- Historic Sites
The Story Of The Pill
How a Crash Program Developed an Efficient Oral Contraceptive in Less Than a Decade
August/September 1978 | Volume 29, Issue 5
Shortly after the Tokyo conference, Puerto Rico was selected as the initial testing ground. There were good reasons: Puerto Rico had a horrendous and officially recognized population problem, it had operating birth control clinics, its government was eager to cooperate, and the island population was relatively immobile, which meant that the experimental subjects and control groups were likely to “stay put.” The trials began in April, 1956, in a suburb of San Juan where slum clearance was being joined with a large-scale housing project.
By that time the decision had been made to field-test Searle’s norethynodrel only. Syntex’s norethindrone was abandoned. The stated reason was that in animal tests norethindrone, unlike norethynodrel, gave some sign of slightly increasing masculinity in the process of inhibiting ovulation. Of course there were other reasons also. Pincus’ long professional association with Searle naturally inclined him to favor Searle’s harvest of whatever profitable fruit might grow from his endeavors. Moreover, Searle had an efficient marketing system through which to promote widespread use of a finished product, whereas Syntex, a wholesale manufacturing firm, did not. (It must be emphasized, however, that Searle in the spring of 1956 and for two or three years afterward was by no means sure that it wanted to go into the contraceptive business, which was regarded as a rather sleazy enterprise. The firm’s public relations people warned that doing so might destroy Searle’s theretofore “impeccable reputation.”)
By that time, too, a significant change had been made in the product to be tested. It had been noted that, among women dosed with one batch of norethynodrel, there occurred “breakthrough” bleeding if not actual ovulation (this last was suspected, because of the bleeding) in a small and yet, by project standards, disturbingly large percentage of cases. Among women dosed with another batch, however, this did not occur. Why? Chemical analysis revealed that the batch permitting breakthrough consisted of absolutely pure progesterone, whereas the other batch contained minute quantities of the starting material for its manufacture (mestranol), which has estrogen in it. So Searle was instructed to add, in future, a tiny amount of mestranol (150 meg.) to the progestogen from which each tablet was made. This, then, was the pill taken by volunteer women in Puerto Rico and, beginning a year later (at the urgent invitation of dictator “Papa Doc” Duvalier), in Haiti. It was patented by Searle as Enovid-10®, thus becoming Searle’s exclusive property. (Pincus might easily have obtained a share of the patent for the Worcester Foundation had he moved to do so. Why didn’t he? mourns Chang, who, while greatly admiring Pincus, has no love for pharmaceutical companies and deplores this lost opportunity to divert to the service of pure science a portion of what became a huge Searle profit.)
Surely nothing could be more revealing of the yetprimitive stage of the science which was now being forced into technology than this abrupt modification of the experimental Pill on the very eve of extensive human testing of it. Every science begins as a loose collection of more or less random observations. Initially, since nothing is known of the “basic mechanisms” whereby observed phenomena or desired results are produced, experiments are conducted “hit or miss,” to quote again from Chang’s Tokyo paper. Not until multiple lucky “hits” have provided a solid ground for logical inference can meaningful patterns be discerned or general descriptive laws be developed for the guidance of future experiment and the prediction, with growing accuracy, of future observations. Empiricism then gives way to induction. Thus a science becomes “mature” to the degree that it becomes inductive—and it may be stated as a general rule for the safety of mankind that no technology having possible massive human or environmental impact should be permitted to be made from other than a fully matured science.
Certainly this rule was in this case broken. Were the reasons for breaking it sufficiently compelling, were the assessments of alternative risks and of the overall riskbenefit ratio sufficiently accurate to justify the act?
One of the key members of the research team that went to Puerto Rico and Haiti was Anne Merrill, a Pincus research assistant at the foundation. She has stressed in conversation the degree of ignorance, and the resultant magnitude of risk, with which the field trials were begun. As regards the tablet’s effectiveness in birth control, the researchers could proceed with confidence: they had by then good reason to believe that Enovid-10 would prove to be a virtually 100 per cent effective contraceptive. But not enough was known about the dynamic hormonal balance in the human body (it is continually shifting, fluctuating, in response to biological needs and environmental stimuli) to permit more than educated guesses as to what the present “disruption” of it would do beyond its single prescribed purpose. There was the recognized possibility that synthetic estrogen might cause cancer. “We didn’t even know for sure that a woman who took the pill, and then went off it to become pregnant, would not produce all boys, or all girls,” says Anne Merrill.