IFPMA_DoH_Cape_Town_6DEC12

International Federation
of Pharmaceutical
Manufacturers & Associations
Expert Conference on the Revision of the
Declaration of Helsinki
© IFPMA 2012
December 6th, 2012
Cape Town, South Africa
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Introduction
• Biopharmaceutical companies are committed to high-quality ethical
research
– Principles on Conduct of Clinical Trials and Communication of Clinical
Trials Results (PhRMA, 2009)
• IFPMA was invited to participate in this meeting and provide industry
expert input on potential revisions to the Declaration of Helsinki in
2014
• Keeping in mind that the original purpose of the Declaration of
Helsinki was to serve as a set of guiding principles for physicians
investigators, IFPMA has developed points for consideration on the
following topics:
– Use of placebo in clinical trials
– Use of comparators based on differences in standard of care and
availability of medicines between developed, emerging and
developing countries
– Conduct of clinical trials in vulnerable patient populations
– Post-study access to medical care
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• Use of placebo in clinical trials
– Principle 32
• Use of comparators based on differences in standard
of care and availability of medicines between
developed, emerging and developing countries
– Principles 32 and 35
• Conduct of clinical trials in vulnerable patient
populations
– Principles 9 and 17
• Post-study access to medical care
– Principle 14
• Placebo-controlled trials allow researchers to reliably evaluate
safety and efficacy of an experimental treatment while minimizing
the number of necessary participants exposed to the treatment
• Regulatory authorities often require the use of placebo as a
comparator in clinical trials
• The use of placebo as an acceptable comparator for new
treatments tested in clinical trials is acknowledged and
addressed by:
– Council for International Organizations of Medical Sciences (CIOMS)
• International Ethical Guidelines for Biomedical Research Involving Human
Subjects (2002, Guideline 11)
– The International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH)
• Choice of control group and related issues in clinical trials E10 (2000)
– Presidential Commission for the Study of Bioethical Issues
• Moral Science. Protecting Participants in Human Subjects Research (2011,
Recommendation 12)
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Use of Placebo in Clinical Trials
Background
Use of Placebo in Clinical Trials
Points for Consideration
• Potential scientific, regulatory, and ethical issues associated with the
use of placebo or any other appropriate comparator should be
carefully assessed in the context of each trial
• When a proven effective therapy exists, and the use of placebo as
comparator is scientifically necessary and ethically acceptable, it
might be valuable, in some instances, to address in the protocol:
– Rationale for selecting placebo as the appropriate single or add-on
comparator
– The potential consequences for participants in the placebo arm of not
receiving a proven effective therapy (when placebo is used as the single
comparator)
– Safeguards whenever appropriate (for example: rescue medication,
randomized withdrawal design with patient discontinuation criteria, data
and safety monitoring board)
• The concept of not exposing patients receiving placebo in clinical
trials to “any risk” of serious harm should be defined more clearly in
the Declaration of Helsinki 5
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• Use of placebo in clinical trials
– Principle 32
• Use of comparators based on differences in standard
of care and availability of medicines between
developed, emerging and developing countries
– Principles 32 and 35
• Conduct of clinical trials in vulnerable patient
populations
– Principles 9 and 17
• Post-study access to medical care
– Principle 14
Use of Comparators Based on Differences
in Standard of Care and Availability of Medicines
Background
• Selection of comparators based on local or regional standards of care is
accepted and acknowledged by:
– Council for International Organizations of Medical Sciences (CIOMS)
• Introduction and Commentary on Guideline 11 (2002)
– Nuffield Council on Bioethics (NCOB)
• The ethics of research related to healthcare in developing countries (2002,
paragraph 7.29)
– National Bioethics Advisory Commission (NBAC)
• Ethical and Policy Issues in International Research: Clinical Trials in
Developing Countries (2001, Volume I)
– Presidential Commission for the Study of Bioethical Issues
• Moral Science. Protecting Participants in Human Subjects Research (2001,
Recommendation 12)
– Council of Europe (CoE)
• Additional Protocol to the Convention on Human Rights and Biomedicine,
concerning Biomedical Research (2004, paragraph 120)
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Use of Comparators Based on Differences
in Standard of Care and Availability of Medicines
Points for Consideration
• Selection of an active comparator when conducting
multiregional trials in developed and emerging or
developing countries should take into consideration:
– Whether the comparator can be considered scientifically and ethically acceptable
for the patient population/s regardless of where the study is conducted
– Healthcare needs of the country
– Medical and logistical infrastructure
– Medical practices
– Compliance with local regulations
– Genetic differences that may alter responses to medications
• The concept of “best proven intervention” should be
reconsidered to address internal discrepancies within the
document (e.g. between principles 32 and 35), and to achieve
better alignment with other major ethical guidance documents
– “Best proven” could be defined as “established effective intervention” or “best
locally proven intervention” (e.g. referenced to the local standard of care)
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• Use of placebo in clinical trials
– Principle 32
• Use of comparators based on differences in standard
of care and availability of medicines between
developed, emerging and developing countries
– Principles 32 and 35
• Conduct of clinical trials in vulnerable patient
populations
– Principles 9 and 17
• Post-study access to medical care
– Principle 14
Clinical Trials in Vulnerable Patient Populations
Background
• The inclusion of vulnerable patient populations in clinical trials often raises
concerns about their:
– Reduced ability to protect their own interests
– Limited capacity or freedom to consent or to decline to consent
• Vulnerable patient populations include a diverse group of people who may
benefit from the development of new medical treatments, for example:
– Pregnant women
– Extreme of ages (e.g. children, elderly)
– Those with impaired cognitive functions
– Persons with life-threatening diseases or in emergency clinical situations
– Those who are in a dependent situation or deprived of liberty
– Those who may lack access to health care
• The inclusion of vulnerable patient populations in clinical trials is
acknowledged and addressed by:
– Nuffield Council on Bioethics (NCOB)
• The ethics of research related to healthcare in developing countries (2002, paragraphs 4.19-
4.21)
– Council for International Organizations of Medical Sciences (CIOMS)
• International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002,
Guideline 13)
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Clinical Trials in Vulnerable Patient Populations
Points for Consideration
• Clinical trials in vulnerable patient populations are necessary to
generate rigorous and reliable information about potential benefits
and risks of treatments, and to increase the validity of the results
• When conducting clinical trials in vulnerable patient populations
particular attention should be given, for example, to:
– Ethical justifications for their inclusion
– Risks of undue influence, abuse or coercion
– Respect for their dignity, rights, safety and welfare, local norms and
culture
– Expertise and experience required to conduct the clinical study
– Challenges of the consent/assent process
– Role of legal/authorized representative
• Sustained collaboration between patients’ associations and
communities, industry, academia, regulators, and disease advocacy
groups is important to encourage participation by vulnerable patient
populations in clinical trials, while ensuring their full protection as
research participants 11
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• Use of placebo in clinical trials
– Principle 32
• Use of comparators based on differences in standard
of care and availability of medicines between
developed, emerging and developing countries
– Principles 32 and 35
• Conduct of clinical trials in vulnerable patient
populations
– Principles 9 and 17
• Post-study access to medical care
– Principle 14
Post-study Access to Medical Care
Background
• Limited clarity is provided in the Declaration of
Helsinki or other ethical guidance documents about:
– What constitutes post-study medical care
– Which population/s should receive post-study access to
medical care
– Who is responsible to provide post-study access to medical
care
– When post-study access to medical care could/should end
• Our comments relate to post-study access to study
medications
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Post-study Access to Medical Care
Points for Consideration
• Post-study access to medicines being studied for an approved indication is the
responsibility of the applicable government agency or other payer as per usual
healthcare programs
– Sponsor is not responsible for any continued healthcare costs for diseases/conditions that
continue beyond the end of such study
• The sponsor may offer post-study access to the study medication in
circumstances (for example, life-threatening diseases, clinical emergencies)
where no appropriate alternative therapies are available locally:
– Subject to local legal and regulatory requirements
– Guided by best available evidence for a favorable benefit/risk profile
– Plan for post-study access (including discontinuation) should be guided by the documented
pre-trial agreement and any potential modifications
• In cases where the sponsor plans to provide post-study access to the study
medication, supply may be discontinued if:
– In the sponsor’s opinion, new information becomes available that affects negatively the
previous benefit/risk assessment of the medication
– The reviewing agency rejects the request for marketing authorization based upon an
assessment of benefit/risk and there are no further plans to seek authorization
– In all circumstances, the sponsor will work with relevant local authorities and caregivers in the
best interest of the research participants
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