1
The Grady Hospital Study
The Corruption of Contraceptive Research
Judith Weiszâs story of the politics of drug risk management begins with the Food and Drug Administrationâs authority to permit a pharmaceutical company to conduct human clinical studies of a drug.1 For her, a critical period in the drugâs approval process occurs after the FDA grants an IND, the agencyâs 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 FDAâs 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 drugâs 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 drugâs 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 drugâs contraceptive use, they crossed the risk assessment boundary and failed to assess Depo-Proveraâs 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 FDAâs Public Board of Inquiry, found the Grady Clinicâs IND plagued with failures; and why the women in the clinicâs 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 drugâs 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 drugâs major domestic clinical trial for use as a female contraceptive.8
Upjohnâs and Grady Memorial Hospitalâs INDs for Depo-Proveraâs contraceptive use became the focus of scientific and political controversy. When the FDA granted and then withdrew Upjohnâs New Drug Approval (NDA) for Depo-Proveraâs 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 drugâs 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 drugâs 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 subjectsâ informed consent and provide no window on the realities of these clinical trials.
The Grady Clinicâs study does, however, allow us to go beyond the face of Upjohnâs and the clinicâs 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 FDAâs supervision and investigation of the clinicâs IND process and the agencyâs 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 Clinicâs.
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 Gradyâs Maternal Health and Family Planning Clinic and the Deputy Chief of Obstetrics at the Grady Hospital, was the chief sponsor of the clinicâs 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. âThe âaverageâ 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.â14
The Grady Clinic IND Protocol
The Grady Clinicâs IND protocol provided for the drug to be given to women âfor 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.â15 Use of Depo-Provera was halted on November 3, 1972, because of a concern about the drugâs teratogenic effects and then reinstated a month later with a revised protocol containing two additional stipulations that the drug be given to women âreceiving the rubella vaccine immediately postpartum and to those unable to use another contraceptive method,â including those who were mentally challenged.16
Women became participants in the Grady study once they complied with the procedures set forth in the clinicâs 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-Proveraâs contraceptive research, which was used to study the drugâs 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 subjectâs 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 Clinicâs study began in 1967, women read and signed a consent form that stated in toto: âI 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.â21
The Grady Clinicâs form raises a basic informed consent issue: What is the duty of researchers to disclose a drugâs 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 drugâs 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 drugâs 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 drugâs 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 Womenâs 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 Clinicâs informed consent practices. One woman cast doubt on whether the clinicâs consent practices were voluntary when she wrote: âMy welfare worker ordered me to take this drug. She said if I didnât my check would be cut off.â24 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 drugâs unapproved status, and twenty-eight indicated that they received no information about the drugâs potential risks or hazards. One woman took the time to write: âI 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.â25 Even Dr. Robert Hatcher, the Director of the Grady Clinic, admitted in his testimony before the Public Board of Inquiry that Depo-Provera was âbeing administered as [if] it were a fully approved drug with established risks.â26 Still, even if the drug had been an approved contraceptive, the Grady Clinicâs consent form did not provide its patients with sufficient information about the drugâs risks for them to make an informed choice.
The FDA Review of Upjohnâs Research
The Grady Clinic had been using its consent form for three years when the future of its clinical trial was jeopardized by Upjohnâs 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...