The EU Clinical Trial Directive Implementation : The Realistic Approach in the Netherlands

1. The EU Clinical Trial Directive Implementation : The Realistic Approach in the Netherlands H.D. Veldhuis, Ph.D. Pharma Bio-Research Group BV PO Box 200 9470AE Zuidlaren, The Netherlands dveldhuis@pbr.nl

2. Contents • EU Clinical Trials Directive (EU-CTD) • Implementation of EU CTD in Dutch law • Conclusions January 2004

3. EU Clinical Trials Directive (2001/20/EC) • “Directive of the European Parliament and of the Council on the approximationof the laws, regulations and administrative provisions of the Member States relatingto implementation of good clinical practice in the conduct of clinical trials onmedicinal products for human use” • Agreement on Directive reached in February 2001 • Final text published May 1st 2003 • Local (Member State) legislation to be drawn up May 1st, 2003 • Application of the local law May 1st 2004 EU Clinical Trial Directive: Introduction January 2004

4. Scope • “…conduct within the EU of clinical trials on medicinal products involving human subjects…” • Some aspects • sets standards for protecting clinical trial subjects, including incapacitated adults and minors • requires Member States to establish ethics committees on a legal basis and imposes legal obligations in relation to certain procedures, such as times within which an opinion must be given • covers certain Licensing Authority procedures for commencing a clinical trial • lays down standards for manufacture, import and labelling of IMPs • requires Member States to set up inspection systems for GMP and GCP • provides for safety monitoring of patients in trials, and sets out procedures for reporting and recording adverse drug reactions and events EU Clinical Trial Directive: Introduction January 2004

5. Implementation of EU Clinical Trials Directive (2001/20/EC) • Transposed into Dutch law at December 16, 2003 • To be implemented May 1st, 2004 (National legislation in force and to be complied with) • Working Party IMPD is preparing proposals for expertise requirements as well as training for certain Independent Ethical Committee (IEC) members ( i.e. hospital pharmacists and clinical pharmacologists) • In the Netherlands the previously adapted law (1999) already included most of therequirements as described in the EU-CTD. EU Clinical Trial Directive: Implementation: January 2004

6. Prior to the start of clinical drug research involving humans • Approval required by two different entities: • - IEC (“Independent Ethical Committee” [METC]) • - CCMO (Central Committee for Research involving Human Beings) part of the Ministry of Health • Dossiers for both entities should be identical EU Clinical Trial Directive: Implementation: January 2004

7. Evaluation of the dossier • METC (“Independent Ethical Committee”): • critical evaluation of the research proposal and the product • CCMO (= “Competent Authority, CA): • evaluation of the possible presence of adverse events with unacceptable risks in the EudraVigilance Database • marginal evaluation of GCP (focused on investigator qualifications) • Major evaluation of the research proposal by IEC; marginal evaluation by CA EU Clinical Trial Directive: Implementation: January 2004

8. Evaluation of the dossier • evaluation by IEC and CCMO in parallel • evaluation IEC within 60 days (dependent upon IEC)* • evaluation CCMO within 21 days (Phase I) or 49 days (other phases)*** IEC review period within the Netherlands varies from 10 – 60 days • ** Maximum periods (21 and 49 days) implemented in law (versus EU-CTD : 60 days) • CCMO intends to provide approval timings according to timings of the local IEC EU Clinical Trial Directive: Implementation: January 2004

9. Content of the dossier (major Headings) • Covering letter • Eudract number (+proof of receipt) • Application Form (according to EU guidance) • Clinical Trial Protocol, including: • Informed Consent Form • Patient Information Leaflet • Advertisement texts (if applicable) • Investigational Medicinal Product Dossier: • Signature page • Investigator’s Brochure (IB) • IMPD addendum and related documents • Amendments, only if substantial EU Clinical Trial Directive: Implementation: January 2004

10. Content of the dossier (details) • List of decisions of other Competent Authorities within EU • Listing of trials with same product • Example of Dutch label • CV’s of all investigators • GCP statement • Information on facilities • Insurance volunteers • Payments to volunteers and investigators EU Clinical Trial Directive: Implementation: January 2004

11. Investigational Medicinal Product Dossier (IMPD) Directive 4.1.6: “The IMPD should give information on quality of any IMP including reference productsand placebos to be used in the clinical trial and data from non-clinical studies and itsclinical use or justify in the application why information is not provided” • For registered drugs : most recent SmPC (product labelling) generally sufficient • For investigational products : complete information to be provided EU Clinical Trial Directive: Implementation: January 2004

12. Investigational Medicinal Product Dossier (IMPD) • IDB for pre-clinical and clinical information • Chemical-pharmaceutical information tabulated with a minimum of text • The dossier is not a large document • The format of the Common Technical Document could be used • Format is not obligatory • Depending on development phase only limited info can be provided • Dossier dependent upon various factors (Type product; indication, phase, etc) • If no data can be provided, an explanation should be given • Certain products (e.g. vaccines, antibodies, gene therapy) will be covered by other EU guidelines EU Clinical Trial Directive: Implementation: January 2004

13. Investigational Medicinal Product Dossier (IMPD) • Recommendations for the Netherlands (by the Competent Authority): • IB with addendum on chemical-pharmaceutical information is suggested • Contents not yet made explicit; investigator should liaise with IEC to discuss and • agree on format and content • Additional information should be ‘limited” • Consequences for IECs: • IECs will continue to review the IDB (incl. chemical-pharmaceutical information) • Additional training to be offered for hospital pharmacists and clinical pharmacologists • Consultation possibilities at certain governmental research institutes (RIVM, CBG) EU Clinical Trial Directive: Implementation: January 2004

14. Confidentiality of Independent Ethics Committees (IECs) “… the Dutch approach requires a number of studies to be evaluated by the CCMO . All other studies are evaluated by a local ethics committee. All ethicscommittees in the Netherlands are governmental bodies by law and have to beseen as agencies of the central committee. They are therefore equally bound tothe requirements of confidentiality and independence that apply to any other State body…” Excerpt from the 1st Newsletter of the Dutch EU directive Implementation Working Party (EUDIWP) December 2003 EU Clinical Trial Directive: Implementation: January 2004

15. Timing of introduction of the EU CTD in the Netherlands “ …There will be no transition period for the implementation. This means that any trial submitted before May 1st will not require any modification to comply withthe new law’…’’ Excerpt from the 1st Newsletter of the Dutch EU directive Implementation Working Party (EUDIWP) December 2003 EU Clinical Trial Directive: Implementation: January 2004

16. Amendments • Substantial amendments • to be provided to CCMO and IEC • CCMO: notification only • IEC: review and approval according to current process • Administrative amendments • To be added to own dossier • Not required to be provided to CCMO and/or IEC (only advised) EU Clinical Trial Directive: Implementation: January 2004

17. Implication of GMP requirements • Each batch of study medication to be released by a Qualified Person (QP) • QP to confirm that trial medication has been produced according to GMP • Study medication produced outside the EU has to be released by QP in one of the EU Member States • Changes for process of obtaining import licenses : • import license will be valid for a ‘manufacturing site’ • license will cover all trials; no need for individual requests for every trial EU Clinical Trial Directive: Implementation: January 2004

18. Study termination reporting procedures to CCMO and IEC • For ‘normal’ completion : 90 days • In case of early termination : 15 days • Final study report (format : SYNOPSIS [ICH-E3]) to be submitted within 12 months after study completion EU Clinical Trial Directive: Implementation: January 2004

19. GMP and GCP Inspections • Required under the EU-CTD directive • Already in place for several years in the Netherlands EU Clinical Trial Directive: Implementation: January 2004

20. Event reporting (Eudravigilance) • Relevant : Suspected Unexpected Serious Adverse Reactions (SUSARs) • Sponsor reports to CCMO, IEC: • Fatal or life-threatening SUSARs within 7 days (= follow-up in 8 days) • Other SUSARs: asap, but within 15 days • Annual safety reports (for every study) to CCMO and IEC • to be submitted within 60 days of data lock point EU Clinical Trial Directive: Implementation: January 2004

21. Conclusions • Most EU-CTD requirements have already been in place in the Netherlands since 1999 • No changes in timing of a CTA approval for Phase I studies • Only a limited, if any, increase in the CTA approval timing for Phase II studies • (IEC approval timing will be the target for the CCMO as well) • IMPD: limited chemical-pharmaceutical information to be added to IB (requirements to be agreed between IEC and CRO/investigator) • Competitive advantage for CROs with a Manufacturing license (GMP) and a QP • Most additional obligations, required under the EU-CTD can be provided by the CRO/investigator EU Clinical Trial Directive: Conclusions January 2004

22. USA Contact George Debski 860-684-5244 gdebski@pbr.nl