Transcript Document

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,
 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
(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
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
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
TCPS
HC
OHRP
All human trials
√
DOH
√
CTA
NIH
√
+ 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