Clinical Trial Review and Approval:

1. Clinical Trial Review and Approval: New Regulations and their implications Siddika Mithani, Ph.D Clinical Trials & Special Access Programme Therapeutic Products Directorate February, 2003 Health Products and Food Branch Direction generale des produits de sante et des aliments

2. Overview • Clinical Trial Reform • New Regulations for Clinical Trials - implemented September 1, 2001 • Clinical Trial Applications – filing requirements Health Products and Food Branch Direction generale des produits de sante et des aliments

3. Objectives of CT Framework • Maintain protection of research subjects • Enhance competitiveness of the research environment • Assure growth of the Canadian research environment

4. Key Considerations… • Risk management is of paramount importance • Research subjects should not be exposed to undue risk • Shared responsibility of study sponsors, investigators, Research Ethics Boards and Health Canada

5. Evolution of the clinical trialreview process • Clinical Trial Review and Approval (1997) • ICH adopted guidelines including the Good Clinical Practice Consolidated Guidelines • TPD guidelines for studying of special populations (women, children, etc.)

6. Need for change….Canadian Context • Review period viewed as internationally non-competitive by industry • Canadian R&D industry interested in establishing Phase 1 CT research facilities in Canada • leading to more R&D • Phase 1 represents only 4% of clinical research conducted by manufacturers of patented medicines in Canada

7. New Regulatory Framework • 30 day default review period for clinical trial applications [C.05.006(1)(b)] • 7 day administrative target for bioequivalence and appropriate Phase 1 clinical trial applications [policy statement] • Framework for inspection program for all clinical trials against generally accepted principles of Good Clinical Practices

8. 30-day Default System • Scope [C.05.002] - clinical trials in Phases I, II, III • applications for Phase IV trials not required [DIN/NOC] • Clinical trial amendments [C.05.008] • Application requirements the same for all sponsors [industry and independent investigators - [C.05.005] • Additional information must be submitted within 2 days [C.05.009]

9. 7-day Target System [Policy] • Scope - Bioequivalence trials • Phase I trials in healthy adult volunteers • Exemptions - Phase I trials in patients • Phase I trials involving: somatic cell therapies, gene therapies, xenografts, prophylactic vaccines or reproductive & genetic technologies • Sponsors must receive No Objection Letter prior to initiation of the trial

10. Regulatory Requirements • Research Ethics Boards (composition and mandate) • Qualified Investigator defined in the regulations • Sponsor’s Obligations: - Good Clinical Practices [C.05.010] - Labelling of Clinical Trial Supplies [C.05.011] - Record keeping requirements [C.05.012] - ADR Reporting [C.05.014]

11. Additional Reporting Requirements • Prior to commencement of the clinical trial [C.05.006(1)(d)]: - information on clinical trial site and qualified investigator - information on REB for each clinical trial site - information on REB refusal if applicable - proposed date for commencement of the clinical trial at each site

12. Suspension and Cancellation • Suspension [C.05.016] - reasonable grounds - written notice indicating applicable site[s] - 30 day window with opportunity to be heard • Cancellation [C.05.017] - safety concern - written notice indicating applicable site[s] - 60 day window

13. Review Process • Pre-CTA meeting • Filing of CTA • Clinical Trial Site Information Form • Notification - Administrative changes to protocol - Discontinuation not related to safety - Some Quality changes

14. Clinical Trial Applications (CTAs) • Regulatory Requirements - HC 3011 Form - Investigator’s Brochure - Proposed Protocol(s) including rationale for study • Operational Requirements - WP format - For pharmaceuticals - PCERT

15. Investigator-Initiated CTAs • Requirements - HC 3011 - Investigator’s Brochure (or Product Monograph - Rationale for proposed study - Informed Consent - Quality information, if drug not marketed in Canada

16. Continuous Assessment • Premature discontinuation of trial - detailed rationale - impact on proposed/ongoing trials - confirm that distribution stopped, unused drug returned and investigators notified • Serious and Unexpected ADRs to be faxed to appropriate Directorate

17. Continuous Assessment • Other Expedited Reports include: - for expected serious ADRs, an increase in the rate of occurrence - significant hazard to patient – eg., drug does not appear to be working in life-threatening disease - major safety finding from newly completed animal study

18. Safety Updates/ IB Updates • Required on a annual basis, or as requested • Processed as Notifications • Investigator’s Brochure annually • New IB should reflect all safety information • Global status of drug

19. More Information….. • TPP Website: www.hc-sc.gc.ca/hpb-dgps/therapeut • Guidance Documents: …../htmleng/draft_guide_industry.html • Contact: siddika_mithani@hc-sc.gc.ca