Learning how to control biases in studies to identify adverse effects of drugs: a brief personal history.

Prior to 1966, almost all available information on drug safety for marketed medicines was strictly qualitative. It was predominantly based on anec-dotal reports and clinical opinions derived primarily from the known pharmacology of particular drugs. While the medical environment for identifying and quantifying drug toxicity was generally informal and undirected, the use of anecdotal reports to detect serious drug toxicity was sufficient for identifying the toxicity associated with thalidomide. 1,2 But the mechanism of discovery was unacceptably inefficient since an estimated 9000 babies were born with thalidomide{caused phocomelia before the toxic effect was recognized and described in 1960. As a result of the thalidomide experience, government agencies in North America and Europe were established to collect spontaneous reports of purported adverse reactions to drugs, primarily from practising physicians. In addition, pharmaceutical companies began to establish departments to collect spontaneous reports of purported adverse reactions to their medicines. This system of collecting information on drug safety has proved useful over the years 3 and several medicines have been withdrawn from the market based primarily on spontaneous anecdotal reports. The early 1960s were a critical time for the development of more formal techniques for identifying and quantifying drug toxicity for the many medicines on the market. In addition to the thalidomide experience, which provided striking evidence that devastating toxicity could be present and unrecognized by doctors, the 1960s saw the development and marketing of a large number of new, highly potent medicines. These included oral contraceptives, postmenopausal hormones, anti-hypertensive agents, major tranquilizers and anti{ tumour agents. As a result of these developments, it became clear that large{scale formal techniques were required to quantify the known toxicity of medicines and to identify unsuspected drug toxicity. Formal methods differ from spontaneous reports in that they imply that studies are performed on defined populations of people with standardized collection of information on exposure to medicines and the illnesses that develop subsequently. I first became aware of the issue of medicines safety in the spring of 1966. At that time, Tom Chalmers, well known for his interest in random-ized trials, came to see me. He was at that time the chief of medicine at Lemuel Shattuck Hospital in Boston, where I was doing research in renal physiology and pharmacology (between 1961 and 1969). Chalmers had just come back from a meeting with other senior public health officials in Washington DC, where it was concluded that there …