Today when a new medication is introduced, we expect it to be backed by evidence gleaned from proper research. Our gold standard is the randomized double-blind controlled trial, but surprisingly the first such trial dates back only to the 1940s. That is not to say that there were no trials before, but they certainly did not provide the kind of evidence that we now seek. In fact, the first semblance of a clinical trial takes us all the way back to the Book of Daniel in the Bible.
When Daniel was taken into captivity by the Babylonian King Nebuchadnezzar in the sixth century BCE, he told his guard that he would not defile himself with the meat and wine he was offered because these were not prepared according to Jewish dietary laws. He asked that he and his fellow captives be given vegetables and water instead, but his guard worried that the King would then notice that the prisoners were looking sickly. Daniel cleverly asked the guard to carry out an experiment by giving the captives vegetables for ten days and then to compare their health to young men who ate the royal food. After ten days the captives looked healthier and better nourished than the “control group” of the King’s men! One might call this the first ever demonstration of the benefits of a vegetarian diet.
The factual basis of biblical accounts is of course questionable, but the story of James Lind and his classic experiment with scurvy in the 18th century is well documented, and is widely regarded as the first authentic clinical trial. Scurvy, a disease now known to be caused by a deficiency in vitamin C, was a scourge of sailors who subsisted on crackers and dried, salted, meat on their long ocean voyages. Lind, a physician, tackled the problem by selecting six pairs of men who were given different combinations of nourishments. He found that scorbutic sailors who had been given citrus fruits were cured of scurvy! Subsequently, British sailors were provided with lime juice, a practice that gave rise to the term “limey” for all Brits.
The first placebo-controlled trial was carried out by American physician Austin Flint in 1863. For the treatment of rheumatism, he compared the use of standard therapies such as opium liniment or dry flannel applied to joints with a placebo consisting of a highly diluted tincture of a plant called quassia. He found that the placebo worked as well as the other treatments.
Flint was sort of a lone wolf because placebo-controlled trials would not become the standard for close to another hundred years. Incredibly, there was no requirement to test the safety of medications until 107 people died in 1937 from being poisoned by diethylene glycol, the solvent used to make an elixir of sulfanilamide, a medication to treat strep throat. This precipitated the Food, Drug and Cosmetic Act signed into law in 1938 by President Roosevelt requiring a drug to be tested for safety before marketing. However, there was still no requirement to demonstrate efficacy.
The first-ever placebo-controlled trial that was also double-blind was published in 1944 in the British Medical Journal, The Lancet. It reported on investigating the use of patulin, produced by the Penicillium patulum mold, often found on apples, as a treatment for the common cold. The press jumped on some preliminary findings and breathlessly reported that a cure for the cold had been found. The final results actually showed that patulin had no effect.
The first randomized placebo-controlled trial that actually found a curative effect for a drug was also carried out in Britain in 1948 and showed that streptomycin was an effective treatment for tuberculosis.
The requirement to demonstrate not only safety but efficacy as well finally came in 1962 via an amendment to the 1938 Act after the thalidomide tragedy that resulted in thousands of babies being born around the world with malformed limbs after their mothers had taken thalidomide for morning sickness while pregnant.
Although today proper trials demonstrating safety and efficacy are obligatory before any drug is released, they cannot guarantee safety. Rare side effects that do not show up in studies can appear when a drug is taken by large segments of the population. The withdrawal on account of cardiac complications of the pain reliver Vioxx and the combination of phentermine and fenfluramine known as “Phen-Fen” for weight loss are such examples. Still, we have come a very long way from Daniel’s first foray into a clinical trial. Taking an approved drug these days is not tantamount to being tossed into the lion’s den.
