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 / Regulatory Approvals of Clinical Trials in Canada
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

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

8. Applicable Guidelines/Regulations (cont’d)
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

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

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

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
Following 2nd world war and the primary Nuremberg trial of the Nazi leadership, there were several supplemental trials including the Nuremberg Doctors Trial
15/23 defendants (20 docs) found guilty of murder, torture
Judgment included set of ethical standards for medical research – “Nuremberg Code”
3rd point - the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment

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
1953 – 1964 (first draft issued)
Statement of ethics principles to guide physicians and others in the conduct of medical research involving humans
Revised many times since

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
Human Research funded by Canadian federal granting agencies (CIHR, NSERC, SSHRC)

15. TCPS: Content REB membership REB procedures for reviewing research
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

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
Trials Governed by OHRP
NCI US Affiliated Trials
Are those trials where an NCI US cooperative group participates on the trial
or there is CTSU participation OR where the NCI US Pharmaceutical
Management Branch supplies an investigational agent for the trial

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)
Assurances are agreements in writing to follow applicable rules and regulations
FWA:
- Any centre participating on an NCI US affiliated trial must have a current FWA issued by OHRP
We remind centres of the expiry date of their assurance every 3 months
if a centre’s assurance has expired we will not activate them on any new NCI US affiliated trial and our randomization program will not allow enrollment if FWA # is expired
56/85 of our member centres are participating on NCI US affiliated trials and all have current valid assurances.
We ensure that Investigators participating on NCI US affiliated studies complete and provide evidence of completion of educational training with respect to human subjects protection. It is worth noting that we require that all investigators in our member centres participating on any trial to complete this education as well as all central office staff. Educational certificates are entered into an oracle database and hard copies are maintained in the ER files.
99% of Investigators who have completed the education have provided certificates of completion from either the web-based program on the NCI US website or the web based program previously offered by NIH. The other 1% have for the most part provided documentation specific courses completed in human subjects protection
In terms of our open NCI US affiliated trials, there are no active investigators listed on the participants list for these trials who have not completed their ethics education.
HIPAA
- Does not apply to our group as we are not a covered entity as defined in the Privacy Rule
Up to the covered entity (i.e. US sites) to develop and implement a compliant authorization for the use and disclosure of personal health information
Once data is provided to us (a non covered entity) they are no longer subject to HIPAA
We do have US sites document that HIPAA compliant authorization was signed by the patient and the date it was signed on the eligibility checklist
We do not review authorizations
We are unrestricted with respect to the Privacy rule in how we handle data with identifiers. If we send data to a covered entity we ensure that data forwarded has all HIPAA identifiers removed to ensure compliance.

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
Canadian regulations

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
Trials conducted under an FDA US IND
FDA may audit any trial submitted for marketing approval – whether or not done under a US IND

23. US Food and Drug Administration (FDA) 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. GCP: Principles 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

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. GCP: Sponsor Responsibilities
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
Sponsor = organization or person making the regulatory submission (i.e. Investigator, Pharmaceutical company, research group)

30. Summary of Applicable Regulations and Guidelines by Trial Type
REB
GCP
DOH
TCPS HC
CTA
OHRP
NIH
FDA
All human trials √
+ New indication
US Govt funding / drug
Under US IND

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 / 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. EuD-CT Safety surveillance
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

39. Keeping Track of Your Responsibilities…..
Checklists
Keeping Track of Your Responsibilities…..

40. Prior to Opening Trial What regulations apply?
Can your REB comply (i.e. OHRP)?
Investigator qualifications, CV, conflicts, trial training
Prepare ethics and regulatory binders
Submit a CTA if required; letter for cross-filing to DMF; drug labels NB
Ensure TCPS, GCP, HC compliance
Informed consent – include all required elements and risks
Initial full board REB approval – submit all required information/documents

41. During the Trial Informed consent prior to trial specific procedures
Comply with the protocol, document/report if not
Source documents
Maintain essential documents (GCP)
Maintain confidentiality
Ensure drug reconciliation / compliance with regs
Ongoing annual approval (full board if OHRP)
REB & HC approval for amendments/changes (may be post-hoc if immediate safety hazard)

42. End of the Trial Inform REB and HC when trial closes
Submit Final report to REB
Monitor long term safety : inform patients and REB as needed
Retain records (included source documents and radiology) according to regulations (25 years for CTA trial)
Audits/inspections may occur during trial or after final analysis