The History of Clinical Research: How it all Began

The first clinical trial focused on the benefits of a particular diet, which is still a burning issue to this day. What is better for daily nutrition - vegetables and water or wine with rich food from the king's table. Records indicate that the trial lasted 10 days. The participants were divided into control and experimental groups. You can find a more detailed description in... the Old Testament.

The book of the Prophet Daniel starts by telling a story of how Daniel and his brothers gave up the rich royal dishes and ended up being healthier than those who ate like King Nebuchadnezzar: “Then Daniel said to the steward whom the chief of the eunuchs had assigned over Daniel, Hananiah, Mishael, and Azariah, “Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let our appearance and the appearance of the youths who eat the king’s food be observed by you, and deal with your servants according to what you see.” So he listened to them in this matter and tested them for ten days. At the end of ten days, it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s food. So the steward took away their food and the wine they were to drink, and gave them vegetables."

Old Testament, Daniel 1:1 - 14

A more modern view on medical experimentation was presented by Avicenna, the great Persian physician. “The Canon of Medicine”, completed in 1025, has a description of his method for testing drugs.

The first Documented Clinical Research in History

The first documented clinical research in history is the experiment of Ambroise Paré, which was conducted accidentally. Paré, a French military surgeon, used a common practice of cauterizing gunshot wounds from an arquebus (gun) with boiling oil. It was believed that gunpowder was poisonous, and the oil neutralized the toxic effect. In fact, the oil inflicted no less harm than the weapon itself.

According to Paré’s records, he ran out of oil and had to use a mixture of egg yolks, rose oil and turpentine instead: “In the night I could not sleep in quiet, fearing some default in not cauterizing, that I should find the sounded to whom I had not used the said oil dead from the poison of their wounds; which made me rise very early to visit them, where beyond my expectation I found that those to whom I had applied my digestive medicament had but little pain, and their wounds without inflammation or swelling." The others, to whom the boiling oil was used, were found feverish, with great pain and swelling about the edges of their wounds. Following the results of such an accidental experiment, the French doctor never again used oil cauterisation for gunshot wounds.

However, Paré is famous not only for this story. He was a court physician and contributed significantly to the development of medicine. You can even read about him in several novels by  Alexandre Dumas the Elder!

The First Paid Research

History also preserved the reference to the first paid research. The Diary of Samuel Pepys, which depicted a portrait of life in London at the time of the Stuart Restoration, documented that on November 21, 1667, a "poor and debauched man" received money from a college for the transfusion of sheep's blood. It seems that the subject's health did not suffer.

The next milestone in the history of clinical research is perhaps the most famous episode in the world chronicle. This is the first deliberate and intentional trial of a treatment that occurred in 1747, with multiple experimental groups. As so often happens now, the immediate introduction of treatment into practice was prevented by the financial problem. The main participants of this story were scurvy, citrus fruits and James Lind, a Scottish naval surgeon.

Thousands of British (and not only) sailors died each year from a terrible disease called scurvy. The fact that it is caused by a lack of vitamin C was not yet known. It was discovered only in 1932. Lind approached the issue like any modern scientist before a new experiment - he started by studying literature. Eventually, he identified six proposed methods of fighting scurvy: diluted sulfuric acid, vinegar, cider, sea water, citrus fruits and nutmeg. Moreover, Lind studied the experience of members of the Society of Naval Services who have personally suffered from scurvy.

He divided the 12 sick sailors into six pairs and separated them from the rest of the crew by transferring test subjects to a closed room. In addition to their regular diet, Lind gave each pair various daily doses of one of six supposed scurvy cures that he found in books. It turned out that two oranges and one lemon a day work wonders: in just six days, it enabled the sick men to get back on their feet and even partially return to work. Such a result had not been achieved after two weeks of other treatments. The cider slightly abated weakness and healed the gums. Sulfuric acid showed little improvement in the condition of the oral cavity but did not affect the other symptoms of scurvy. The remaining methods obviously did not work. In 1753, James Lind published his book "A treatise on scurvy" and described the results of the experiment and the processing of other sources.

Unfortunately, economic realities could not be neglected: citruses were expensive and almost unavailable. For that reason, sailors could not add the fruits to their diets for another 40 years.

James Lind's work received appropriate recognition and fame. Therefore, his portrait was placed on a postage stamp, and the Royal College of Physicians established a library named after Lind. This was done in order to commemorate the 250th anniversary of the publication of his “A treatise on scurvy”.

When was the First Placebo Trial?

Gradually, a growing number of characteristics of clinical trials became common among doctors from around the world. For example, the word "placebo" appeared in the medical literature in the early 19th century. According to Hooper's 1811 Medical Dictionary, this is the definition for any medicine adapted more to please than to benefit the patient.

The first-ever study using a test group and a group receiving placebo was conducted by Austin Flint in 1863. When comparing the two groups, it turned out that the rheumatic fever symptoms pass naturally with or even without treatment.

Around the same time, French physiologist Claude Bernard encouraged colleagues to apply experimental methods and scientific approaches to medicine, rather than mindlessly use traditional treatments.

As time went on, it became obvious that the old methods were not always effective and there was a need to adopt more stringent criteria for medical research. All this led to the expansion of hospitals, the clarification of the role of microbes in the spread of disease and the emergence of new fields of biology. Consequently, the drug industry has grown significantly. There is a pressing need for the fight against fraudsters and new methods of testing the effectiveness of drugs.

First Randomized Controlled Study

The random assignment of participants to the experimental and control groups helps not only to achieve homogeneity of the groups themselves but also to avoid accidental or deliberate falsification of the results. After all, someone can assign the sickest patients to the control group, and healthier ones to the group receiving the medicine... The very idea of randomization (random distribution) appeared a couple of decades earlier, but was fully realized only in 1946 in Great Britain.

The organization ordered Austin Bradford hill and Philip Hart to investigate the effect of the streptomycin antibiotic on the treatment of tuberculosis. Based on a random sequence of numbers, they divided the participants into two groups: experimental S (streptomycin + bed rest) and control C (bed rest only).

Distribution information was unknown to neither the researchers nor to the study coordinators at the various hospitals. Patients from the control group, up to a certain point, did not even know that they were taking part in the experiment - they were simply treated according to all the standards of that time. This experiment and a detailed description of randomization, published in 1948, was seen by some as the beginning of a "new era of medicine."

Finally, an important point in the shaping of drug research in its current form was the loud tragedy associated with thalidomide... It was advertised for being a sedative and sleeping pill. Manufacturer in the USA Chemie Grünenthal focused the ad on how it helps women cope with unpleasant pregnancy symptoms. Later it turned out that the drug did not pass due safety checks: full studies were carried out only on rats. Thalidomide caused fetal development defects. In Europe, Australia and Japan, about 10,000 babies were born with malformations of internal organs and limbs.

The drug was banned for widespread use in most countries in 1961. After this sad experience, it became clear that drugs must be very carefully studied before being released on the market. The results of animal studies cannot be directly transferred to humans, as species differ in their sensitivity to active molecules. This is how the methodological part of clinical research was formed by trial and tragic error.

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