4/22/2015
Evolving History of
Human Research
Protections
Monika Markowitz
WHY SO MUCH TIME ON HISTORY?
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How did we arrive at this point?
– Human nature being what it is…
– “The 3 R’s”: Rationalization, Reaction, Regulation
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History
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places ethics in perspective
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Your subjects know, so you should know
“Those who fail to study history are
condemned to repeat it”
- Our obligation to prevent unethical research
“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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The ‘beginnings’ of Research Ethics…
Nazi Medical Experiments WWII
High Altitude Test Chamber at Dachau
Twin Studies in Auschwitz
Dr. Josef Mengele
reviewed and funded by grant
from Reichsforschungsrat
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Hypothermia Experiments at Dachau
Dr. Sigmund Rascher (r), executed by Gestapo for violating marriage laws
Case No. 1 of the Nuremberg Military Tribunal U.S.A. vs. Karl Brandt et al.
Dec 9, 1946 ‐ Aug 20, 1947
Defendants and Defense Counsel
15 of 23 guilty, 7 hanged, 5 life sentences
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NUREMBERG CODE
1947
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Voluntary informed consent absolutely essential
Research should yield useful results
Base research on prior work
Avoid physical and mental suffering
No expectation of death or disabling injury
Risk must be outweighed by importance
Subjects must be protected from injury
Qualified scientists, adequate facilities
Subject free to stop at any time
Investigator must be ready to withdraw subject
Willowbrook State School Staten Island, 1956‐1963
• Institutionalized children
• Deliberate infection with hepatitis A
• Coercive
recruitment
through
restricted
admission
• Rationalization
Introducing Jerry Rivers, 1971
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• Deception?
– consent form seemed to say that children were to receive a vaccine against the virus
• Coercion?
– Alleged that parents who enrolled their children in the study were g
p
y
initially offered more rapid admission to the school through the hepatitis unit and later found, due to overcrowding, that the only route for admission of new patients was through the hepatitis unit
• Direct harm?
– deliberate attempt to infect the children as opposed to studying the course of disease in children who naturally became sick
Wichita Jury Taping Study
1953
• Researchers tape recorded jurors’ deliberations in six cases to
measure influence of attorney comments on decision making
• Research was conducted with knowledge of judge and attorneys,
but jurors not aware
• Tapes played at law conference concerns over repressive effect on juror
deliberations
• Resulted
esulted in federal law banning all
recording of jury proceedings in 1956
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Staged Experiments on Obedience to Authority
Stanley Milgram, Yale University, 1960’s
Fake“Student”
Researcher
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Subject - “Teacher”
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Was there harm?
“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
He pulled on his earlobe, twisted his hands, and at one point pushed his fist into his forehead and muttered: ‘Oh, God, let’s 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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Jewish Chronic Disease Hospital Brooklyn, 1963
• Elderly debilitated patients injected with live cancer cells (HeLa) to study immunologic response (re: transplant rejection)
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• Patients not informed of cancer cells
– investigators did not wish to frighten unnecessarily
– a priori hypothesis that cells would be readily rejected
”…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
DECLARATION of HELSINKI World Medical Association, 1964
Consent… preferably 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
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revised 1975, 1983, 1989, 1996, 2000, 2002, 2004, 2008
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Henry Beecher – a physician indicting medical research
• Studied Nazi medical experiments
• U.S. was also guilty of violating research
violating research participants’ rights
• “Ethics and Clinical Research” (NEJM 1966)
• Prompted NIH and FDA to revise guidelines
• Twenty‐two examples of potentially serious ethical violations in experiments found in recent issues of medical journals
• Reduced from 50 "for reasons of space"
• research had not taken place "in a remote corner, but [in] . . . leading medical schools, university hospitals, top governmental military departments, governmental institutes and industry.
Tearoom Trade Study
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Laud Humphreys, 1970
Sociological study of homosexual
encounters
• Several stages involving
deception...
• Observation in public
restrooms
• Obtaining names and
addresses through
license plates
• In
In--home interviews
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“Untreated Syphilis in the Male Negro”
Macon County, Alabama
1932‐1972
“Bad Blood”
“This examination
is a very special
one and after it is
finished you will
be given a special
treatment if it is
believed you are in
a condition to
stand it
it.”
“Remember this is
your last chance
for special free
treatment.”
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Published Papers 1936‐1964
PHS Syphilis Study
• In February 1969 the CDC convened a blue ribbon panel to review study
– Panel concluded (with one dissension) that treatment would not help subjects and therefore the study should continue
– "You will never have another study like this; take advantage of it"
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IGNORE THIS SYPHILIS PATIENT (EXPERIMENT IN PROGRESS)
Philadelphia Inquirer, 1972
“Sometimes, with the best of
intentions, scientists and public
officials… working for the benefit of
us all, forget that people are people.
They concentrate so totally on
plans and programs,
programs experiments,
experiments
statistics- on abstractions- that
people become objects, symbols on
paper, figures in a mathematical
formula…”
Atlanta Constitution, July 27, 1972
US National Research Act
July, 1974
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Established National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974‐1978)
– The Belmont Report (1979)
Code of Federal Regulations (1981)
– Institutional Review Boards (IRBs)
– Informed consent
Common Rule (1991)
Public Law 93-348
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Charge to the National Commission
–Identify the basic ethical principles which should underlie the conduct of biomedical and behavioral research g
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involving human subjects
–Develop guidelines to assure that such research is conducted in accordance with those principles
National Research Act, 1974 (PL 93-348)
National Commission
• "investigators should not have the sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others who are independent of the research must share in this responsibility"
Report and Recommendations on
Institutional Review Boards (1978)
Belmont Conference Center
Baltimore, MD
Site of National Commission meetings in Feb 1976 that led to
“The Belmont Report”
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Belmont Report (1979)
• three basic ethical principles that should govern human subject research:
– respect for persons
– beneficence
– justice
RESPECT FOR PERSONS
Treat individuals as autonomous agents
Don’t use people solely as a means to an end
Allow people to choose for themselves
Fundamental right to be left alone
Fundamental right to be left alone Extra protections for those with diminished autonomy
• Practical application: informed consent, privacy protections, confidentiality
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BENEFICENCE
• Acts of kindness or charity that go beyond duty
– (bene = good, fica = to make)
• Corollary:
Corollary: Non‐maleficence
Non maleficence
• Maximize benefits & minimize risk of harm
• Practical application: study design, risk:benefit, competent investigators, manage conflicts of interest
Beneficence
• "Beneficence is understood … as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do no harm, and (2) maximize possible benefits and minimize possible harms"
Belmont Report, 1979 JUSTICE
• Burdens and benefits of research should be distributed equitably
• Treat people fairly
• Practical application: selection of subjects, recruitment, populations under study
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Distributive vs. Procedural Justice
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www.cartoon
nstock.com
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Conflict Among Ethical Principles
Respect for Persons
Beneficence
Justice
• Principles carry equal moral weight
•This tension was anticipated and expected
•Requires subjective judgment calls
•Reasonable people will disagree
Case
22 children in the custody of the state were told they were to receive speech therapy. Instead they were placed in intervention and control groups, to try to induce stuttering in healthy children and to see whether stutterers would improve if told that their speech was fine. Many of the normal h i
h
fi
M
f h
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speaking orphan children who received negative therapy in the experiment suffered negative psychological effects and some retained speech problems for the rest of their lives.
• University of Iowa publicly apologized for the Monster Study in 2001.
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Translating Ethical Principles Into
Regulations
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