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 trial review 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