Objectives/Agenda

1. Overview of the Role of the Regulatory Agencies and of Regulations in Product Development for PharmaRemit of EMA/FDA

2. Objectives/Agenda • The role of regulation • History of regulation • Control points • Control of clinical trials • NDA/MAA submission • Comparison of pharma and device controls

3. Objectives/Agenda, contd • Review of FDA and EMEA • ICH • Post marketing surveillance • Health technology and comparative efficacy

4. Role of Regulation • Consumer protection (consumer = a patient) • Controls the placing on the market (a European Term) • Post marketing surveillance

5. Extended Controls • Manufacturing • Clinical trials • Life cycle management • Post marketing surveillance • Advertising

6. History of Regulation • Pharmacopoeias (quality standards) London Pharmacopoeia 1618 B.P. 1853 • 1906 FDA • 1914 Health Select Committee • 1950’s therapeutic substances • 1960’s thalidomide tragedy – the real trigger for the modern regulatory environment

7. History of Regulation, contd • 1965 first EU Directive 65/65 • 1968 UK Medicines Act • 1995 EMEA established; Centralised procedure • 1995 EU Device regulations introduced • 1998-2001 Extended to medical diagnostics

8. Clinical Trial Controls • Phases I to IV, • Clinical Trials Applications (Europe) • Marketing Authorisation (Europe) • Investigational New Drugs Program (US) • New Drug Applications (US)

9. Application Dossier • Pharma NDA/MAA • Full dossier covers: • safety • efficacy • quality • Determination of Risk/Benefit • Output: • authorisation/licence • SmPC/labelling • conditional approval

10. The FDA Route • The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information. • The prescribing information is widely available on the web, from the FDA drug manufacturers, and frequently inserted into drug packages.

11. The FDA Route • The main purpose of a drug label is to provide healthcare providers with adequate information and directions for the safe use of the drug.

12. The FDA Route • The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.

13. The FDA Route • Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the U.S. • Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD format.

14. The European Route • Before any medicines can be used in the Europe they have to be licensed. Drugs are licensed for use in the Europe with a European licence through the European medicines Agency

15. The European Route • The EMEA co-ordinate drug licence applications within the European Union (EU). There are 6 committees within the EMEA. Each committee looks at a particular area. • There is a Committee for Proprietary Medicinal Products (CHMP) who are responsible for medicines for human use

16. The European Route • There are different systems within the EMEA that pharmaceutical companies can use to license drugs. • The first is called the ‘centralised system’. Any drugs for AIDS, cancer, neuro-degenerative conditions, diabetes or orphan drugs have to be licensed this way.

17. The European Route • The committee that reviews drugs for human use (the CHMP) assess the application, and then recommend whether a drug should have ‘marketing authorisation’ (a licence) or not.

18. The European Route • The other ways that pharmaceutical companies apply for a license is either the ‘decentralised system’ or the mutual recognition system. They will use these systems for medicines that don't fit into the categories within centralised system.

19. The European Route • With the decentralised system the company applies to several member states at the same time. One member state assesses the application (this is the MHRA in the UK). • If they recommend that the drug be licensed, the other member states then either agree or object. If everyone agrees, the drug is given marketing approval. If someone objects, the CPMP will step in and decide. • They then advise the EU Commission whether to license the drug or not.

20. The European Route • Once a drug has EU marketing authorisation, it is ‘licensed’, ‘registered’ or ‘approved’. All these terms mean the same thing. This means the company can market the drug in any EU country - but they don’t have to. For one reason or another, they may choose to market the drug in some countries but not others.

21. The European Route • When a drug has marketing authorisation, it is not available straight away. The company first have to apply to market their product in each individual country. In the UK, they will apply to the MHRA. When this last small step is done, the product is ‘launched’, and doctors can prescribe it.

22. EMA? MHRA? • These bodies follow the usual European Structure. • The European Marketing Agency is the European Body • Each state ahs a competent authority – in the U.K. this is the Medicines and Healthcare Regulatory Products Regulatory Authority (MHRA)

23. Line Extensions • Life cycle management • Abridged/abbreviated files -new indications, new dosage forms -variations • Generic applications • OTC products

24. Post Marketing Surveillance • Spontaneous reporting systems • Yellow card reports • Vigilance reporting • User reporting • Structured data bases • Data mining/signal detection

25. Post- Marketing • Risk management plans (Europe) • REMS (FDA)

26. FDA • Structure • Commission • Advisory panels • Fees • Independence

27. EU • National agencies – MHRA, AFSSAPS, MPA • EMA role • Centralised procedure, CHMP • Decentralised procedure • Mutual Recognition Procedure • CMD(h) • EU Commission grants the MAA

28. InternationalHarmonisation • ICH (International Conference on Harmonisation) • GHTF (Global Harmonisation Task Force) Devices • ICDRA (International Conference Drug Regulatory Authorities) • ISO and EN, BSI standards • Pharmacopeias (EP, VSP, BP, JP)

29. Health Technology Assessment (HTA) • NICE • Requirements for comparative efficacy • Quality of life data • Role of the payers

30. HTA Development • Comparative effectiveness • Cost effectiveness • Value based pricing • Pricing for risk

31. Japanese Regulatory AuthoritiesRoles and Responsibilities • Ministry of Health, Labour & Welfare (MHLW) • makes all final decisions based on recommendations of PMDA

32. The PMDA (Pharmaceuticals and Medical Devices Agency) was established in April 2004 • Incorporated Administrative Agency of the MHLW

33. PMDA • Integrated Regulatory Agency • Pharmaceutical Affairs Law • GMP inspections collaboration with the prefecture administrations

34. Office of General Affairs Office of Planning & Co-ordination Senior Councillor Office of Relief Funds PMDA Structure Office of Review Administration Office of New Drug 1 Office of New Drug II Chief Executive Office of New Drug III Director, Centre for Product Evaluation Priority Review Director Office of Biologics Executive Director Office of OTCs / Generic Evaluation Associate Centre Directors Office of Medical Devices Office of Conformity Auditor Office of Safety Division Chief Safety Officer Office of Compliance Standards Office of R&D Promotion

35. Rest of the World • Primary evaluation countries/regions: FDA, EMA, PMDA, Australian, Canada, Switzerland • Countries requiring local studies a evaluation: China, South Korea, India, Taiwan

36. Conclusion • In this lecture we have looked at the way the FDA and the EU regulate market access • They are different but broadly achieve the same end • We have briefly looked at other approaches