The ethical conduct of research with human participantsNancy E. Kass, ScDDepartment of Health Policy and ManagementJohns Hopkins Berman Institute of Bioethics

Five minute history of research ethics in the U.S.

• Nuremberg Code• Declaration of Helsinki• Public becomes more aware of potential research

ethics problems in U.S. funded/conducted studies– Jewish Chronic Disease Hospital

– Henry Beecher 1966 NEJM article

– Tuskegee study• Tuskegee Ad Hoc panel convened 1972

The National Commission and The Belmont Report

• 1974-1978: National Commission for the Protection of Human Subjects in Behavioral and Biomedical Research

• produced Belmont Report , which defined principles for ethical research

• Beneficence• Respect for persons• Justice

Three principles of bioethics (from The Belmont Report)• Beneficence:

– duty to protect the welfare of participants• Respect for persons

– duty to respect autonomous persons, their choices, and their information

– Out of respect, duty to protect those less than fully autonomous

• Justice

– Duty to distribute benefits and burdens fairly

How principles apply to research: beneficence• Risks/benefits: to individuals and communities

– Physical

– Psychological

– Social• Considerations when assessing risk:

– Nature of risk

– Likelihood of risk

– Severity/magnitude of harm

– Permanence/reversibility of harm

Study design often consideration of beneficence

– Valid design? Valid findings? If not, no benefit

– Sufficient sample size?

– Is randomization appropriate?

– Are placebos appropriate?

– Surrogate markers vs. clinical endpoints?

– Often can change design to reduce risk

Respect for persons• Requires we go through informed consent

process• Requires we provide additional protection

for persons who cannot consent themselves

• Requires we respect privacy and maintain confidentiality

Elements of informed consent• Disclosure• Understanding• Voluntariness• Capacity (competence)

Evidence and consent forms• Average reading level >8th grade (numerous

studies)• 65 approved forms: avg. 15th grade

(Hammerschmidt and Keane 1992)

– Ann Landers columns avg 7.7 grade

– Reader’s Digest avg 9.95 grade readability

– IRB review never improved by >1 grade level• IRBs’ own boilerplate often >8th grade

(Paasche-Orlow et al 2003)

Participant Understanding: US data• Appelbaum: “therapeutic misconception”

– 69% didn’t know how random assignment had been made

– 32% thought they were in group best for therapeutic needs

– 44% did not know some patients who wanted tx would not get it

– 39% did not understand MD would not know which tx they received

• Riecken and Ravich– 28% didn’t know they were in study, despite

having just signed consent form

Interventions to consent forms can improve understanding• Shortening form (Epstein 1969)

• Overall comprehension: 67% vs. 35%• Lowering readability level (Young 1990)

• Purpose: 77% vs. 44%; Side effects: 72% vs. 58%

• More sections, headings, lay language (Bjorn 1999)

– Randomization: 26% vs. 42%• Corrected feedback or verbalization

– Quiz and correct wrong answers (Taub 1984)

– Verbalization of surgical risks (Wadey 1997)

Justice• Fair selection of individuals• Fair selection of populations• Opposite is exploitation

Justice relevant on many levels• Overall research portfolio

– What diseases do we study? • Who gets them? How many people? Which groups?• Fair distribution of who benefits from overall

research?• Which population do we pick for individual studies?

– Is study particularly relevant to THEM?

– If not, is there a fair distribution/broad inclusion?• What happens after study is over?

– Access to successful intervention?

– Does fairness require this?

U.S. regulations (The Common Rule)• Passed in Congress in 1974

• Additional subparts added later: pregnant women/fetuses; prisoners; children

• Created IRB requirement• Institutions must review all federally funded human research (or all human research, depending on institution’s policy)• Review happens locally, at institution, not at central or national level

• Independent committee• at investigator’s institution• at participants’ institution (“performance site”)

U.S. regulations• IRB must review studies for adherence to ethics

principles, including:– Review risk/benefit; risks minimized

– Review consent elements/procedures and documentation

– Review proper selection of subjects• 1991: adopted by 17 US federal agencies as

“Common Rule”

Investigators’ responsibilities• Think through ethics issues for your project

– minimize harms, choose populations fairly, develop respectful procedures

• Submit protocol to IRB, submit annual reviews to IRB, submit changes to IRB, submit adverse or unanticipated events to IRB

• Maintain records (with IRB, with subjects)• Honesty and integrity as an investigator

Regulations and ethics• You must follow regulations• You must be thoughtful about the ethics of

your studies• If you’re lucky, these will happen at the

same time