Contraceptive Risk
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Contraceptive Risk

The FDA, Depo-Provera, and the Politics of Experimental Medicine

William Green

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Contraceptive Risk

The FDA, Depo-Provera, and the Politics of Experimental Medicine

William Green

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About This Book

The story of Depo-Provera joins the national struggle over the drug's FDA approval to the state legal issues raised by its contraceptive and criminal justice uses. Depo-Provera is known as an injectable hormonal birth control method, but few are familiar with its dark and complicated history. Depo-Provera was tested on women since the mid-1960s without their informed consent until it was FDA-approved in 1992, but never FDA-approved as chemical castration for male sex offenders. Contraceptive Risk is William Green's landmark study of Depo-Provera. Based on a fascinating combination of archival materials and interviews, the book is framed as three interconnected stories told by Judith Weisz, who chaired the FDA's Public Board of Inquiry on Depo-Provera, a scientific court; by Anne MacMurdo who brought a products liability suit against Upjohn, the drug's manufacturer, for the deleterious side effects she suffered from the drug's use; and by Roger Gauntlett, an Upjohn heir who, when he was convicted of sexual assault, refused to take a dose of his family's own medicine as a probation condition. Together these three stories of Depo-Provera's convoluted fifty year odyssey call for a paradigm shift in pharmaceutical drug development.

Contraceptive Risk is a thoroughly researched and engrossing approach to the scientific, political and institutional forces involved in health law and policy, as well as the multifaceted politics of measuring risk.

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Publisher
NYU Press
Year
2017
ISBN
9781479891320

1

The Grady Hospital Study

The Corruption of Contraceptive Research

Judith Weisz’s story of the politics of drug risk management begins with the Food and Drug Administration’s authority to permit a pharmaceutical company to conduct human clinical studies of a drug.1 For her, a critical period in the drug’s approval process occurs after the FDA grants an IND, the agency’s official authorization for the conduct of human clinical testing,2 and before the company submits a New Drug Approval application.3 During this time, drug testing is out of the FDA’s hands and in those of the company and its researchers, who are required to follow the IND protocol and make periodic reports to the agency. The research protocol, the defining feature of the IND process, is designed to provide evidence of the drug’s safety and effectiveness, which is necessary for the FDA to make a marketing approval decision.4
The IND research protocol is supposed to create a boundary between evidence of risk assessment and risk acceptability. Inside this boundary, the IND study can be assessed on scientific criteria: Is it sufficient in scale, design, and execution to establish the drug’s safety and effectiveness? Yet the temptation is to cross the boundary at the research site and allow decisions to be influenced by practice-of-medicine standards and by social, economic, and political interests.
When the FDA allowed human clinical trials to continue in spite of animal study evidence suggesting that Depo-Provera was a suspected carcinogen and when the Grady Memorial Hospital Family Planning Clinic conducted its IND studies of the drug’s contraceptive use, they crossed the risk assessment boundary and failed to assess Depo-Provera’s risk to the research subjects. This chapter will examine why this boundary was crossed by the FDA and the Grady Clinic; why two FDA medical officers, Drs. J. W. Armistead and Michael Popkin, found fault with Upjohn animal studies and why Dr. Alan Lisook, head of the FDA team investigating the Grady Clinic study, and Dr. Judith Weisz, chair of the FDA’s Public Board of Inquiry, found the Grady Clinic’s IND plagued with failures; and why the women in the clinic’s study failed to find a legal remedy for the harms they had suffered.5

Depo-Provera Contraceptive Research

The Food and Drug Administration first approved Depo-Provera, a synthetic progestogen, in 1960 to treat endometriosis and miscarriage.6 When Upjohn found that the drug could also prevent conception by suppressing the hormones that induce ovulation, it conducted an initial screening and animal tests. In 1963, the company received an IND to conduct human clinical trials of the drug’s contraceptive safety and effectiveness.7 Two years later, it initiated clinical trials in seventy-six foreign countries. In 1967, the Grady Memorial Hospital Family Planning Clinic in Atlanta, Georgia, received its own IND to conduct the drug’s major domestic clinical trial for use as a female contraceptive.8
Upjohn’s and Grady Memorial Hospital’s INDs for Depo-Provera’s contraceptive use became the focus of scientific and political controversy. When the FDA granted and then withdrew Upjohn’s New Drug Approval (NDA) for Depo-Provera’s limited marketing approval in 1974,9 refused to grant the drug a general marketing license in 1978,10 and created a public board of inquiry to resolve scientific issues about the drug’s safety,11 the agency was concerned that the animal studies revealed a risk of breast and endometrial cancer, and the human clinical studies also suggested an increased risk of breast, endometrial, and cervical cancer.12 The Upjohn-sponsored clinical studies and the medical reports and journal articles they generated were also criticized for their research designs and conclusions about the drug’s safety. These studies, reports, and articles, which will be examined in Chapter 2, became the subject of substantial public debate, but they make only passing references to their subjects’ informed consent and provide no window on the realities of these clinical trials.
The Grady Clinic’s study does, however, allow us to go beyond the face of Upjohn’s and the clinic’s scientific reports and journal articles to explore how its protocol, informed consent procedures, record-keeping, and research findings crossed the boundary between the conduct of scientific research and the practice of medicine and to grasp the impact of the Grady Clinic study on the lives of women who were its subjects. The Grady Clinic study also allows us to examine the FDA’s supervision and investigation of the clinic’s IND process and the agency’s role and that of its Obstetrics and Gynecology (OB/GYN) Advisory Committee and its Depo-Provera Public Board of Inquiry in reviewing the scientific evidence and making risk assessments and risk acceptability judgments related to all Depo-Provera clinical trials, including the Grady Clinic’s.

The Grady Memorial Hospital Study

Grady Memorial is a large inner-city public hospital in Atlanta, Georgia, which serves an almost exclusively low-income and indigent African American population. Dr. W. Newton Long, the Director of Research and Training in Grady’s Maternal Health and Family Planning Clinic and the Deputy Chief of Obstetrics at the Grady Hospital, was the chief sponsor of the clinic’s IND study of Depo-Provera.13 The clinic drew its subject population for the study from its inner-city clientele and enrolled women throughout their childbearing years. “The ‘average’ Depo-Provera user at Grady, [was] 28.8 years old, black and unmarried. She [was] most likely to have attended school through between 10th and 12th grade, have two children and be acting as the head of her family. She [was] earning 100 dollars per month per family member, and [was] subsidized by [M]edicaid or Title XX.”14

The Grady Clinic IND Protocol

The Grady Clinic’s IND protocol provided for the drug to be given to women “for whom pregnancy was contraindicated (cardiac patients), women with medical problems associated with menses (sickle cell disease, menorraghia), [and] women who had experienced contraceptive failure with two other methods.”15 Use of Depo-Provera was halted on November 3, 1972, because of a concern about the drug’s teratogenic effects and then reinstated a month later with a revised protocol containing two additional stipulations that the drug be given to women “receiving the rubella vaccine immediately postpartum and to those unable to use another contraceptive method,” including those who were mentally challenged.16
Women became participants in the Grady study once they complied with the procedures set forth in the clinic’s IND protocol. At their first visit, they completed a questionnaire about their age, marital status, education, reproductive experience, and medical history. Then they were given a physical examination that included a pregnancy test, a pelvic examination, and a Pap smear to test for cervical cancer.17 Once they read and signed the consent form, they were given an injection of the drug. At the three-month follow-up visits, they were given a pregnancy test and counseled about any complications they were experiencing. At their fourth injection, they received an annual examination, which repeated the elements of the initial examination.18
The Grady Clinic IND provided a large data base for Depo-Provera’s contraceptive research, which was used to study the drug’s discontinuation rates; estrogen use to manage bleeding; breast, uterine, and ovarian cancer; and mortality among black contraceptive users.19 Journal articles based on the Grady Clinic data were published in Public Health Reports, Contraception, and the Journal of the American Medical Association; and unpublished reports appeared in Medroxyprogesterone Acetate, a Grady Clinic research collection.20 In spite of this large volume of research and the clinical procedures that appear to have been unexceptional, the Grady Clinic study was deeply flawed.

The Grady Clinic and Informed Consent

A research subject’s participation in an experimental drug program requires that she give her voluntary and knowing consent to the health risk involved. Assuming that her decision is voluntary, a key element in making a knowing decision is the information in the consent form. When the Grady Clinic’s study began in 1967, women read and signed a consent form that stated in toto: “I hereby acknowledge that I am Voluntarily [sic] receiving an injection of Depo-Provera. I am also aware that as a result of the injection I may experience the following side effects: 1. Amenorrhea (loss of periods), 2. Irregular bleeding, 3. Possible absence of return to fertility.”21
The Grady Clinic’s form raises a basic informed consent issue: What is the duty of researchers to disclose a drug’s risk to their subjects? Assuming, once again, that the subjects gave their voluntary consent, the Grady consent form they signed was seriously deficient in providing them with the information necessary for them to give their knowing consent to the use of Depo-Provera. The form failed to disclose that the drug was not an FDA-approved contraceptive, nor did it disclose that the drug’s only approved uses were treatment for amenorrhea, irregular uterine bleeding, miscarriage, endometriosis, and kidney and endometrial cancer. The form also failed to identify, nor was it ever modified to include, the evolving body of clinical research that documented that the short-term side effects from the drug’s use included loss of libido, depression, and weight gain, and suggested that it was a suspected human carcinogen. The form failed to list any contraindications for the drug’s use, including thrombophlebitis, thromboembolic disorders, cerebral vascular disease, liver dysfunction or disease, undiagnosed vaginal bleeding, known or suspected pregnancy, and miscarriage.22 Finally, the consent form did not inform the women that they were subjects in an experimental drug study, but implicitly represented the drug as an approved contraceptive and the clinical experiment as the practice of medicine.
When the National Women’s Health Network created a registry of Depo-Provera users in 1979 and encouraged women nationwide to request questionnaires, thirty-two women who had received the drug at the Grady Clinic prior to 1973 requested and returned the registry questionnaire.23 Their answers provide anecdotal data on the Grady Clinic’s informed consent practices. One woman cast doubt on whether the clinic’s consent practices were voluntary when she wrote: “My welfare worker ordered me to take this drug. She said if I didn’t my check would be cut off.”24 The thirty-two Grady women overwhelmingly agreed that they did not give their knowing consent. Thirty informed the Network that they were not given any information about the drug’s unapproved status, and twenty-eight indicated that they received no information about the drug’s potential risks or hazards. One woman took the time to write: “I do not remember signing any papers. I did not know until over three months later that it was experimental. They told me nothing at the hospital just that it would protect me from getting pregnant. I would not have taken the shot knowing it was experimental.”25 Even Dr. Robert Hatcher, the Director of the Grady Clinic, admitted in his testimony before the Public Board of Inquiry that Depo-Provera was “being administered as [if] it were a fully approved drug with established risks.”26 Still, even if the drug had been an approved contraceptive, the Grady Clinic’s consent form did not provide its patients with sufficient information about the drug’s risks for them to make an informed choice.

The FDA Review of Upjohn’s Research

The Grady Clinic had been using its consent form for three years when the future of its clinical trial was jeopardized by Upjohn’s report to the Food and Drug Administration in September 1970 that its seven-year dog study had found tumors in three of the beagles.27 FDA policy required the agency to termi...

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