This document discusses the evolution of ethics in research from ancient times to modern day. It covers several important historical cases that shaped research ethics, including the Nazi medical experiments, the Tuskegee Syphilis Study, and the Willowbrook Hepatitis studies. It also outlines some key ethical guidelines and codes developed over time, such as the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. Overall, the document examines how medical ethics and standards for ethical research involving human subjects have developed in response to scandals and abuses.
4. It is not cruel to inflict
on a few criminals
sufferings which may
benefit multitudes of
innocent people
through all centuries.
-Aulus Cornelius Celsus (a 1st
century Roman physicist,
experimented on prisoners.
De Medicina )
5. NAZI MEDICAL WAR CRIMES
• The Medical Case, U.S.A. vs.
Karl Brandt, et al. (also known
as the Doctors' Trial)
• 1946-47
• Twenty-three doctors and
administrators
• Accused of organizing and
participating in war crimes
and crimes against humanity
Freezing Water Experiment in the form of medical
experiments and medical
procedures inflicted on
prisoners and civilians
6. Nuremberg Trials: The Doctors Trial
• Ignorance
• Orders from superiors
• Medically justified
• Others
• 16 found guilty
• Verdict contained a
section “Permissible
Medical Experiments”
The 23 defendants
• Nuremberg Code
7. According to Hermann Goering (one of the defendants in
the Nuremberg Trial) the trial had been nothing more
than an exercise of power by the victors of a war:
justice, he said, had nothing to do with it.
8. ……. most Nuremberg defendants never aspired to be
villains. Rather, they over-identified with an
ideological cause and suffered from a lack of
imagination or empathy: they couldn't fully appreciate
the human consequences of their career-motivated
decisions.
- Douglas O. Linder
9. Lack of:
• Thinking:
…authentic inability to think. Thoughtlessness.
Inability to have an internal dialogue with oneself,
which would permit self-awareness
• Judgment: To exercise imagination, to contemplate
the consequence of actions
Hannah Arendt: Eichmann in Jerusalem. A Report On The Banality Of Evil.
10. THE TUSKEGEE SYPHILIS STUDY
•Initiated in the 1930s by US
Public Health Service (PHS)
•Examination of the natural
history of untreated syphilis
•Continued until 1972
•About 400 black men with
syphilis participated
•About 200 men without
syphilis served as controls
11. • Nature of study not
disclosed
• Treated for ‘bad blood’
Last Chance for
Special Free Treatment
12. • Penicillin was accepted as the treatment for syphilis
in 1943. Deliberately withheld from study subjects.
• Story broke in the Washington Star on July 25, 1972
(Article by Jean Heller of the Associated Press)
• By the end of the experiment, 28 of the men had died
directly of syphilis, 100 were dead of related
complications, 40 of their wives had been infected,
and 19 of their children had been born with
congenital syphilis.
13. • For the greater good of science
• Were just carrying out orders, mere cogs in the
wheel of the PHS bureaucracy, exempt from
personal responsibility.
• The men had been ‘volunteers’ and ‘were always
happy to see the doctors’
• An Alabama state health officer who had been
involved claimed ‘somebody is trying to make a
mountain out of a molehill’
14. • Public outrage prompted Congress to pass the
National Research Act in 1974
• The National Research Act also created the National
Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research
• This commission published the ‘Belmont Report’ in
1979
15. The United States Government did
something that was wrong, deeply,
profoundly, morally wrong. It was an
outrage to our commitment to integrity
and equality for all our citizens.
- President Clinton's apology for the Tuskegee
Syphilis Experiment to the eight remaining
survivors, May 16, 1997
16. The people who ran the study at
Tuskegee diminished the stature of
man by abandoning the most basic
ethical precepts. They forget their
pledge to heal and repair.
They had the power to heal the survivors and all the
others and they did not. Mr. Shaw, the others who are
here, the family members who are with us in Tuskegee,
only you have the power to forgive. Your presence
here shows us that you have chosen a better path than
your government did so long ago.
17. JEWISH CHRONIC DISEASE
HOSPITAL STUDY
• At New York’s Jewish Chronic
Disease Hospital
• In 1963
• To understand whether the body’s
inability to reject cancer cells was
due to cancer or debilitation
• Studies involved the injection of
foreign, live cancer cells into
patients who were hospitalized
with various chronic debilitating
diseases
18. Violations Defense
• Consent oral, not • Documentation
documented unnecessary, much
• Did not include more dangerous
injection of cancer medical procedures
cells were performed
• Study had not been without consent
presented to the
hospital’s research • Would unnecessarily
committee frighten the patients
• Physicians responsible • Good science –
for the patients’ care Cancer cells were
had not been consulted going to be rejected
19. • State of New York brought charges against Dr.
Chester M. Southam (investigator) and Dr.
Emmanuel E. Mandel (hospital’s medical director)
• Board of Regents of the University of the State of
New York suspended the licenses of the
doctors.Subsequently, subsequently stayed the
suspension and placed the physicians on probation
for one year
20. WILLOWBROOK STUDY
• From 1963 through 1966
• Studies at the Willowbrook State
School, a New York institution of
"mentally defective persons"
• Designed to gain an understanding of
the natural history of infectious
hepatitis and
Investigator • Subsequently to test the effects of
"gamma" globulin in preventing or
Dr. Saul Krugmann
ameliorating the disease
21. Children were deliberately infected with the
hepatitis virus
• Early subjects were fed extracts of stools
from infected individuals
• Later received injections of more purified
virus preparations.
Defense by pointing out:
• That the vast majority of them acquired
the infection anyway while at
Willowbrook, and
• It would be better for them to be infected
under carefully controlled research
conditions.
• Informed consent taken
22. • Claiming overcrowded conditions,
Willowbrook closed its doors to
new patients during the course of
these studies
• The hepatitis program, because it
occupied its own space at the
institution, was able to continue to
admit new patients
• Thus to get their children admitted
parents had to agree to their
participation in the studies
23. • Adequacy and freedom of consent
• Inadequate disclosure of risk of later developing
chronic liver disease
• Inadequate information about dosages of gamma-
globulin
24. RADIATION EXPERIMENTS
• 1944-1974
• To advance US national interests (Biomedical
sciences, defense, space exploration)
• Mostly radioactive tracers unlikely to cause harm
25. • Eskimos in Alaska were given
radioactive iodine-131 by the Air Force
in the 1950s
• To study thyroid activity in men
exposed to cold.
• Government is negotiating
compensation
• Cancer patients at the University of
Cincinnati College of Medicine were
given full-body radiation
• More than 60 percent of the patients
were indigent African-Americans with
low IQs
26. • 1946 to 1956
• Fernald State School in Massachusetts
• Researchers from Harvard University and the
Massachusetts Institute of Technology
• Fed radioactive forms of iron (n=17) and calcium
(n =57) to mentally retarded boys from the school’s
science club
• To study the body's ability to digest minerals.
27. • Issue of fairness of selection of participants
• Participants not likely to derive any direct benefit
• Research on participants without their awareness
or (complete) consent
28. • Advisory Committee on Human Radiation
Experiments created by President Clinton in
January 1994
• Recommendations:
Individualized apology, financial compensation
Elimination of all exemptions from informed consent
requirements
29. MILGRAM’S OBEDIENCE STUDY
• 1960-1964
• Examine whether people will
follow orders under the
presence of authority
• Explore explanations for the
atrocities of German soldiers
during World War II
Stanley Milgram
Social Psychologist
• Deception: Effects of
punishment on learning
30. Study Set Up
Electrical Control Panel (115 V switch highest expected)
Switches from 15-450 Volts
31. Violations Defense
• Inadequate measures • Participants could
to protect subjects withdraw at anytime
from stress and the
realization that they • Deception was
were capable of brutal necessary and was
actions explained at end of
• Should have been study
terminated at the first • Stress undertaken
sign of discomfort in would have not have
subjects lasting or injurious
• Non-deceptive effects
methods could have
been used
32. JOHN HOPKINS ASTHMA STUDY
• The study was described as a baseline
physiologic test
• Togias wanted to observe how normal
lungs respond to irritants and asked
healthy volunteers to inhale
hexamethonium.
• A volunteer, Ellen Roche was
coughing, running a fever within days
and had to be hospitalized for lung
Dr. Alkis G. Togias problems (May 2001)
• She had to be put on a ventilator, and
on June 2, she died.
33. In its letter of findings OHRP cited multiple violations,
some as basic as:
• Failure “to obtain published literature about the known
association between hexamethonium and lung toxicity.
Such data was readily available via routine MEDLINE
and Internet database searches, as well as recent
textbooks on pathology of the lung. ”
• Failure “to obtain sufficient information regarding the
source, purity, quality, and method of preparation and
delivery of the hexamethonium used in the research"
prior to approval.”
34. • Failure by the IRB to “receive or request from the
investigators any information regarding the
pharmacology and toxicity of inhaled hexamethonium
in animals or sufficient information regarding the safety
of inhaled hexamethonium in humans.”
• “The informed consent document failed to indicate that
inhaled hexamethonium was experimental and not
approved by the FDA. Furthermore, hexamethonium
was referred to as a "medication" in the informed
consent document.”
35. • OHRP shut down all of Hopkins’ federally
funded human-subject protocols, some 2,800
studies
• Although many ongoing studies were quickly
reinstated, about 1,700 were re-reviewed over
the next several months before they could begin
again
36. CERVICAL DYSPLASIA STUDY
• ICMR sposnored
• 1976-1988
• To observe the natural course of precancerous
uterine cervical lesions without treatment
• 1158 women
• End point: Development of carcinoma in situ
37. • Women with mild and moderate dysplasias at the
beginning of the study who developed severe
dysplasias were also observed until the lesions
regressed or progressed to carcinoma in situ
• In at least nine women the lesions progressed to
invasive cancer, and 62 women developed
carcinoma in situ of the cervix before they were
treated
38. Violations Defense
• No written informed • Most of the women in
consent the study were
• Allegations that the illiterate
investigators had • Study helped India
neither informed the
evolve screening
women that their
guidelines for the
lesions were known to
progress to cancer nor national cancer control
offered them treatment programme
at the outset
39. • The controversy about the study became public in
1997
• ICMR started developing ethical guidelines for
biomedical research in humans, finalised in 2000
40. RCC/JHU ORAL CANCER STUDY
• Novemeber 1999- April2000
• 25 oral cancer patients
• M4N or G4N (could arrest
growth of mouse tumours)
• Regional Cancer Center,
Thiruvananthapuram , Kerala
• Ru Chih Huang, JHU
Dr. Ru Chih Huang
41. • Patients not informed of that drug was being
injected for the first time in humans
• No warning of risks
• Patients not informed that they were being denied
an established treatment.
• Trial had not been approved by the Drugs
Controller of India (approval was obtained
retroactively)
• No ethics clearance from JHU
42. • JHU barred Dr. Huang from serving as
principal investigator on any future research
involving human subjects
43. RAGAGLITAZAR TRIAL
• Discovered by DRL and licensed to Novo Nordisk
• Phase III trials in 32 countries; >2000 patients
• 130 patients from 8 centres in India
• Trial initiated without full animal testing
• Stopped on reports of urinary bladder tumours in
rats and mice
45. LETROZOLE INFERTILITY TRIAL
• Letrozole approved for treatment of breast cancer
in postmenopausal women
• Sponsor: Sun Pharmaceuticals Limited
• 2003
• Research cum promotion: Use of letrozole for
inducing ovulation (infertility)
• >430 women
46. • Contraindicated in pre-menopausal women
• Embryotoxic, fetotoxic, teratogenic
• Schedule G drug; to be sold against prescriptions
of oncologists only
47. • Sponsor: Some marketing people went overboard.
• Sponsor: Off-label prescription of drugs is a
common practice
• Investigator(s): Did not realize that the company
had not received approval from the DCGI for this
indication
• Patients’ protection: Approval of IEC; Information
that the trial was for an unapproved indication
49. PRUSSIAN DIRECTIVE
(BERLIN CODE)
• 29 December, 1900
• First ever government issued directives on human
experimentation
• Conditions for exclusion ‘under all circumstances’
of ‘all medical interventions for other than
diagnostic, healing and immunization purposes,
regardless of other legal or moral authorization’
50. Conditions of exclusion:
• The human subject is a minor or not competent
due to other reasons
• The human subject has not given his unambiguous
consent
• The consent is not preceded by a proper
explanation of the possible negative consequences
of the intervention
51. REICH HEALTH COUNCIL
REGULATIONS
• Regulation on New Therapy and Human
Experimentation
• 28 Feb, 1931. Circular of the Reich Minister of the
Interior
• Acknowledge need for human experimentation
• Focuses on the consent and the well-being of the
subjects
• Responsibility of medical profession
52. NUREMBERG CODE
(1946. Permissible Medical Experiments)
1. Voluntary consent essential
2. Experiment for fruitful results for the good of
society and should be necessary
3. Animal experiments first and human study in
anticipation of scientific benefits
4. Avoid physical and mental suffering and injury
5. No intentional death or disability
53. 6. Risks not to exceed humanitarian importance of
problem
7. Proper preparation and adequate facilities to
protect against even remote possibilities of injury
8. Study only by qualified persons
9. Subject at liberty to discontinue
10. Investigator to stop if harm occurs or is
anticipated
54. BELMONT REPORT
(National 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
55. Respect for Persons
• Individuals should be treated as autonomous
agents (capable of self-determination)
• Persons with diminished autonomy deserve
protection
• Application: Informed consent
56. Beneficence
• Do no harm
• Maximize possible benefits and minimize
possible harms
• Application: Risk/Benefit assessment
57. Justice
• Fairness in the distribution of the benefits
and burdens of research (distributive
justice)
• Application:
Fair procedures and outcomes in the selection
of subjects
Protection of vulnerable subjects
58. DECLARATION OF HELSINKI
• Developed by the World Medical Association
• As a statement of ethical principles to provide
guidance to physicians and other participants in
medical research involving human subjects
• First adopted in 1964 (Helsinki, Finland). Has
undergone 5 revisions; the most recent in October
2000
59. • Research must be based on sound scientific
background
• Considerations related to the well-being of the
human subject should take precedence over the
interests of science and society
60. ETHICAL REQUIREMENTS FOR A
RESEARCH TRIAL
1. Social or scientific value
2. Scientific validity
3. Fair subject selection
4. Favourable risk-benefit ratio
5. Independent review
6. Informed consent
7. Respect for potential and enrolled subjects
