Clinical Research History

c. 500 BCE / King Nebuchadnezzar and His Legume and Lentil Trial
The first recorded clinical trial can be found in the “Book of Daniel” in The Bible. King Nebuchadnezzar, ruler of Babylon, ruled that his subjects should only eat meat and drink wine, for he thought this was the best diet to keep people in good physical condition. Several men of royal blood rebelled, because they preferred vegetables and legumes. Nebuchadnezzar allowed them to continue their diet of legumes, lentils, and water, but for ten days only. At the end of Nebuchadnezzar’s experiment, he found that the men eating legumes seemed healthier and stronger. Nebuchadnezzar allowed the men to continue their vegetable and legume diets.
1025 / Avicenna’s “Canon of Medicine”
Persian scientist and philosopher Avicenna compiled medical knowledge and experience s in five books entitled the Canon of Medicine. Within the encyclopedia, Avicenna described how to test drugs, suggesting the use of contemporary clinical trial methods nearly a thousand years ago.
1537 / First Clinical Trial of Novel Therapy
Famous surgeon AmbroiseParé was responsible for treatment of battlefield soldiers. Because of the high volume of injured soldiers, Paré ran out of treatment oil and was forced to improvise on the battlefield with a digestive made of egg yolks, rose oil, and turpentine. Upon examining the wounds treated with this new digestive, Paré found the soldiers in little pain with little swelling and inflammation. In contrast, soldiers treated with the oil were feverish and in pain. Though an accident, Paré had conducted the first clinical trial of novel therapy.
1667 / First Documented Paid Research Subject
Samuel Pepys, an English diarist, recorded that a poor man was paid to have sheep blood “let into his body” buy the local college.
1747 / James Lind’s Scurvy Trial
James Lind is credited with being the first physician to conduct a controlled clinical trial in the modern era. He selected twelve sailors with scurvy, all in similar condition. Splitting the sailors into pairs, Lind tested five potential treatments along with the treatment that the hospital surgeon recommended. Lind was able to determine that the sailors that were given oranges and lemons were fit for duty within 6 days. Keeping meticulous records of the trial, Lind eventually wrote a treatise in 1753. However, the Royal Navy did not mandate lemon juice as a part of a sailor’s diet for nearly 50 years after Lind’s discovery.
1796 / Edward Jenner and Smallpox Inoculation
Upon hearing that many milkmaids had acquired immunity to smallpox after exposure to animal forms of the disease, Edward Jenner conducted his own experiments. Using fresh cowpox lesions from a milkmaid, Jenner inoculated his own son, and later another young boy. Both boys recovered from the initial illness, and when exposed again to smallpox, no disease developed.
1820s / William Beaumont’s Document of Indenture
As an army doctor, Beaumont treated a young soldier who eventually acquired a gastrocutaneous fistula from the initial gunshot wound. With the soldier debilitated and destitute, Beaumont used the opportunity to perform medical experiments on the soldier. The patient agreed to the experiments and signed a “document of indenture”, which gave him lodging and payment of $150 a year in exchange for his cooperation in Beaumont’s experiments. Though not exactly informed consent, the document was one of the first giving human research subjects some rights. Beaumont documents the experiments in Psychology of Digestion (1833).
1862 / President Lincoln Creates the Department of Agriculture
The Department included the Bureau of Chemistry, which was the predecessor of the FDA.
1863 / First Placebo Use
American physician Austin Flint compares the use of an active treatment for rheumatism with a placebo in order to test the effects of the active treatment. The experiment set precedence for other physicians to use the same method in order to test the effects of active drugs.
1865 / Claude Bernard’s Introduction to the Study of Experimental Medicine
Bernard, a French physiologist, published this text and detailed that it is the researcher’s right to and duty “to perform an experiment on man whenever it can save his life, cure him or gain some personal benefit.” Bernard also stated that it was wrong to “perform on man an experiment which might be harmful to him to any extent.”
1907 / William Osler at the Congress of American Physicians and Surgeons
Osler, a noted physician and professor at Johns Hopkins Medical School, gave an address stating the importance of experiments benefitting the patient. He also stated the importance of receiving “full consent” from patients after giving them “full knowledge of the circumstances.”
1932 - 1972 / Tuskegee Syphilis Study
The Public Health Service collaborated with the Tuskegee Institute to study the natural history of syphilis. The study initially consisted of 600 black men who were not informed about the true purpose of the study. Instead, researchers told the men they were being treated for “bad blood”. The study was only supposed to last six months, but ended up spanning 40 years.
In the summer of 1972, the Associated Press exposed the unethical treatment of the Tuskegee men. Public outcry resounded upon hearing that the researchers did nothing to treat the syphilis, even when penicillin became the treatment of choice in 1947. It also exposed the lack of knowledge the research subjects had about the actual research. The project was solely meant to observe syphilis, but many of the subjects thought they were given treatment. The public outcry forced an advisory panel to review the case, which eventually called the study “ethically unjustified”, immediately stopping the study.
Mid 1930’s – 1945 / Nazi Medical War Crimes
During World War II, Nazi physicians often performed experiments on prisoners in concentration camps. The prisoners were involuntarily placed in the experiments without giving consent and without being given information about the experiments. Most experiments resulted in the death, disfigurement, or permanent disability. The inhumane experiments did not end until the end of the war, at which point 23 of the German doctors were prosecuted, with 15 found to be guilty.
1938 / Federal Food, Drug, and Cosmetic Act
The act leads to the need for human subject trials, because it establishes that drugs must be proven safe before being approved by the FDA and marketed to the public. Sponsors must submit a New Drug Application (NDA) in order to market a new drug.
1944 – 1974 / Cold War Human Radiation Experiments
A 1994 investigation performed by the Advisory Committee on Human Radiation Experiments (ACHRE) found thousands of human radiation experiments were funded by various governments. The experiments intentionally released radiation on humans on hundreds of occasions during the Cold War.
1947 / The Nuremberg Code
The Nuremberg Code was one of the results of the Nuremberg trials after World War II. The trials convicted Nazi doctors for war crimes and crimes against humanity for their inhumane experimentation on concentration camp prisoners. Outlining research ethics when experimenting on humans, the Nuremberg Code is arguably the most important document pertaining to ethics in human medical research.
1950s-1970s / MK-ULTRA
CIA program on human subjects trying to develop drugs for interrogation and torture. Prisoners, used as subjects, were not informed about trials.
1953 / Department of Health, Education, and Welfare (HEW) Is Created
Enacted as part of the Reorganization Plan under President Dwight D. Eisenhower.
1953 / Wichita Jury Study
In order to study the effect of attorneys’ comments on jurors, the University of Chicago audio-taped jurors during the deliberation process without their permission. Public outrage caused congressional hearings that resulted in a federal law banning the recording of jury deliberations. The incident also raised questions about research and how many research questions may not be answered sufficiently without compromising some social institutions.
Late 1950’s – 1962 / Thalidomide Tragedy
Thalidomide entered the Germen market in 1957 and a sedative claiming to be completely safe, even for pregnant women. By 1960, 46 countries had approved thalidomide as a sedative, the United States not being one of them. As the drug popularized, it became a common practice to prescribe it as a morning sickness remedy. By 1961, physicians realized that this harmless drug was actually causing severe birth defects in newborns. By 1962, the drug was banned by most of the countries that had previously sold it.
Even though the tragedy did not affect the United States, it caused the FDA to make regulations on drug approval stricter. Following the tragedy, the Kefauver-Harris Drug Amendments Act was passed in 1962. The act stated that drug manufacturers had to prove the safety and effectiveness of the drug before approval, creating a basis for more tightly regulated human clinical trial guidelines.
1963 / FDA Establishes Regulation 21 CFR 130.3 (incorporated into 45 CFR 46)
Clinical investigators must certify informed consent.
1964 / Declaration of Helsinki
A set of ethical principles developed by the World Medical Association in order to guide physicians in medical research pertaining to human subjects. The Declaration governs international research ethics, stressing the importance that the degree of risk incurred does not exceed the knowledge gained from the information.
1966 / Henry Beecher’s “Ethics of Clinical Research” in the New England Journal of Medicine
Beecher’s article brought forth 22 different studies that violated serious ethical principles. The piece brought attention to the ethical issues that were still present in human research trials. The article caused a stir among an already wary public.
1966 / FDA Establishes Regulation 21 CFR 130.37 (incorporated into 45 CFR 46)
Creates specific requirements for informed consent
1969 – 1961 / San Antonio Contraceptive Study
The study aimed to study the efficacy of different types of contraceptives. Researchers did the study at a contraceptive clinic, catering to mainly lower income women who would not be able to afford the care otherwise. The women were told that the study was to research the side effects of contraceptives; however, they were not informed that they may also be given a placebo or inactive form of the contraceptive. As a result, many unplanned pregnancy occurrences were noted in the placebo group.
1970 / Tearoom Trade Study
Laud Humphreys studied anonymous male homosexual encounters in public restrooms (known as tea-rooming) by acting as a watch outside. Humphreys copied down license plate numbers and other identifiers in order to determine where the men lived. Humphreys would later visit their homes and interview them about their family and personal lives. Humphreys never informed the men that he was doing research for his Ph.D. dissertation. Though Humphrey’s never mentioned specific names, there was enough personal information in his published studies to identify the identities of the men, many of whom were living lives where disclosure of their homosexuality would be upsetting.
1974 / National Research Act
As a result of the Tuskegee Syphilis Study, the National Research Act was passed. It established the National Commission for the Protection of Human Subjects and Behavioral Research. The commission identified basic research conduct principles and established ways to ensure the enforcement of the principles,
The Act established the use of Institutional Review Boards (IRBs) at the local level to review all federally funded human research studies.
1974 / FDA Establishes Regulation 45 CFR 46
Regulation establishes IRB procedures
1974 / FDA Establishes Regulation 45 CFR 46 subpart B
Special protections for women and fetuses
1978 / FDA Establishes Regulation 45 CFR 46 subpart C
Special protections for prisoners
1979 / Department of Health and Human Services (HHS)
After the Department of Education became a separate entity under the Department of Education Organization Act, the Department of Health, Education, and Welfare was renamed the Department of Health and Human Services.
1979 / The Belmont Report is Published
The National Commission for the Protection of Human Subjects and Behavioral Research publishes the Belmont Report, which outlines three basic principles the IRB should use to evaluate study ethics:
  • Respect for Persons
  • Beneficence
  • Justice

1986 / FDA Establishes Regulation 45 CFR 46 subpart D
Special protections for children
1989 / The Agency for Health Care Policy and Research Established
Now known as the Agency for Healthcare Research and Quality (AHRQ), the Agency works under the Department of Health and Human Services. The task of AHRQ is to ensure the quality of healthcare, as well as ensuring patient safety.
1991 / Federal Policy for the Protection of Human Subjects (“Common Rule”)
The rule of ethics in the United States regarding all medical and behavioral research concerning human subjects. The Common Rule governs the Institutional Review Boards as they review human research. It is encapsulated in the HHS revision title 45 CFR 46 subparts A, B, C, and D. The baseline standard, which only includes the Common Rule and subpart A was adopted by 16 agencies, while the other subparts have also been adopted by many agencies.
1995 / National Bioethics Advisory Commission Board (NBAC) is Established
Created through executive order by President Clinton, NBAC was created to advise government entities on the ethical issues that arise from the research on human biology and behavior.
1996 / ICH Finalizes ICH-GCP
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) developed the Topic E6 Guideline for Good Clinical Practice (ICH-GCP) in order to overcome international Good Clinical Practice inconsistencies. Authorities and pharmaceutical companies from the US, EU, Canada, Japan and Australia met to participate in creating an internationally accepted guideline for the protection of human subjects in biomedical research. ICH-GCP regulation is not required by the US government as long as the Common Rule is followed, but many investigators also utilize the ICH-GCP guidelines to streamline approval outside of the US.
1996 / The Health Insurance Portability and Accountability Act (HIPAA) Is Enacted
HIPAA protects health insurance coverage for citizens. The Privacy Rule within HIPAA regulates the use of Protected Health Information (PHI).
1999 / Death of Volunteer Jesse Gelsinger
Born with an X-linked genetic liver disease, Gelsinger volunteered in a gene transfer trial. Researchers injected Gelsinger with a corrected gene, and Gelsinger died four days later. The primary investigator at the University of Pennsylvania had a conflict of interest for he owned shares in the startup that owned the technology. Investigators also ignored liver damage in lab mice trials. Lastly, investigators did not present the IRB-approved consent form that reported mild liver toxicity as a side-effect.
1999 / ClinicalTrials.gov is Founded
The purpose is to keep the public informed about federally and privately funded clinical research.
2001 / Death of Healthy Volunteer Ellen Roche
Roche volunteered in the asthma study which aimed to determine mechanisms that protected the lungs by provoking a mild asthma attack. Investigators had her inhale hexamethonium, a drug used for high blood pressure in the 1950s and 1960s. Roche died a month later and it was found that hexamethonium was not an FDA approved drug, even though the study was approved by the IRB and NIH. Roche’s death highlighted the problems with IRB reviews at the time, and caused many of the country’s IRBs to strengthen their own review procedures.
2002 / National Bioethics Advisory Commission Board (NBAC) is Not Renewed
Created through executive order by President Clinton, NBAC was created to advise government entities on the ethical issues that arise from the research on human biology and behavior.
2004 / Death of Dan Markingson
University of Minnesota researchers may have coerced vulnerable patients and many had potential COIs with drug companies. Ignored Markingson’s deteriorating condition possibly leading up to his suicide.
2007 / Death of Healthy Volunteer Jolee Mohr
Mohr was volunteering in an experimental gene therapy to treat rheumatoid arthritis. The trial was suspended when Mohr died of a massive fungal infection complicated by internal bleeding. A few months after her death, the FDA lifted the hold on the clinical trial after it was found that an immunosuppressive drug Mohr took for her arthritis independent of the trial was the main factor leading up to the infection that killed her.