Historical Clinical Trials

Any general work must include these classic bits of history. Perhaps unusually, clinical trials appear to be a European scientific invention. There is no evidence that either the ancient world or the mediaeval Arabs carried out prospective studies (although there are some anachronisms in recent fiction). It is generally accepted that the earliest clinical trial was held by James Lind.

Thomas (1997) has pointed out that sailing men-of-war frequently went many months without docking, e.g. Nelson spent 24 unbroken months on HMS Victory while blockading French ports, and it is said that Collingwood once went 22 months without even dropping anchor. Scurvy was rampant in the Royal Navy, often literally decimating ships' crews. Sailors survived on the poor diets carried aboard for long months, with water-weevils and biscuit-maggots constituting important dietary protein! Before Lind's time, the Dutch had already learned to treat scurvy by replenishing their ships at sea with fresh fruit and vegetables. This was also known by Cook: when in command of HM Barque Endeavour, men were flogged for not eating their vegetables.

Lind had been pressed into the Royal Navy, as a surgeon's mate, in 1739, and with some experience as an apprentice surgeon in Edinburgh. It is a nice irony that the first prospective clinical study was actually conducted by a surgeon!

The clinical trial was held at a single site, HMS Salisbury, a frigate in the English Channel, during the early summer of 1747 (Lind 1753; Frey 1969; Thomas 1997). The experimental controls included that all 12 patients met the same inclusion criteria (putrid gums, spots on the skin, lassitude, and weakness of the knees). All patients received the same diet, except for the test materials. All treatments were administered simultaneously (parallel group). Compliance with therapy was confirmed by direct observation in all cases. The trial had six groups, with n = 2 patients per group. The test medications were (daily doses): (a) cider, 1 quart; (b) elixir of vitriol, 25 drops; (c) vinegar, two spoonfuls plus vinegar added to the diet and used as a gargle; (d) seawater, 'a course'; (e) citrus fruit, two oranges, plus one lemon when it could be spared; and (f) nutmeg, a 'bigness'. Lind noted, with some disdain, that this last treatment was tested only because it was recommended by a surgeon on land. The famous result was that within 6 days only 2 of the 12 patients had improved, both in the citrus fruit group, one of whom became fit for duty, and the other at least fit enough to nurse the remaining 10 patients.

We should note the absence of dose-standardization and probably of randomization, because Lind's two seawater patients were noted to have 'tendons in the ham rigid', unlike the others. However, the result had been crudely replicated by using n = 2 in each group. If we accept that the hypothesis was that the citrus-treated patients alone would improve (Lind was certainly skeptical of the anecdotal support for the other five alternative treatments), then, using a binomial probability distribution, the result has p = 0.0075. But statistics had hardly been invented, and Lind had no need of them to interpret the clinical significance of this brilliant clinical trial.

Lind was not quick to publish his most famous treatise reporting this clinical trial (Lind 1753). Indeed, in 1748, his Edinburgh MD thesis was on an entirely unrelated subject. Subsequently, Lind was Treasurer of the Royal College of Surgeons of Edinburgh, and then appointed physician to the Royal Naval Hospital, Haslar (one-fifth of his first 6000-odd admissions were for scurvy). He subsequently developed a large private practice, but little fame amongst his peers, and was buried at Gosport in 1794. The Royal Navy was even slower to act on his findings, and did not introduce citrus juice in sailors' diets until the year after Lind's death, following much administrative resistance but no scientific controversy (Bardolph and Taylor 1997). The British, especially those in the Royal Navy, are still known as 'limeys', which is the unique example of a national nickname based on a therapy proven by clinical trial.

Thus, Lind illustrates some other aspects of clinical trials: first, he had little academic kudos, although he was clearly qualified by experience and training (a requirement of trialists by law in the USA). Second, he did not publish his results rapidly. Third, his results were not implemented promptly in the interests of the public health. It is important to realize that these undesirable aspects of clinical trials persist to this day.

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