EVOLVING PROTECTIONS FOR HUMAN RESEARCH SUBJECTS: History and Ethical Principles

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EVOLVING PROTECTIONS FOR HUMAN RESEARCH SUBJECTS
History and Ethical Principles

• Daniel Nelson
• Director, Office of Human Research Studies
  Associate Professor of Social Medicine
• and Pediatrics
• University of North Carolina-Chapel Hill

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PROTECTING HUMAN RESEARCH SUBJECTS

• History
• Ethical Principles
• Current Issues
• QA

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WHY SO MUCH TIME ON HISTORY?

• How did we arrive at this point?
• Human nature being what it is
• The 3 Rs Rationalization, Reaction,
  Regulation
• History places ethics in perspective
• Those who fail to study history are condemned to
  repeat it

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It is not cruel to inflict on a few criminals
sufferings which may benefit multitudes of
innocent people through all centuries.
Celsus, 1st century AD
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Informed consent contract used by Maj. Walter
Reed for experiments that resulted in yellow
fever infection in Cuba, signed 26 Nov
1900 (duplicate in Spanish)
Courtesy of Col. Arthur Anderson, U.S. Army
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Berlin Code of 1900

• medical interventions for purposes other than
  diagnosis, therapy, and immunization are
  absolutely prohibited if
• 1. human subject is a minor or not competent
• 2. human subject has not given unequivocal
  consent
• 3. consent is not preceded by proper explanation
  of possible adverse consequences of intervention

Directive to medical directors of all hospitals
from the Royal Prussian Minister of Religious,
Educational and Medical Affairs, Berlin City
Council, Dec 1900
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German Government Directive of 1931

• Medical science must advance, but individual
  physician has special duty and major
  responsibility for life and health of
  patient-subject
• Risks proportionate to anticipated benefits
• Tested in advance on animals
• Unambiguous consent
• Special caution if minors
• Exploitation of social hardship is unethical
• Academic training should stress special
  obligations when conducting research or publishing

Regulations on New Therapy and Human
Experimentation from the Reich Minister of the
Interior, Feb 1931
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Nazi Medical Experiments in WWII Concentration
Camps
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High Altitude Test Chamber at Dachau
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Twin Studies in Auschwitz
Dr. Josef Mengele
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Romanian Gypsy in Potable Seawater Experiments at
Dachau
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Deliberate Phosphorous Burn to Test Medications
at Buchenwald
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Hypothermia Experiments at Dachau
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Dr. Leo Alexander with Survivor of Experiments at
Ravensbrueck
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Case No. 1 of the Nuremberg Military Tribunal
U.S.A. vs. Karl Brandt et al.Dec 9, 1946 - Aug
20, 1947
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Defendants and Defense Counsel
15 of 23 guilty, 7 hanged, 5 life sentences
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NUREMBERG CODE

• Voluntary consent of the subject is absolutely
  essential
• Research must be for benefit of society
• Research should build on animal experiments and
  previous knowledge
• Procedures must avoid unnecessary mental and
  physical suffering, and include provisions to
  avoid risk of injury and death

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NUREMBERG CODE(continued)

• Degree of risk must not exceed the importance of
  the problem
• Adequate facilities and qualified investigators
• Subject must be free to stop at any time
• Investigator must be prepared to stop if there is
  risk of injury, disability or death

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Before IRBs, the only consent required was that
of a researcher's department head. The Nuremberg
Code was ignored in practice. As I look back on
it, the interpretation of these codes was that
they were necessary for barbarians, but not for
fine upstanding people... In this prestigious
unit we had a very strong obligation to behave in
a civilized manner.
Dr. William Silverman, Columbia pediatrician, on
the postwar mentality
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Willowbrook State School Staten Island, 1956-1963

• Institutionalized children
• Deliberate infection with hepatitis A

• Coercive recruitment after admission closed due
  to overcrowding

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Birth Defects from Thalidomide during Pregnancy
Revised Food and Drug Administration (FDA)
requirements, 1962
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Thalidomide Finally Approved by FDA in 1998
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(No Transcript)
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Staged Experiments on Obedience to AuthorityYale
University, 1960s
FakeLearner
Experimenter
Subject - Teacher
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• I observed a mature and initially poised
  businessman enter the lab smiling and confident.
  Within 20 min he was reduced to a twitching
  stuttering wreck rapidly approaching a point of
  nervous collapse. He pulled on his earlobe,
  twisted his hands, and at one point pushed his
  fist into his forehead and muttered Oh, God,
  lets stop it. And yet he continued to respond
  to every word of the experimenter, and obeyed to
  the end.

Stanley Milgram, 1963
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Tearoom Trade Study

• Sociological study of homosexual encounters

• Several stages involving deception...
• Observation in public restrooms
• Obtaining name and address through license plates
• In-home interview

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Jewish Chronic Disease Hospital Brooklyn, 1963

• Elderly debilitated patients injected with live
  cancer cells to study immunologic response (per
  transplant rejection)
• Patients not informed of cancer cells
• investigators did not wish to frighten
  unnecessarily
• a priori hypothesis that cells would be readily
  rejected

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the judgment of the investigator is not
sufficient as a basis for reaching a conclusion
concerning the ethical... set of questions."
NIH panel that investigated studies at Jewish
Chronic Disease Hospital
The investigator's judgment must be subject to
prior peer review to ensure an independent
determination of risks and benefits and
...voluntary informed consent."
NIH Director James Shannon, endorsed by Surgeon
General William Steward, Feb 1966
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DECLARATION of HELSINKI World Medical
Association, 1964

• Consent should be in writing
• Research should build on previous work
• Research must follow written protocol
• Review by an independent committee
• Caution if subject is in dependent relationship
  with investigator
• Subjects must receive best proven diagnostic and
  therapeutic methods
• studies in sub-Saharan Africa on perinatal
  transmission of HIV

revised 1975, 1983, 1989, 1996, 2000
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Landmark Article on U.S. Abuses
Henry Beecher, NEJM, 1966
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Birth Control ClinicSan Antonio, 1971

• Impoverished Mexican-American women with multiple
  pregnancies
• Placebo-crossover trial
• Without knowledge/consent
• 10/76 became pregnant on placebo

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Untreated Syphilis in the Male Negro Macon
County, Alabama1932-1972
Tuskegee Syphilis Study
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In beginning the study, schedules of the
blood-drawing clinics throughout the county were
announced through every available source,
including churches, schools, and community
stores. The people responded willingly, and 600
patients were selected for the study--400 who had
syphilis and, for controls, 200 who did not. The
patients who had syphilis were all in the latent
stage any acute cases requiring treatment were
carefully screened out for standard therapy.
From Twenty Years of Followup Experience in a
Long-Range Medical Study, Rivers et al, Public
Health Reports, 69391-5, 1953
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Bad Blood
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Spinal Tap, 1933
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Nurse Rivers and the Government Doctors in the
early 1950s
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NOW can we give him pencillin?
Philadelphia Inquirer, 1972
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US National Research Act1974

• Established National Commission for Protection of
  Human Subjects
• The Belmont Report, 1979
• Code of Federal Regulations, 1974, 1981
• Institutional Review Boards (IRBs)
• Informed consent
• Common Rule, 1991

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THE BELMONT REPORTEthical Principles and
Guidelines for the Protection of Human Subjects
of Research

• Respect for Persons
• Beneficence
• Justice

National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research,
1979
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RESPECT FOR PERSONS

• Treat individuals as autonomous agents
• Fundamental right to be left alone
• Dont use people as a means to an end
• Extra protections for those with diminished
  autonomy
• Practical application informed consent, respect
  for privacy