1. EORTC EU Clinical Trials Directives Organisation and Implementation of Cancer Clinical Trials Anastassia Negrouk EORTC Regulatory Affairs Manager Intergroup Officer

2. EORTC Contents Introduction Scope Definitions Main Issues Impact

3. EORTC Introduction (1) Full Title Directive 2001/20/EC of The European Parliament and of The Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

4. EORTC Introduction (2) Directive means it is directed towards the Member States, obliging the member states to achieve the result, but they remain free to choose the forms and methods to achieve that result

5. EORTC Introduction (3) Time Lines Released 4 April 2001 To be Adopted and published before 1 May 2003 To be Applied on 1 st of May 2004 at latest

6. EORTC Status of Implementation into National Legislation Effective from 1 st May or before Austria Belgium Czech Republic Denmark Hungary Ireland Italy Latvia Lithuania Poland Slovakia* Spain Sweden UK Late implementation Estonia Cyprus Finland Germany Greece Portugal Malta Slovenia Luxemburg Implemented, but not applicable yet The Netherlands (01/03/2006) Not yet fully implemented France (decree awaited)

7. EORTC Scope The Directive establishes specific provisions regarding the conduct of clinical trials, including multi-centre trials. Does not apply to non-interventional trials Detailed guidelines published by the commission All clinical trials shall be designed, conducted and reported in accordance with the principles of good clinical practice

8. EORTC Definitions ‘clinical trial’: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more IMP(s) and/or to study absorption, distribution, metabolism and excretion of one or more IMP(s) with the object of ascertaining its (their) safety and/or efficacy;

9. EORTC Definitions ‘non-interventional trial’: a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study…..

10. EORTC Definitions ‘investigational medicinal product’: a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or used for an unauthorised indication, or when used to gain further information about the authorised form;

11. EORTC Definitions ‘sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial;

12. EORTC Main Issues of Directive 2001/20/EC Protection of trial subjects Opinion of the Ethics Committee Authorisation by Competent Authority Conduct European Database (EUDRACT) Suspension of the trial Manufacture, import and labelling of IMPs Inspections

13. EORTC Protection of clinical trial subjects The foreseeable risks and inconveniences have been weighed against the anticipated benefit ……… Trial subject (or legal representative) has had the opportunity to understand the objectives, risks and inconveniences ……. Written consent Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor

14. EORTC Minors and incapacitated adults Those incapable of giving consent must be protected Informed consent of the parents or legal representative The minor or person not able to give informed legal consent has received info according to its capacity of understanding The explicit wish of a minor …… is considered

15. EORTC Ethics Committee - timelines 60 days maximum from receipt of a valid application May send a single request for supplementary information Clock stops until receipt of the supplementary information No extension to 60 day period except in case of  Gene therapy  Somatic cell therapy  Medicinal products containing genetically modified organisms  30 day extension, plus further 90 days if consultation with group or committee No time limit for xenogenic cell therapy

16. EORTC Ethics Committee - application The Ethics Committee shall give its opinion before a trial commences, considering: Relevance and design Risks and benefits Protocol Suitability of investigator and supporting staff IB Quality of facilities PIS / IC documentation and process Provision for indemnity or compensation in the event of injury or death attributable to a clinical trial Insurance or indemnity to cover the liability of the investigator and sponsor Rewards / compensation to investigators / trial subjects Relevant aspects of any agreement between sponsor and site Arrangements for recruitment

17. EORTC Competent Authority Sponsor may not start until Ethics Committee has issued favourable opinion CA concerned has not informed the sponsor of any grounds for non-acceptance Can run in parallel, or not 60 days maximum from receipt of a valid application 30 day extension as for Ethics Committee If CA does not accept, sponsor may amend request ONLY ONCE

18. EORTC Competent Authority - application Covering letter Clinical Trial Application Form Protocol IB IMPD Full IMPD if:  No previous applications for the product and cannot cross refer to info submitted by another sponsor Simplified IMPD if:  If info previously assessed as part of a Marketing Authorisation in any MS in the Community  If within the SPC – SPC is sufficient  If outside SPC – SPC plus non-clinical data, clinical data

19. EORTC Conduct of a clinical trial Amendments may be made If deemed substantial an approval is required Sponsor will notify  MSCA concerned  Ethics Committees concerned EC to give an opinion within 35 days  If favourable and CA raised no objection, amendment may be implemented  If unfavourable, cannot be implemented

20. EORTC Conduct of a clinical trial The sponsor and investigator shall take appropriate urgent safety measures to protect subjects against immediate hazard Sponsor has 90 days to notify CA and EC of end of a trial 15 days if trial is terminated early

21. EORTC European Database Member States shall enter info into a European database: Extracts of the request for authorisation Any amendments to the request Any amendments to the protocol The favourable opinion of the EC A reference to any inspections carried out Only accessible to MSCA, EMEA and the European Commission

22. EORTC Suspension of the trial or infringements MSCA may suspend or prohibit the clinical trial, and shall notify the sponsor, for reasons of safety, scientific validity, if conditions of request are no longer met Will ask the sponsor and/or investigator for opinion MS CA shall inform the other CAs, the EC, the Agency (EMEA) and the Commission of its decision

23. EORTC Investigational Medicinal Products Manufacture and import is subject to authorisation To obtain the authorisation, the applicant shall meet the requirements: At least one qualified person who ensures  GMP  If manufactured in a third country, GMP standards  Comparator from a third country with no GMP equivalent documentation, retesting to confirm the GMP status IMPs (and the devices used for their administration) shall be made available free of charge by the sponsor unless MSs have established precise conditions for exceptional circumstances

24. EORTC Labelling of IMPs At least the official language(s) of the MS on outer packaging, or when no outer packaging, on the immediate packaging Guidelines – GMP Annex 13

25. EORTC Inspections MS shall appoint inspectors to verify compliance Trial sites Manufacturing site Labs used for analysis Sponsor’s premises MS shall inform the Agency Results recognised by the other MSs Inspections coordinated by the Agency

26. EORTC Impact Differences between member states Increased administrative requirements Increased manpower Increased cost All of the above, plus Fees for CA applications Fees for CA amendments Fees for Ethics Committees

27. EORTC Concerns for multinational non commercial trials Sponsorship Definition of IMP and related provisions Pharmacovigilance Increased Costs Amendments Contractual Issues Lack of Communication and Harmonisation Free access to IMPs Clinical trial insurance

28. EORTC IMP supply “Unless Member States have established precise conditions for exceptional circumstances, investigational medicinal products and, as the case may be, the devices used for their administration shall be made available free of charge by the sponsor” Article 19, Directive 2001/20/EC

29. EORTC Ethics Committees Confusion and lack of coordination  Who makes the submission?  Timelines for approval unclear/coordination between the Central/Local EC unclear Does the single opinion really exist? Language Barriers Supporting texts for National legislations not available / not user friendly Administrative Requirements  Belgium: 18 copies  Luxembourg: 13 copies  Austria: 21 copies  Estonia: 11 copies

30. EORTC Competent Authorities Administrative Issues  Level of information increase  Quantity of information increase (France: 8 Copies, U.K.: 6 copies)  Additional requirements not mentioned in the Guidance documents Language Barriers (Spain, Poland) Lacking Information for some Member States Cyprus, Malta Additional National Requirements  National application forms (Ireland, Poland)  National databases (Italy Osservatorio)

31. EORTC

32. Clinical Trial Insurance Huge variability per country in term of Compensation Juridical background Duration of compensation Exclusion Costs Major misunderstanding by ECs leading to delays, variability within countries Urgent need to initiate a European forum to address this critical issue.

33. EORTC Insurance costs related to patients in EORTC clinical trials (in euros)

34. EORTC Current Challenges Clinical Trials Directive 2001/20/EC Increase in trial costs Increase in complexity EORTC Standard Operating Procedures (SOPs) Adapt to changing regulatory environment Impact on  Regulatory Affairs Unit / Safety Desk  Statistics Department  IT Unit  Coordinating Physicians

35. EORTC Future Challenges Communication Competent Authorities Ethics Committees Academic partners Commercial partners Harmonisation of Ethics Committee procedures Meeting the increased costs

36. EORTC European Legislation GCP DIRECTIVE 2005/28/EC 8 th April 2005 Released Details :  the principles of GCP referred to in Directive 2001/20/EC  the requirements for the authorisation of the manufacture or importation of IMPs as foreseen in Directive 2001/20/EC;  guidelines on the documentation relating to clinical trials, archiving, qualifications of inspectors and inspection procedures in accordance with Directive 2001/20/EC  to be implemented in all Member States by January 29 th 2006

37. EORTC Questions?