James Lind (1716–1794)
In 1747, James Lind, a Scottish physician in the British Royal Navy, conducted the first controlled clinical drug trial on 12 sailors. Six year later, in 1753, he published the results in A Treatise on the Scurvy, in which he established that scurvy could be prevented and cured by the simple addition of citrus fruits to the diet. By contrast, it now takes approximately ten years, at a cost of some billion dollars, from the time a drug is merely a chemical of interest until it is approved for marketing by a drug regulatory agency, such as the Food and Drug Administration or the European Medicines Agency.
Animals or animal cells are the first test subjects. If the test drug looks sufficiently promising based on its effectiveness versus its toxicity, it is evaluated in humans, but only one in a thousand test drugs reach this stage. Human (clinical) trials are conducted in three phases, and a drug can be dropped at any step. Phase 1 trials primarily assess the drug’s safety at different doses and are conducted in small groups of 20–100 healthy volunteers. During Phase 2, dozens to several hundred subjects are tested to determine whether the drug works in subjects with a specific medical condition.
Phase 3, the longest and most expensive stage, may involve hundreds to thousands of subjects with the medical disorder, at multiple institutions. Researchers rigorously compare the effectiveness of the test drug with a placebo, and to eliminate investigator bias, double-blind studies are conducted, in which neither the researcher nor the subject knows whether the drug or a placebo has been administered. Drug versus placebo effectiveness is compared by statistical analyses, and the results of animal and clinical trials—including toxicity data and adverse effects—are submitted to the drug regulatory agency for a benefits-to-risks analysis.
If the drug has been approved for marketing, Phase 4 (Post-Marketing Surveillance) studies may be conducted to determine whether rare or long-term adverse effects occur. These effects can only be detected when the drug is used under “real-life” conditions in large patient populations over an extended time. Not all marketed drugs survive Phase 4 evaluation. Some, such as Vioxx and Avandia, have been unceremoniously withdrawn from the market.
SEE ALSO Placebo (1955), Off-Label Drug Use (1962), Celebrex and Vioxx (1998), Avandia (2010), Weight-Loss Drugs (2010).
On board a ship like this one, Scottish physician James Lind conducted the first systemic clinical trial in 1747. His results, published in 1753, demonstrated that citrus fruits (containing vitamin C) cured scurvy.