A brief jaunt through the history of clinical trials before the 20th century
06.05.16
So much for the success of the brief past, but we might spare a brief thought for the long, historical process that has brought us to this point.
People who are familiar with clinical trials may be aware of the first recorded study, which was written down in the Old Testament. It details King Nebuchadnezzar II’s decision to make children of Royal blood eat meat and wine for three years. At the same time, the children of Judah (Daniel, Hananiah, Mishael, and Azariah) asked only to be given pulses and water. The end result was that Judah’s children came out healthier. In his book, “Trial by Fire”, Allan Gaw refers to this trial as being pivotal to the importance of publication.
There is also vague evidence of clinical “testing”, if not an organised trial, in the words of the great 2nd century Greek physician, Galen: “All who drink this remedy recover in a short time, except those whom it does not help, who all die and have no relief from any other medicine. Therefore it is obvious that it fails only in incurable cases.”
It would be remiss of us not to laud the contribution made by the great 10th-11th century Persian medic Ibn Sina – known to the west as Avicenna. I might be slightly biased, given his origin, but his sublime Canon of Medicine, published in 1025, laid down rules for the experimental assessment and utilisation of medicines. It suggests a comparison between two differing types of drugs after which a study should be compiled detailing the action and reproducibility of the effects.
In Mediaeval Europe, by contrast, the Catholic Church had a grip on most things medical, sometime accusing medics of being witches (and subsequently burning them); banning the dissection of corpses; and avoiding research and development, for the most part, by suggesting that prayer was the answer to many ailments.
Nevertheless, some medical advances were made in Europe over this period. For example, Hugh of Lucca, a 13th century surgeon in Bologna and subsequent medic in the 5th crusade, stumbled upon a primitive form of antiseptic, in the form of wine. It’s unlikely any large-scale clinical trial was involved, this being rather a triumph of pure observation.
Let us not forget the work by the French 16th century barber surgeon Ambroise Paré who undertook a comparison of soldiers with injuries treated with boiled elderberry oil and wound cauterisation and those treated with a combination of egg yolk, oil of roses and turpentine. The antiseptic properties in the turpentine meant that this group of soldiers recovered more swiftly, while the cauterisation group was still suffering.
In an age where women sadly were not permitted to contribute as fully to society as men, one of the stand-out figures in the clinical trials arena is Lady Mary Wortley Montagu. In a sense, she pioneered the introduction into the west of smallpox variolation, having witnessed its use as the wife of the ambassador to Turkey in the 18the century. Variolation consists of immunising patients by infecting them with a substance from the pustules of patients with a mild form of the original disease. When smallpox hit England in 1721, seven death-row prisoners at Newgate Prison were offered a choice between variolation and execution. Needless to say they chose the former, survived and were set free.
Any historical treatise on clinical trials would be incomplete without the mention of the Scottish surgeon James Lind. In what is probably the forerunner of the modern clinical trial, Lind discovered that citrus fruit could be used as a cure for scurvy. In 1754 offered 12 scurvy patients a variety of foods and discovered that those who ate citrus fruits such as lemons and oranges recovered at a much swifter pace than patients who ate other foods.
Around the same time, a perhaps less medical, but nonetheless interesting, trial was taking place in Sweden. King Gustav III viewed the consumption of coffee as a threat to public health and therefore ordered that two identical twins, both convicted of crimes and sentenced to execution, should instead be given life imprisonment, provided they agreed to be part of an experiment. One was ordered to drink three pots of coffee for the rest of their life and the other an equivalent amount of tea over the same period. Sadly, the overseeing doctors died before the prisoners, as did the king, who was assassinated in 1792. The tea-drinking prisoner died at he age of 83, but was outlived by the coffee-drinker, whose death date remains unknown.
In 1799, the English physician John Haygarth compared metal pointers – known as Perkins tractors, and supposedly used to draw out disease – with wooden equivalents in patients with rheumatism. As both metal and wooden pointers proved equally effective (or ineffective in reality) – thus was born the “placebo effect”. A direct translation of the Latin for “I will please”, placebo was already introduced into English earlier in the 18th century, but only entered Hooper’s Quincy’s Lexicon-Medicum in 1811.The first placebo-controlled trial took place in 1863, when US physician Austin flint offered patients a diluted remedy for rheumatism.
In an 1885 Paper, Charles S. Peirce and Joseph Jastrow introduced the idea of randomisation, based on an experiment involving playing cards – and later mental telepathy – and designed to avoid bias in tests.
There is not enough time or space here to pay homage to all those who contributed to the clinical trials process that was improved upon significantly in the 20th century, with the enhancement of safety issues and the laudable and well overdue introduction of ethical review. Nevertheless, in memory of the magnificent developments that have led to the celebration of the next International Clinical Trials Day on 20 May 2016, must all remember that these great advances have only been achieved through standing on the shoulders of giants.
