Jonathan D' Moreno, Ph'D' Center for Biomedical Ethics University of Virginia

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Jonathan D. Moreno, Ph.D.Center for Biomedical
EthicsUniversity of Virginia
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Ethics of Clinical Investigation

• Pre- WWII
• Nuremberg Code and aftermath
• 1962-1972-Scandals and Tragedies
• National rules and international codes
• Current issues

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The Nuremberg Code, 1947

• The voluntary consent of the human subject is
  absolutely essential.

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Army Inspector General, 1975

• Following revelations of Army LSD experiments in
  the 1960s
• ...a startling lack of consistency in the
  interpretation of the regulations.

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The thalidomide tragedy,early 1960s
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Henry Beecher

• NEJM paper, 1966
• Brooklyn Jewish Chronic Disease Hospital
• Willowbrook State Hospital

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The U.S. P.H.S. Syphilis Study
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Syphilis study physical exam
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Nurses examine a study participant
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Charlie Pollard, one of the survivors who
accepted President Clintons apology in 1997
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THE BELMONT REPORTNational Commission for the
Protection of Human Subjects of Biomedical and
Behavioral Research 1979

• A. Boundaries between research and practice
• B. Ethical principles underlying the conduct of
  research
• Respect for persons
• Beneficence
• Justice

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45CFR.46, Department of Health and Human Services

• PHS policy (1966)
• National Research Act (1974)
• DHEW regulations (1981)
• Part A is the Common Rule for 17 Federal
  agencies (1991)
• Parts B,C,D for vulnerable populations
• B Fetuses, pregnant women, infants of uncertain
  viability
• C Prisoners
• D Children

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Common Rule

• Composition and function of a local institutional
  review board (IRB)
• IRB to assure that risks are minimized, research
  risks are reasonable in relation to expected
  benefits, subject selection is equitable, and
  informed consent will be obtained from each
  subject.

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Common Rule

• Risks to subjects are reasonable in relation to
  anticipated benefits, if any, to subjects, and
  the importance of the knowledge that may
  reasonably be expected to result.
• IRB review need not be local
• Exempt researche.g., educational tests, unlinked
  biomaterials from public sources
• Expedited reviewe.g., minimal risk

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FDA REGULATIONS

• Primarily found in 21CFR.56 and 21CFR.50
• 21CFR.50 Protection of Human Subjects
• 21CFR.56 IRB composition and function
• Minor differences from the common rule.

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FDA REGULATIONS

• Part 54-Financial disclosure
• Part 312- IND applications
• Part 314- applications to market a new drug
• ICH-GCP- represents the agencys current
  thinking on good clinical practices

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The Office for Human Research Protections and the
FDA

• OHRP
• Office of the DHHS Secretary
• Responsible for insuring compliance with common
  rule and department-specific regs
• Has authority to halt human research programs

• FDA
• Regulates research and development of new drugs
  and devices
• Drugs and devices must be developed in compliance
  with common rule
• Has authority to prohibit violators from further
  research

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Renewed concerns about clinical trials

• UCLA suicide, 1994
• Normal volunteers deaths (Rochester, Hopkins,
  Case Western), 1996-2002
• Gelsinger death at Penn, 1999
• Kennedy-Krieger lead study, 2001

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Jesse the day he learned he had qualified for the
study.

• The adenovirus stimulated a fatal immune
  response. Later it was learned that one of the
  investigators had a financial interest in the
  company that held the patent, and that previous
  adverse events were unreported. The researchers
  are barred from human studies, and Penn shut down
  its HGT program

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The perinatal AZT trial in Thailand

• Could a shorter and cheaper course of AZT prevent
  perinatal transmission?
• Harvard group, NIH funded
• Double-blind, placebo controlled
• Was placebo control ethical?

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Declaration of Helsinki (2000)

• The benefits, risks, burdens and effectiveness of
  a new method should be tested against those of
  the best current prophylactic, diagnostic, and
  therapeutic methods. This does not exclude the
  use of placebo, or no treatment, in studies where
  no proven prophylactic, diagnostic, and
  therapeutic method exists.

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Declaration of Helsinki (October 2002 statement)

• ... a placebo-controlled trial may be ethically
  acceptable, even if proven therapy is available,
  under the following circumstances- Where for
  compelling and scientifically sound
  methodological reasons its use is necessary to
  determine the efficacy or safety of a
  prophylactic, diagnostic or therapeutic method,
  or - Where a prophylactic, diagnostic or
  therapeutic method is being investigated for a
  minor condition and the patients who receive
  placebo will not be subject to any additional
  risk of serious or irreversible harm.

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Current Issues in the Ethics of Clinical Trials

• International research
• Pediatric research
• Persons lacking decision making capacity
• Human biomaterials
• Innovative surgery
• National security

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Institute of Medicine report, October 2002

• IRBs should focus on ethics, not science or
  conflict of interest
• Non-partisan congressional advisory body
• No-fault compensation system for harms
• Informed consent should not focus on protecting
  institutions, but on protecting subjects

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• For here we are not afraid to follow the truth
  wherever it may lead.