Bioethics and translational research
Benjamin S. Wilfond MD
Seattle Children’s Hospital
Treuman Katz Center for Pediatric Bioethics
Center for Clinical and Translational Research
University of Washington
Division of Bioethics, Department of Pediatrics
Center for Genomics and Health Equity, Department of Bioethics and Humanities
Regulatory Support and Bioethics Core, Institute of Translational Health Sciences
What Makes Clinical Research Ethical?
• Informed consent
• Compliance with the 10 commandments
• IRB review
• Informed consent and IRB review
• Compliance with Nuremberg, Helsinki, and Belmont
• Compliance with 45 CFR 46
• All of the above?
From Ezekiel Emanuel
Translational Cycle
Center for Genomics and Healthcare Equality
University of Washington
Discovery
Development
Assessment &
Priority
Setting
Outcomes
Delivery
Case
• BY is a 46 year old post-menopausal mentally disabled
woman with DCIS.
• Caregivers from her “home” with power of attorney for
health care decisions, bring her to the clinic for
enrollment in STAR trial, randomized trial of tamoxifen
vs. raloxifene for the prevention of breast cancer in high
risk women.
• She fulfills all entry criteria but cannot consent.
The Question
• The physician who saw BY wants the IRB to reconsider
the subject selection criteria for the STAR trial
• The IRB debates the question:
• Is it ethical to enroll a mentally incompetent patient in a Phase III
randomized chemo-prevention trial?
Wide Array of Ethical Guidelines
• 1947
Nuremberg Code
• 1964
Declaration of Helsinki
• 1979
Belmont Report
• 1982
CIOMS
• 1991
Common Rule
• “born in scandal”; not systematic; often incomplete;
sometimes contradictory
Goals are constrained by ethical obligations
Benefit to
patient and
family
Clinical Care
Promote
scientific
knowledge
Research
Joffe and Miller. Hastings Center Report 2008
Why Do We Need Ethical Guidelines?
• Clinical research develops generalizable knowledge that
improves health or increases understanding
• People who participate in clinical research are a means
to securing that generalizable knowledge
• As a means, these people can be exploited, that is be
used as a means for the benefits of others
• Ethical benchmarks for clinical research are meant to
minimize the possibility of exploitation
8 Ethical Benchmarks
1.
Collaborative Partnership
2.
Social Value
3.
Scientific Validity
4.
Fair Subject Selection
5.
Favorable Risk-Benefit Ratio
6.
Independent Review
7.
Informed Consent
8.
Respect for Human Subjects
Emanuel et al. (2000) JAMA; (2004) J Infect Dis
Collaborative Partnership
• Clinical research should involve the community in which
it occurs
• This requires:
• Community participation in planning, conducting and overseeing
research, and integrating research results into the health system.
• Avoidance of supplanting existing health care services and the
sharing rewards with the community.
Collaborative Partnership
• Mechanisms to achieve collaborative partnerships
include:
• Community based participatory research
• Community advisory boards
• Patient advocates on scientific advisory boards and IRBS
• Advocates for funding of research
Social Value
• Clinical research should lead to improvements in health
or advancement in generalizable knowledge
• Must consider how the research will affect:
•
•
•
Participants in the research
Community in which research is conducted
World
Valueless research
• non-generalizable studies
• “Me too” studies
• Non-disseminated research
Scientific Validity
• Research should produce reliable and valid data that can
be interpreted
• Research must be conducted in a methodologically
rigorous manner that is practically feasible
Invalid research
• Studies with biased endpoints, instruments or
statistical tests
• Studies that cannot enroll sufficient subjects
• Underpowered studies
Fair Subject Selection
• The scientific objectives of the study—not vulnerability or
privilege—should guide inclusion criteria and targeted
populations
• Lowering risk and enhancing generalizability can then be
considered
Fair Subject Selection
• Convenient groups should not be selected.
• Groups should not be excluded without scientific
reasons.
• Higher risk is a reason to exclude certain groups.
• Should not select rich, politically powerful or otherwise
well connected people for “promising research” studies.
Favorable Risk-Benefit Ratio
•
Risks to participants should be balanced by the benefit
to individual participants, and when appropriate, the
benefit to society.
•
The approach
1. Risks identified, assessed and minimized.
2. Potential benefits to individuals enhanced.
3. If potential benefits to individual outweigh risks to the individual,
then proceed.
4. If risks outweigh the benefits to the individual then evaluate
risks against the benefits to the society.
5. Consider risks to the community
Risks
• Potential risks to consider include:
•
•
•
•
•
Physical —death, disability, infection
Psychological —depression and anxiety
Social —discrimination
Economic —job loss
Community risks to others not directly involved in the research
• Evaluate the:
•
•
Likelihood of harm
Magnitude of harm
• Identify mechanisms to minimize risks:
• Additional diagnostic tests
• Hospitalizations
• Confidentiality protections
Benefits to the individual
• Consider physical, psychological, social, and economic
benefits to the individual
• Consider only benefits from research interventions not
benefit from added health services or payment that are
not necessary to the research goals
• Benefits related to payment or other services may be
justified and even obligatory, but are independent of the
benefit/risk calculation
• Respect
• Beneficence
• Justice
Independent Review
• Because investigators have multiple legitimate interests,
they have potential conflicts of interest
• Independent review of the research minimizes these
conflicts
• Independent review also assures society it will not
benefit from abuse of subjects
Informed Consent
• Informed consent ensures individuals decide whether
they enroll in research and whether research fits with
their own values, interests, and goals.
• For those who cannot consent—such as children and
mentally impaired—must be sure research fits with their
interests.
Four Elements
• Competence/capacity of the subject
• Disclosure of information to the subject
• Understanding or comprehension by the subject
• Voluntariness of the decision
Federal Regulations for Disclosure
•
•
•
•
•
•
•
•
Purpose and duration of participation
Risks
Alternatives
Benefits
Confidentiality of records
Compensation for injuries
Person to contact for answers to questions
Voluntariness and right to withdraw
Respect for Human Subjects
•
The ethical requirements of research do not end with a signed
consent document. Also include:
•
•
•
•
•
•
Protecting confidentiality
Permitting withdrawal
Providing new information
Monitoring welfare
Informing participants what was learned from the research
Providing “fair benefits” for participation in research
8 Ethical Requirements
1.
Collaborative Partnership
2.
Social Value
3.
Scientific Validity
4.
Fair Subject Selection
5.
Favorable Risk-Benefit Ratio
6.
Independent Review
7.
Informed Consent
8.
Respect for Human Subjects
Emanuel et al. (2004) J Infect Dis
Required
• All 8 benchmarks are necessary and essential to make clinical
research ethical.
• Independent review and informed consent are procedural
benchmarks to ensure certain values are achieved.
• Other procedures may achieve these values. In some
circumstances, independent review and informed consent can be
waived.
Universal
• All 8 ethical benchmarks are universal. They do not apply only to the
US or Europe. They apply to clinical research everywhere.
• The 8 ethical benchmarks must be adapted to the local health,
economic, cultural and technological circumstances. For instance,
disease risk effects risk-benefit evaluation.
Benchmarks may Conflict
• What is fair in subject selection may increase risks
• What enhances scientific validity may increase risks
• What is necessary to respect enrolled subjects or obtain informed
consent may compromise scientific validity
Resolving Conflicts
• No simple formula for resolving conflicts.
• Adjust design to meet the requirements. This is sometimes termed
“balancing”, “weighing” or “specifying” the principles.
• The important point is to be clear about what is being done and give
reasons why.
• Different approaches may equally ethical.
Expertise
• The expertise necessary to implement these
benchmarks includes:
•
Educated and trained investigators
•
IRBs with investigators, statisticians, ethicists, and community
representatives.
Back to Our Question(s)
• Is it ethical to enroll a mentally incompetent patient in a
Phase III randomized chemo-prevention trial?
• Is it ethical to enroll BY in a randomized trial to
determine which of two hormonal therapies is better at
preventing cancer with the fewest side effects?
Emphasize Informed Consent
• BY cannot consent
• There are many eligible participants for the STAR trial
• BY is not necessary to the trial
• Enroll patients who can consent
Emphasize Risk-Benefit & Social Value
• Informed consent is not an absolute requirement.
• The risk-benefit ratio is positive
• BY is at least as well off in the trial as in clinical care and
will be contributing to scientific knowledge
•
As long as mentally disabled patients are not being
unfairly targeted, enroll BY
Emphasize Fair Subject Selection
• To deny BY access to the STAR trail would be unjust.
• She meets eligibility criteria and has a similar risk-benefit
ratio to other potential participants.
• The only reason for excluding her is unrelated to science
but related to mental condition.
What is our mission?
Protect participants
and communities
Promote scientific
knowledge
Trustworthy research practices
ITHS Bioethics Consultations (www.iths.org)
• Providing a forum for discussion and analysis of ethical issues in
clinical and translational research
• For researchers, research staff and trainees, IRBs, research
participants and their families, and communities
• Advisory to requestor
• Supplemental to IRB or DMC oversight
• Conducted via phone, email or in person
• Written report can be provided
Research Bioethics Consult Questions
•
Community engagement:
• How can I establish sustainable relationships with communities?
• How should I negotiate disagreements with community stakeholders?
• How should I share the research data with the community?
•
Study Development:
• Should I provide incentives for participation?
• What if informed consent isn't practical for my study?
• When is a placebo-control ethically appropriate?
•
Study Implementation:
• What should I do if a participant doesn't have the capacity for consent?
• Can I withdraw a participant against his/her wishes?
• What must I do if my participants need medical care or other help?
•
Study Analysis:
• Should I tell participants about their research findings?
• What if a participant requests their data be withdrawn?
• Who should be an author on the publication of my study?
Thanks to…
• Members of the ITHS Bioethics Team of the Regulatory Support and
Bioethics Core: Kelly Edwards, Malia Fullerton, Maureen Kelley, and
Ben Wilfond
• Department of Bioethics, National Institutes of Health Clinical Center
(from whom we adopted some slides from the “ethical and
regulatory aspects of clinical research course”)
• Slides, webcast, and podcasts at
• http://www.bioethics.nih.gov/hsrc/index.shtml