Enovid: First FDA-Approved Oral Contraceptive Pill

Before 1960, American couples relied mainly on the condom and the diaphragm, both used at the time of intercourse and both with meaningful failure rates. The diaphragm also required a clinician to fit it, and in several states laws derived from the 1873 Comstock Act still restricted the distribution of contraceptive information or devices. The pill came out of work in the 1950s by Gregory Pincus, John Rock, and Celso Garcia, paid for largely by the birth control campaigners Margaret Sanger and Katharine McCormick.

Pincus, a biologist at the Worcester Foundation for Experimental Biology, worked out the basic idea of a hormonal pill with Min-Chueh Chang, and G.D. Searle and Company supplied a synthetic progestin, norethynodrel, that worked by mouth. Carl Djerassi's team at Syntex had made a related progestin, norethindrone, in 1951; it went into other pills, but Enovid used Searle's norethynodrel. Rock, a Boston gynecologist, conducted early human trials beginning around 1954. Garcia then helped run large field trials in Puerto Rico starting in 1956, enrolling hundreds of women and establishing efficacy and tolerability data sufficient for regulatory submission.

The FDA approved Searle's Enovid for contraception in June 1960, for married women, by prescription only, and at first for no more than two years of use. The approved formulation contained 9.85 mg of norethynodrel and 150 mcg of mestranol, doses far higher than later preparations. The same drug had been on the market since 1957 for menstrual disorders, and its approval as a contraceptive came before the thalidomide disaster and the 1962 Drug Amendments tightened drug regulation.

The first report of a blood clot in a woman taking Enovid appeared in 1961, and it took almost a decade to prove a statistical link between the pill and thromboembolism. In January 1970 Senator Gaylord Nelson's subcommittee held hearings on whether women were being told of the pill's risks; members of D.C. Women's Liberation, angered by an all-male panel of witnesses, disrupted them. The hearings led the FDA to require an information leaflet for women taking the pill, at a time when medicines carried no patient information on use or side effects, and the requirement was later extended beyond contraceptives.

Subsequent decades brought progressively lower hormone doses. In 1969 Britain's Committee on Safety of Drugs stated that the risk of clots rose with the estrogen dose, and estrogen content fell from 75 mcg or more to 50, then 30 and 20 mcg; some pills now contain 10 mcg of ethinyl estradiol, against 150 mcg of mestranol in Enovid. Progestin-only pills, long-acting hormonal implants, and the hormonal intrauterine device extended hormonal contraception far beyond Enovid's original design.