMP (Global Malaria Programme) Other Programmes Medicines Regulatory Support WHO Regional Offices WHO Country Offices National Medicines Regulatory Authorities

Faster access to medicines through sharing of regulatory information MRS 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; without challenging their sovereignty.

Sharing of expertise vs. recognition of decision Acceptance of expertise is not equal to acceptance of decision: 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; Acceptance of decision is a formal legal act, frequently requiring international treaties; may modify liabilities of involved parties and requires legal specification of acceptance and non-acceptance.

New regulatory approaches Smaller or less resourced regulatory authorities more and more starting to rely on the approvals or opinions issued by the well-resourced regulatory authorities 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 territory; Canada's Access to Medicines Regime – assessment of products according to WHO Model List of Essential Medicines; Other – orphan medicines, paediatric medicines.

Regulatory harmonization 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 differ in complexity, from one type of marketing authorization application to another; To start with innovators or with generics? Or both?

What we do mean under Harmonization? True harmonization goes further than just development of 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 future.

What we do not mean under Harmonization? Harmonization doesn't mean a loss of national sovereignty / autonomy (and certainly not in the early stages) Common documentation 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

Scope and objectives for harmonization Objective of drug regulation: TO IMPROVE AND PROMOTE PUBLIC HEALTH In case harmonization is supported by International Community – main objective should be: There may be other gains, but these should be in the centre. MEASURABLE PUBLIC HEALTH GAINS

Potential public health gains from harmonization Less risk of being harmed by medicines (safety risks combined with no treatment effect risks) as gradual improvement of quality, safety and efficacy of products on the markets is expected; More rapid access to needed medicines (high priority essential medicines, new medicines…); Better value for money (both for out of pocket and public funds), as no waste on substandard and of poor- quality medicines; Increasing trust in generic medicines (also better value for money).

Potential gains have to be balanced with… potential losses Increased price level of medicines (quality has its price); Reduced access – not all medicines on the market may meet new harmonized standards; Increasing price for medicines regulation (harmonization has its price too); Local industry may not always win; Wholesale and retail businesses may loose many of the products that were bestsellers for them.

Potential scope for harmonization in Africa Harmonization of technical requirements Generic drugs vs NCEs – move from generics to NCEs Priorities (CTD, modules for generics, GMP), timeframes and working methods for creation of guidelines to be determined; Implementation of harmonized technical requirements; Establishing for priority products a special pathway – one set of assessments/inspections – access to all markets Either via "centralized procedure" (one application, one process and one result for all) or "mutual recognition" (same application for all or some, one MRA does the job and others recognize without duplication).

Regulatory harmonization in Africa Africa – a continent of huge diversity and complex unity, with numerous Regional Economic Communities (REC); … overlaps and politically complicated environment.

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

African Medicines Registration Harmonization Initiative (AMRHI) Further discussions and orientation in the meeting in Johannesburg, South Africa, 24-26 February 2009, 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 (RECs) 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.

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 was to invite summary project proposals (SPPs) from committed RECs and seek financial and technical support for the most sound and promising proposals among them. Several RECs have submitted their SPPs and at this stage one of them has been approverd – East African Community

Conclusions Medicines regulation is not anymore a "single-player" activity; Prioritization of regulatory activities, work sharing and collaboration can help reduce workload and improve public health by improving overall regulatory performance. It can help to direct the expert knowledge and resources to performance of the functions that can improve public health and facilitate access to essential medicines; Formation of effective networks between regulatory authorities nationally and internationally may facilitate sharing of scarce resources and eliminate duplicating of activities.

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