Promoting Integrity in Research Involving Human Subjects

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Promoting Integrity in Research Involving Human
Subjects

• Elise A. Ralph, Ph.D.
• Assistant Vice Chancellor for Sponsored Research
• UW Tacoma
• eralph_at_u.washington.edu

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Objectives

• Discuss historical abuses of participants that
  influenced guidelines for human subject research.
• Describe the three Belmont Report principles that
  guide ethical conduct of research.
• Describe how the institutional review boards
  (IRBs) consider these issues

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Objectives (continued)

• Describe the types of IRB reviews.
• Describe the content required in a consent form.
• Given case studies, recognize human subjects
  issues and discuss ways to prevent and/or resolve
  these problems.

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Moral problem in research involving humans

• The goal of research is the generation of useful
  knowledge about humanity
• Research is systematic investigation including
  research development, testing and evaluation
  designed to develop or contribute to
  generalizable knowledge.
• Benefit to participants is not the purpose of
  research (although it does occur)
• People are the means to developing useful
  knowledge and are thus at risk of exploitation

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It was presumed that lofty goals meant ethical
practices until recognized abuse led to rules
for Human Research

• Questions about research arose because of failed
  ethics
• Nazi medical experiments in concentration camps
  1930-1945
• Federally funded Tuskegee syphilis study
  1932-1972

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Nazi Medical War Crimes

• So-called medical experiments conducted on
  uninformed and unwilling concentration camp
  prisoners
• Most carried through to death
• After WWII, 20 MDs 3 laypersons found guilty of
  crimes against humanity.
• 7 sentenced to death, the others to 10 yrs to
  life imprisonment
• Resulted in the NUREMBERG CODE
• First international code of medical research
  ethics
• (United States Holocaust Memorial Museum, n.d.)

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Tuskegee Syphilis Study (continued)The Ethical
Beginning

• 1926 An estimated 35 of men of reproductive age
  have syphilis. There is no effective and safe
  treatment
• 1929 Drs. Clark and Vondelehr at Tuskegee begin
  research on effects of topical Mercury and
  Bismith on syphilis. Funding lost after Wall
  Street Crash reduces foundation funds.
• 1931 Drs. Clark and Vondelehr continue to follow
  participants to show need for treatment program
• (Centers for Disease Control and Prevention,
  2005)

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Tuskegee Syphilis Study (continued) The Slippery
Slope

• 1932 US Public Health Services funds "Tuskegee
  Study of Untreated Syphilis in the Negro Male to
  document natural course of syphilis in black men
  and possibly justify treatment programs for
  African Americans.
• At the time there is no safe effective treatment
  for syphilis
• 399 poor black sharecroppers with syphilis and
  201 men without (controls) agree to participate.
  They are falsely told that some of the
  assessments being performed (e.g. spinal taps)
  are treatment.
• (Centers for Disease Control and Prevention,
  2005)

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Tuskegee Syphilis Study (continued) The Slippery
Slope (continued)

• 1934-36 Study begins publishing findings.
  Infrequent concerns are raised about whether the
  men are receiving any treatment. There is no
  general outcry.
• 1940s Local black and white MDs agree not to
  treat the study men for syphilis. Study is
  widely known in Tuskegee and few questions are
  raised.
• (Centers for Disease Control and Prevention,
  2005)

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Tuskegee Syphilis Study (continued) The Clear
Unethical Turn

• 1945 Penicillin becomes known as an effective and
  safe drug for syphilis.
• 1947 Penicillin readily available to the US poor
  via federally funded Rapid Treatment Centers
  (RTCs) established to treat poor people with
  syphilis.
• Participants are denied access to Penicillin from
  all controllable sources (e.g., RTCs, general
  public clinics, local black and white MDs, Armed
  Forces).
• Participants not given option to withdraw from
  study.
• (Centers for Disease Control and Prevention,
  2005)

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Tuskegee Syphilis Study (continued) The Fallout

• 1968 Public concerns raised about ethics of the
  study
• 1969 Center for Disease Control and AMA defend
  studys continuation
• 1970 Newspaper and magazine articles condemn the
  study
• 1971 Congress holds hearings
• 1972 Front-page NY Times article causes large
  public outcry
• 1972 Per panel recommendation, the study is ended
  
• 1973 Class action suit - participants compensated
  with cash and continued medical care for
  themselves and their families.
• (Centers for Disease Control and Prevention,
  2005)

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Tuskegee Syphilis Study (continued) The Effect
on US Policy

• 1974 National Research Act, creates the National
  Commission for the Protection of Human Subjects
  of Biomedical and Behavioral Research
• Requires that all researchers get voluntary
  informed consent from all research participants
  in Dept. of Health, Education and Welfare funded
  studies.
• 1997 President Bill Clinton apologizes to all
  participants and their families on behalf of
  nation. Reparations paid
• (Centers for Disease Control and Prevention, 2005)

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What Guides Responsible Study of Humans?

• Since the 1974 National Research Act, the Belmont
  Report (the result of the National Commission for
  the Protection of Human Subjects of Biomedical
  and Behavioral Research) has been the dominant
  research ethics statement

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Belmont Report Principles

• Autonomy/ Respect
• Beneficence
• Justice

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Principle of Autonomy/Respect

• Persons have a right to decide if they will or
  will not participate in a study
• Persons who cannot make a competent decision
  (i.e., vulnerable individuals) must be protected
  by outside decision makers and must be closely
  monitored
• Persons invited to participate must know
  understand risks and benefits, and be informed if
  these change while in the study
• Individuals may decline or withdraw without
  penalty
• Children must give assent before participating in
  study

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Principle of Beneficence

• Research design and method should yield valid
  results
• If possible, do no harm
• If harm in an inescapable risk, minimize it and
  maximize direct benefits to study participants
• Inform participants of risk and benefits.

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Principle of Justice

• Access to risk benefit must be fairly
  distributed in society.
• Studies should not exclude by age, race, sex,
  etc. without strong reason.
• When possible, studies should randomly assign
  participants to treatment groups to ensure that
  risk and benefits are equally distributed

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The Unexpressed Belmont Principle

• The researcher cannot decide whether she or he is
  conducting reasonable research, meeting ethical
  requirements, or has a conflict of interest
• The Tuskegee studies (among others) show that
  researchers can be myopic when it comes to their
  own studies.
• There must be external review and oversight by
  individuals and groups not directly involved in
  the study.

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Federal Rules and Regulations

• Seventeen federal agencies have regulations
  governing research involving humans.
• The Common Rule 45 CFR 46
• Contracts and grants from these agencies require
  that rights of participants be ensured and
  overseen by both federal and institutional bodies

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Academic Institutions Rules and Regulations

• Educational institutions generally require that
  all faculty all students performing research
  have their studies reviewed by the College or
  University Institutional Review Board (IRB) or
  Human Subjects Protection Office.
• This is typical regardless of research locale,
  regardless of whether faculty/students are being
  paid or conducting the research gratis, and
  regardless of whether faculty/student are
  conducting the research as part of their
  faculty/student roles or as external jobs.

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Ethical framework 7 principles

• Valuable scientific question
• Valid scientific methodology
• Fair subject selection
• Favorable risk-benefit evaluation
• Independent review
• Informed consent
• Respect for enrolled subjects

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Valuable Scientific Question

• Is the research question one that will generate
  new knowledge or understanding about human health
  or illness, i.e. a socially, clinically, or
  scientifically useful question ?
• Minimize Exploitation and Responsibly use
• resources

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Valid Scientific Methodology

• Is the study designed in a way (methodology,
  design, statistical power and methods, etc.)
  that is feasible?
• Will it yield valid, reliable, generalizable,
  and interpretable data?
• Minimize Exploitation and Responsibly use
• resources

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Fair Subject Selection

• Selected for reasons of science and study
  purpose, not because of ready availability,
  vulnerability, or favor?
• Consistent with scientific goals, selected so to
  minimize risks and maximize benefits, and fairly
  distribute research burdens and benefits
• Excluded only for good reasons of science,
  vulnerability, or susceptibility to risk or
  burden.

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Balance of Risks and Benefits

• Are risks to subjects necessary and minimized?
• Are risks justified by benefit to individual
  subjects and/or the importance of the knowledge
  to society?
• Are benefits maximized?
• Non-maleficence and Beneficence

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Independent Review

• Has the study received independent review to
  ensure the public that investigator biases have
  been checked, that ethical requirements have been
  fulfilled, and that subjects will not be
  exploited?
• Minimize conflict of interest Public
  Accountability

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Informed Consent

• Does the plan for informing participants about
  the objectives, risks, benefits, and alternatives
  of the study, assessing understanding, and
  seeking their voluntary agreement seem adequate?
• Extra protections for those with limited capacity
  to consent
• Respect for Persons

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Respect for Enrolled Subjects

• Are there adequate plans for respecting the
  rights and welfare of enrolled subjects during
  and at the end of the study?For example, plans
  for protecting confidentiality of data,
  monitoring their welfare, informing them of new
  information and of study results, respecting
  their right to withdraw at any time?
• Beneficence and Respect for Persons

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Institutional Review Board

• Uses prospective review. Review and permission
  required before any research takes place
• Assign review type based on level of risk vs
  benefit, and according to the Federal guidelines
• Exempt public info, use of anonymous data, no
  subject contact
• Expedited (quicker - single reviewer) minimal
  risk, adults, typical daily activities
• Full committee (requires individual review
  followed by discussion of committee) research on
  children, study of treatment or assessment that
  have risk, sensitive topics
• The IRB, not the researcher, makes category
  decision

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IRB (continued)

• The IRB must review each study
• Regardless of the type of study (qualitative vs.
  quantitative descriptive vs experimental
  natural history vs intervention), and
• Regardless of the researcher (student vs faculty)

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The Consent Form

• The Consent Form is only 1 part of the informed
  consent process
• Consent forms should be readable at lt8th grade
  reading level
• Consent Forms are used for adults gt18 years old
• Assent Forms are used for subjects 8-17 years old
• Verbal or nonverbal consent/assent can be
  accepted for young children, non-competent
  persons non-literate adults
• Nonverbal consent/assent may be documented by
  witness or by videotape/ audiotape of
  explanation and participant response

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Contents of Consent Form (Elements of Informed
Consent, 21 C.F.R. 50.25, 2000)

• Purpose and details of the research study,
  including description of drugs or devices (tools
  or pieces of equipment) or procedures used in the
  research study and type of assignment and odds of
  assignment to different study groups.
• Identification of the researching individuals and
  affiliations. Students should be identified as
  students, but should not indicate that the
  research is to complete degree requirements
• Explanation of research procedures, schedule and
  timeline of the research study.
• Costs of research procedures, drugs, devices,
  etc. and who is responsible to pay.
  Differentiation of research expenses from those
  of usual care.

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Contents of Consent Form (continued)

• Payment or non-payment to participant.
• Risks, dangers, and discomforts of the study, and
  means that will be used to control for these.
• (physical, psychological, social/economic, legal,
  etc.)
• Benefits and advantages of participating in the
  research study. Direct benefits, not payment or
  good to society.
• Alternatives to study participation.
• Medical treatment available if participant is
  injured by the research, and who will pay for
  this treatment.

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Contents of Consent Form (continued)

• Who, if anyone, will have access to subject data,
  and whether study results will identify
  participant
• Will study create or use any Protected Health
  Information (PHI), and if data will be part of
  chart.
• Assurance that participation is voluntary and
  person may quit without affecting future
  treatment or current relationships. Description
  if treatment requires withdrawal or monitoring
  after quitting.
• Statement that data may be withdrawn from study
  or why this is not possible.

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Contents of Consent Form (continued)

• Assurance that new information will be shared
  with participants
• Chance to ask questions about the research study.
• Outside-of-study contact information.
• Place to sign consent/assent form,
• Notice that they will be given a copy of
  signed/dated form for their records.
• Place for investigator to sign, date form.
• Place for witnesses signature/date, if witness is
  needed

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Consent Forms for Non-English Speakers

• Generic forms may be used with more detailed oral
  explanation, to obtain consent from occasional
  non-English speaking participants.
• Generic forms cannot substitute for properly
  translated consent form in studies of primarily
  non-English speakers.

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Adverse Events Unexpected Experiences

• Definitions
• Adverse events are any experience that suggests a
  significant hazard, contraindication, side
  effect, or precaution even if it is already
  listed as possible in IRB materials
• Unexpected adverse experiences are any adverse
  experience whose nature, severity, incidence
  are not described in the information provided for
  IRB review or in the consent form
• Immediately report events/experiences to the IRB
  change procedure and consent accordingly.
• If event/experience is significant, IRB may pause
  or stop study

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Unanticipated Problems or Events

• Report unanticipated problems that might affect
  subject
• Risk/benefit analysis,
• Confidentiality,
• Participants willingness to continue
• The IRB will consider the effect of the problem
  on the study and on the participants already
  enrolled.

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More Information

• Please contact UWs Human Subject Division
• http//www.washington.edu/research/hsd/