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
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
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]
