TSR History Week: Clinical Trials Throughout HistoryWatch
A clinical trial is an investigative study, involving human subjects, to examine and evaluate the safety and effectiveness of new interventions intended to prevent, diagnose or treat human diseases.
Clinical research has often been a contentious issue throughout history, and is now one of the most regulated areas of healthcare. Here is a brief overview of how this came to be and important moments which shaped how clinical research is today.
The first documented experiment which bears similarity to a clinical trial is described in the Bible. This was the first example of an uncontrolled experiment to have a direct impact upon public health. The trial was conducted by King Nebuchadnezzar, who ordered his people to eat only meat and drink only wine, whilst some followed a diet of legumes and water. When it appeared that the group who ate legumes appeared to be better nourished, they were permitted to continue with their diet.
In 1747, James Lind conducted a trial to determine whether various treatments would cure scurvy. He found that citrus fruits were able to bring about an almost full recovery.
Until the mid-twentieth century, medical products, such as drugs and medical devices were largely unregulated. Medical products were freely produced and sold. As a result, therapeutic and preventative claims were unproven by scientific research, and products were adulterated, contained harmful contaminants and ingredients or had undisclosed ingredients. It was not until the 1800s that placebo-controlled trials begun to emerge.
The first double-blinded controlled trial occurred in 1943, and tested whether Patulin was an effective remedy for the common cold. Whilst the data was disappointing, this paved the way for the reduction of bias in clinical research.In 1944, multicentre clinical trials were introduced. This involves multiple studies being conducted at various sites all following the same protocol. This provided wider testing and better statistical data.The first official randomised controlled trial was conducted in 1947, testing streptomycin in pulmonary tuberculosis. This was a landmark trial, as it included systematic enrolment criteria and meticulous data collection, compared to the ad hoc nature of previous trials.
Ethics and Regulation
All medical practice has been subject to the Hippocratic Oath, the key ethical framework which aims to prevent patients from harm, which has often been ignored throughout history.
The Nuremberg trials formed the first international guidance on the treatment of subjects involved in clinical research, and emphasised the need for voluntary consent.
Following the Thalidomide tragedy, the US was able to pass the 1962 requirement for informed consent.
The Food and Drugs Administration (FDA) was founded in 1862 and became a law enforcement agency in 1906. The role of the FDA today is to monitor the marketing of drugs.
More recently, in 1990, the International Conference on Harmonisation (ICH) was assembled to provide structured guidance for the conduct of trials in the US, Europe and Japan.
Throughout history, there have been many tragic events involving human research. These events were the result of unethically conducted clinical research.
Some examples of unethical research:
- MK-Ultra (1953-1973) USA - Run by the CIA as a program of research in behavioural modification. LSD was secretly given to patients causing mental breakdowns.
- Stanford Prison Experiment (1971) USA - Subjects put into a mock jail and divided into ‘prisoners’ and ‘guards’. Terminated after 6 days due to brutal abuse by the ‘guards’.
- The Monster Study (1939) USA - Stuttering experiment in which orphans were belittled for speech impediments. A lifetime of self-consciousness and reluctance to speak ensued.
- Project ARTICHOKE (1951-1953) USA - People were forcibly addicted to morphine and the effects of withdrawal were studied. The CIA aimed to produce unquestioning human drones.
- Porton Down Experiments (1945 - 1989) UK - The world’s longest running set of chemical weapons experiments on humans. Over 20,000 people were tested with agents such as sarin gas.
- Tuskegee Syphilis Experiment (1932-1972) USA - Nearly 400 African-American men with syphilis were left untreated for 40 years. Most died, as scientists withheld the cure for the disease.
- Project 4.1 (1954-1970’s/80’s) Marshall Islands - Residents of the Marshall Islands were exposed to US nuclear tests. US scientists used the opportunity to study the effects of radiation poisoning.
- North Korean Medical Experiments (Ongoing) North Korea - Prisoners are subjected to chemical experiments in suffocation chambers. Student doctors allegedly practice surgery on un-anaesthetised inmates.
- Unit 731 (1930’s-1940’s) Japan - Biowarfare unit that experimented on over 10,000 people per year. Tests included vivisections, germ warfare and fatal pressure chamber studies.
- Nazi Medical Experiments (1930’s-1940’s) Germany - Nazi experiments on prisoners were brutal and widespread. Forced sterilisation, amputation and poison gas tests were common.
Tragic events following unethical clinical research share common themes:
- Violation of the rights, safety and welfare of human research subjects
- Exploitation of vulnerable populations
- Imbalance of risks and benefits involved in a clinical trial
- Lack of scientific validity and social value
- Lack of informed consent.
Did you find any of this surprising?
What was the most important event which shaped clinical research today?