International and Canadian Standards:

Ethics and Regulatory

Melanie Walker, PhD Candidate

Learning Objectives

Understand:

1. Clinical trial regulations and guidelines in Canada

2. International regulations and how they differ from Canada (USA, European Union)

3. Investigator responsibilities for compliance with regulations and guidelines

Not a learning objective…

Canada

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

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

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)

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

Applicable Guidelines/Regulations (cont’d)

• 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)

• Clinical Trials Involving Natural Health Products

• Clinical Trials Involving Medical Devices

Natural Health Products Regulations (Health Canada)

Medical Devices Regulations (Health Canada)

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

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

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)

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

TCPS: Content

• 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

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

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)

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

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

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

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

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

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

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

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

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

GCP: Research Ethics Board (REB) Responsibilities

• Composition, function and procedures

• Documents to obtain & review

• Records

GCP: Investigator Responsibilities

• Qualifications & resources

• Care of subjects

• Communication with REB

• Drug

• Patient consent process

• Records/reports

• Safety reporting

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

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 √ √ √ ± √

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)

International Standards

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

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

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.

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

European Union

• EuD-CT issued in 2001 (2001/20/EC)

• Member states implemented thereafter

• Essentially addresses GCP implementation in clinical trials

EuD-CT

• 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

Checklists

Keeping Track of Your Responsibilities…..

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

During the TrialInformed 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)

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