S6-1 Coleman DoH Vatican

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Human Research Protection Program
Session 6
Post-trial access and the
Declaration of Helsinki (Part B)
19 January 2024
11:15 AM – 12:30 PM
Vatican City
Linda Coleman, JD, CIP, CHC, CHRC, CCEP-I
Director, Human Research Protection Program
Yale University
linda.coleman@yale.edu
WMA Conference on the Revision of the Declaration of
Helsinki: Research in Resource-Poor Settings
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Human Research Protection Program
Agenda
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Topic # Topic Description SLIDE #
1 Overview of Guidelines and Policies 03
2 Ethics Considerations 10
3 Global Definitions and Approaches 13
4 Options for Access to Investigational Products/Study Examples 21
5 Scenarios and Considerations 34
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Declaration of Helsinki Relevant Provisions
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22. … In clinical trials, the protocol must also
describe appropriate arrangements for post-trial
provisions.
34. In advance of a clinical trial, sponsors,
researchers and host country governments
should make provisions for post-trial access for
all participants who still need an intervention
identified as beneficial in the trial. This
information must also be disclosed to
participants during the informed consent
process.
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Human Research Protection Program
Council for International Organizations of
Medical Sciences (CIOMS) – 2016
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Reference:
Post-Trial Access to Treatment: How Expanded Access
May Offer A Strategic Solution (mytomorrows.com)
Author: Dennis Akkaya, September 2, 2020
“Post-trial availability for communities and populations. Even if research
addresses a question that has social value for the community or
population where it is carried out, the community or population will not
benefit from successful research unless the knowledge and interventions
that it produces are made available to them and products are reasonably
priced. Post-trial access plans are of particular concern for research
conducted in low-resource settings where governments lack the means
or infrastructure to make such products widely available.”
https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
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Council for International Organizations
of Medical Sciences (CIOMS) – 2016
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https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
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Human Research Protection Program
Council for International Organizations
of Medical Sciences (CIOMS) – 2021
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Clinical research in resource-limited settings – CIOMS 2021
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Council for International Organizations
of Medical Sciences (CIOMS) – 2021
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Clinical research in resource-limited settings – CIOMS 2021
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Human Research Protection Program
Good Clinical Practice (E6 R2)
Does not include language
related to Post Trial Access.
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Sponsor Policies
§ Many sponsors have developed policies in regard to
access to investigational products, including Post
Trial Access. (See Attachment for examples.)
§ Depending on the type of study, sponsors often cite
to the Declaration of Helsinki and whether
investigational products will or will not be available
post trial in study protocols.
§ Consent forms may also include language regarding
what will happen at the end of the study and may
specifically address post trial access.
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Human Research Protection Program
Respect for Persons Beneficence Justice
Potential research participants
must have the freedom to make
voluntary decisions regarding
whether or not to participate in
research without coercion or
undue influence from others.
The proposed research must be
designed to maximize benefits and
minimize harms.
The third principle requires the
equitable selection of research
participants and research that is
designed so that the benefits and
burdens are shared equitably.
q Participants voluntarily consent
to participate in the research.
q Privacy and Confidentiality are
protected.
q Participants have the right to
withdraw from research.
YouTube: The Belmont Report
Dr. Bob Levine
http://www.youtube.com/watch?v
=jD-YCDE_5yw
q The risks of research are justified
by potential benefits to the
individual or society.
q The study is designed so risks are
minimized, and benefits are
maximized.
q Conflicts of interest are managed
adequately.
q Individual Justice- Should not
offer potentially beneficial
research or opportunities to
some individuals OR exploit
certain populations.
q Social Justice – Equitable
selection of research participants
is required (participants who may
benefit from participation not be
excluded without good cause).
The National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research
Ethical Considerations-Belmont Report – 1979
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Ethical Considerations-Beauchamp and Childress
Tom Beauchamp and Jim Childress identify four principles that form a
commonly held set of pillars for moral life.
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Human Research Protection Program
Ethics Review Approval
Ethics Committees do not uniformly address Post Trial
access in their review of studies.
1. Continuation of Drug Therapy After Study Closure ☐Not applicable to this
project
Are subjects provided the opportunity to continue to receive the study drug(s)
after the study has ended?
☐ Yes If yes, describe the conditions under which continued access to study drug(s)
may apply as well as conditions for termination of such access. Write here
☐ NO If no, explain why this is acceptable. Write here
Example
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Therapeutic Use of Investigational Drugs
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There is no Common Global
Definition or Approach
Reference:
Post-Trial Access to Treatment: How Expanded Access
May Offer A Strategic Solution (mytomorrows.com)
Author: Dennis Akkaya, September 2, 2020
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Human Research Protection Program
Post Trial Access – No Global Definition
Examples
• Brazil
• Kenya
• South Africa
• Japan
• Canda
• European Medicines Agency
• United States
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Human Research Protection Program
See International Compilation of Research Standards located on the HHS website:
http://www.hhs.gov/ohrp/international/index.html.
International Compilation
of Human Research
Standards
There are also local
requirements within
jurisdictions in a
country
requirements
Local Requirements
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Human Research Protection Program
Post Trial Access – Brazil
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https://clinregs.niaid.nih.gov/
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Kenya
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https://clinregs.niaid.nih.gov/
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Human Research Protection Program
South Africa
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https://clinregs.niaid.nih.gov/
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Japan
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Characteristics of the Compassionate Use Program in Japan: An Analysis of
Expanded Access Clinical Trials from 2016 to 2021 – PMC (nih.gov)
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Human Research Protection Program
European Medicines Agency (EMA)
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Compassionate use |
European Medicines
Agency (europa.eu)
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Human Research Protection Program
Options for Access to Investigational Drugs
There are several mechanisms to obtain access to
investigational drugs:
• Post Trial Access
• Expanded Access / Special Access
• Managed Access
• “Right to Try” or equivalent law, etc.
• “[O]pen-label trial extension studies, long-term
extension studies, rollover clinical studies, separate
protocols, or protocol amendments” (Post-Trial Access to
Treatment: How Expanded Access May Offer A Strategic Solution (mytomorrows.com))
• Phase IV Study
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Human Research Protection Program
Study Example: Post Trial Access (Access Not Provided)
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Consent Form Language
Protocol Language
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Human Research Protection Program
Study Example: Post Trial Access (Access Provided)
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Protocol
Consent Form
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Human Research Protection Program
Study Example: Post Trial Access (dependent on local
regulation)
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Protocol
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Post Trial Access and Expanded Access-U.S. FDA
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FDA Issues Statement on Post-Trial
Treatment via Expanded Access | Early
Access Care
FDA-Press_PTA_29Mar2019.pdf
(earlyaccesscare.com)
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Human Research Protection Program
• Single Patient Expanded Access Program for X
unapproved drug in Patients with Compulsive
Disorder
• Intermediate Size Expanded Access Program for X
unapproved drug in Patients with Multiple Myeloma
• Expanded Access Program of Ruxolitinib for the
Emergency Treatment of Cytokine Storm From
COVID-19 Infection
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Study Examples – Expanded Access
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Human Research Protection Program
Study Example – Expanded Access
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Protocol
Consent Form
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Human Research Protection Program
Study Example – Managed Access
• The FDA approved the drug treatment Kymriah CAR-T cell therapy (Tisagenelcleucel) for adults with
relapsed or refractory follicular lymphoma.
• Patients are offered the drug and undergo the leukapheresis to collect T-cells to send off for
modification with Kymriah.
• The FDA approved the use of the drug as long as the target number of T-Cells can be obtained. But
if that target is not reached then the drug cannot be given as approved.
• What was created was an expanded access program to allow the lower number (as long as all other
parameters are met) to be infused.
• The MAP also allows enrollment of minors because the treatment offers the chance of cure rather
than the chemotherapy and transfusion dependent treatments – relatively few – that are approved.
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Canada – Special Access
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Health “Canada’s Special Access Program for drugs (SAP) enables drugs
that are not marketed in Canada to be requested by practitioners for
the treatment, diagnosis, or prevention of serious or life-threatening
conditions when conventional therapies have failed, are unsuitable, or
unavailable. Non-marketed drugs may be unauthorized if they have not
been approved by Health Canada. This means they have not been
assessed for safety, effectiveness and quality. It may also mean that the
sale of the drug has not commenced in Canada, or the product has
been discontinued or removed from the market due to regulatory
actions under the Food and Drug Regulations (FDR).
The SAP administers the saleFootnote1 of these drugs for “emergency
treatment” under Part C Division 8 of the FDR. An authorization for the
sale of drugs that are not available on the Canadian market is based on
sufficient evidence supporting the requested use and the drug
information available to the SAP at the time of the request.
Special Access Program for drugs: Guidance
document for industry and practitioners – Canada.ca
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Human Research Protection Program
Study Example – Open Label Extension
Bepranemab for Prodromal or Mild Alzheimer’s Disease
“Bepranemab (UCB0107) is a monoclonal antibody targeting the mid-domain of the tau
peptide that is being developed to block and reduce the cell-to-cell spread of tau pathology.
This is a Phase 2, double-blind, placebo-controlled study designed to evaluate the safety,
tolerability, and efficacy of bepranemab in individuals with prodromal or mild Alzheimer’s
disease. Participants will be randomly assigned in a 1:1:1 ratio to receive bepranemab at one
of two active doses or placebo, administered intravenously every 4 weeks for up to 80
weeks (67% chance of receiving active study drug). All participants will undergo either a 18F-
Florbetapir PET scan or a lumbar puncture (as part of an optional CSF substudy) to confirm
the presence of cerebral Aβ accumulation. All participants will also receive 4 MRI scans and
3 18F-GTP1 tau PET scans. …
Participants will have the option of continuing in an open-label extension period after
completion of the double-blind treatment period. Permits concurrent treatment with
cholinesterase inhibitors and memantine. HIC# 2000031213”
Reference: Clinical Trials < Alzheimer's Disease Research Unit (yale.edu)
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Study Example – Behavioral Clinical Trial
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Protocol Language
§ Total involvement 5 months.
§ There is a plan if there is no
improvement or worsening of
condition.
§ There is no plan in the protocol
for referral at end of treatment.
§ There is also no consideration
for the need to continue
treatment or provide access
through referrals at the end of
this feasibility study.
§ There is no end of treatment
assessment.
Use of Cognitive-behavioral
Therapy (CBT) for Binge Eating
(Self-Help Test)
OUTCOME
IRB required IRB to provide
access.
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Human Research Protection Program
Comparison
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Reference:
Post-Trial Access to Treatment: How
Expanded Access May Offer A Strategic
Solution (mytomorrows.com)
Author: Dennis Akkaya, September 2, 2020
Are there different
considerations for research
conducted in resource limited
settings in regard to Post Trial
Access OR Access to
Investigational Products in
general?
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Human Research Protection Program
Post Trial Access Decision Tree
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Reference:
Post-Trial Access to Treatment: How Expanded Access May Offer A Strategic Solution (mytomorrows.com)
Author: Dennis Akkaya, September 2, 2020
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Human Research Protection Program
Access to Investigational Products – Scenarios
1. Access to IP for individuals who are not a part of
clinical trial
2. Access to IP for individuals who meet
inclusion/exclusion criteria, but cannot be in a
clinical trial (e.g., due to time commitment, distance,
etc.)
3. Access to IP post trial, including early termination.
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Possible revision to the Declaration of
Helsinki to include guidelines that address
each of the scenarios above.
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Considerations
Considering the scenarios outlined on the previous
slide, what are the similarities and differences in regard
to impact for the following:
§ Global
§ Global North versus Global South
§ Continent/Region
§ Country
§ Regions within countries
The answer to this question will help inform possible
revisions to the Declaration of Helsinki and applicable
guidelines.
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Human Research Protection Program
Acknowledgments
The presenter would like to thank the following colleagues for their contribution to this presentation content.
Madelon Baranoski, PhD
Professor
Director, Forensic Psychology
Law and Psychiatry Division
Department of Psychiatry, Yale School of Medicine
IRB Chairperson
Yale Institutional Review Board
Yale University
Monika Lau, MEd, CIP
Assistant Director, Human Research Protection Program &
Deputy HIPAA Privacy Officer for Research
Yale University
Cathleen Montano, JD, CIP
Assistant Director, Human Research Protection Program &
Yale University
Kathryn Picanso, JD
Senior Contract Manager
Office of Sponsored Projects
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