‘The Fifth Freedom’: An Exchange

To the Editors:

In “The Fifth Freedom” [NYR, October 8, 1992], M. F. Perutz, a winner of the Nobel Prize, misstates key facts and sows misleading impressions about oral contraceptives and tilts toward the pharmaceutical industry.

Recalling the synthesis of norethindrone, a progestogen, in 1951, he wrote: “Eleven years later, after conducting a great many tests, the US Food and Drug Administration approved norethindrone for contraceptive use.” From this single sentence at least four problems arise.

First, the sentence implies that the era of oral contraception began in 1962, with FDA’s approval of pills containing norethindrone; it had begun in 1960, with FDA’s approval of G. D. Searle & Company’s Enovid, in which the progestogen was norethynodrel.

Second, Perutz implies that norethindrone is unique. Actually, oral contraceptives contain various pharmacologically indistinguishable progestogens. That’s why they are collectively called The Pill and why the FDA labels them uniformly.

Third, the FDA doesn’t conduct drug tests; rather it evaluates studies submitted by a drug’s sponsor.

Fourth, “a great many tests” implied sufficiency. This is highly misleading. The FDA’s approval of Enovid launched the greatest uncontrolled medical experiment in history: tens of millions of healthy humans taking potent drugs twenty or twenty-one days a month for up to three decades for a purpose other than controlling a disease. In this unique context the tests were appallingly insufficient. William Kessenich, director of the FDA’s Bureau of Medicine, confirmed this in a May 1960 internal document obtained and released by Senate investigators in 1962. “[T]he entire series of clinical cases” upon which the agency would adjudge Enovid safe, he revealed, had enrolled a mere 64 women who had taken Enovid continuously for 12 to 21 consecutive menstrual cycles, and another 64 for 24 to a maximum of 38 cycles. Searle did larger studies, but simply to establish efficacy.

By August 1962 Searle had acknowledged nine fatal and 123 nonfatal cases of blood-clotting diseases among Enovid users. Four months later—more than two years after approving Enovid—the FDA appointed an advisory committee to investigate whether The Pill could cause such thromboembolic phenomena. Several months later, the committee made one—only one—recommendation: for “a carefully planned and controlled prospective study … [to obtain] more conclusive data….” Obviously, no such recommendation would have been made had manufacturers and the National Institutes of Health sponsored such a study. Ultimately, the British Medical Research Council did a first-rate retrospective study; it found a seven to tenfold increase in serious and fatal clotting in pill users as compared with nonuser peers.

Moreover, in addition to numerous other adverse reactions for which causal relationships have been demonstrated, the possibility that The Pill causes or catalyzes breast cancer and heart disease remains unresolved.¹ In sum, untold millions of women are human guinea pigs even today, contrary to the implication of “a great many tests.”

Echoing a questionable claim by Carl Djerassi, whose book he reviewed, and the Committee on Contraceptive Development of the National Research Council Institute of Medicine, Perutz wrote that “development of contraceptives has become so expensive that most [US] pharmaceutical firms, including Syntex, have abandoned” it. But Congress has yet to compel them to submit the data that might justify the abandonment. Meanwhile, the firms tirelessly defend their outrageous prices and profits as the mother’s milk of R&D.

Perutz perceives a “widespread public misunderstanding of the effects of the prolonged use of any drug on a large population,” but ignores a primary source: immoral drug-industry practices, including fraudulent testing, necessary but unperformed testing, concealment and understatement of adverse reactions, corruption of research institutions and physicians with grants and junkets, and false and misleading promotion.

According to Perutz, the purported misunderstanding partially explains why contraceptive R&D is “uneconomic.” Once millions of people use a new drug, “and affected persons sue the manufacturers for negligence, litigation and damages may cost that firm [sic] many millions of dollars.” This ignores the reality that the penalties—financial fleabites—have been imposed not only for proved negligence, but also for intentional exposure of massive numbers of people to needless harm. Just such behavior led to successful criminal prosecutions involving, for example, SmithKline Beckman’s Selacryn for high blood pressure, Eli Lilly’s Oraflex for arthritis, and Hoechst-Roussel’s Merital for depression. Much more such behavior has eluded exposure, particularly under Reagan-Bush deregulation.

The behavior of contraceptive makers differs only in detail. In 1967–1968, FDA compelled three—Johnson & Johnson’s Ortho Pharmaceutical unit, Bristol-Myers’ Mead Johnson subsidiary, and Syntex—to admit to misleading advertising. Numerous pill product-liability lawsuits produced voluminous evidence of shocking misconduct. Ortho, for example, was less forthright with Canadians than Americans. A healthy, nonsmoking Ontario mother, Paule Jane Buchan, 23, had no predisposition to a stroke. Yet a few weeks after she began taking Ortho-Novum 1/50 in 1971, a lifelong-disabling stroke damaged her brain and significantly paralyzed her left limbs. In the United States, Ortho’s entry for Ortho-Novum 1/50 in the 1971 Physicians’ Desk Reference (PDR) warned of the “statistically significant association between cerebral thrombosis and the use of oral contraceptives.” In Canada, Ortho Pharmaceutical (Canada) Limited didn’t mention cerebral thrombosis in the PDR’s counterpart.

The Ontario Court of Appeals upheld a $606,795 award to Mrs. Buchan. “[I]t can properly be assumed,” Judge Sydney L. Robins wrote in 1986, that Ortho Canada “was aware of or had available to it all of the information possessed by Ortho US with respect to their mutual products including adverse reaction reports, medical and scientific studies on birth control pills, and, in particular, the information which led to the warning given physicians in the United States.” Would Perutz immunize pill makers from lawsuits for such conduct?

As Perutz says, the FDA began to require extensive animal trials as a condition of approval of contraceptives. Unfortunately, he omits that this happened late in the game. Djerassi “points out that these rules make the development of new contraceptives excessively expensive [as noted, we don’t know this]; yet they could never assure complete safety,” Perutz says. But who claimed “complete safety”? He doesn’t say (doesn’t know?) that it was the Pill’s fanatic pushers and paid consultants to the industry, such as Dr. Joseph W. Goldzieher.² He also doesn’t say (doesn’t know?) that the goal of the Food, Drug, and Cosmetic Act was never the absurd, unattainable one of “complete safety.” Rather, it seeks relative safety: substantial evidence from well-controlled studies must establish a favorable ratio of benefits to risks; “adequate” premarket tests must show a drug “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof.”

Perutz says: “There is no way of introducing better contraceptives or indeed any new drugs without risk to some people, and if the press, Congress, and the courts refuse to accept this, efforts to develop new contraceptives will move elsewhere.” But the press, Congress, and the courts have always accepted this. What they reject is inhumane, unethical, and illegal conduct. Nor do they excuse such conduct on the ground that it advances the cause of birth control. It’s a cause, it happens, which I embrace.

Morton Mintz

Chevy Chase, Maryland

M. F Perutz replies:

I am not in a position to reply to Mr. Mintz’s litany of accusations against the drug industry. Instead I will try to explain the intrinsic difficulty facing those who tried to assess the risks of oral contraceptives in the early years.

Genetic diversity, previous medical history, or life habits like smoking ensure that there are always some people in whom any particular drug will cause adverse symptoms. If the percentage of such people among the total population is substantial, then the symptoms show up in trials carried out on several hundred or a few thousand people before the drug is released on the market, but if these symptoms manifest themselves only, say, in one person out of 10,000, then very large numbers are needed to give statistically meaningful results.

The numbers depend critically on whether or not the symptoms would be expected also among people who have never taken the drug. If none are normally expected, and if symptoms among at least three of the treated people must be detected to be statistically meaningful, then, according to experts in medical statistics, for an expected incidence of symptoms among one in a thousand, 6,500 people have to take the drug, or ten times as many if the expected incidence is one in 10,000. On the other hand, supposing the normal incidence of the symptoms among untreated people is one in a thousand, and the number of untreated people is equal to the number of treated ones, then, if one is looking for an additional incidence of one in a thousand, 32,000 people would have to take the drug; if one is looking for an additional incidence of one in ten thousand, 2,300,000 would have to take the drug.

Blood-clotting disorders are a case in point, because they occur but rarely among either users or non-users of oral contraceptives. The question was whether they occur more rarely among non-users. In 1963, the FDA reviewed some 350 reports of thrombosis or pulmonary embolism among women taking Searle’s Enovid and estimated mortality from these diseases to be 12.1 per million contraceptive users per year compared to 8.4 per million in the general populations, a difference that was not considered statistically significant. In 1965, the British Committee on Safety of Drugs was informed of sixteen deaths from thrombosis or pulmonary embolism among 400,000 oral contraceptive users compared to thirteen deaths expected among the same number of women in the general population. Again the difference was not thought significant. This, rather than negligence, was the reason why no further action was taken then.

As the use of oral contraceptives spread and more reports of blood-clotting disorders came to the notice of the British committee, it charged two epidemiologists, W. H. W. Inman and M. P. Vessey, to embark on a larger-scale study of the problem. They obtained the transcripts of 499 death certificates of women aged 20 to 44 who had died from blood-clotting episodes in England and Wales during 1966. After eliminating spinsters and others whose clots could clearly be attributed to other causes, there remained 334 deaths to be investigated. Thirty-five medical officers then interviewed the general practitioners who had attended each of these women in order to find out whether they had taken oral contraceptives or whether they had died of a blood clot during pregnancy or childbirth or had been predisposed to clotting disorders for a variety of reasons. The final results showed that sixteen women using oral contraceptives had died from pulmonary embolism and eighteen women from coronary thrombosis without any other predisposing cause, compared to 4.2 and 11.4 women respectively who had used no oral contraceptives. The almost fourfold greater incidence of pulmonary embolism among contraceptive users was statistically significant, while the merely 1.5 times greater incidence of coronary thrombosis was not. The authors concluded that the risk of dying of pulmonary embolism during one year’s use of oral contraceptives was comparable to the risk when bearing a child: 2.2 per 100,000 per year for women aged 20 to 34 and 4.5 per 100,000 per year for women aged 34 to 44. Even so, that risk was unacceptably high, because women in industrialized countries rarely give birth to more than two or three children, while they may take contraceptives for most of their fertile lives.

The rarity of these deaths would have made it impossible for even the largest drug firms to obtain meaningful results in a trial. The British study was done on a nationwide scale and was facilitated by the data and personnel available under the National Health Service. It would have been far more difficult to undertake by the FDA among the uncoordinated medical services in the United States. Mintz’s accusations are therefore unfounded.

All this is now past history. In response to the risks revealed in these and other studies, drug firms have made oral contraceptives safer by reducing the doses of estrogen and progestogen contained in them. In 1989, Vessey and others published the results of a twenty-year follow-up study of mortality among 17,000 women who had attended one of seventeen family planning clinics in England and Scotland between 1968 and 1970. This showed deaths from circulatory diseases, which included blood clots, to be 8.4 per 100,000 per year among oral contraceptive users, compared to 7.6 among users of diaphragms and intra-uterine devices, a difference that is not statistically significant. There was no relation between the incidence of breast cancer and the duration of oral contraceptive use. Deaths from cancer of the cervix were more frequent, while deaths from ovarian and endometrial cancer were less frequent among oral contraceptive users. Overall mortality was slightly lower among contraceptive users. A further study of 60 women aged between 16 and 39 who died from thromboembolism in England and Wales between 1986 and 1989 showed no evidence for an increased incidence among users of oral contraceptives.

I have the impression that drug firms have taken reasonable precautions to minimize the risk of clotting disorders while maintaining the efficacy of oral contraceptives. I cannot share Mr. Mintz’s hostility to the drug firms; because I owe them my life several times over, and so, I suspect, does he.