(Brandt, 1978a; Thomas and Quinn, 1991). Particular questions have been raised about children and women.
The ethical issues inherent in including children in trials, long debated for other diseases, are even more complex in relation to HIV disease. In general, candidate AIDS drugs are moving into trials on the basis of relatively less preclinical and toxicologic data, which increases traditional concerns over possible adverse outcomes for children in trials. Most children with HIV disease have mothers who themselves have the disease, many of whom are unable to care for their children. For this reason, and in some cases because of ongoing maternal drug use, many HIV-infected children are in foster care (see Chapter 8). It has proven difficult to obtain consent for enrolling such children in trials (Martin and Sacks, 1990). Yet the natural history of HIV disease in children differs appreciably from that in adults, which is an argument for earlier and fuller trials involving children. Lacking such trials, therapy for children has lagged behind that for adults, and guidelines for translating the results of trials to clinical practice have been limited to adults, leaving practicing pediatricians uncertain as to how to treat children.
In the case of AZT, use in symptomatic children was not approved until April 1990—fully 3 years after the drug was licensed for adult use. Moreover, licensing was granted by virtue of a regulatory waiver because the limited trials conducted among children did not satisfy minimal FDA requirements. As a result of that experience, pediatric trials of ddI were started very soon after adult trials were initiated and were designed to satisfy FDA licensing requirements. In addition, it has recently been suggested that because opportunistic infections occur in children too infrequently to warrant separate pediatric trials, children should instead be included in adult trials, with appropriate modification of dosage (Nolan, 1990). Thus, it is likely that, at least for AIDS, and possibly for other life-threatening diseases, there will be a shift toward earlier, larger trials among affected children.
The issue of inclusion of women of childbearing age in trials, especially pregnant women, has been the subject of much debate (Levine, 1990). Early trials often explicitly excluded pregnant women. At a minimum, all trials have required a negative pregnancy test at entry and have stipulated that birth control must be practiced. Whether because of these restrictions or because women are less aware of trials and more likely to face numerous