Global Review of Medicines Regulation: Current Highlights and Future Trends

1. Global Review of Medicines Regulation: Current Highlights and Future Trends National Regulatory Conference 2005 Kuala Lumpur, Malaysia 6 September 2005 Dr Lembit Rägo Coordinator, Quality Assurance and Safety: Medicines Medicines Policy and Standards World Health Organization E-mail: ragol@who.int

2. Content • Introductory remarks • Global regulatory environment • Harmonization • New challenges and trends • Role of WHO • Challenges remaining

3. Medicines regulation: What is it all about? Taste Appearance Smell Usual perceptions may not help in making judgements about medicines …

4. Why Stringent Standards for Medicines? • Medicines are different from other goods as patients (consumers) and even health care professionals are not able to judge their "quality" or "fitness for use" • "… 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 Gro Harlem Brundtland, former Director General of the World Health Organization) • This is the reason why medicines belong to one of the most regulated group of products

5. What Standards for Medicines? • Medicines must meet quality, safety and efficacy criteria. • These three sets of requirements are complementary to each other and each product has to be of good quality, safe and efficacious. • It is possible that a product is of good quality, but may not necessarily be effective or safe • It is possible that a product is effective, but may not necessarily be of good quality or safe • It is possible that a product is safe but may not be of good quality or effective

6. What type of medicines we have?1. Innovator products • For these products one has to prove their safety, efficacy and quality. Basis for these criteria is created by respective scientific disciplines. Implementation is executed through respective laws and regulations. • Proving safety and efficacy is the key for these products. It is based on the results of pre-clinical (i.e. animal toxicology) and clinical (clinical studies carried out in healthy volunteers and patients) research • Innovator (or originator) products • New innovative products that nobody yet has marketed, usually based on the new active ingredient (chemical compound which is responsible for its effects in human subjects) • The manufacturer has also to prove that its processes to produce the product and methods invented to control its quality are meeting established quality requirements.

7. Who sets the scene for regulating innovator products?

8. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Six Co-sponsors - members of Steering Committee European Commission EC European Federation of Pharmaceutical Industry Associations EFPIA Japanese Ministry of Health and Welfare MHW Japanese Pharmaceutical Manufacturers Association JPMA US Food and Drug Administration FDA Pharmaceutical Manufacturers Association PhRMA

9. ICH Steering Committee Observers World Health Organization (WHO) Canada - Health Protection Branch European Free Trade Area (EFTA)

10. ICH SC latest press release 2005

11. ICH Global Cooperation Group (GCG)

12. ICH Global Cooperation Group (GCG) - challenges • Very different by composition (countries with very different level of socioeconomic development) and objectives regional harmonization initiatives • Often in some countries indirectly involved ABC not yet fixed whereas other countries may have much higher levels of development • Relatively low level of resource investments available in harmonization as compared to ICH • Some may more have interest in regulating generic medicines well first (but this is not exactly ICH objective)

13. How can non-ICH countries benefit from ICH products? Challenges for policy makers • Priority setting (ABC first) … may be long way to go • Real control of market, functional DRA and inspectorate • Basic quality assurance measures like GMP, etc. • If market 90 % generics, regulate well generics first … • Implementation of ICH products vs recognition of registrations based on ICH guidelines? • Availability of resources • What is the cost of implementation of ICH guidelines and training? • What is the minimum number of regulators needed to assess a new drug according to ICH guidelines • Step-by-step approach

14. Where are we going with innovation? • Do we need new medicines? • Which type of new medicines we need? • What needs to be done to get new medicines out? • Is increase of spending on R&D the only solution? • What about new medicines for public health needs? • What can regulators do?

15. New initiatives to streamline drug approval process

16. Research spending

17. … and product submissions to FDA

18. Increase in certain segments of development costs

19. 90% 80% 79% 14 mnths $40m 70% 28 mnths $160m 66% 60% 57% 50% 20 mnths $40m 40% 37% 30% 20% 10% 11% 0% Phase I Phase II Phase III File and Launch Phase I to Launch Project Failure is Highest in Phase II Mean Probability Of Success Of Completing Stage PoS CMR data based on cohort approach looking at fate of NCEs entering phase 1996-1998, with progression decision made by 2001* *adapted from Ashton GA, Joshua PJ. Industry success rates 2002. CMR International Ltd

20. Three dimensions of Critical Path

21. Poorly developed areas – Paediatric medicines • Paediatric indications based on evidence – only approximately 50% of use has backing by clinical research • Incentives for paediatric research created in several countries (exclusivity rights increased etc.) • US • EU • Not much specific regulatory guidance • Lack of paediatric formulations needed – ARVs

22. Recent safety concerns and withdrawals – COX2 inhibitors in focus • Are regulatory models used to assess safety appropriate? • Independence of pharmacovigilance from authorization staff • US Congress interested and investigates issues • Can safety be predicted in a better manner? • Are new regulatory guidance documents needed?

23. Pharmacogenetics (PGx): significant potential to address some of the challenges • Pharmaceutical companies and regulators are actively exploring PGx applications. Draft guidance issued by some regulators, discussions in ICH environment • CIOMS report “Impact of Pharmacogenetics on Drug Discovery and Development,” • key development drivers and hurdles relevant to the implementation of PGx in drug development • the potential role PGx may play in the drug development process

24. New regulatory pathways to assure quality, safety and efficacy of medicines for public health needs in developing world • WHO Prequalification Program • US FDA tentative approval process for ARVs • EU Article 58 process

25. WHO Prequalification • The UN prequalification program is an action plan for expanding access to medicines for the hardest hit by • HIV/AIDS • Tuberculosis • Malaria • by ensuring quality, efficacy and safety of medicines procured using international funds

26. Why the prequalification is needed? • Problems • Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment • Substandard products widely available and in circulation • Weak/absent QA systems of medicines supply chain • Lot of money invested in procurement no harmonized quality assurance system available for procurement organizations/initiatives • Risks • Sourcing of poor quality products or even counterfeit medicines risk to patients, treatment failure, resistance

27. Prequalification basic principles • Rigour regulatory approach to ensure quality, safety and efficacy • Voluntary for participating manufacturers • Legitimate- General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies • Widely discussed • FIP Congress, Nice 2002 • Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authorities • Transparent (all information available on the web site http://www.who.int/medicines/) • Open to both innovators and multisource/generic manufacturers • No costfor applicants (manufacturers) during pilot phase

28. Prequalification: misunderstandings and critics • Too high standards increasing prices • … Too high and unnecessary standards for developing countries • … Too bureaucratic and slow, not proactive and not able to provide products… • Too low standards • …. " This leaves the impression with readers that the ARVs approved by WHO are in fact generic products that are interchangeable with their innovator cousins. From available documents, however, we conclude that they are copy products with unknown quality, safety and efficacy profiles".

29. How prequalification is organized • Role of WHO: Managing and organizing the project on behalf of the United Nations. • provide technical and scientific support and guarantee that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control • Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility) • Actors: Mainly assessors and inspectors of National DRAs as well as National Quality Control Laboratories of PIC/S and ICH member countries

30. Assessment procedure • I. Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. • teams of professionals from national drug regulatory authorities (DRA):Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, UK, Zimbabwe ... • II. Inspections • Manufacturing site (final product, packaging) • Active pharmaceutical ingredient (API) • Research laboratory or Contract Research Organization (CRO) • Teamwork of inspectors • WHO representative (qualified GMP inspector) • Inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme countries): Australia, Canada, UK, France, Italy, Switzerland, … • Quality control analysis - upon need but not always necessarily before prequalification and supply, increasingly as part of follow-up

31. Current status – 2005 • Started with HIV/AIDS products in 2001 – malaria and TB products joined later • Prequalified products Submitted • 95 HIV related medicines - 289 • 8 anti-tuberculosis medicines - 153 • 2 anti-malarial medicines - 46 • 105 488 • Ongoing assessments and follow-up • Products • Manufacturing sites • CROs

32. Ongoing monitoring and requalification • Samples taken after supply • Routine inspections and additional inspections • Changes and variations controlled • Products and manufacturers • Requalification (re-assessment) every 3 years • World Health Assembly resolution: WHA57.14 of May 2004 • Public reports • WHO Public Assessment Report (WHOPAR) • WHO Public Inspection Report (WHOPIR)

33. Prequalification • Good news • Relatively large number of products and suppliers indicated • Many potential suppliers appreciating feedback and willing to improve • Unique knowledge obtained about generic products • De-listed products coming back to the prequalified products list • Bad news • Only limited number of products have met the required standards • A number of de-listings from the prequalified products list in 2004 • Takes time to get into compliance • Data to be generated, tests carried out • GMP upgrade needed • Bad quality generics may undermine the public confidence in generics • Quality assurance has its price!

34. Lessons to be learned Quality can not be assessed, tested or inspected into the product, BUT It has to be built into it!

35. http://mednet3.who.int/prequal/

37. US FDA tentative approvals • Exactly the same standards for assessment as for US internal market • The same inspection standards • The same post approval surveillance • When IP rights allow (patents and other exclusivity rights) can enter US market • Limited to ARVs as linked to specific program – does not cover other product groups

38. Article 58: LEGAL BASIS AND SCOPE • Article 58 of Regulation (EC) No 726/20041 (“the Regulation”) establishes a mechanism whereby the European Medicines Agency (EMEA) may give a scientific opinion, in the context of cooperation with the World Health Organization (WHO), for the evaluation of certain medicinal products for human use intended exclusively for markets outside the Community. • The Committee for Medicinal Products for Human Use may, after consulting the World Health Organization, draw up a scientific opinion in accordance with Articles 6 to 9.

40. Article 58 – Why? • Under new EU legislation the EU Commission will no longer license medicinal products unless they are to be placed on the market in the EU. • Applicants were not able to get marketing authorization in the EU for products that had no market • WHO CPPs not issued under such circumstances – no basis for acceptance by other DRAs • Commission did not intend to kill incentives from companies to address public health issues outside the EU

41. How Article 58 will work? • Strong cooperation with the WHO • WHO gate keeper (determines if product is of high public health value) • WHO can send observers to CHMP • WHO can provide experts to EMEA • Procedure resembles centralized procedure – same standards • Outcome not MA but "scientific opinion for WHO" • WHO type CPP will be issued • EPAR like document will be made public

42. Specific non-EU medical needs • Medicines for non-EU use only due to - Specific epidemiological situation - Specific socio-economical conditions - Specific logistical conditions • Vaccine examples: - Pneumococcal vaccines with adapted composition - Multidoses containing thiomersal etc.

44. What type of medicines we have? 2. Generic products • The term generic product has somewhat different meanings in different jurisdictions. Therefore, term multisource pharmaceutical product is preferred by WHO. • Where the term generic product is used, it means a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a license from the innovator company and marketed after expiry of the patent or other (e.g. data) exclusivity rights. • Multisource pharmaceutical (generic) products are pharmaceutically equivalent products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable

45. What standards are need for generic medicines? • For generic medicines the manufacturer has to prove that the product meets all quality requirements • In case of safety and efficacy it refers to the originator's research • To prove the therapeutic interchangeability it has, as a rule, to carry out bioequivalence studies (small scale clinical trials in healthy volunteers to examine if the test drug has essentially the same blood concentration pattern of active ingredient as the originator. • It is assumed that if the blood concentrations are essentially the same the safety and efficacy profile is also the same.

46. Standards for generic drugs: first priority • WHO continues to issue Global standards for generic medicines and regulatory topics for public health importance

47. 39th WHO Expert Committee on Specifications for Pharmaceutical Preparations, 25-29 October 2004 (I) • Draft Guidelines • FDC -WHO-QAS04_108 (Fixed Dose Combination guidelines) • GMP_Herbal_RevJuly-04_QAS050 • Interchangeability-WHO-QAS_093Rev3_23Sept04 (bioequivalence) • QAS_055_Rev1_validation (supplementary to GMP) • QAS_066_Rev3_sampling(to replace 1990 guideline) • QAS_068_GDP – see next slide for details • QAS047_Rev1_Water (GMP) • Guidelines on MP HVAC (Rev 4) (GMP; Heating, ventilation and air conditioning for non-sterile dosage forms) • http://www.who.int/medicines/organization/qsm/expert_committee/expertcomm.shtml

49. What is WHO doing in order to reduce quality and regulatory gaps? • Assessing regulatory capacity upon request • Supporting capacity building and training of regulators • Issuing norms and standards and guidance materials • Preparing training tools, organizing training seminars and workshops on variety of topics as requested by countries - GMP, MA of Generic Drugs, GCP, GLP, Pharmacovigilance etc. • Facilitating information exchange • Supporting regional harmonization initiatives • Favoring networking and cooperation • Providing technical assistance upon request Ultimate goal: improve access to quality drugs for all citizens

50. International Conference of Drug Regulatory Authorities • Biennial unique forum of regulators • Brings together more than 100 countries