bioethics and translational research

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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 - PowerPoint PPT Presentation


  • Bioethics and translational researchBenjamin S. Wilfond MDSeattle Childrens HospitalTreuman Katz Center for Pediatric BioethicsCenter for Clinical and Translational ResearchUniversity of WashingtonDivision of Bioethics, Department of PediatricsCenter for Genomics and Health Equity, Department of Bioethics and HumanitiesRegulatory Support and Bioethics Core, Institute of Translational Health Sciences

  • What Makes Clinical Research Ethical?Informed consentCompliance with the 10 commandmentsIRB reviewInformed consent and IRB reviewCompliance with Nuremberg, Helsinki, and BelmontCompliance with 45 CFR 46All of the above?From Ezekiel Emanuel

  • Translational CycleCenter for Genomics and Healthcare EqualityUniversity of Washington

    Assessment &PrioritySettingDevelopmentDiscoveryDeliveryOutcomes

  • CaseBY 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 QuestionThe 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 Guidelines1947Nuremberg Code

    1964Declaration of Helsinki

    1979Belmont Report


    1991Common Rule

    born in scandal; not systematic; often incomplete; sometimes contradictory

  • Goals are constrained by ethical obligationsJoffe 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 BenchmarksCollaborative Partnership Social Value Scientific Validity Fair Subject Selection Favorable Risk-Benefit Ratio Independent Review Informed Consent Respect for Human Subjects Emanuel et al. (2000) JAMA; (2004) J Infect Dis

  • Collaborative PartnershipClinical 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 PartnershipMechanisms 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 ValueClinical 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 researchnon-generalizable studies

    Me too studies

    Non-disseminated research

  • Scientific ValidityResearch should produce reliable and valid data that can be interpreted

    Research must be conducted in a methodologically rigorous manner that is practically feasible

  • Invalid researchStudies with biased endpoints, instruments or statistical tests

    Studies that cannot enroll sufficient subjects

    Underpowered studies

  • Fair Subject SelectionThe scientific objectives of the studynot vulnerability or privilegeshould guide inclusion criteria and targeted populations

    Lowering risk and enhancing generalizability can then be considered

  • Fair Subject SelectionConvenient 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 RatioRisks to participants should be balanced by the benefit to individual participants, and when appropriate, the benefit to society.

    The approach

    Risks identified, assessed and minimized.Potential benefits to individuals enhanced.If potential benefits to individual outweigh risks to the individual, then proceed.If risks outweigh the benefits to the individual then evaluate risks against the benefits to the society. Consider risks to the community

  • RisksPotential 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 HospitalizationsConfidentiality protections

  • Benefits to the individualConsider 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 calculationRespectBeneficenceJustice

  • Independent ReviewBecause 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 ConsentInformed consent ensures individuals decide whether they enroll in research and whether research fits with their own values, interests, and goals.

    For those who cannot consentsuch as children and mentally impairedmust be sure research fits with their interests.

  • Four ElementsCompetence/capacity of the subject

    Disclosure of information to the subject

    Understanding or comprehension by the subject

    Voluntariness of the decision

  • Federal Regulations for DisclosurePurpose 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 SubjectsThe 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 researchProviding fair benefits for participation in research

  • 8 Ethical RequirementsCollaborative Partnership Social Value Scientific Validity Fair Subject Selection Favorable Risk-Benefit Ratio Independent Review Informed Consent Respect for Human Subjects Emanuel et al. (2004) J Infect Dis

  • RequiredAll 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.

  • UniversalAll 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 ConflictWhat 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 ConflictsNo 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.

  • ExpertiseThe 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 ConsentBY 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 ValueInformed 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 SelectionTo deny BY access to the STAR trail would be unjust.

    She meets eligibility cr