History

The concepts behind clinical trials are ancient. The Book of Daniel chapter 1, verses 12 through 15, for instance, describes a planned experiment with both baseline and follow-up observations of two groups who either partook of, or did not partake of, "the King's meat" over a trial period of ten days. Persian physician Avicenna, in The Canon of Medicine (1025) gave similar advice for determining the efficacy of medical drugs and substances.^[13]

Development

Edward Jenner vaccinating James Phipps, a boy of eight, on 14 May 1796. Jenner failed to use a control group.

Although early medical experimentation was often performed, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy, was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed.^[13]
The first proper clinical trial was conducted by the physician James Lind.^[14] The disease scurvy, now known to be caused by a Vitamin C deficiency, would often have terrible effects on the welfare of the crew of long distance ocean voyages. In 1740, the catastrophic result of Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy.^[15] John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit (it has an antiscorbutic effect) from the 17th century, but their use did not become widespread.^[16]
Lind conducted the first systematic clinical trial in 1747.^[17] He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment.^[18]
After 1750 the discipline began to take its modern shape.^[19][20] John Haygarth demonstrated the importance of a control group for the correct identification of the placebo effect in his celebrated study of the ineffective remedy called Perkin's tractors. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the 1860s.^[13]
Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He also founded the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials."^[21]

Modern trials

Austin Bradford Hill was a pivotal figure in the modern development of clinical trials.

Sir Ronald A. Fisher, while working for the Rothamsted experimental station in the field of agriculture, developed his Principles of experimental design in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas, was the importance of randomization - the random assignment of individuals to different groups for the experiment;^[22] replication - to reduce uncertainty, measurements should be repeated and experiments replicated to identify sources of variation;^[23] blocking - to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of factorial experiments - efficient at evaluating the effects and possible interactions of several independent factors.^[13]
The British Medical Research Council officially recognized the importance of clinical trials from the 1930s. The Council established the Therapeutic Trials Committee to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease.^[13]
The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The trial, carried out between 1946-1947, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled.^[24]
The methodology of clinical trials was further developed by Sir Austin Bradford Hill, who had been involved in the streptomcyin trials. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, amongst others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of over 30,000 doctors over a period of several years. His certificate for election to the Royal Society called him "...the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and prophylactic agents."
International clinical trials day is celebrated on 20 May.^[25]