Ethical and Legal Issues of Including Women in Clinical Studies

Abstract

HISTORY OF DEVELOPMENT AND TESTING OF DES
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Ethical and Legal Issues of Including Women in Clinical Studies

Diethylstilbestrol (DES) is a synthetic estrogen. It was first produced in London in 1938 and was prescribed from 1945 to 1971 to prevent spontaneous abortions. The earliest studies of DES in pregnant women in the United States were conducted at Harvard University in the late 1940s. Although the studies were criticized because they were conducted without the use of controls, the physicians directing the studies concluded that DES was effective against a variety of pregnancy complications and resulted in a healthier maternal environment. In 1947 the FDA approved new drug applications (NDAs) to market DES for the purpose of preventing miscarriages.

Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1, Chapter: Appendix C: DES Case Study, (1994).

In the 1950s, however, controlled studies of DES in pregnant women yielded different results. At Tulane University, researchers found that more of the DES-treated women had miscarriages and premature births, while the controls had bigger, healthier babies. At the University of Chicago, every pregnant woman at the University’s Lying-In Hospital became part of a clinical trial: one-half were randomized to receive DES and the other half received placebos. None of the women were told they were part of a study, nor were they told what drug they were taking. The study found that twice as many of the DES-treated mothers had miscarriages and small babies. Despite growing evidence that DES was ineffective, for the next 20 years the drug was administered to pregnant women to prevent miscarriage. In 1951 the FDA concluded that DES was safe for use during pregnancy and stopped requiring manufacturers to complete NDAs prior to marketing the drug as a preventive against miscarriage.

DES-RELATED INJURIES

In 1971 an article in the New England Journal of Medicine reported that between 1966 and 1971 seven cases of clear-cell adenocarcinoma (CCA) had been found in teenage girls. CCA is an extremely rare cancer, particularly in young women. The common element to these seven cases was that their mothers had taken DES during their pregnancies. In that same year, the FDA contraindicated the use of DES as a miscarriage preventive; but by that time, an estimated 1.5 million babies had been exposed to DES. Thirty thousand were exposed in 1971 alone.

Research has found that DES interferes with the formation of normal genital tissue during fetal development. Many studies have found possible associations between DES exposure and abnormalities in daughters of women who took DES while pregnant. These studies, including one looking at DES daughters whose mothers were involved in the University of Chicago experiments, have found possible associations between DES exposure and vaginal and cervical dysplasia (a type of abnormal tissue that either reverts with time or progresses slowly to cancer); adenosis (glandular proliferation); cervical ridges and cervical erosion; uterine structural abnormalities, such as a T-shape of the endometrial cavity and/or an unusually small uterus; uterine hypoplasia (underdeveloped cells); infertility; menstrual irregularities; ectopic pregnancies; fetal death and premature birth; and breast and reproductive-tract cancers. The pathologic changes were more common in women exposed to high DES doses and those exposed early in gestation. It is estimated that there are almost two million ”DES daughters” now of childbearing age (NIH, 1992).

Injury to male babies, or DES sons, has also been reported. No malignant tumors have been reported, but certain genital and semen abnormalities are more common in men exposed to DES in utero than in men not exposed to DES. These abnormalities include penile bleeding, testicular masses, epididymal cysts, hypoplastic testes, and cryptorchidism (undescended testicle) (NIH, 1992). One article reported that one in three DES sons is sterile. Other authors call for more studies to determine whether the observed abnormalities are correlated with an increased risk of infertility (NIH, 1992).

There have also been allegations of injury to third generations. Two legal actions were initiated on behalf of DES granddaughters who claim that their disabilities were caused by their premature birth, which resulted from damage to their mothers’ reproductive organs from in utero DES exposure (see Enright v. Eli Lilly & Co. and Sorrels v. Eli Lilly & Co.). In addition, one DES son filed a legal action alleging that his teenage daughter’s fatal case of clear-cell adenocarcinoma was caused by his exposure to DES in utero.

In addition to reproductive abnormalities, research in animals has shown that DES may induce certain autoimmune disorders. Two small studies done on humans have shown altered T-cell and natural killer cell function in women exposed in utero to DES, and data from one cohort of “DES daughters” shows an increase in reported incidence of autoimmune diseases. Whether DES exposure is associated with an increased risk of developing an autoimmune disorder is an active area of research (NIH, 1992). Concern over the effects of DES on persons exposed in utero continues to prompt further study. The National Cancer Institute (NCI) recently issued a request for applications (RFA) inviting cooperative agreement applications from investigators to assist NCI in studies of women with DES-associated clear-cell adenocarcinoma of the cervix or vagina (The Blue Sheet, 1993). Another RFA from NCI and the National Institute of Child Health and Human Development (NICHD) invites cooperative agreement applications to develop a national program to inform health professionals and the public on the adverse effects of DES (NIH, 1993). Initial awards for both RFAs were expected to be made in September 1993. In addition, an added $2.9 million in federal funds was recently allocated to fund further studies of health problems in DES sons, as well as in daughters and their mothers.

LIABILITY

There have been numerous legal actions initiated by daughters whose mothers were exposed to DES during pregnancy; more than a thousand were pending nationwide as of February 1991. Because over 300 companies manufactured DES according to the same formula and pharmacists often filled prescriptions at random, the chief barrier to recovery for most DES plaintiffs is identifying the manufacturer who supplied the drug that a particular mother ingested. Many of the successful cases have relied on theories of joint and several liability.

There have been two reported cases coming out of the University of Chicago experiments in the 1950s.

  1. In Mink v. University of Chicago, three women filed an action against Eli Lilly, a pharmaceutical company manufacturing DES, and the University of Chicago to recover for their daughters’ development of abnormal cervical cellular formations and for their daughters’ increased risk of vaginal and cervical cancer. They also alleged that they themselves and their sons had suffered reproductive and other abnormalities and an increased cancer risk. In addition, the plaintiffs asked the court to allow them to represent the other women in the experiment who were given DES by certifying their case as a class action. The court declined to certify the case as a class action, but issued an opinion on whether the plaintiffs’ claims of injury to themselves and their daughters had merit.

    The plaintiffs claimed they were not told that they were part of an experiment, nor were they informed that they were taking DES. They also claimed that since the DES-cancer link was known by 1971, the manufacturer should be liable for making no effort to warn them until late 1975-1976. The plaintiffs maintained that the University had committed a battery by performing a medical experiment on them without their knowledge. They also asserted that the University had breached a duty to notify them that they had taken DES and that their children should be regularly examined. The plaintiffs claimed that Eli Lilly was strictly liable for the manufacture of a defective and unreasonably dangerous drug.

    In a hearing on whether the case should be dismissed, the court held that Eli Lilly had a duty to notify the plaintiffs about the DES risks when the company became aware of them or should have become aware of them. Under Illinois tort law, however, in order for the plaintiffs to recover under theories of breach of duty to warn and in strict liability, they must allege physical injury to themselves. Because the plaintiffs in their complaint cited risk of injury or physical injuries to others (their children) under their claims of breach of duty to warn and strict liability, the court dismissed these complaints.

    The court did not dismiss the battery allegations. The court held that performing nonemergency treatment without consent or knowledge is an unauthorized contact with another person, or a battery. The court stated that the resolution of the case would not turn on the issue of informed consent or whether there was incomplete disclosure of risks before consent was obtained; because there was a complete absence of consent, the issue to be resolved was whether the University had committed battery against these women.

    The case was settled before trial, and the plaintiffs together received a monetary settlement of $225,000 from the University of Chicago for the battery claim. Although the court declined to certify the case as a class action, attorneys for the plaintiffs were able to get the University to agree to provide some services to the other women and their offspring as part of the settlement agreement. The University agreed to treat, free-of-charge, the daughters of any women involved in the 1950 experiments who develop DES-associated vaginal or cervical cancer. They also agreed to provide free annual or biannual medical exams for all offspring exposed to DES in utero during these experiments (Schultz, 1982).

  2. In the second reported case of DES injury from the University of Chicago experiments, two DES daughters initiated legal action against the University of Chicago and Eli Lilly, alleging their injuries resulted from their mother’s participation in the experiments while they were in utero. The plaintiffs also based their legal claims on theories of battery, strict liability, and breach of duty to warn/lack of informed consent. The case was settled out of court for an undisclosed amount (Wetherill v. University of Chicago).

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