Ethical Issues in Human Subjects Research

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Ethical Issues in Human Subjects Research

• Judy Stone, MD

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The first step in the evolution of ethics is a
sense of solidarity with other human
eings. Albert Sweiter
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Milestones in Ethical Development
193272 Tuskegee experiment on syphilis 193945
Nazi experiments 194474 Human radiation
experiments by U.S. government 1946 Nuremberg
Trial of doctors responsible for the Nazi
experiments 1947 Nuremberg Code outlining ethical
principles required for research 1948 United
Nations adoption of Universal Declaration of
Human Rights
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Milestones in Ethical Development

• 1953 NIH policy, the first U.S. federal policy
  introducing independent reviewers to
• examine research, forerunners of the IRBs
• 196366 Willowbrook Study, involving hepatitis
  research on mentally retarded children,
• raising issues access to care, consent, and
  coercion
• 1964 Declaration of Helsinki international
  agreement on recommendations for the ethical
• conduct of medical research
• 1972 Public exposure of Tuskegee syphilis study
• 1974 First federal protections for human research
  participants

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Milestones in Ethical Development

• 1979 Belmont Report promoting three principles
  for research
• 1980 Food and Drug Administration regulations
  (CFR 21 (50)
• 1982 Council for the International Organization
  of Medical Sciences (CIOMS) publication of the
  International Ethics Guidelines for Biomedical
  Research Involving Human Subjects
• 1985 U.S. Public Health Service Task Force on
  Womens Health issues report encouraging
  inclusion of women in research
• 1990 Society for Womens Health Research

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Milestones in Ethical Development

• 1993 Public exposure of U.S. human radiation
  experiments
• 1993 NIH Revitalization Act mandating inclusion
  of women and minorities in research
• 1993 NIH Office of Research on Womens Health

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Milestones in Ethical Development

• 1997 Food and Drug Modernization Act (FDAMA)
  requiring the FDA, NIH, and pharmaceutical
  industry to develop guidance on the inclusion of
  women and minorities in trials
• 1998 Pediatric Rule passed by Congress,
  stipulating that new drugs for children must
  include specific pediatric labeling information
• 2000 Further publicized ethical abuses prompting
  establishment of the Office of Human Research
  Protections (OHRP)

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Belmont Report

• National Commission for the Protection of Human
  Subjects of Biomedical and Behavioral Research
• 3 basic principles for research

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Belmont Report

• Respect for persons, or an individuals autonomy-
• elements of the informed consent requiring that
• Information necessary to make a decision must be
  presented that is,the risks and benefits, if any,
  of participation.
• The information must be presented at a level that
  can be understood by the patient or study
  subject.
• Participation must be voluntary.

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Belmont Report

• Benificience, or benefit to the participant
• Who decides whether there is benefit?

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Belmont-Beneficence

• Loss of substantial benefits that might be gained
  from research
• Paternalism
• Pregnancy
• Life-threatening illness (AIDS/Cancer)

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Belmont-Justice

• Risks and benefits should be equitably
  distributed among different populations
• Do onto others rather than taking advantage of
• Vulnerable populations

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Vulnerable Populations

• Military
• 1944-1979 radiation, chemical,
• Mustard gas, lewisite
• Venezuelan equine encephalitis virus and the
  nerve
• gas agent VX
• Operation Whitecoat (tularemia, anthrax, Q fever)
• 1994 Congressional review the Department of
  Defense
• has demonstrated a pattern of misrepresenting
  the danger of various military exposures that
  continues today

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Vulnerable Populations

• Unsuspecting civilians
• Radiation experiments atomic weapons testing in
• South Pacific
• Oak Ridge
• Los Alamos
• Hanford, Washington
• Plutoniaum injections (ACHRE report)

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Vulnerable Populations
What studies are being done now under the guise
of counter terrorism, hidden from the public by
the Patriot Act?
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Vulnerable Populations-Children

• Pint-size people vs. real data
• 10 drugs most commonly prescribed for children
  that lacked pediatric labelingdrugs were
  prescribed more than 5 million times
• HIV studies in foster children
• Too vulnerable? vs denying access to potentially
  life-saving drugs
• (all HIV kids were being offered the trials)

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Vulnerable Populations-Women

• Pregnancy
• Paternalism
• Woman vs Fetus

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Daily Ethical Encounters

• Participants who are vulnerable from
• Abuse from Doctor-patient relationship
• whatever you say, doc syndrome
• Indigent patients

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Daily Ethical Encounters

• Financial Pressures and Conflict of Interest
• Financial
• Income for Department
• Bonuses
• Structure of grant (pay per visit or end-loaded)
• Pay for screening
• Pay for quality of data, rather than of
  patients
• Avoid disincentives for dropping a patient (e.g.,
  due to adverse reaction
• Pressure re prestiege, publication, tenure

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Other Conflicts of Interestat the Site

• Use of a class of drug in a study-e.g.,
  Quinolones, that you might not use otherwise
• Access to care for indigent patients
• Access to novel drug (pt may lie)
• Adverse event classification

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Yet more COI

• IRB related
• Voluntary, unpaid
• Lack of training
• Paid by drug company
• Pressure from administration
• Personal competition/conflict

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Mrs. G?
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Evaluating a Study

• Does the study ask an important/valuable
  question?
• Is the study design reasonable?
• Would I be willing to be in this trial?

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Evaluating a Potential Volunteer

• Level of understanding based on
• Education, life experience
• Motivation
• Financial need
• vs. ethics of lack of universal health care
• What will happen to the pt when the study ends?
• Stage of illness
• Risk vs. Benefit
• What do they have to lose?
• Would I take this drug or give it to my family
  member?

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Politics of Research Women

• Viewed as vulnerable population
• Paternalism
• Woman vs. fetus
• e.g. AIDs clinical trials
• Religion
• Exclusion of women from participation due to
  restrictions about contraceptive use

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Politics of Research Race

• one-fourth of the U.S. population is made up of
  people of color
• Only 5 of trial participants
• Legacy of distrust
• Tuskeegee
• HIV-foster children study (despite evidence)
• Nigerian Pfizer meningitis trial gt resistance to
  polio vacciination

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Politics of Research Race and Gender Overlap

• 1980 and 1983, fully one-fifth of contraceptive
  research was conducted in developing countries
• Oral contraceptive research in Puerto Rico
• Adverse events analysis was inadequate
• Quinacrine
• The effect of power inequities between men and
  women
• Lack of social support for many women
• Coercion by medical providers or government
  agencies

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Quinacrine-Belmont Principles

• Beneficence
• No safety or toxicity studies of intrauterine
  installation
• Distributive Justice
• Almost all the women were low income, poorly
  educated women of color in developing countries.
• Respect for Persons, autonomy, self-determination
• No explanation of experimental nature of
  quinacrine and no informed consent or offer of
  alternatives

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Shifting Research to Developing Countries

• United States accounts for 4 percent of the
  worlds population vs. 84 for dev. Countries
• 90 percent of is spent on the illnesses of the
  wealthiest countries,
• leaving 10 of monies to care for 84 of the
  global population

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Vulnerable international populations

• Limited economic development
• Inadequate protection of human rights
• Inadequate community and cultural experience
  with, or understanding of, scientific research
• Limited availability of healthcare and
  treatment options
• Limited ability of individuals in the community
  to provide informed consent due to illiteracy and
  language, educational, or cultural barriers

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Vulnerable international populationsWhat
standards should apply?

• Meningitis trial
• Maternal-fetal HIV transmission trials
• Absolute standard of care vs. local standard?
• What if the local standard is to do nothing?
• International consensus is that it is ethical if
• it is based on a valid scientific purpose for
  using a lesser standard, provides social benefits
  for the local host community, and shows a
  favorable risk-benefit ratio for the individual
  research participants

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Vulnerable international populations

• Distributive justice is violated
• the local study populations will not
  significantly benefit from the research if the
  new therapies will not be affordable to them,
  although they are taking a higher proportion of
  the risk.