Brief Timeline of Clinical Research
and Patient Protections
Clinical research has had a long and at times, problematic history. Fortunately, there are now laws creating strict oversight of all clinical research to prevent the abuses of the distant and recent past. The timeline on this page contains only a small sample of the full history of clinical research and patient protection efforts. As you scroll down, please note the opportunities for further reading, and if you are curious about a particular topic, please do not hesitate to contact iTHRIV.
1988 - ACT UP and the Parallel Track
During most of the first decade of the HIV epidemic in the U.S., the government remained largely indifferent to the people dying from AIDS- there was silence, denial, and death. The activist group “ACT UP” organized protests and demonstrations to force the research establishment, including the NIH and FDA, to get “Drugs into Bodies”. In 1990, nearly 10 years and thousands of deaths (mostly of gay men) since the first reports of a new syndrome that would be known as AIDS, the FDA adopted the Parallel Track for expanded access which allowed some drugs under study to be available to people living with HIV before officially approved. The concept of making treatments and vaccines for deadly diseases available quickly continues today and is seen in the emergency use authorization for COVID-19 vaccines.
1979 - Data Safety Monitoring Boards (DSMBs)
Data safety monitoring boards (DSMBs) watch the progress and results of Phase 3 clinical trials with human subjects. The DSMB can stop a clinical trial before it is complete if: 1. the new treatment is much more or much less effective than existing treatments to allow all people on the clinical trial to get the better treatment, or 2. if there are safety concerns that could expose participants to possible harm.
The clinical investigator is in charge of all parts of a clinical trial. In some settings this person is called the principal investigator, or PI. The main responsibility for patient safety in a clinical trial belongs to the clinical investigator. This includes letting the study sponsor know right away when severe side effects occur.
1974 - Institutional Review Boards (IRBs)
Created after changes were made to the 1966 United States of Public Health Service, which issued the first set of regulations, IRBs at research institutions make sure that people in clinical trials are protected and that federal laws are followed. In turn, the federal Office of Human Research Protections (OHRP) makes sure that IRBs follow laws that direct their process. Before starting, researchers must send the clinical trial protocol (the plan that describes the study in detail) to the IRB for review. The IRB must decide if the study asks a worthwhile question and ensures the safety and consent of the people participating in the trial. Once a clinical trial begins, the IRB watches over it to look for problems or ethical concerns.
Hippocrates - 460 BCE
Hippocrates of Kos was a Greek physician who lived from about 460 B.C. to 375 B.C. At a time when most people attributed sickness to superstition and the wrath of the gods, Hippocrates taught that all forms of illness had a natural cause. He established the first intellectual school devoted to teaching the practice of medicine. For this, he is widely known as the "father of medicine."
Approximately 60 medical documents associated with his name, including the famous Hippocratic oath, have survived to this day. These documents were eventually gathered into a collection known as the Hippocratic Corpus. While Hippocrates may not have written all of them himself, the papers are a reflection of his philosophies. Through Hippocrates' example, medical practice pointed in a new direction, one that would move toward a more rational and scientific view of medicine.
1747 - One of the First Clinical Trials
In 1747, Dr. James Lind was working as a surgeon on a ship with sailors who were sick with scurvy. He selected 6 groups of 2 patients each to take part in a study. Each group had to take a different treatment each day (including vinegar, sea water, and citrus fruits) so that Lind could see if any of these treatments helped with the disease symptoms.
The scurvy symptoms (bleeding gums, weakness, joint pain, etc.) of the two patients who ate the citrus fruits began to go away much more quickly than the other groups. Though they didn’t know it at the time, scurvy is cause by severe vitamin C deficiency and the citrus fruits could help both prevent and treat the disease.
1796 - The Smallpox Vaccine
Smallpox has killed many millions of people throughout its thousands of years of infecting humans. Around the world, from the 1600s and earlier, “variolation” - purposefully inoculating someone with a small amount of pus from a smallpox blister - led to less serious disease and immunity. In 1796, after hearing tales that dairymaids with cowpox blisters didn’t get smallpox, Edward Jenner inoculated a young boy with pus from a cowpox lesion. A few weeks later, he purposely exposed the boy to smallpox and no disease developed. While today we would have serious concerns about the ethics of his work, Jenner’s writings about his experiments allowed for the expansion of vaccination and the eventual eradication of smallpox. The word “vaccine” comes from “vacca” the Latin word for cow.
1887 - The National Institutes of Health (NIH)
The Marine Hospital Service (MHS) preceded the Public Health Service and was originally formed to provide medical care to sailors. As epidemics like cholera and yellow fever spread, the MHS was directed by Congress to screen people arriving in the U.S. by ship.
As the germ theory of disease took hold, a one-room laboratory was established in Staten Island, New York where physicians used microscopes to identify disease and serve the public’s health. By 1891 the “Hygienic Laboratory” moved to Washington, D.C.
1906 - The Pure Food and Drug Act
President Theodore Roosevelt signed into law the Pure Food and Drug Act which sought to regulate product labeling and prohibit interstate transport of unlawful food and drugs. Food and drug labels were not able to be false or misleading in any particular, and the presence and amount of eleven dangerous ingredients, including alcohol, heroin, and cocaine, had to be listed.
1910 - The Flexner Report
Financed by a group of physicians, educators, and philanthropists, Abraham Flexner visited every medical school in the United States and Canada to assess their standards of education. In the aftermath of his 1910 report, more than half of all United States medical schools merged or closed by 1935 as medical school curriculums became more standardized, lengthened and academically entrenched in science. The report had a major drawback, in that only a few medical schools remained open that predominately educated women and African Americans.
1927 - The Food and Drug Administration (FDA) Founded
Clinical trials for any new drug, device or treatment must be approved by the FDA before they can begin. The FDA also has the final say about whether a new treatment, drug or device can be approved for use. Once phase III clinical trials are completed, the FDA reviews the data and results of all clinical studies and decides if the new treatment is safe and effective enough to be approved for retail sale.
The FDA also inspects (audits) sites conducting clinical trials, especially if there is reason to think that the site is not following proper procedures. If serious problems are found, the FDA can prevent a site or doctor from doing any further research.
1932 - The Tuskegee Study Begins
The Tuskegee Study was an infamous 40 year-long project. From 1932 to 1972, the U.S. Public Health Service recorded the natural progression of syphilis in low-income African American men who lived in Macon County, Georgia. For forty years, the research team provided medical exams, meals, and transportation as they monitored the men who enrolled in the study. In 1947, penicillin began to be used to cure many diseases, including syphilis, but it was not offered to the infected men in the study. During this period, many participants died of syphilis or transmitted the bacteria to their partners because of the lack of treatment.
1944 - The First Multicenter Study
In 1944 The British Medical Research Council conducted the first multicenter study, to see if the antibiotic patulin cured the common cold. Almost 1500 patients were enrolled; they were divided into 4 groups, two placebo and two treatment groups. The study was conducted at multiple locations including post offices, factories, and schools. Unfortunately, ‘no evidence was found that patulin is effective in the treatment of the common cold’.
1948 - The Nuremberg Trials and Code
On December 9, 1946, an American military tribunal charged 23 Nazi physicians and administrators for war crimes and crimes against humanity committed during World War II. German physicians conducted medical experiments on thousands of concentration camp prisoners without their consent, some of whom were severely injured or killed as a result.
This directly led to the creation of the Nuremberg Code in 1948, which stated, “The voluntary consent of the human subject is absolutely essential,” and that the benefits of a trial must outweigh the risks. The code is not a legal document that could be enforced, but it was the first international document that called for voluntary participation and informed consent.
1951 - Henrietta Lacks and HeLa cells
Henrietta Lacks, a tobacco farmer from Roanoke, VA and a young, black woman, mother of five, was diagnosed with cervical cancer in 1951. During treatment, Dr. Howard Jones (John Hopkins Hospital) retrieved a sample of her cancer cells without telling her or her family, and sent the cells to a colleague, a prominent cancer and virus researcher, Dr. Gey. Henrietta Lacks passed away on October 4th, 1951 at the age of 31, without knowing her cells had been taken. After many failed attempts to find human tissue cells that could be kept alive in a lab, Dr. George Gey found that Mrs. Lacks’ cells not only survived but doubled every 20 to 24 hours. Her cells became known as HeLa cells and are the first immortal human cells ever grown in culture. These cells have been part of thousands of research studies and continue to benefit medical science and care. Mrs. Lacks’ case, because the doctors did not ask her before taking her cells and therefore did not have her consent, has sparked legal and ethical debates over the rights of an individual to their own genetic material.
1962 - Thalidomide Effects Identified
Thalidomide is a drug initially used to help with insomnia (lack of sleep) and morning sickness caused by pregnancy. It was widely used overseas in the late 1950s and early 1960s. In early 1962, it was found that taking this drug during pregnancy could cause severe birth defects. Thalidomide was never approved in the United States by the FDA, mainly because Dr. Frances Oldham Kelsey rejected the application for approval due to lack of evidence of safety. Though thalidomide was given to Americans during two large clinical trials, Dr. Kelsey and the FDA helped avert a public health disaster.
1964 - Declaration of Helsinki
The World Medical Association established recommendations guiding medical doctors in clinical research involving human subjects, material and data. While not binding, this document is considered foundational to human research ethics.
1972 - The Tuskegee Study Ends
In 1972, an Associated Press reporter broke the news that the federal government had let hundreds of black men in rural Alabama go untreated for syphilis for 40 years for research purposes. The study was stopped in 1972 only after its existence was publicized, and it became a political embarrassment. Many of those men died and many more suffered needlessly.
1979 - The Belmont Report
The Belmont Report outlined the basic principles and guidelines to resolve ethical issues related to research with human subjects.
The Report outlines the importance of boundaries between medical care and research. The three general ethical principles included in the report are: respect for persons (people have a right to make their own decisions and those who cannot are entitled to protection), beneficence (do no harm, maximize benefits, minimize harm), and justice (selection of participants should not be biased and benefits and risks should be shared fairly).
1991 - The Common Rule
The Federal Policy for the Protection of Human Subjects, the “Common Rule”, was adopted by all departments and agencies that conduct or fund research. The policy outlines requirements for research institutions and researchers including rules for IRBs, informed consent, and Assurances and Compliance. It also outlines additional protections for certain vulnerable research subjects including pregnant women, prisoners, and children.
1997 - Tuskegee Apology
In 1997, the White House invited 5 elderly black men who had survived the Tuskegee Syphilis study to attend a ceremony in which then President Bill Clinton apologized for the decades of mistreatment. The study was revealed in 1972 when The Associated Press reported that the U.S. government had conducted a study involving about 600 black men, without informing them that they were in a research study. The study ran for 40 years; though penicillin was a common cure by 1943 it was never given to the men in the study who had the disease.
2000 - Office of Human Research Protections (OHRP)
The Office of Human Research Protections is the main governmental agency helping to protect the rights, welfare, and wellbeing of participants involved in research. OHRP provides guidance and oversight of IRBs, develops educational programs, and provides advice on ethical and regulatory issues.
While government agencies create and enforce the regulations, the site where the research is conducted is required to have additional protections in place.
2013 - Lacks Family, NIH Agreement
The NIH announced an agreement with the Lacks family which enables access to the whole genome data of the cells derived from their matriarch without her consent. This agreement enables scientific progress while acknowledging the enormous contribution made by the late Henrietta Lacks. The Lacks family will now have a hand in reviewing applications which request access to the Henrietta Lacks’ whole genome of data.
2020 - COVID-19 Vaccine Development and Emergency Use Authorization
There were several factors that allowed for the rapid development of mRNA COVID-19 vaccines: 1) worldwide collaboration to sequence the viral genome; 2) mRNA vaccine technology had been developed decades earlier, so these vaccines built on an existing platform; 3) the U.S. government approved considerable funding and speedy approval processes, removing “red tape” that would delay development; 4) clinical trials for safety and efficacy of the vaccine candidates were overlapped to speed up the process and many more people were recruited in each phase trial than usual; and 5) manufacturers created massive stockpiles while awaiting the U.S. FDA and CDC Emergency Use Authorization.