Clinical Trials & Patient Protections
The First Clinical Trial
James Lind conducted the first clinical trial in 1747, while working as a surgeon on a ship. Many sailors were dying of scurvy, and Lind discovered that scurvy was caused by a lack of vitamin c.
He selected 6 groups of 2 patients each to take part in the study. Each group had to take a different “medicine” each day so that Lind could see which one had a positive effect.
A group drank cider.
A group took elixir vitriol (a “medicine” used to use for scurvy consisting of alcohol and sulfuric acid)
A group drank vinegar
A group drank seawater
A group ate two oranges and one lemon
A group drank a medicine recommended by a surgeon
The two patients who had citrus fruit became healthier and recovered. Those patients helped discover the cause and cure for the disease called scurvy!
Portrait of James Lind
The Nuremberg Trials
On December 9, 1946, an American military tribunal opened criminal proceedings against 23 German physicians and administrators for their willing participation in 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 these experiments lead to the death or the permanent crippling of these individuals.
Among many issues, individuals were experimented on without their consent.
This directly led to the creation of the Nuremberg Code in 1948, which stated “The voluntary consent of the human subject is absolutely essential.” The code makes clear that subjects must give their consent to participate in clinical trials and the benefits of the trial must outweigh the risks.
It was not a legal document that could be enforced but it was the first international document that called for voluntary participation and informed consent.
Courtroom at the Doctors' Trial - Nuremberg, 1946
Henrietta Lacks circa 1945–1951
Henrietta Lacks, a black tobacco farmer from Roanoke, Virginia and a young mother of five, got diagnosed with cervical cancer in 1951 and began undergoing radium treatments by a well-known gynecologist named Dr. Howard Jones at The John Hopkins Hospital. During treatment, Dr. Jones retrieved a sample of her cancer cells without telling her and sent the cells to Dr. George Gey, a prominent cancer and virus researcher, who also worked at The John Hopkins Hospital. Dr. Gey had been collecting cells from patients at the hospital for years in an attempt to grow tissues himself, but each sample died quickly. What was important and impactful about Mrs. Lacks’ cells were that her cells would not die like the others but actually doubled every 20 to 24 hours, a phenomenon that cannot be explained. Her cells became known as HeLa cells, which kept the first two letters of Henrietta and Lacks, and are the first immortal human cells ever grown in culture. Mrs. Lacks’ case has sparked legal and ethical debates over the rights of an individual to his or her own genetic material.
Her cells have transformed medical science, as they have allowed landmark developments in health without experimenting on humans. They have helped with research into cancer, sexually transmitted diseases, gene mapping, cloning, and more while also being used to develop drugs for treating herpes, leukemia, polio, Parkinson’s disease, and many more. HeLa cells even went up into space on the first space missions to see what would happen to cells in zero gravity.
Henrietta Lacks passed away on October 4th, 1951 at the age of 31, but her cells continue to impact the world.
Henrietta Lacks’ cells were taken without her consent or knowledge and have been used in over 100,000 publications. Her family did not find out about the cells for several decades, and have never though used throughout the world, have not been compensated. Mrs. Lacks’ case has sparked legal and ethical debates over the rights of an individual to his or her own genetic material. This case also brought to the forefront recognition of the exploitation of people of color in clinical research and the need for equity in health. Sixty two years after Mrs. Lacks’ cells were taken, the National Institute of Health (NIH) and the Lacks family reached an agreement about the sharing of HeLa cells.
Patient and researchers discuss the collection of cells. Patients must consent prior to enrolling in a research trial (patient consents).
HeLa Cells Website- Explore HeLa’s impact on research over the past six decades.
Thalidomide was a drug that was not approved in the United States by the FDA, but it was prescribed by doctors in other countries to control sleep and nausea throughout pregnancy. Unfortunately, many women took Thalidomide when pregnant or just prior to pregnancy. After several years, t was found that taking this drug during pregnancy caused severe deformities in the fetus.
Thalidomide caused about 12,000 babies to be born with severe deformities.
Drug manufacturers marketed their medicines without disclosing the side effects.
In 1962, amendments were passed to the Food, Drug and Cosmetic Act that ensured drug efficacy and greater drug safety. For the first time, drug manufacturers were required to prove to the FDA the effectiveness of their products before marketing them.
In 1962 FDA pharmacologist Frances Oldham Kelsey received the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy Kelsey was influential in blocking sale of thalidomide in the United States, despite pressure from Richardson-Merrell Pharmaceuticals
Tuskegee Syphilis Study
From 1932 to1972, the U.S. Public Health Service recorded the natural progression of syphilis in men who lived in Macon County, Georgia. For forty years, the research team provided medical exams, meals, and transportation as they monitored the 600 low-income African-American men who enrolled in the study. Many were infected with syphilis, but not told. 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 subjects died of syphilis during the study due to having no access to treatment.
The study was stopped in 1973 only after its existence was publicized and it became a political embarrassment.
The uproar against the lack of informed consent and the deliberate mistreatment of participants caused the National Research Act of 1974 to be passed, which lead to the development of the Belmont Report in 1979.
The Belmont Report focused on resolving the ethical issues that were found in research with human subjects and created regulation and requirements to address these issues. This report still applies today.
Subjects talking with study coordinator, Nurse Eunice Rivers, c.1970
Additional studies, including the Willowbrook study of hepatitis, the Fernald State School trial, and the Jewish Chronic Disease Hospital case were conducted under the thought of “the end justifying the means.” All of these contributed to the writing of new regulations, for patient consent and other principles on acceptable human-subjects research
How are participants in clinical research now protected?
Additional studies, including the Willowbrook study of hepatitis, the Fernald State School trial, and the Jewish Chronic Disease Hospital case were conducted under the thought of “the end justifying the means.” All of these contributed to the writing of new regulations, for patient consent and other principles on acceptable human-subjects research.
It is true that past clinical trial history has led many to hesitate to sign up for a research study. Research abuses, like the Tuskegee Syphilis Experiment, caused laws to be passed and created strict oversight of all clinical research. Researchers are required to follow rules that are enforced by government agencies to make sure every participant is as safe as possible. Here are some government agencies and laws that oversee the protection of research participants.
1927 - Food and Drug Administration (FDA) (initially called the Pure Food and Drug Act of 1906)
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 continue on to the next step.
Once phase III clinical trials are completed, the FDA reviews the data and results from 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 doing clinical trials, especially if there’s 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.
1964 - The Declaration of Helsinki
The World Medical Association established recommendations guiding medical doctors in clinical research involving humans. This is the basis for Good Clinical Practices used today.
Created after modifications were made to the 1966 United States of Public Health Service, which issued the first set of regulations. IRBs 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 looks at a worthwhile question and ensures the safety of the people on the trial.
The IRB also makes sure that the informed consent form that people sign before going on a trial is accurate, complete, and easy to understand. Once a clinical trial begins, the IRB watches over it to look for problems.
The Institutional Review Board is an administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities.
The IRB is charged with the responsibility of reviewing, prior to its initiation, all research (whether funded or not) involving human participants. The IRB is concerned with protecting the welfare, rights, and privacy of human subjects. The IRB has the authority to approve, disapprove, monitor, and require modifications in all research activities that fall within its jurisdiction as specified by both the federal regulations and institutional policy.
1979 - The Belmont Report
...Respect for persons Individuals should be able to have the ability to make their own decisions. Persons with less of an ability to make their own decisions are entitled to protection.Subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them. The consent process must include three elements:
Human subjects should not be harmed, research should maximize possible benefits, and minimize possible harms. Assessment of risks and benefits: The nature and scope of risks and benefits must be assessed in a systematic manner by an Institutional Review Board. The benefits and risks of research must be distributed fairly …There must be fair procedures and outcomes in the selection of research subjects...
Data safety monitoring boards (DSMBs) are used for phase III (and some earlier phase) clinical trials. The job of the DSMB is to watch the progress and results of the clinical trial. The DSMB can stop a clinical trial before it is done if:
It becomes clear that the new treatment is much more (or much less) effective to allow all people on the clinical trial to get the better treatment.
Safety concerns come up, such as risks being much greater than benefits, so that no one else is exposed 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.
1991 - The Common Rule
The Federal Policy for the Protection of Human Subjects, or “Common Rule” was adopted by all departments and agencies that conduct or fund research. The main elements include:
…requirements for assuring compliance by research institutions; requirements for researchers obtaining and documenting informed consent; requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping. Additional protections for certain vulnerable research subjects-- pregnant women, prisoners, and children…
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 IRB’s, 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 has additional protections in place.
Additional websites with more information about participant protection
It is important to remember, participating in a clinical trial is voluntary. Participants may choose to stop participating for any reason at any time.
Individuals are protected at every step of the way