History of Clinical Trials

Dr. Bhaswat S Chakraborty

http://fcit.coedu.usf.edu/holocaust/gallery2/77021.htm

The Nazi Medical War Crimes

• “Medical experiments” were performed on thousands of concentration camp prisoners

• Included deadly studies and tortures such as injecting people with gasoline and live viruses, immersing people in ice water, and forcing people to ingest poisons

Dachau

Execution of Dachau SS

Eisenhower at Ohrdruf

War Crimes Tribunal at Nuremberg

• Indictments:– Conspiracy to commit crimes against peace– Planning, initiating and waging wars of

aggression– War-Crimes– Crimes against humanity

War Crimes Trial at Nuremberg

In his closing remarks Robert Jackson, the U.S. Chief Prosecutor issued the following warning:

“….. If we cannot eliminate the causes and prevent the repetition of these barbaric events, it is not an irresponsible prophecy to say that this twentieth century may yet succeed in bringing the doom of civilization”

The Nuremberg Trial• December 1946

– 23 physicians and administrators– for their willing participation in the systematic torture,

mutilation, and killing of prisoners in experiments– Despite the arguments of the German physicians that the

experiments were medically justified, the Nuremberg Military Tribunals condemned the experiments as “crimes against humanity”

– 16 were found guilty and imprisoned– 7 were sentenced to death

• August 1947 verdict– A section called “Permissible Medical Experiments.” This

section became known as the Nuremberg Code

1. The voluntary consent of the human subject is absolutely essential.  This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.   2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.  3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.  4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.  5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

Directives for Human Experimentation

NUREMBERG CODE

6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.  7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.  8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.  9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.  10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject._____________________

Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182.. Washington, D.C.: U.S. Government Printing Office, 1949.

Directives for Human Experimentation

NUREMBERG CODE

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study• 1932-72, More than 400 black men with syphilis &

about 200 men without syphilis– recruited without informed consent– misinformed that some of the procedures (e.g., spinal

taps) were actually “special free treatment”

• 1940s, Penicillin found to be effective in syphilis– the study continued, however, and the men were neither

informed nor treated with the antibiotic

• 1972, Congress established regulation for human research

• 1997, President Clinton apologized

Jewish Chronic Disease Hospital Study

Jewish Chronic Disease Hospital Study

• 1963, New York City's Jewish Chronic Disease Hospital– studies to develop information on the nature of the human transplant

rejection process– involved the injection of live cancer cells into patients who were

hospitalized with various chronic debilitating diseases

• Researchers said that consent had been given orally, but was not documented– felt that documentation was unnecessary– because much more dangerous medical procedures are undertaken

without the use of consent forms– would frighten the patients unnecessarily– good cause

• Researchers were found guilty of fraud, deceit and unprofessional conduct

Harold Blauer • Dec 1952, Harold Blauer

– voluntarily admitted to the New York State Psychiatric Institute for treatment of depression

– Injected with three different mescaline derivatives supplied by the U.S. Army Chemical Corps to determine the clinical effects of chemical warfare agents in a research project that was classified secret

– consented to the first injection, which was fraudulently offered to him as a treatment for his depression

– after each of the first four injections, the subject told the nurses that he did not want any further injections, because of his adverse reactions

– after the fifth injection, which was 16 times stronger than the previous injection of this new compound, his body stiffened, his teeth clenched, and he began frothing at the mouth for 2 hours until he lapsed into a coma and died

• The death certificate attributed the death to "coronary arteriosclerosis; sudden death after intravenous injection of a mescaline derivative

• A lawsuit was filed against State of New York, which operated the Institute• 1955, Malpractice claim was settled for money

Willowbrook Study• From 1963 through 1966, studies were carried out at the Willowbrook State School, a

New York State institution for "mentally defective persons." • These studies were 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.

• The subjects, all children, were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations.

• Investigators defended the deliberate injection of these children by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and perhaps it would be better for them to be infected under carefully controlled research conditions.

• During the course of these studies, Willowbrook closed its doors to new inmates, claiming overcrowded conditions.

• However, the hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients. Thus, in some cases, parents found that they were unable to admit their child to Willowbrook unless they agreed to his or her participation in the studies.

• This case caused a public outcry because of the perception that parents and their children were given little choice about whether or not to participate in research.

Willowbrook Study

Willowbrook Study• From 1963 through 1966, studies were carried out at the Willowbrook State School, a

New York State institution for "mentally defective persons." • These studies were 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.

• The subjects, all children, were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations.

• Investigators defended the deliberate injection of these children by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and perhaps it would be better for them to be infected under carefully controlled research conditions.

• During the course of these studies, Willowbrook closed its doors to new inmates, claiming overcrowded conditions.

• However, the hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients. Thus, in some cases, parents found that they were unable to admit their child to Willowbrook unless they agreed to his or her participation in the studies.

• This case caused a public outcry because of the perception that parents and their children were given little choice about whether or not to participate in research.

Cincinnati Radiation Experiments

• 1960-72, Cancer patients mostly Blacks of below-average intelligence– Exposed to large doses of whole body radiation as part of an

experiment sponsored by the U.S. military– None of the subjects gave informed consent, they thought they

were receiving treatment for their cancer– Subjects experienced nausea and vomiting from acute radiation

sickness, pain from burns on their bodies, and some died prematurely as result of radiation exposure.

• In re Cincinnati Radiation Litigation, 874 F.Supp. 796 (S.D.Ohio 1995)

• May 1999, a settlement was announced

The Radioactive Milk Study

• From 1946 to 1956, at the Fernald State School in Massachusetts. Researchers from Harvard University and the MIT,19 boys who thought they were participating in a science club were fed radioactive milk by researchers who wanted to learn about the digestive system.

The Belmont Report

• Respect for Persons (autonomy)– Individual should be treated as autonomous agents– Persons with diminished autonomy may need additional

protections

• Beneficence– Obligates the researcher to maximize possible benefits and

minimize possible harm

• Justice– Attempts must be made at all times in a study to distribute the

risks and benefits fairly and without bias. Also, unless there is clear justification, research should not involve persons from groups that are unlikely to benefit from subsequent applications of the research

Thank You Very Much