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

Regulatory Approval
Conducted by Govt
regulatory agencies:
Health Products and
Food Branch of Health
Canada
Mandated by:

funding source/agency

Clinical Trial
Regulations for Drugs

Health Canada
regulations

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

Tri-council Policy
Statement

NSERC, SSHRC)

Human Research
funded by US federal
funds (i.e. National
Institutes of Health
(NIH))

US Federal
Regulations re:
Human Subjects
Protections
NIH Guidelines

Applicable Guidelines/Regulations
(contd)
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
(contd)
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 its agencies (i.e.
National Cancer Institute or NCI US)
Ethics education requirement for researchers working on
NIH funded projects
NIH collect CVs, FD and 1572s 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

7. medical care by a
qualified physician
8. qualified individuals
conduct trials
9. free informed consent

4. drug info supports trial

10 data accurate etc.

5. trial scientifically
sound, protocol

11. confidentiality

6. protocol REB
approved

13. quality assurance

12. drugs: GMP/protocol

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

Informed consent
requirements

Trial management, data

handling and record
keeping

Serious Adverse Event

Reporting

Monitoring & Auditing

Investigator selection

patients rights/well-being
protected

Regulatory
submissions

data is accurate,
complete, verifiable

Confirmation of REB
review
Drug

Conduct of trial by
everyone is GCP
compliant

Summary of Applicable Regulations and

Guidelines by Trial Type
REB

GCP

TCPS

DOH

HC

OHRP

CTA

NIH

All human trials

+ New indication

US Govt funding / drug

Under US IND

FDA

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 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)

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