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Brief History

Prior to 1906 there were no consumer regulations regarding the ethical use of human subjects in research until the Pure Food and Drug Act was passed.  What follows is a brief history of the events that contributed to the federal rules and regulations governing human subjects in research.

Below is a brief history of the events that contributed to the development of research regulations and ethics rules.

1932 thru 1972

Tuskegee Syphilis Study

Between 1932 and 1972, the U.S. Public Health Service funded a study to evaluate the natural history of untreated syphilis in human beings. When the study was conceptualized, the basic concept was considered scientifically important and ethically justifiable because there was no known treatment for the disease. The research population included one of the most vulnerable research populations-approximately 300 mostly indigent African-American sharecroppers in Macon County, Alabama.

The subjects did not have a meaningful understanding of their condition or the nature of the research that was being conducted.  Many subjects thought they were receiving beneficial medical care and did not understand they were participating in research designed to specifically observe the course of their illness. The subjects were followed, untreated, many years after penicillin was known to cure syphilis.

The study was stopped in 1972 after high profile stories in the national media generated public outrage over the exploitation of this vulnerable segment of society. This study was also instrumental in the passage of the National Research Act in 1974.

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1935 thru 1945

Nazi Medical War Crimes

Nazi physicians conduct experiments during World War II, which were unprecedented in their scope and degree of harm to human subjects

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1938

 

Food & Drug Act is Established (U.S. Law)

The act requires drugs to be shown to be safe before marketing which leads to the need for human subject trials.

Link to the most recent Federal, Food, Drug, and Cosmetic Act  http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm

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1944 thru1974

 Cold War Human Radiation Experiments

U.S government secretly performs thousands of radiation experiments on U.S. citizens.

The Department of Energy's (DOE) published  Human Radiation Experiments: The Department of Energy Roadmap to the Story and Records ("The DOE Roadmap").  The Roadmap summarizes the history of the events and includes a summary of the experiments performed across the country.

Link to DOE’s Roadmap:  http://www.hss.energy.gov/healthsafety/ohre/roadmap/index.html

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1947

Nuremberg Code:  International Code of Research Ethics

Nazis physicians are tried at Nuremberg, Germany, for research atrocities performed on prisoners of war.  Sixteen physicians/administrators are found guilty and their actions are condemned as crimes against humanity. This resulted in the Nuremberg Code, the first internationally recognized code of research ethics, issued by the Nazi War Crimes Tribunal.

Basic Elements of the Nuremberg Code are requirements for experiments:

        ◦ voluntary and informed consent

        ◦ experiments must be scientifically necessary and conducted by qualified personnel

        ◦ favorable risk/benefit analysis: benefit to science must be weighed against risks andsuffering of human research                subjects

        ◦ the right to withdraw without penalty

Resulting Regulations and Ethical Guidelines link: http://ohsr.od.nih.gov/guidelines/nuremberg.html

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1949

International Code of Medical Ethics of the World Medical Assembly

The World Medical Association adopts the International code of professional ethics at its Third General Assembly in London.  The code outlines the duties of physicians in general, the duties of physicians to the sick, and the physicians of doctors to each other.

Detail of the amended policy: http://www.wma.net/e/policy/c8.htm

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1953

First Federal Policy for Protection of Human Subjects                          

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1955

The Wichita Jury Study: Protection of Social Institutions

Researchers at the University of Chicago conducted a study that audio-taped jurors deliberating on cases, without their permission. The public reacted strongly to the concern that deception was used in a setting where privacy and confidentiality were critically important. 

Congressional hearings were held and a federal law was passed barring any future recording of jury deliberations.  This was the first time that well intentioned research resulted in the establishment of federal guidelines to protect the public. It focused attention on how, in some settings, important research questions cannot be answered without compromising the integrity of important social institutions

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1960’s

Milgram Studies of Obedience to Authority

Stanley Milgram, a psychologist at Yale University, conducted a study focusing on the conflict between obedience to authority and personal conscience. He examined justifications for acts of genocide offered by those accused at the World War II, Nuremberg War Crimes trials. Their defense often was based on "obedience" - - that they were just obeying orders whilst under the authority of their superiors.

The experiment began in July 1961, a year after the trial of Adolf Eichmann in Jerusalem. Milgram devised the experiment to answer the question "Could it be that Eichmann, and his million accomplices in the Holocaust were just following orders? Could we call them all accomplices?"

The purpose of the Milgram studies was to understand why people follow the directions of authority figures even when they are told to do things that are cruel or unethical. Subjects were instructed to deliver, at increasingly higher intensities, shocks to others. After they were "debriefed," subjects complained of extreme psychological distress after understanding the potentially lethal level of shocks administered.

The results of the study were made known in Milgram's Obedience to Authority: An Experimental View (1974).

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1962

Thalidomide Experience:  Federal Enforcement of Informed Consent

The drug, Thalidomide (a new sleeping pill) was used in the 1950’s to treat a variety of unpleasant symptoms associated with pregnancy. At the time drug was being used, it was not standard practice to inform patients of the investigational nature or medications that were still in the testing phase of regulatory practice.  After a large number of pregnant women treated with thalidomide, it became clear the drug caused severe growth deformities in their infants.

Public outrage led to an amendment to the Food, Drug and Cosmetic Act (The Kefauver-Harris Bill) to ensure greater drug safety.

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1962

Kefauver-Harris Bill (U.S. Law) – Expansion of Principles from the Nuremberg Code

The Kefauver-Harris bill is passed to ensure greater drug safety in the United States after thalidomide (a new sleeping pill) is found to have caused birth defects.  The 1938 Food, Drug, and Cosmetic Act is amended, empowering the FDA to ban drug experiments on humans until the animal trials for the drug’s safety test have been completed.  

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1963

FDA Establishes Regulation  21 CFR 130.3, later incorporated in 45 CFR 46

        ◦ Requires clinical investigators to certify informed consent as required by the Kefauver-Harris Bill.

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1963

Jewish Chronic Disease Hospital Study

Experiments were performed on chronically ill, mostly demented patients in the Jewish Chronic Disease Hospital. The purpose of the research was to determine how a weakened immune system influenced the spread of cancer. To evaluate this, live cancer cells were injected into the bloodstream of the subjects.

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1963 thru1966

Willowbrook Hepatitis Study

Willowbrook State School was a state-supported institution for children with mental retardation located in central Staten Island in New York City. The school gained notoriety in the 1960s for an unethical hepatitis study conducted at the school. 

The frequent outbreaks of hepatitis at the school led to a highly controversial medical study being conducted at the school between 1963 and 1966.   The study design involved intentionally infecting healthy children with the virus that causes Hepatitis without informing the children or the parents.  The children were mentally retarded and residents of the Willowbrook, a state school.  

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1964

Helsinki Declaration signed by the U.S.  (revised in 1975, 1983, 1989): Expansion of Principles from the Nuremberg Code

The 18th World Medical Assembly met in Helsinki, Finland, and issue recommendations to guide physicians in biomedical research involving human subjects. The guide was known as the Helsinki Declaration.

The declaration reinforced the principles of the Nuremberg Code and added three key points:

        1) The interest of the subject has higher priority than society;

        2) Every subject should get the best known treatment

        3) Requires independent review of all human subject research.

                ◦ Origin of Institutional Review Board (IRB)

Link: http://www.wma.net/e/policy/

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1966

The New England Journal of Medicine (NEJM), Ethics of Clinical Research by Henry Beecher

Described the ethical violations of 22 studies that had been conducted by well-respected researchers and published in prestigious research journals. It was an unprecedented attempt by a respected member of the research community to focus attention on the need to improve ethical standards.

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1966

FDA Establishes Regulation  21 CFR 130.37, later incorporated in 45 CFR 46

        ◦ Establishes specific requirements for  informed consent  

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1970s

San Antonio Contraceptive Study

In the early 1970’s a study was conducted in a contraception clinic in San Antonio, Texas to evaluate the efficacy of different kinds of contraception pills. The clinic served predominantly indigent patients who had no other place to go for contraceptive advice and medication. The study involved randomizing subjects between active contraceptive pills and placebos. The women were not informed that they were the subjects of this type of research or that they might be receiving inactive medication. As expected, there were high numbers of unplanned pregnancies in the placebo group.

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1970’s

Tearoom Trade Study

Social scientist, Laud Humphries posed as a "watch queen" outside public restrooms where people gathered to engage in anonymous homosexual behavior. He recorded the license plate numbers and other identifying information, which he used to obtain their names and addresses. He then presented himself at their homes to interview them about their background and family life. Many subjects were living with their family in a situation where it would be devastating to reveal information about homosexual activity. At no time did the subjects understand they were participating in a study about homosexuality. In his published reports, the level of detail was such that the identity of some of the subjects becomes known.

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1973

Congressional Hearings on the Quality of Health Care and Human Experimentation

The hearings were held in response to public concern about human subject concerns. Some of the studies that raised concern:

        ◦ Cold War Human Radiation Experiments

        ◦ 1960’s Willowbrook Hepatitis Study

        ◦ 1963 Jewish Chronic Disease Hospital Study

        ◦ 1960’s Milgram Studies of Obedience to Authority

        ◦ 1970’s San Antonio Contraceptive Study

        ◦ 1970’s Tearoom Trade Study

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1974

National Research Act  (U.S. Law)

Due to the publicity from the Tuskegee Syphilis Study, the National Research Act of 1974 was passed. The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was charged with identifying the basic ethical principles for conducting biomedical and behavioral research involving human subjects.

This Act prompted the establishment of IRBs at the local level and required IRB review and approval of all federally funded research involving human participants. (IRB procedures were established)

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1974

FDA Establishes Regulation  45 CFR 46, Regulations for the Protection of Human Subjects of Biomedical and Behavioral Research

        ◦ Establishes Institutional Review Board (IRB) procedures  

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1974

FDA Establishes Regulation  45 CFR 46, Subpart B

        ◦ Establishes special protections for pregnant women and fetus

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1978

FDA Establishes Regulation  45 CFR 46, Subpart C

        ◦ Establishes special protections for prisoners

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1979

Belmont Report (U.S. Ethical Guidelines)

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research publishes the Belmont Report: the Ethical Principles and Guidelines for the Protection of Human Subjects of Research.

Three basic ethical principles which all IRB members should use to evaluate the ethics of research proposals.

        1) Respect for Persons

                ◦ individuals should be treated as autonomous agents

                ◦ persons with diminished autonomy are entitled protection

        2) Beneficence

                ◦ do no harm

                ◦ research should maximize possible benefits and minimize possible harm

        3) Justice

                ◦ the benefits and risks of research must be distributed fairly

Link to Belmont Report: http://ohsr.od.nih.gov/guidelines/belmont.html

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1980 thru1983

President’s Commission for the Study of  Ethical Problems in Medicine and Biomedical and Behavioral Commission

The commission recommends that all federal agencies adopt the human subject regulations of the Department of Health and Human Services (DHHS). 

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1981

FDA revises regulations to correspond to DHHS regulation, 21 CFR 50, Informed Consent

The Department of Health and Human Services (DHHS) establishes the IRB regulations (45 CFR 46) which are commonly referred to as the “common rule”.

Main elements of the Common Rule (Subpart A):

        ◦ requirements for assuring compliance by research institutions

        ◦ requirements for researchers obtaining and documenting informed consent

        ◦ requirements for IRB membership, function, operations, review of research and record keeping

        ◦ requirements for additional protections for certain vulnerable research subjects

                ~ pregnant women and fetuses

                ~ prisoners

                ~ children

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1986

FDA Establishes Regulation  45 CFR 46, Subpart D

        ◦ Establishes special protections for children

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1991

16 agencies adopt the regulations of 45 CFR 46, Subpart A – many adopted Subparts B, C  and D  

 

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1993

Albuquerque Tribunal publicizes Human Radiation Experiments

The Albuquerque Tribunal publicizes 1940s experiments involving plutonium injections of human research subjects and secret radiation experiments. Indigent patients and mentally retarded children were deceived about the nature of their treatment.

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1994

National Bioethics Advisory Commission Formed

President Clinton creates the National Bioethics Advisory Commission (NBAC).

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1995

Human Radiation Experiments Report

The President's Advisory Commission on Human Radiation Experiments concludes that some of the radiation experiments from the 1940s were unethical and special care must be taken when research must be kept secret.

Catalyst for establishing the National Bioethics Advisory Committee (NBAC)

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1996

Death of a healthy volunteer, Nicole Wan

         ◦ University of Rochester  Medical Center

         ◦ Lung function study

Link to article http://query.nytimes.com/gst/fullpage.html?res=9C03E0DF153CF934A1575AC0A960958260

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1966

FDA Regulations revised, 21 CFR 50.24

Allows exceptions from informed consent requirements for research studies involving emergency research.

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1997

Apology to Tuskegee Experimental Subjects

President Clinton issues a formal apology to the subjects of the Tuskegee syphilis experiments. NBAC continues investigations into genetics, consent, and privacy.

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1999

Death of a healthy volunteer, Jesse Gelsinger

         ◦ University of Rochester  Medical Center

         ◦ Lung function study

Link to article http://www.gene.ch/gentech/1999/Dec/msg00005.html

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2001

Death of a healthy volunteer, Ellen Roche

         ◦ Johns Hopkins

         ◦ Asthma Study

Link to article http://newsbreaks.infotoday.com/nbreader.asp?ArticleID=17534

Link to Johns Hopkins Medical News  http://www.hopkinsmedicine.org/hmn/f01/postop.html

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2002

NBAC Charter is not Renewed

The U.S. Department of Health and Human Services (DHHS) under President Bush appointee Tommy Thompson decides not to renew the charter of the National Bioethics Advisory Commission (NBAC)

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2004

Secretary’s Advisory Committee on Human Research Protection

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