General Principles of Medicines Regulation

1. General Principles of Medicines Regulation Meeting on WHO Prequalification Programme on Priority Essential Medicines, WHO/EMRO 6-7 June 2007, Cairo, EGYPT Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards(PSM) WHO Headquarters, Geneva, Switzerland ragol@who.int 1

2. Topics • Innovative and generic medicines • Product information • Structure of the dossier of medicinal products

3. Usual perceptions may not help to make judgments about medicines …and even pharmacists and medical doctors may not be in capacity of taking decisions without specific training Taste Appearance Smell

4. Why medicines are special category of products? • Consumers, patients and health care workers have limited capacity to judge there • SAFETY • QUALITY • EFFICACY

5. Are all medicines safe, effective and meet quality criteria? • No, they are not, and no they do not • Some are safe, but not effective or necessarily meet the quality criteria • Some may be effective, meet quality criteria but are not safe • Some meet quality criteria but are not necessarily safe or have any efficacy

6. Quality - Safety • Some safety parameters are determined by quality • Some safety parameters are determined by the intrinsic properties of active pharmaceutical ingredient • However, in fact QUALITY in general perception (and often in policy documents) is incorporating also expectations for efficacy and safety without necessarily saying so

7. What type of medicines we have? • Originator products • Multisource (generic) products • KEY – INTERCHANGEABILITY, more important THERAPEUTIC INTERCHNGEABILITY • ALL LITERATURE IS BASED ON ORGINATORS • No interchangeability – NEED FOR NEW SAFETY and EFFICACY DATA, NEW BOOKS HAVE TO BE WRITTEN

8. What type of regulations exist and how they differ? • 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 about interchangeability (bioequivalence, clinical testing, in certain cases dissolution data)

9. Generics and not generics • FDA requirements for generic drugs (www.fda.gov/cder/ogd) • Generic drugs must: 1. contain the same active ingredients as the innovator drugs as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. meet the same batch requirements for identity , strength, purity and quality 5. be manufactured under the same strict standards of GMP required for innovator products. 6. be bio-equivalent

12. Generic drugs • In case of safety and efficacy the only way is to refer to originator product • Thus the efficacy (indications, dosing) and safety information (side effects, warnings etc.) can not be different • But are they?

13. Regulations: Global vs National • National regulations still differ a lot – especially for generics • What is ICH and what it is not? • Regional harmonization initiatives • Do global norms exist for generics?

14. Who sets the standards?Is the WHO Involved? • WHO has the unique mandate to set standards • WHO Constitution (Chapter II, Article 2), inter alia, states (6): • In order to achieve its objective, the functions of the organization shall be: … to develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products; Example of WHO work from 1966

16. Good Regulatory Practice : 9th ICDRA 29/4/1999 • Mission and objectives clearly stated • Possibility to assess attainment of objectives • Procedures and outcomes transparent to applicants, health professionals, and public • Arguments used to reach decision accessible to the public • Reasonable duration of assessment without compromising quality, safety & efficacy • Expedite review for orphan and outstanding public-health-value drugs • Accountability to government, those regulated, and the public • Personnel adequately trained, highly qualified, of high integrity • Human resource development programme • Mechanisms for appeal and for citizens' complaints • Access to appropriate knowledge and technology • Citizens are provided with accurate and appropriate drug information • Mechanisms to ensure quality of operating procedures

17. Intrinsic safety issues (NOT quality related) • Not a single drug is completely safe! • Predictable and preventable ADRs/ADEs • New, unpredictable and unpreventable ADRs • New concepts - safety through whole life cycle of a drug • Preclinical testing • First in man trials • Clinical trials to prove efficacy (pre-marketing) • Post-marketing activities for gathering new data (Phase IV trials, prosepective pharmacovigilance planning, targeted monitoring etc) • ADR reports and data analysis • Constant improving of INFORMATION on medicine and communication

18. Completely safe medicines are a myth: low dose aspirin case • Usefulness of low dose aspirin (75-325 mg) in secondary prevention of thrombotic cardiovascular or cerebrovascular disease proven • In many countries it is also approved for primary prevention of vascular events of coronary heart disease (US FDA has approved only secondary prevention). • Usefulness and efficacy is ALWAYS balanced against the risk – the higher the risks the higher risks in terms of safety we may wish to take • If NO DISEASE low dose aspirin can increase a risk to die (from hemorrhagic stroke) …

19. How big is a problem? • A recent US study estimated that 106 000 patients die and 2.2 million are injured each year by adverse reactions to prescribed drugs (Lazarou et al, 1998). • RATIONAL USE is a key to avoid ADRs that are predictable and avoidable • Important role of INFORMATION

21. Specific reviews of medicines • Review of Kava • Pharmacovigilance for antiretrovirals • Amodiaquine + artemisinin

23. Correct information and its proper communication can reduce (preventable) ADRs • 27th Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring Dublin, Ireland, 4 - 6 October 2004 • The summary of product characteristics (SPC) could be an effective tool in preventing ADRs. Accurate and recent information should be provided in the SPCs. The SPC should be appropriately worded and presented to help health professionals get the summary quickly and with the least effort. Doctors should be advised to read all package inserts and labels.

24. Two different regulatory approaches to medicines information: Australian example • Therapeutic Goods Regulations 1990 (compliant 1 October 2004) Schedules 12 and 13 for prescription and pharmacy only products • Content based regulation whereby a list of required information is prescribed • Therapeutic Goods Roder 69A for non-prescription and complementary products • Performance based regulation whereby regulation identifies the tasks that consumers ought to be able to carry out using the information

25. Conclusions on iformation • Medicine = tablet + information • Good quality drug information including PILs is a shared responsibility of industry and regulators • Regulators with limited resources could do more for public health by trusting scientific assessments by well resourced DRAs and concentrating more on ensuring the accuracy of drug information in national settings • Not only accuracy of information but also its proper communication is important

26. …and realities • In many countries do not have enough resources to check information or approve SPCs and PIL • In some countries prescription only medicines do not have PIL (OTC medicines have) …but can be obtained without any prescription • Most of the World population has only one prescription for all medicines – banknote. Can this give them also the information they need and understand?

27. Realities…

28. Structure of the dossier • Would it be harmonised a lot of resources would be saved • Industries would have one dossier structure for different submissions • Regulators could communicate better