The EU Clinical Trials Directive: What next for the pharmaceuticals industry? RAPS Annual Conference Washington DC 11 O

1. The EU Clinical Trials Directive: What next for the pharmaceuticals industry?RAPS Annual ConferenceWashington DC 11 October 2004 Linda Horton, JD, LLM Hogan & Hartson L.L.P. Brussels and Washington, DC

2. What was not new • Much was not new, due to: • Existing Member State requirements • Declaration of Helsinki, ICH guidance, Council of Europe, FDA requirements etc. • Global SOPs of global companies

3. What has been new: Enlargement! on 1 May

4. Sponsor Responsibilities:Not much new, but articulated • Quality Assurance and Quality Control (written SOPs) • Appropriate Medical Expertise • Trial Design • Trial Management, Data Handling, Record-keeping • Investigator Selection & Monitoring • Notification/Submission to Regulatory Authorities • Confirmation of IRB/IEC Review • Investigational Products Good Manufacturing Practices • Ongoing Safety Evaluation/ Adverse Event Reporting

5. EU-level requirements for Ethics Committees • Ethics Committee opinions • Single opinion per Member State • Increased responsibilities and increased professionalism • “Unfunded mandates” decline in number? • Commission guidance on applications for Ethics Committee opinions, especially • Information given to trial subjects • Protection of personal data

6. Lead investigator in Member State • In each country, sponsor must decide how to handle the requirement for a “single” Ethics Committee opinion to go to the Competent Authority. • This requirement has led sponsors to designate one investigator to be the lead national investigator. • The term “principal investigator” is used as the lead person at a site so that term does not work to describe this individual.

7. Oversight: Notification • To commence trial: • Need OK from Ethics Committee, and • No disapproval from competent authority • Must have prior approval for gene or somatic cell therapy, genetically modified organism products • May need prior approval for certain products (e.g., biological products of human/animal origin)

8. Oversight: Notification • To Ethics Committee(s) and Competent Authorit(ies) • Significant protocol amendments • e.g., likely to impact safety • Ethics Committee opinion within 35 days of receipt • End of trial or early termination • Within 90 days: end of trial • Within 15 days: early termination

9. What is new regarding Competent Authority oversight • Submission to Competent Authority (CA) • No more “CTX” in the United Kingdom (UK) • Sponsor can amend request once to address deficiencies • CA review may not exceed 60 days • 30 day extension for gene, somatic cell, GMO • No time limit for xenogenic studies • Member States can shorten review timeframe • Can be simultaneous with Ethics Committee submission

10. Legal representative requirement • Sponsor must have a legal entity or legal representative in the EU or the European Economic Area (EEA) • More impact on small companies, especially companies with only investigational products. • Even larger companies re-examined relationships with European entities and wrote new agreements or SOPs.

11. Manufacturing (GMPs) • Authorization to manufacture/import IMPs • Must designate qualified person (QP) • Manufacture of IMPs • In Member State • In Non-EU Country: equivalent to EU GMPs • Compliance with product specifications • Requirements for placebos and marketed comparators from 3d countries • Import requires batch release certification • Member State must keep batch certification for 5-year minimum • New GMP Directive 2003/94/EC supersedes 91/356/EEC

12. Qualified persons • QP release requirement has affected all sponsors of clinical trials in the EU. • Affects how clinical trial materials are distributed • For smaller companies and especially ones with only investigational products, the requirement has forced decisions on who will be QP: • Legal representative? • CRO? • Can same person handle GMP QP requirement and pharmacovigilance QP responsibilities?

13. EUDRACT registration • Database of EU clinical trials (EUDRACT) • Sponsor must register trial and get number • Confidential: only for Competent Authorities (CAs), European Medicines Agency (EMA), Commission • e.g., extracts of clinical trial information, amendments, inspections • CA must provide details at substantiated request of any Member State, EMEA, or Commission

14. Pharmacovigilance • “Adverse reaction” reporting • Fatal/life-threatening suspected, unexpected serious adverse reactions (SUSARs) • Report ASAP to CA & Eth-Com, no later than 7 days after knowledge • Follow-up info within 8 additional days • Other SUSARs • Report within 15 days after knowledge • Annual reports to all Member States in which trial conducted • Info added to database and EMEA notifies other CAs

15. Pharmacovigilance • “Adverse Event” Reporting • Report “serious adverse events” (SAEs) immediately to sponsor (some exceptions) • Follow-up written reports • In general, follow protocol for other AEs • Sponsor recordkeeping and submission to Member States where trial conducted upon request

16. What has been difficult • Delayed implementation by Member States • Non-transparency (more difficult than it should be to obtain regulations)

17. EU Privacy Directive • Ascertaining whether study requires a filing with the Member State’s “Data Protection Authority” • New EMEA leaflet on pharmacogenetic studies tries to help sort out the relationship • Avoiding HIPAA problems; make sure your European case reports do not go to a U.S. covered entity like a hospital

18. Barnett International Philadelphia, May 5, 2004 The challenges ahead Delayed implementation Compliance by partners Meeting EU and FDA rules More GMP audits, enforcement Combination product issues More changes on horizon

19. More changes on horizon • Amendments to Community Code on medicinal products: the “Clinical Studies Requirement”: • Studies conducted in non-EU countries must be conducted in accordance with ethical requirements of EU Clinical Trial Directives • FDA has proposed to change regulation on non-IND studies to substitute delete reference to Declaration of Helsinki and substitute reference to ICH GCPs

20. 1 July draft Commission directive on GCPs • The European Commission has published a draft Commission Directive that ties together and builds upon earlier legislation and guidance on good clinical practices (GCPs) in investigations of medicinal products for human use and on the manufacturing and importation of these products.

21. Why a new Directive? • Commission legal advisors concluded that, in order to for GCPs to apply at the Member State level as binding norms, a directive rather than mere guidance is required. • The proposal also was influenced by earlier Commission consultations, in 2002, on the requirements to obtain an authorisation to manufacture or import an investigational medicinal product and on the key elements of the Trial Master File, inspections procedure and qualification of inspectors to be included in a Directive.

22. Also, the “non-commercial research” debate • Another key aim of the draft Directive is to respond to complaints from academic researchers, received by EU and Member State officials, about the applicability of the Clinical Trials Directive to non-commercial clinical trials. • The new Draft Directive refers to the great benefit of such trials to the patients concerned and would enable Member States to relax certain requirements through application to non-commercial trials of “specific modalities,” particularly as to manufacturing, importing, and documentation requirements. • Member States must ensure that the objectives of the protection of the rights of the patients and the principles of GCPs generally are achieved

23. Stronger legal basis for obligations • Should the draft Directive be adopted in its current format, the legal obligation of sponsors, investigators and other participants to take into account the scientific guidelines concerning quality, safety and efficacy of medicinal products for human use as agreed by the relevant EU bodies, i.e., the Committee for Medicinal Products for Human Use (CHMP) and the EMEA (the European Medicines Agency),and the European Commission, would be on a firmer legal basis.

24. Key elements of the Trial Master File • The Trial Master File consists of essential documents that enable the evaluation of the conduct of the trial and the quality of the data produced. • The draft Directive provides that the sponsor and the investigator must retain essential documents for 5 years after the completion of the trial. • Also, documents would have to be archived in a coherent way, to ensure their prompt availability in case of a request on the part of public authorities. • Any transfer of ownership of the data or of the documents would have to be documented.

25. Qualification of inspectors • Guidelines on minimum standards would be required on the qualification, education and training of clinical trials inspectors conducting GCP inspections. • Member States would be responsible for ensuring that inspectors had completed adequate university education, that their training is appropriate, and that their knowledge includes the provisions of applicable EU law, national legislation, and guidelines on conduct of clinical trials and marketing authorizations.

26. GCP inspection procedures • The draft Directive states that Good Clinical Practices inspections may take place at any time (before, during, and after the conduct of clinical trials). Inspections may be requested and coordinated by the EMEA.

27. GCP inspection procedures • Member States would be requested to: • define what access inspectors and the Member State drug regulatory agency would have to clinical trials sites and relevant data found there; • establish procedures for verification of compliance with good clinical practices; • establish rules in order to ensure confidentiality by inspectors and other experts; and • maintain a database on the inspectors, their qualifications, training and experience.

28. Current Status and timeline • The Draft Directive is currently being examined and comments from Member States were requested by 30 July 2004. • Final adoption of the draft Directive is not expected before the end of 2004. • Member States would be expected to transpose the text of the Directive into national legislation within 6 months after the entry into force of the Directive, which would be 20 days following publication in the Official Journal of the European Communities, probably sometime during 2005.

29. Strategic issues • Do we want to continue to do clinical trials in the EU? What alternatives are there? • Should we continue to do global studies under an FDA IND? • Should we instead conduct the EU component as a non IND study under an identical protocol and use meta analysis to pool data?

30. Contact Information Linda R. Horton, Partner Hogan & Hartson L.L.P. Lrhorton@hhlaw.com www.hhlaw.com Washington, DC 20004 AS OF 27Sept: Rue de l’Industrie 26 Brussels, 32 2 505 0931 OR 202.637.5795

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