American Journal of Law & Medicine

Dying children and medical research: access to clinical trials as benefit and burden.

I. INTRODUCTION

There is perhaps no greater tragedy in a parent's life than learning that one's child is terminally ill. Today, more than at any time in the past, when conventional treatment fails, dying children are given access to experimental treatment. To a surprising extent, society takes for granted the participation of dying children in medical experiments. In part, this is because we have come to view participation in clinical trials as a potential benefit. This view contrasts sharply with the dominant perception of the mid to late 20th century, which viewed medical research as a potential threat to vulnerable populations. Upon closer scrutiny, both of these perspectives carry with them some important truths. This Article seeks to build upon those truths by undertaking a critical analysis of contemporary ethical and legal policies governing the inclusion of terminally ill children in clinical research.

Well-documented abuses of human subjects in medical experimentation, including research with children, created concern in the latter decades of the 20th century. This led to the perception that children were vulnerable, given their inability to protect their own interests, and that the mere fact that parents gave informed consent was insufficient to safeguard their children from the potential harms of medical experimentation. Federal regulations put into place in 1981 sought to provide the necessary additional safeguards. Such rules might have led to a relatively small percentage of sick children enrolling in clinical trials in pediatric oncology. Yet today, a strikingly large majority of U.S. children with cancer are enrolled in Phase III clinical trials and receive therapy under experimental conditions. This is unlike the situation of adults with cancer, where approximately fifteen percent participate in clinical trials. The overwhelming majority of children with cancer become subjects in medical experiments.

These numbers might be unsurprising as pediatric cancer research involves children suffering from life-threatening diseases, which until the 1960s had virtually no effective therapy. In the mid-twentieth century, clinicians and families agreed that clinical studies offered the best chance to save the lives of the affected children. The partnership between pediatric cancer research and clinical studies proved remarkably effective. In less than half a century, clinical research in pediatric oncology produced great progress. The most common form of childhood leukemia went from being a nearly always fatal disease to one cured more than seventy-five percent of the time. Such success no doubt contributed to a willingness to permit children to become the subjects of medical experiments, and perhaps reflected a more general shift in American thinking about the nature of medical research. Beginning in the mid-1980s, in response to scientific progress achieved through clinical research in cancer and AIDS, Americans began to demand access to clinical trials.

These factors help to explain the high percentage of children with cancer who participate in clinical studies, and may also explain the limited ethical and legal scrutiny this issue has received. It may seem needlessly academic to analyze the pros and cons of enrolling pediatric cancer patients in clinical trials. Nonetheless, it is far from clear that the sickest of children--those whom conventional treatment cannot cure--personally benefit from enrollment in early-phase studies.

To the extent that we fail to explore the legal and ethical issues surrounding children's participation in clinical studies, particularly in Phase I clinical trials, we run the risk of replicating the historical abuses of this exploitable population. Toward this end, this Article undertakes a critical analysis of the legal and ethical norms governing the enrollment of sick children in early-phase trials. The Article begins with a brief overview of the history of medical experimentation involving children, assessing both its great promise and its inherent limitations. Part II describes contemporary practices governing research with this population, particularly in regard to Phase I studies. Part III then explores the key legal and ethical problems with the manner in which Phase I pediatric trials are conducted. Finally, the Article concludes by exposing, critiquing and refining the justifications for and the ramifications of permitting and promoting children's access to Phase I trials.

II. A BRIEF HISTORY OF MEDICAL RESEARCH INVOLVING CHILDREN

Since the dawn of modern public health medicine in the West, there has been a remarkable transformation of childhood morbidity and mortality. In the past two hundred years, infant and child mortality has plummeted. In just the last fifty years, research has led to cures for many, if not most, of the common childhood illnesses and many of the ravages of premature birth. Children with major chronic conditions, such as cystic fibrosis, diabetes and sickle cell disease, used to die before reaching the age of majority. Now many live well into adulthood. As a result, parents in Western industrial or post-industrial societies now expect their children to survive and thrive--even children with life-threatening disorders.

During this period, some "medical progress" has come with a high price: undignified and harmful research practices involving children and others unable to protect themselves. Beecher documented several of these cases in a landmark paper in 1966: (1)

* In an effort to learn about the functional anatomy of the urinary tract, doctors inserted catheters into the bladders of healthy newborns, injected radio-opaque dye and performed multiple X-ray studies.

* Physicians suspected liver injury might result from administration of an antibiotic. Investigators administered the drug to "inmates of a children's center," including "mental defectives or juvenile delinquents" without any "disease other than acne." The researchers stopped the study early because of "high incidences of significant hepatic dysfunction." Several subjects subsequently required liver biopsies. (2)

Beginning in the 1970s, governments and professionals acted to prevent research-related harms to those lacking adequate decision-making capacity. (3) In the United States, decades-long practices of the Food and Drug Administration (FDA) tended to exclude children from research aimed at establishing the safety and efficacy of new medications. Regulations regarding human research subject protection included special sections restricting the inclusion of minors in clinical studies.

This regulatory process--and parallel concerns about prolonged liability that might result from claims about research-related harms to children--had a double-edged effect. The regulations required researchers to demonstrate that the benefits of the proposed research outweighed the possible burdens to child subjects. As such, the regulations called attention to the developmental vulnerability of children who were potential research subjects. This caution may have helped to prevent unnecessary, or simply foolish, harms to children from medical studies. On the other hand, the bureaucratic hurdles and liability fears have no doubt slowed, or in some cases, halted potentially valuable biomedical progress.

Concern over the latter possibility has led to federal policy changes in recent years. Beginning in 1998, for example, Phase III clinical trials conducted with the support of the National Institutes of Health (NIH) were required to include children or provide a justification for their exclusion. (4) The FDA also requires companies to include children in their new drug approval process, using both incentives and penalties to insure compliance. In addition to rejecting studies that unjustifiably limit access to children, the FDA encouraged companies to conduct research regarding the pediatric safety of already marketed drugs by providing a six-month patent extension for drug manufacturers who submitted their applications to the FDA on or before January 1, 2002. (5)

This policy shift in favor of including children in clinical studies occurred as part of a broader movement wherein consumer groups demanded access to clinical trials. By the mid-1980s, the absence of effective treatment, much less cures, for AIDS led advocates to demand access to clinical trials arguing, "A Drug Trial is Health Care Too." (6) This campaign helped to transform the public perception of medical experimentation from a risky, exploitative venture into the best response to an incurable disease. Then in the 1990s, advocates for women's health endorsed this image of medical research by decrying the decades-long exclusion of women of reproductive age from clinical research and the resulting ignorance about the safety and efficacy of treatments when used by women.

Progress in the development of treatments for HIV and cancer, among other conditions, has transformed society's perception of the nature of medical research, making inclusion much more desirable than previously perceived. Nonetheless, the same justifications for access to clinical trials may not apply with equal force to those who have exhausted their options for established therapy, or Phase II and Phase III studies, and have become eligible for Phase I studies. This is particularly true for sick children.

There has long been considerable debate about the acceptability of children as subjects of biomedical and behavioral research. …

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