Sharing of expertise among medicines regulatory authorities

1. Sharing of expertise among medicines regulatory authorities Milan Smid Quality Assurance and Safety: Medicines Prequalification Programme

2. Agenda • Background • Regulatory considerations concerning sharing of expertise • Examples of expertise available • WHO Prequalification Project • European Union Scientific Opinion (Article 58) process • Discussion on existing issues complicating transfer of expertise and possible solutions

3. Scientific and regulatory complexity concerning medicinal products is growing • New technologies • New therapeutic approaches • Evidence based medicine • Globalization of commerce • Telematic instruments • Information and transparency requirements • Speed of change • Regulatory resources rarely reflect the demands and expectations of society • Regulators are required to demonstrate rational spending of resources Paradigms of drug regulation are evolving

4. Strategies used to cope with increasing demands? • Concentration on priority issues most relevant for public health • Improved effectivity of work • Co-operation with partners in order to increase regulatory capacity • Facilitated by comparable standards and administrative requirements

5. Different initiatives to increase regulatory capacity and assemble needed scientific / inspection resources WHO – standards, international expert teams, pharmacovigilance UMC ICH – common standards for developed markets, involvement of regulators as well as industry experts EU – coordination of expertise available to EU/EEA Member States by EMEA and EDQM, common EU procedures and sharing of expertise Australia and New Zealand – merger of NRAs Monaco, Liechtenstein – recognition of regulatory decisions of France, resp. Switzerland FDA, EMEA, WHO, TGA … etc. – MoU on sharing of information Canada, Switzerland, Japan, EU etc. – MRA on mutual acceptance of GMP standards PIC/S – share of standards and expertise on GMP, trainings, building confidence Regional and subregional initiatives – different extent of co-operation National initiatives – involvement of external experts to support NRAs, recognition of expertise or decisions, co-operation with industry and learned societies

6. Areas of co-operation • Sharing of Development of standards • Global standards: WHO, ICH • Regional standards: FDA, EMEA/EC, EDQM, USP etc. • Sharing of information and expertise • MoU, PQP, EMEA, FDA, etc. • Sharing of capacities for inspections and monitoring • MoU, MRA, PQP, EMEA, EDQM, FDA, TGA etc. • Recognising decisions if applicable to given population

7. Example 1: Trans-Tasman Therapeutic Products Agency • Regulatory Impact Assessments undertaken by the New Zealand Institute of Economic Research (NZIER) in 2000 and 2002 confirmed that New Zealand's current system for regulating therapeutic products is not sustainable. New Zealand does not have sufficient capacity in terms of technical expertise to continue to evaluate the risks and benefits of increasingly complex high risk products (such as medicines of biological origin). Such expertise is in demand internationally and is scarce in some disciplines. Australia may face a similar challenge to its regulatory capacity in the longer term.

8. Example 2: Cooperative arrangement between the FDA (USA) and the TGA (Australia) • The information in the inspection reports will allow the FDA and the TGA to make their own decisions concerning the compliance of manufacturers and appropriate follow up. Each agency may carry its own inspections in the other's territory if it deems necessary. • The agreement applies to GMP inspections of pharmaceutical facilities where the inspections have been conducted using the current FDA GMP requirements for drugs or the current TGA GMP Code for medicinal products.

9. Example 3Consideration of other regulators’ decisions • Switzerland • Medicinal products and procedures authorised abroad (Art. 13 of Act on Medicines): If a medicinal product or procedure is already authorised in a country with a comparable control system, the results of the assessments conducted (by this/these country/ies) shall be taken into account. • Singapore • Verification procedure: Evaluation & Regulatory Decision is based on assessment report by benchmark regulatory agency

10. Example 4aEU procedures for sharing the expertise • Mutual recognition procedure (simplified) • Medicinal product is registered in one EU member state (RMS) and manufacturer (MAH) intends to register it also in other/s EU MS/s (CMS/s): MAH provides CMS/s with the same (updated) product dossier as is valid in the RMS. RMS circulates to CMS product information (SPC, PIL and labelling) and the Assessment Report issued by him. CMS/s may comment in given time and RMS amends product information and AR, if necessary. Differences in opinions are discussed by committee of all EU MSs (CMD). If no agreement is achieved, top EU scientific committee gives final opinion binding for all EU MSs. This may be either positive or negative.

11. Example 4bEU procedures for sharing the expertise • Decentralised procedure (simplified) • Medicinal product is not registered in any EU MS and applicant intends to register product simultaneously in more EU MSs. The same dossier must be submitted to all MSs. One EU MS is identified by the applicant as "Reference member state" (RMS). This RMS evaluates the product and in given time provides other MS/s (CMS/s) with the proposal of product information (SPC, PIL and labelling) and draft Assessment Report. CMS/s may comment in given time and RMS amends product information and AR, if necessary. Differences in opinions are discussed by committee of all EU MSs (CMD). If no agreement is achieved, top EU scientific committee gives final opinion binding for all EU MSs. This may be either positive or negative.

12. Example 4cEU procedures for sharing the expertise • Centralised procedure (simplified) • Medicinal product is submitted for registration to the EMEA. Specified categories of medicines are eligible or mandatory for the procedure. Dossier is evaluated independently by 2 members of EU scientific committee for medicines (CHMP - Rapporteur and Co-rapporteur), who are supported by teams of experts, organised by their NRA. Proposals of product information (SPC, PIL and labelling) and of the Assessment Report are commented by members of CHMP from all EU MSs. Differences of opinions are discussed by the CHMP. Voting is organised, if no consensus is achieved. Final opinion on registration, either positive or negative, is valid for all EU MSs. Formally registration is issued by European Commission. Procedure has strict timetable.

13. Example 5"CADREAC" procedures • Registration procedures for products registered in the EU which were introduced by countries waiting for EU membership Applicant for registration was asked: • To submit the same dossier as for the registration in the EU • To submit valid EU product information and updated full AR (not EPAR) • To provide agreement with information sharing with relevant EU authorities • To declare, that product is the same as in the EU and will be kept the same to the future (minor formal deviations were accepted) • To provide commitment that all post-registration measures will be organised simultaneously as in the EU

14. Example 5"CADREAC" procedures • NRA organised simplified review and issued their sovereign national product registration • Almost 100% national registrations were concluded identically with the EU • Whenever the difference of opinions appeared, it has been communicated between NRA and EMEA or RMS

15. Example 6WHO pre-qualification programme Scope:WHO 2000, Prequalification of selected essential medicinal products for procurement by UN agencies and other purchasers Outcome: Opinion on benefit/risk of medicinal product and product monitoring Listing of the product and manufacturer(s) Documents available:Public domain: WHOPAR (SPC, PIL, labelling); WHOPIRRestricted domain: full WHOAR; WHOIR Supportive documents: WHO guidelines, description of PQ procedure

16. Example 7Opinion on pharmaceutical product according to Art. 58 of Regulation 726/2004 in the EU Scope:Defined by Regulation 726/2004 EU Guideline EMEA/CHMP/5579/04 Outcome: Opinion on benefit/risk of medicinal product (+ commitment of product monitoring) Documents available:Public domain: PAR (SPC, PIL, labelling), Restricted domain: full assessment report, inspection reports Supportive documents: EMEA/CHMP guidelines and SOPs

17. Common features observed concerning sharing the expertise • Standards are agreed • Same facts discussed (same data, same dossier) • Scientific reasoning provided (assessment report, inspection report, product information) • Common format is useful • Open communication is established (commercially sensitive information is discussed) • Rules exist for resolution of different opinions and disputes • Procedure follows agreed timetable • Follow-up mechanisms are agreed

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 NRA

19. May I trust the expertise? • Is there available information how expertise has been processed? • Is expertise based on the same data that I have (or may have) available? • Is expertise based on the technical standards that I recognize? • Is expertise based on the scientific standards that I recognize? • Is expertise complete? • Are there controversies of expert opinions?

20. Is expertise relevant for me? • Is expertise done for the same purpose for which I will use it? • Is expertise based on data that are valid for me? • Is expertise valid for me in full extent? • Is outcome of expertise definitive or conditioned by something? • Are there some gaps identified in the expertise?

21. How will I use the expertise? • May I use the expertise at all? • Is it worth for me to use the expertise? • Is there the need for additional expertise? • Are the gaps identified in the expertise relevant for public health? • Do I have available capacity and competence for additional expertise and is it worth to be invested? • Is there possibility to share additional expertise with someone? • Is there the need to modify formal outcomes of the expertise?

22. What will I do after accepting the expertise?(in part or in full) • What are for me the legal consequences of acceptance? • What are the legal consequences of my acceptance for all other involved parties? • Is there the need to keep the expertise continuously updated? • Do I have the instruments, capacity and competence to keep expertise updated? • Am I bound some duties after accepting the expertise? • Should I communicate to someone acceptance of expertise? • Is there the need for special public communication? • Is acceptance of expertise regular in such a way that deserves proper implementation into quality system and SOPs / public guidance?

23. Should be considered • Identity of dossier • Identity of product • Commitments of PQ holder • Access to full expertise • Post-authorisation follow-up • Product information • National legal requirements • Specific national authorisation procedures • Other issues?

24. Summary • Not to share expertise - 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 • Targeted, risk-based approach may be appropriate in some situations