IRB 101: Highlights of the History of Human Subjects Protections Columbia University Medical Center IRB September 22, 2005

Objective Provide an overview of the events that have led to the system of protections that are currently in place to protect individuals who volunteer for research. IRB 101, Part I provides a more in-depth look at the history.

Pre-20 th Century Medical practice developed from medical research No formal, widely-accepted codes Reliance on morals, ethical principles of culture, Hippocratic Oath

20 th Century 1900: Walter Reed’s Yellow Fever experiments –1898: Spanish American War –968 soldiers killed in combat –5000+ died of disease, mostly Yellow Fever –United States Army Yellow Fever Commission –Major Walter Reed –Conducted experiments outside of Havana –Proved that the mosquito transmits Yellow Fever –First systematic use of informed consent in research

Elements present in Yellow Fever Consent Form: Autonomy (respect for persons): “gives his consent…for the reasons and under the conditions…” Voluntary Participation : “being in the enjoyment and exercise of his own free will” Risks : “In case of the development of yellow fever in him, that he endangers his life to a certain extent.” Benefits : “He will receive from the said commissioner the greatest care and the most skillful medical service.” Compensation: “he will receive the sum of $100 in American gold...” Study withdrawal conditions : “The undersigned binds himself not to leave the bounds of this camp during the period of the experiments and will forfeit all right to the benefits named in this contract if he breaks this agreement.”

1932: PHS Study of Syphilis Significant health problem No initial intent to deny treatment –Complete physical exam, medical history taken –Followed for 6-8 months without treatment New follow-on study started in late 1933 –New procedures to strengthen scientific validity, control group –No information provided about true nature of study: “government doctors” were examining people for “bad blood” Penicillin accepted as curative treatment in 1943 –Not provided –Exemption from draft to keep subjects in study

Nazi Experimentation Findings of the Tribunal: In every single instance appearing in the record, subjects were used who did not consent to the experiments;… In no case was the experimental subject at liberty of his own free choice to withdraw from any experiment. … All of the experiments were conducted with unnecessary suffering and injury and but very little, if any, precautions were taken to protect or safeguard the human subjects from the possibilities of injury, disability, or death. In every one of the experiments the subjects experienced extreme pain or torture, and in most of them they suffered permanent injury, mutilation, or death, either as a direct result of the experiments or because of lack of adequate follow-up care.

Findings of Nuremberg Trial THE NUREMBERG CODE [from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, October 1946–April Washington, D.C.: U.S. G.P.O, 1949–1953.] First Tenet - The voluntary consent of the human subject is absolutely essential.

Nuremberg Code and Voluntary Consent This means that the person involved should: –Have legal capacity to give consent –Situated as to be able to exercise free power of choice, …; 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 reasonably to be expected; 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

1946, Fernald School Massachusetts Institute of Technology researchers and Fernald staff members Studies with radioisotopes at the school The first study, in 1946, exposed seventeen students to radioactive iron. The second study exposed fifty seven subjects to radioactive calcium between 1950 and 1953.

Fernald Consent Documents Misleading information implies benefits No mention of radioisotopes Coercive Active consent not required

Late 1950’s Thalidomide Tragedy –Approved in Europe as sedative –Not approved in U.S. –Samples provided to U.S. physicians paid to study safety and efficacy 1962 Amendments to U.S. Food, Drug and Cosmetic Act (Kefauver-Harris Amendments)

Willowbrook New York University researchers Willowbrook State School for the Retarded located on Staten Island Residents were injected with a mild form of hepatitis serum The researchers hoped to find a treatment for the virus by studying the disease in it’s earliest stages

1961 Milgram Obedience Study Recruitment by newspaper ad: –$4.50 for one hour's work –Psychology experiment investigating learning and memory Involved deception Individuals were asked to give what appeared to be real electric shocks to another person The researchers wished to test how far subjects would follow the orders of an experimenter Post-experiment interview

1960’s 1964 Declaration of Helsinki – Expansion on Informed Consent –In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed NIH Policies for the Protection of Human Subjects issued –Established the IRB as one mechanism through which human subjects would be protected.

1970’s 1972 Syphilis study exposed –Study stopped in March 1973 and treatment provided 1974 National Research Act passed (raised NIH policy to regulation) – Required regulations for protection of human subjects Informed consent Institutional Review Boards –Created National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979 Belmont Report published by National Commission –Respect for persons (informed consent) –Beneficence (minimize risk, evaluate risk/benefit ratio) –Justice (selection of subjects)

1981 Based on Commission’s reports and recommendations: –Significant revisions to HHS and FDA human subject regulations Clarified IRB role No change in general principles of review –DHHS regulations codified at Title 45 Part 46 of the Code of Federal Regulations (45 CFR 46) Effective 1/16/81; revised 3/4/83; 6/18/ revision involved adoption of Federal Policy for Protection of HS – “Common Rule” (Subpart A) – by 16 agencies Subparts B,C,D adopted 1978, 1978, 1983 respectively –FDA regulations codified at Title 21 Parts 50 (1980), 56 (1981) Additional regulations for drugs, devices, device classification

Summary Formal codes for protection of human subjects relatively recent Subsequent to abuses of human subjects in research Limited in extent of protection