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

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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
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Objectives of CT Framework

• Maintain protection of research subjects
• Enhance competitiveness of the research
  environment
• Assure growth of the Canadian research environment

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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

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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.)

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Need for change.Canadian Context

• Review period viewed as internationally
  non-competitive by industry
• Canadian RD industry interested in establishing
  Phase 1 CT research facilities in Canada
• leading to more RD
• Phase 1 represents only 4 of clinical research
  conducted by manufacturers of patented medicines
  in Canada

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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

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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

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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

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Regulatory Requirements

• Research Ethics Boards (composition and mandate)
• Qualified Investigator defined in the regulations
• Sponsors 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

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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

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Suspension and Cancellation

• Suspension C.05.016
• - reasonable grounds
• - written notice indicating applicable sites
• - 30 day window with opportunity to be heard
• Cancellation C.05.017
• - safety concern
• - written notice indicating applicable sites
• - 60 day window

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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

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Clinical Trial Applications (CTAs)

• Regulatory Requirements
• - HC 3011 Form
• - Investigators Brochure
• - Proposed Protocol(s) including rationale for
  study
• Operational Requirements
• - WP format
• - For pharmaceuticals - PCERT

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Investigator-Initiated CTAs

• Requirements
• - HC 3011
• - Investigators Brochure (or Product
  Monograph
• - Rationale for proposed study
• - Informed Consent
• - Quality information, if drug not marketed in
  Canada

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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

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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

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Safety Updates/ IB Updates

• Required on a annual basis, or as requested
• Processed as Notifications
• Investigators Brochure annually
• New IB should reflect all safety information
• Global status of drug

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More Information..

• TPP Website
• www.hc-sc.gc.ca/hpb-dgps/therapeut
• Guidance Documents
• ../htmleng/draft_guide_industry.html
• Contact
• siddika_mithani_at_hc-sc.gc.ca