International and Canadian Standards: Ethics and Regulatory

1. International and Canadian Standards: Ethics and Regulatory Melanie Walker, PhD Candidate

2. Learning Objectives Understand: • Clinical trial regulations and guidelines in Canada • International regulations and how they differ from Canada (USA, European Union) • Investigator responsibilities for compliance with regulations and guidelines

3. Not a learning objective…

4. Canada

5. Ethics Approval Conducted by Research Ethics Boards: institutional (local) or central board or both Mandated by any/all: institution funding source/agency Health Canada regulations Regulatory Approval Conducted by Gov’t regulatory agencies: Health Products and Food Branch of Health Canada Mandated by: Clinical Trial Regulations for Drugs Medical Devices Regulations Natural Health Products Regulations Ethics / Regulatory Approvals of Clinical Trials in Canada

6. Current Ethics Guidelines/ Regulations Applicable to Clinical Trials in Canada • Vary by trial • Invoked/required by: • use of human subjects • source of funding • intervention being studied • local/institutional requirements

7. Any Medical Research involving humans Nuremberg Code Declaration of Helsinki Local/Specific requirements (i.e. REB, hospital, university, industry or other sponsor) Applicable Guidelines/Regulations

8. Human Research funded by Canadian federal granting agencies (CIHR, NSERC, SSHRC) Human Research funded by US federal funds (i.e. National Institutes of Health (NIH)) Tri-council Policy Statement US Federal Regulations re: Human Subjects Protections NIH Guidelines Applicable Guidelines/Regulations (cont’d)

9. Clinical Trials Involving Drugs Canada: Health Canada Food and Drug Act Regulations re: Clinical Trials US: FDA Regulations ICH - Good Clinical Practice Guidelines (ICH-GCP) Applicable Guidelines/Regulations (cont’d)

10. Clinical Trials Involving Natural Health Products Clinical Trials Involving Medical Devices Natural Health Products Regulations (Health Canada) Medical Devices Regulations (Health Canada) Applicable Guidelines/Regulations (cont’d)

11. Nuremberg Code • 10 standards physicians must conform to when carrying out experiments on humans i.e. • Informed Consent -- participation voluntary • Research must be necessary & based on prior animal experimentation • Risk proportionate to importance • No unnecessary physical/mental suffering • Freedom to withdraw participation at any time

12. Declaration of Helsinki • Medical progress based on research; research improves treatments and understanding of disease but involves risks and burdens; must be subject to ethical standards • Content of protocol • Compliance with Declaration • Independent REB must give continuing approval • Well-being of subject overrides interests of science/ society • Voluntary and informed participation • Protect privacy and confidentiality of subjects • Informed consent requirements • Publication requirements

13. REB Guidelines/Requirements • Address • Requirement for SOPs • Membership • Types of approval • What information must be provided to the REB • What must be approved by the REB (protocol, informed consent, patient information, advertisements etc)

14. Tri-Council Policy Statement (TCPS)Ethical Conduct for Research Involving Humans • Policy statement for Canadian Granting Agencies: • CIHR-Canadian Institute for Health Research (formerly MRC) • NSERC-Natural Sciences & Engineering Research Council • SSHRC (Social Sciences and Humanities Research Council) • Granting agencies will only fund individuals and institutions which certify compliance • No force of law in Canada, but a widely adopted ethical standard for human research • Compliance/monitoring programs being considered

15. REB membership Number Composition REB procedures for reviewing research Documents/Events Level of review Meeting procedures Record Keeping Free and Informed Consent Evidenced in writing Necessary consent elements listed Privacy and confidentiality Conflicts of Interest Clinical Trials Human Genetic Research Human Tissue TCPS: Content

16. US Federal Regulations • US Code of Federal Regulations Title 45, Part 46, Protection of Human Subjects • Includes research funded by the US National Institutes of Health (NIH) or it’s agencies (i.e. National Cancer Institute or NCI US) • Ethics education requirement for researchers working on NIH funded projects • NIH collect CVs, FD and 1572’s annually – investigator # • OHRP (US Office for Human Subjects Protection) ensures compliance with this policy • Assurance required for each participating site

17. US CFR Title 45, Part 46 • REB membership and function • Level of review (expedited/full board) • Informed consent requirements • REB and Institutional Assurances must be obtained • Documentation of HIPAA compliance (patient authorization)

18. Canada Food & Drug Act Regulations • Part C, Division 5: “Drugs for Clinical Trials Involving Human Subjects” • Apply to clinical trials involving: • Investigational drugs (i.e. drugs that are not marketed, approved for use, in Canada) or • Marketed drugs being used outside of their approved use in Canada • i.e. clinical use, dose/formulation, route of administration or target patient population

19. Clinical Trials Regulations • Require the submission of a ‘Clinical Trials Application’ (CTA), formerly called an Investigational New Drug Application (IND) • Protocol, consent, drug information, investigator brochure • CTA Submitted to Health Canada – 30 day review period • No objection letter issued

20. Clinical Trials Regulations Require… • Approved Clinical Trials Application (CTA) • Compliance with ICH-Good Clinical Practice Guidelines • Submission and approval of changes to the protocol (i.e. amendments, revisions) • Drug labeled specifically for the trial • Investigator signature on ‘Qualified Investigator Undertaking Form’ which indicates agreement to perform trial in accordance with GCP • Notification of pre-mature discontinuation of the trial • Reporting serious adverse reactions • Health Canada may inspect (audit) sponsors and/or sites participating on trials

21. Clinical Trials Regulations - Ethics Requirements • Protocols and any changes to protocols (including informed consent) must be approved by an REB • REB composition defined in regulations (similar to Tri-Council composition + Cdn component) • REB chair must sign an attestation (agrees to follow Health Canada regulations, ICH-GCP) • REB refusals to approve a protocol or changes to a protocol must be reported to Health Canada

22. US Food and Drug Administration (FDA) Regulations • Applicable to studies conducted in Canada where Study is being done directly under a US IND • US INDs required when: • Drug (s) is not marketed Or • Drug is marketed but one of the following conditions exist: • intention to submit trial to FDA as a well-controlled study • intention to change labeling as a result of study results • indication/dose etc. involves a significant increase in risk

23. US Food and Drug Administration (FDA) Regulations • Regulations: • Code of Federal Regulations, Title 21, Section 312 • Require the submission of an Investigational New Drug Submission (IND) • Requirements for labeling, safety reporting, investigators, REB review etc. specified in regs • In practical terms • FDA 1572 required • FDA Financial disclosure required

24. ICH Good Clinical Practice Guideline (GCP) • International ethical and scientific quality standard for trials involving humans. It addresses: • Design; conduct; recording; reporting Follow when conducting a trial: • Intended for submission to a regulatory agency in an ICH region • Any trial being conducted under a Clinical Trials Application in Canada

25. ICH-GCP • GCP: Basic Structure • 1. Glossary • 2. Principles • 3. REB responsibilities • 4. Investigator responsibilities • 5. Sponsor responsibilities • 6. Protocol and amendments • 7. Investigator Brochure • 8. Essential Documents

26. 1. ethical principles 2. benefits/risk 3. rights/safety of subjects most important 4. drug info supports trial 5. trial scientifically sound, protocol 6. protocol REB approved 7. medical care by a qualified physician 8. qualified individuals conduct trials 9. free informed consent 10 data accurate etc. 11. confidentiality 12. drugs: GMP/protocol 13. quality assurance GCP: Principles

27. GCP: Research Ethics Board (REB) Responsibilities • Composition, function and procedures • Documents to obtain & review • Records

28. GCP: Investigator Responsibilities • Qualifications & resources • Care of subjects • Communication with REB • Drug • Patient consent process • Records/reports • Safety reporting

29. Quality assurance and quality control Trial management, data handling and record keeping Investigator selection Regulatory submissions Confirmation of REB review Drug Informed consent requirements Serious Adverse Event Reporting Monitoring & Auditing patients rights/well-being protected data is accurate, complete, verifiable Conduct of trial by everyone is GCP compliant GCP: Sponsor Responsibilities

30. Summary of Applicable Regulations and Guidelines by Trial Type

31. Summary of Investigator Requirements • Appropriately qualified by education and training • Qualifications (curriculum vitae) on file • Complete/file required forms (i.e. Health Canada Qualified Investigator form) • Declare financial conflicts of interest (i.e. own a company) to REB, sponsor, subjects • in some cases, should not conduct trial • Training on trial protocol • NIH ethics education certificate (if applicable)

32. International Standards

33. Background • Regulations that apply to trials conducted in Canada are described in previous section • Even if Canadian centres are not subject to international regulations, may be of interest/relevance when participating in international trials - may impact on overall protocol conduct / logistics

34. USA: Food and Drug Agency (FDA) • Largest market. Pharmaceutical companies are US-driven in their registration / development plans • Trials may be conducted under a US IND • May receive comments from the FDA requiring protocol amendments even after approved by Health Canada • Even if not conducted under a US IND, protocol may be submitted for Special Protocol Assessment if NDA planned • May have to amend protocol based on FDA comments

35. USA FDA • IND is drug specific. Once an IND is in place, any new trials are ‘filed’ to the IND. The FDA have 30 days to comment, but no formal approval is given (no news is good news): BUT they may issue a ‘Clinical Hold’ • In Canada, each trial has a unique CTA & NOL. The Drug is filed under a Drug Master File, and each CTA submitted must cross reference that DMF.

36. FDA • Unless the trial is conducted under a US IND, FDA1572 and financial disclosures are not needed – even if later FDA NDA is planned. • If the trial is conducted under an IND • Must conform to US regulations including REB and informed consent regulations • Essentially = HC/GCP requirements + 1572 / FD forms

37. European Union • EuD-CT issued in 2001 (2001/20/EC) • Member states implemented thereafter • Essentially addresses GCP implementation in clinical trials

38. Trials require regulatory approval (Ph I exempt) and have EUDRACT number Investigational Medicinal Product Manufactured to GMP - authorization needed Trial pharmacy/MD may pack / label for the trial Trial medications supplied to patient free of charge All trials conducted to GCP Regulatory authority enforcement Safety surveillance SUSARs Report to RAs and investigators for sponsors trials Report to EU central pharmacovigilance database SSARs Annual listing to RA and REBs for sponsors trial EuD-CT

39. Checklists Keeping Track of Your Responsibilities…..

40. Prior to Opening Trial

41. During the Trial

42. End of the Trial