ETHICS IN RESEARCH

Evolution and Fundamentals

Primum non nocere(First, do no harm)-Hippocrates (in Epidemics)

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 )

Freezing Water Experiment

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 in the form of medical experiments and medical procedures inflicted on prisoners and civilians

Nuremberg Trials: The Doctors Trial

• Ignorance

• Orders from superiors

• Medically justified

• Others• 16 found guilty

• Verdict contained a section “Permissible Medical Experiments”

• Nuremberg CodeThe 23 defendants

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.

……. 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 appreciatethe human consequences of their career-motivated decisions.- Douglas O. Linder

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.

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

• Nature of study not disclosed

• Treated for ‘bad blood’

Last Chance for

Special Free Treatment

• 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.

• 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’

• 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

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

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.

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

Violations Defense• Consent oral, not

documented• Did not include

injection of cancer cells

• Study had not been presented to the hospital’s research committee

• Physicians responsible for the patients’ care had not been consulted

• Documentation unnecessary, much more dangerous medical procedures were performed without consent

• Would unnecessarily frighten the patients

• Good science –Cancer cells were going to be rejected

• 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 probationfor one year

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

• Subsequently to test the effects of "gamma" globulin in preventing or ameliorating the disease

InvestigatorDr. Saul Krugmann

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

• 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

• Adequacy and freedom of consent

• Inadequate disclosure of risk of later developing

chronic liver disease

• Inadequate information about dosages of gamma-

globulin

RADIATION EXPERIMENTS

• 1944-1974

• To advance US national interests (Biomedical sciences, defense, space exploration)

• Mostly radioactive tracers unlikely to cause harm

• 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

• 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.

• Issue of fairness of selection of participants

• Participants not likely to derive any direct benefit

• Research on participants without their awareness

or (complete) consent

• 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

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

• Deception: Effects of punishment on learning

Stanley MilgramSocial Psychologist

Study Set Up(115 V switch highest expected)Electrical Control Panel

Switches from 15-450 Volts

Violations Defense• Inadequate measures

to protect subjects from stress and the realization that they were capable of brutal actions

• Should have been terminated at the first sign of discomfort in subjects

• Non-deceptive methods could have been used

• Participants could withdraw at anytime

• Deception was necessary and was explained at end of study

• Stress undertaken would have not have lasting or injurious effects

• 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 problems (May 2001)

• She had to be put on a ventilator, and on June 2, she died.

Dr. Alkis G. Togias

JOHN HOPKINS ASTHMA STUDY

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.”

• Failure by the IRB to “receive or request from the investigators any information regarding the pharmacology and toxicity of inhaled hexamethoniumin 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, hexamethoniumwas referred to as a "medication" in the informed consent document.”

• 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

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

• 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

Violations Defense• No written informed

consent• Allegations that the

investigators had neither informed the women that their lesions were known to progress to cancer nor offered them treatment at the outset

• Most of the women in the study were illiterate

• Study helped India evolve screening guidelines for the national cancer control programme

• The controversy about the study became public in 1997

• ICMR started developing ethical guidelines for biomedical research in humans, finalised in 2000

• 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

RCC/JHU ORAL CANCER STUDY

Dr. Ru Chih Huang

• 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

• JHU barred Dr. Huang from serving as principal investigator on any future research involving human subjects

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

• Citing confidentiality no details of the 8 centers given by the company

• No patient details

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

• Contraindicated in pre-menopausal women

• Embryotoxic, fetotoxic, teratogenic

• Schedule G drug; to be sold against prescriptions

of oncologists only

• 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

HISTORICAL DOCUMENTS

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’

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

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

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

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

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 personsBeneficenceJustice

Respect for Persons

• Individuals should be treated as autonomous agents (capable of self-determination)

• Persons with diminished autonomy deserve protection

• Application: Informed consent

Beneficence

• Do no harm• Maximize possible benefits and minimize

possible harms• Application: Risk/Benefit assessment

Justice

• Fairness in the distribution of the benefits and burdens of research (distributive justice)

• Application:Fair procedures and outcomes in the selection of subjectsProtection of vulnerable subjects

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

• 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

ETHICAL REQUIREMENTS FOR A RESEARCH TRIAL

1. Social or scientific value2. Scientific validity3. Fair subject selection4. Favourable risk-benefit ratio5. Independent review6. Informed consent7. Respect for potential and enrolled subjects

• Compliance + Conscience

• Active, dynamic

•Compliance

•Passive