The development of clinical research has gone through a long and fascinating journey so far and is always evolving. Let us walk you through the history, challenges, and milestones of the field, from experiments recorded in biblical times to the first controlled trial to treat scurvy, and current safety practices.
First clinical trial in history
The world’s first clinical trial is recorded in the ‘Book of Daniel’ within the Bible. This clinical-type experiment was conducted not by physicians, but by the ingenious military leader, King Nebuchadnezzar. As the story goes, during his reign in Babylon, Nebuchadnezzar ordered his people to eat only meat and drink water, thinking that such a diet would keep them in good health. Yet, a few young royals were against it. The King allowed the rebels to follow a diet of beans and water, but only for ten days and, as it turns out, the group felt better and stronger than the other subjects. The test is what many consider to be the first comparative study in human history.
Groundbreaking clinical trials in history
“A Treatise on the Scurvy”
In 1747, the first official comparative study was carried out and its process and results appropriately documented. It was an attempt to find a cure for what we know now to be Scurvy, a Vitamin C deficiency due to a lack of fresh fruit and vegetables in a person’s diet. At the time, the cause of the disease was unknown. It was an enemy to fleets around the world, as they embarked on long sea voyages that exposed them to an ailment that would rot their gums, open sores on their skin, and leave them bedridden, causing their death.
James Lind, a Scottish doctor who had joined the Navy, decided to test the idea that the effects of the disease could be prevented with acids. Twelve sailors, divided into six pairs, were chosen for the experiment. Besides the same core diet, each pair was given a different supplement: cider, vitriolic elixir (dilute sulfuric acid), vinegar, seawater, two oranges and one lemon, or a purgative mixture. The group that took the fruit was the one that exhibited the most sudden and visible improvement.
This study and its results were documented in “A Treatise on the Scurvy”, but it was not recognized until a few years later, when lime juice began to be included in the crew’s diet.
Evolution of clinical trials: studies on humans
Nuremberg code
In the 1940s Nazi medical experiments were carried out on large numbers of prisoners in concentration camps, who were coerced and forced to participate. The abuses were carried out in the name of research thus, after World War II ended, fundamental ethical codes started to be implemented in the field of clinical trials.
The first of these was the Nuremberg Code in 1947, which represented a landmark in ethical research principles. It stated that informed consent is required for the performance of any test in human beings. Any study conducted should be beneficial to society and avoid physical and mental suffering. If there is any risk of injury or death, the trial should be dismissed. The statement highlighted the participants’ right to freely withdraw from the study at any point and the need to haul all tests if they became a risk to the patient at any point.
Helsinki declaration
Another key moment in the evolution of clinical research is the infamous case of thalidomide. A drug developed in the 1950s that acted as a sedative and was used to treat colds and the flu; as well as to calm nausea and dizziness during the first three months of pregnancy.
During the pre-clinical phase of development, the drug was tested on animals and found to have no side effects. Because of these amazing results, it was expected to be safe for humans, and the drug was commercialized in around 40 countries around the world. Eventually, the use of this drug would result in tragedy, with over 150,000 newborns worldwide born with malformations, directly related to the mothers’ use of thalidomide. The USA was spared of the devastation because of Frances Kelsey, a FDA worker who prevented the approval of the drug, demanding further information and study into the side effects seen in previous studies.
It was later discovered that the results from studies that had been carried out and led to the approval of thalidomide in so many countries, had been insufficient, and in some cases even falsified. This crisis became a turning point in the history of clinical trials, and resulted in more rigorous pre-clinical testing, more demanding monitoring of patients, and more restrictive approval criteria.
In response to this, the Helsinki Declaration was issued in 1964 by the World Medical Association. It was developed to clearly outline the ethical principles that must be followed by physicians and others conducting medical research on human subjects, including research on human biological material and the use of information that might identify a person. It emphasizes the procedures needed to ensure subject safety, such as informed consent and the implementation of the review process carried out by the Research Ethics Committee. In addition, the statement called attention to the physician’s responsibility to promote and safeguard the health of individuals.
Belmont report
The Belmont Report was published in 1979 as an attempt to explain and unify the basic ethical principles of different codes developed through time. Three core principles were identified:
- Respect for persons, which is two-fold: recognizing the autonomy of the participant in the trial and protecting those whose autonomy has been compromised.
- Beneficence: the core of the “Do not harm” principle. It implies the obligation not only to respect people’s decisions and protect them from suffering, but also to ensure their well-being.
- Justice: equal distribution of both risks and benefits incurred from research, tailoring actions based on individual situations, as well as avoiding prejudice in patient selection.
Good clinical practices
In 1997, the Good Clinical Practice (GCP) Guidelines came into operation, encompassing a series of rules aimed at guaranteeing the rights of subjects participating in a clinical trial, ensuring data quality, and avoiding errors in clinical research world-wide. These guidelines include the ethical principles and rights achieved throughout history (Nuremberg Code, Belmont Report, Declaration of Helsinki) and represent the standard to which all clinical trials should adhere nowadays.
The progress of medicine is based on research, which ultimately often requires experimentation on human subjects. Given its history, concerns are natural, but the world of clinical trials has evolved tremendously, and the priority is clear: to ensure the safety and well-being of those participating in the studies, above scientific advancement.
Today, the process through which a drug is developed and approved involves a range of checkpoints, each with different restrictive requirements that need to be met, before moving to the next phase of the drugs development. From the extensive pre-clinical testing that must be carried out in animal models before starting human clinical trials, to the different phases of clinical testing, each focusing on different aspects, all studies have a special focus on safety.