The Drug Hunters

by Donald R Kirsch

  Believing that schizophrenia was hereditary, she vowed never to have children. So in the early 1900s, Katharine Dexter McCormick was a young, bright, beautiful woman with near-unlimited money, an insane husband, and no children. She needed something to occupy her keen mind, so she turned to one of the most prominent social causes of her time, the women’s suffrage movement.

  McCormick jumped into the fight for women’s right to vote with “the force of a grenadier,” as one friend described her, becoming the vice president of the League of Women Voters, funding the Women’s Journal, and organizing much of the successful effort to gain ratification of the nineteenth amendment giving women the right to vote. During her suffragette days, in 1917, McCormick attended a lecture in Boston by a woman who immediately impressed McCormick with her passion and conviction. Margaret Sanger held great influence over McCormick from the moment she met her. And from the moment that Sanger first told McCormick about her dream of a contraceptive drug as easy to take as aspirin, the heiress was sold.

  McCormick, educated as a biologist at MIT, believed in the power of biochemistry. After the successful ratification of the nineteenth amendment, Sanger’s crusade for a birth control pill injected McCormick’s life with a renewed sense of meaning and purpose. McCormick frequently aided Sanger’s contraceptive efforts by smuggling diaphragms into the country for Sanger’s birth control clinics. Yet, despite her immense wealth, McCormick was not able to fund research into a birth control pill. As her husband fell deeper and deeper into psychosis, she became ensnared in a litigious battle with her husband’s family over his estate. McCormick was compelled to guide her philanthropy toward domains that her in-laws approved of, such as schizophrenia research.

  Everything changed when her husband finally died in 1947. According to his generous will, she inherited full control over his $35 million estate—$350 million in today’s dollars—making her, as one friend put it, “rich as Croesus.” At long last, at the ripe age of seventy-two, Katharine Dexter McCormick was free to pursue her own agenda—and her agenda was oral contraception.

  Sanger initially suggested that McCormick should fund research at multiple institutions around the world. But McCormick worried that such a scattershot approach would not work. She wanted a highly targeted approach that would produce a practical pill, not the open-ended uncertainty of basic research. After all, she was getting on in years and wanted to see the creation of a pill while she was still alive.

  On June 8, 1953, Sanger took McCormick on a trip to Clark University in Massachusetts, where Pincus worked. He took the two septuagenarian ladies on a tour of his facilities—a short tour, since his lab was quite skimpy. Nevertheless, McCormick was persuaded by Sanger’s enthusiasm and Pincus’s confidence. “I believe you are the man to finally see our dream realized,” McCormick said, and right there in the lab wrote Pincus a check for $40,000. This sizable sum (about $350,000 in 2016 dollars) was more than 1 percent of the entire National Science Foundation budget. Pincus, whose lab at Clark University had been struggling just to stay afloat, now had more funding than many of the top biology laboratories in the country.

  This scandal-tainted Jewish outsider had just formed the unlikeliest of alliances with two elderly feminists, one fantastically rich, one raised in poverty, neither one at all qualified to judge the likelihood of his actually developing an effective oral contraception drug. Nevertheless, they all shared a common bond. They had all courted public controversy and faced public scorn. They were a battle-hardened group who recognized that they were embarking upon another war.

  Pincus explained to Sanger that their goal was to develop an orally active version of progesterone. Ever since the earliest studies of the corpora luteum inspired by Professor Zschokke’s paper on cow fertility, it was known that when progesterone was injected into a female mammal it inhibited ovulation. But progesterone did not work orally; the body would not take up the hormone through the digestive system. And even though it was possible in theory to convert an injectable version of a drug into an oral version, the oral absorption of drugs in animals’ bodies differs from oral absorption in the human body. The only way to know for sure whether an oral version of progesterone would work was by testing it on people.

  Through the 1960s, pharmaceutical companies usually did not even bother to manufacture a drug unless they already had a compound that could be swallowed, since devising an oral drug from an injectable one can be very expensive. When I was working for Squibb, we received FDA approval for an antibiotic called aztreonam, but the compound was active only via injection. We worked to put together a version we thought should be orally active, but to win FDA approval for the pill we would need to run expensive and time-consuming clinical trials—trials that might ultimately demonstrate the oral version did not work. Was there any way we could increase our confidence about the oral version before initiating the hassle and expense of clinical trials? There was. I swallowed the untested oral version of aztreonam myself.

  Along with a few of my braver Squibb colleagues, one morning we all gulped down the drug with a cup of water, waited, then urinated into a cup for testing. Later that afternoon, the impromptu test results came back. Triumph! Our bodies had successfully absorbed the oral version of the antibiotic. That meant we could go forward with the clinical trials confident they would be worth the expense. However, as I celebrated at home that evening, I suddenly had to run to the bathroom to deal with a bout of wrenching diarrhea. Ironically, it did not even occur to me that my rogue testing could have caused my gastrointestinal distress. I wanted the drug to work so badly that I never considered the possibility that my incessant bathroom visits were due to the oral aztreonam. Instead, I recalled that I had eaten egg salad for lunch—and convinced myself that my waves of diarrhea must have been the result of food poisoning from spoiled egg salad. I forgot about the entire incident until the clinical trials commenced and multiple subjects reported explosive diarrhea. Needless to say, we never received FDA approval of our orally active drug.

  Pincus started searching for an oral version of progesterone by testing progesterone compounds on rabbits. There were more than two hundred different commercially available progesterone compounds—all produced using the Marker degradation method—and Pincus fed every one of them to the rabbits in his Clark University laboratory. Three of the compounds reliably prevented pregnancy without producing adverse effects. That was enough. Now he could test these three drug candidates on humans.

  There was one final hurdle to surmount, and it was a big one. According to federal law, only a clinical physician could direct human drug trials. Pincus would need to find a partner who was willing to endure the inevitably scrutiny and controversies that would attend such a scandalous project—a project that, strictly speaking, violated both state and federal anti-contraception laws. Pincus must have wondered if it was easier to get a $40,000 check than to locate a physician willing to test the world’s first oral contraception.

  A silver crucifix always graced the wall of Dr. John Rock’s office. The lifelong Catholic attended mass at seven in the morning every day, at St. Mary’s in Brookline or sometimes at the Immaculate Conception Church. He was always gracious and unwaveringly polite, holding the door for his patients at Harvard Medical School and always addressing them as Mrs. or Miss. Rock taught obstetrics for more than three decades at Harvard, and he believed that the most prominent form of suffering among his patients was the anguish of unwanted pregnancies.

  He had seen destroyed wombs, premature aging, and financial catastrophe all resulting from a mother having too many babies. Although Rock was a staunch social conservative—early in his career he opposed the admission of women to Harvard for their own good—he had slowly developed progressive ideas about birth control. Despite the Catholic Church’s strident opposition to contraception, Rock believed that birth control could reduce poverty and eliminate the medical problems resulting from repeated pregnancies. He felt certain that Christ would approve of birth
control.

  In the 1940s, Rock began teaching his Harvard students about contraception, something unheard of in medical schools at the time. He believed that if people merely heard the logic and facts, they would come to embrace birth control as both rational and compassionate. He published a book about birth control, which he thought would lead to a sea change in people’s attitudes. It did not. However, it did draw the attention of a Jewish biologist at Clark University.

  After completing his progesterone trials on rabbits, Pincus bumped into Rock, an old acquaintance from his Harvard days, at a medical conference. Knowing about Rock’s progressive position on birth control from his book, Pincus struck up a conversation about the possible use of an oral progesterone as a contraceptive, hoping to feel out whether Rock might be interested in running human trials with him. To Pincus’ utter astonishment, Rock informed him that he was already testing progesterone on his patients—on infertile women.

  While Pincus had been giving progesterone to rabbits to directly inhibit their ovulation, Rock was giving it to women to indirectly stimulate their ovulation. Rock’s methodology struck Pincus as counterintuitive. The gynecologist injected his patients with a daily regimen of progesterone for several months, theorizing the inhibitory effects of the drug would allow their bodies to rest from the “stress” of ovulation. Then, after ceasing the progesterone injections, Rock speculated that the women’s well-rested reproductive organs would “rebound” vigorously, enabling them to conceive more easily. Remarkably, Rock’s instincts proved correct.

  After Rock administered his daily progesterone therapy to eighty women, thirteen of them conceived within four months of finishing the hormone treatments—an astonishing number in fertility research at the time. This effect became known as the “Rock Rebound.” But for Pincus, the real headline from Rock’s research was the fact that Rock was already testing progesterone on human beings.

  Even so, Rock was sixty-eight—an age when most physicians began to settle into a comfortable and noncontroversial retirement. Pincus suspected that Rock might be hesitant to participate in a project as scandalous and demanding as human trials of an oral contraceptive. But to Pincus’s delight, Rock readily agreed to join the project.

  Pincus felt that Rock was the perfect choice to oversee the clinical trials. Still stinging from the negative publicity that had dogged his in vitro fertilization research, Pincus hoped Rock’s prestige, handsome looks, and staunch Catholic faith would help deflect the inevitable blowback once their contraception research became publicly known. For his part, Rock was confident—many would have said naively confident—that the pope would approve of a progesterone-based oral contraceptive; after all, progesterone was a natural hormone that already existed in the body in order to prevent fertility and therefore should be an acceptable form of birth control. Surely the pope would appreciate the Christian need to help poor women control their pregnancies.

  Pincus was not merely concerned with negative publicity. The Comstock Act was still in full force, as were Massachusetts’s rigid anti-birth control laws banning the distribution of contraceptives. Together, Rock and Pincus devised a way around the anti-contraception laws. Taking advantage of Rock’s existing studies, they would conduct the oral progesterone trials as “fertility research” rather than “contraception research.” Although Pincus and Rock camouflaged its true purpose, the study would be historic, nothing less than the first human trials of an oral contraceptive.

  In 1954, Rock gathered together fifty female volunteers from his fertility laboratory and began giving them the three versions of the progesterone that Pincus had successfully tested on rabbits. Month after month, Rock carefully checked whether these women were ovulating. Not one ovulated while taking oral progesterone. Simultaneously, in a decision that would be considered highly unethical by modern standards (though typical for the time), another group of patients was given the progesterone compounds without their consent. Twelve female and sixteen male patients at the Worcester State Mental Hospital were used as guinea pigs to evaluate the rudimentary safety of the drugs and see whether they produced any adverse physiological effects. Fortunately for the twenty-eight psychiatric patients, they did not.

  Pincus and Rock were ecstatic. But there was still one more crucial question to be answered. Even though the progesterone pills did not seem to elicit any obvious physical problems, Pincus and Rock fretted that the hormone might damage women’s reproductive systems. Specifically, would women become fertile again after they stopped taking progesterone? Yes, they did. The oral contraceptive was not only effective but temporary, eliminating any fear that the Pill would have a permanent sterilizing effect.

  After the success of the Boston trials, Rock and Pincus were confident they had a true oral contraceptive in hand. Pincus and Rock selected one of the three progesterone compounds known as noretynodrel for all future drug development efforts, based on results from animal studies that suggested that it had the least potential for side effects. But to actually turn noretynodrel into a commercial product, they needed FDA approval. And to get FDA approval, they needed to run more comprehensive experiments on humans. But since clinical trials of a contraceptive were both prohibited by law and contrary to religious dogma, how could Pincus and Rock get the necessary trials off the ground?

  Hoping to find a location outside the reach of the law, Pincus visited the island of Puerto Rico in the summer of 1951. It was perfect. The American territory was densely populated and one of the poorest regions in North America, conditions that made Puerto Rican officials very supportive of birth control methods. At the time, many American companies were building factories in Puerto Rico and women could find good-paying jobs … if they could find a way to control their pregnancies. Even better, sixty-seven separate clinics across the island were already sharing non-drug-based methods of contraception with women.

  In April, 1956, Pincus and Rock initiated their first drug trial at the clinic in the town of Rio Piedras. As soon as word got out that the clinic was offering a drug to prevent pregnancy, the trial filled to capacity with female volunteers. Encouraged, Pincus and Rock quickly expanded the trials to other clinics. After a year of testing, the results came in. Pincus and Rock were joyous. The Pill was 100 percent effective when taken properly.

  Nevertheless, there was a major caveat to these wondrous findings. About 17 percent of the women in the study complained of nausea, dizziness, headaches, stomach pain, or vomiting. In fact, the director of the Puerto Rico trials informed Pincus that a 10-milligram dose of progesterone produced “too many side reactions to be generally acceptable.” Rock and Pincus brushed aside the warning. With an attitude distressingly common among drug hunters who believe they are this close to success, the two men suggested that the women’s complaints might be psychosomatic. After all, their patients in Boston—whom Rock had inspected in person—experienced far fewer negative reactions. The two male drug hunters dismissed nausea and female bloating as minor nuisances compared to the outstanding benefits of their new medication.

  This disgraced biologist and the ivory tower idealist, working without the support of either industry or academia, having dodged federal and state laws by holding their drug trials in an offshore American territory and willfully ignoring disturbing signs of deleterious side effects, had nevertheless demonstrated that it was possible to create an inexpensive and reliable oral contraceptive. Now all they needed was a way to manufacture and distribute the possibly unsafe drug on an industrial scale so it could be provided to any woman who needed it. Of course, there was only one kind of institution capable of making and selling drugs on an industrial scale. Big Pharma.

  When Pincus had first approached the pharmaceutical company G. D. Searle in the early 1950s about funding research for an oral contraceptive, Searle’s response was a resounding no. At the time, many pharmaceutical companies were raking in profits from several new kinds of miracle drugs, including antibiotics, psychiatric drugs, and glucocorticoids—a rec
ently discovered class of medication, such as hydrocortisone, that possessed amazing anti-inflammatory properties. Since glucocorticoids were used to treat everything from poison ivy to autoimmune disease, they were flying off the shelves. Searle had built up a very lucrative glucocorticoid business, so the idea of making a controversial drug that might put their other sales at risk of a Catholic boycott was a non-starter. Searle executives believed that such a boycott could result in the loss of one fourth of Searle’s employees and a considerable portion of its hospital business.

  Moreover, beyond the legal and religious risk factors, Searle executives simply did not believe there would be much of a market for an oral contraceptive. The prevailing wisdom among the all-male executives was that no healthy woman would ever willingly take a drug that neither treated nor prevented disease—especially a drug they would need to take every single day. However, when Pincus and Rock returned from Puerto Rico with the results from their surreptitious trials, Searle completely reversed its long-standing position.

  Though Pincus and Rock believed it was their hard-earned data that did most of the convincing, Searle was secretly influenced by developments of which Pincus and Rock were unaware. Searle had already marketed progesterone to women as a treatment for various gynecological disorders. To the amazement of Searle executives, many of these women spontaneously began to use the drug as an ad hoc contraceptive method, a use that Searle had in no way encouraged and that was definitely not approved of by the FDA. Thus, Searle was already open to the possibility of a market for an oral contraceptive when Pincus and Rock showed up on their doorstep with FDA-ready human data.