American Journal of Law & Medicine

Minority children in pediatric research.

I. INTRODUCTION

Medical research is heavily funded: the National Institutes of Health had a budget of over $20 billion in 2001, and even more money was spent by the pharmaceutical industry on research. (1) Children's health issues, however, receive only a small fraction of these funds. In 2001, for example, less than $1 billion of NIH funding was allocated to the National Institute of Child Health and Human Development (NICHD). (2) In part, the problem stems from a modern predisposition to protect children from participating in research. (3)

Several federal policies in the 1990s changed the face of the "typical research subject." Historically, researchers sought "white men," but the NIH announced in 1994 that all research would need to include women and minorities, (4) and in 1998, the NIH added the requirement of including children. (5) The shift in policies reflects a shift in focus. When the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research addressed fairness in subject selection in the Belmont Report of 1979, the main concern was ensuring fairness in the distribution of risks. (6) By 1994, the tide had turned, and the concern now focused on the fairness in the distribution of benefits. (7)

There are data to indicate that despite the initiatives to include women and minorities, these groups remain underrepresented in clinical research. (8) Little is known, however, about whether these discrepancies hold in pediatric research.

II. AN OVERVIEW OF POLICIES AFFECTING THE PARTICIPATION OF CHILDREN IN MEDICAL RESEARCH

Children have often been subjects of medical research. One researcher has described their historical participation as a form of child abuse because children were often selected as convenient and cheap subjects, and they often participated without adequate protection of their rights or well-being. (9) Following World War II and the Nazi war crimes, however, there was a focus on research subject protections. Although the Nuremberg Code focused on the informed consent of the competent individual and made no provisions for the enrollment of incompetent subjects, including children, (10) the Declaration of Helsinki did provide guidelines for proxy consent in 1964. (11)

In the United States, the first systematic examination of the ethical issues raised by the participation of children in research was the report on children by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1977. (12) The National Commission concluded that children were an especially vulnerable population because they could not consent for themselves and, therefore, suggested that research should be done first on animals, then, when possible and appropriate, on adult humans, then on older children and finally on younger children. (13) Most of the Commission's recommendations regarding children in research were incorporated into subpart D of the federal regulations for the protection of human research subjects. (14)

In June 1996, the American Academy of Pediatrics (AAP) and the NICHD sponsored a workshop on the "Inclusion of Children in Clinical Research" (15) in which the theme was that current policy may be too little, too late. (16) The concern itself is not new. In 1968, Harry Shirkey coined the phrase "therapeutic orphans" to express his frustration with the lack of financial support by the government and the drug industry for pediatric drug investigation, when most of the laws empowering the Food and Drug Administration (FDA) to regulate drugs were passed in response to drug-induced adverse effects in the pediatric population. (17)

Part of the support for increasing pediatric participation in research, particularly in pharmaceutical research, is that major advances have been made during the past half century in adult medicine, with more modest advances being made in pediatrics. Consider, for example, that more than eighty percent of drugs prescribed to children have never been tested on children. (18) The danger is that unless they are tested, every child is an experiment because there are no data for safety or efficacy and no guidelines for dosing. Policies promulgated by the federal government in the 1990s attempted to overcome this gap.

In 1994, the FDA published a final rule regarding specific requirements on the content and format of pediatric labeling for human prescription drugs. (19) It was an attempt to improve pediatric labeling by requiring drug manufacturers to survey existing data and determine whether those data were sufficient to support additional pediatric use information on drug labels. The response was disappointing and did not substantially increase the pediatric use information for marketed drugs and biological products. Approximately 430 drugs and biologic supplements were submitted, seventy-five percent of which did not improve pediatric use information. More than half simply requested the addition, "Safety and effectiveness in pediatric patients have not been established." (20)

The Pediatric Rule was proposed in 1997, finalized in 1998 and became effective on April 1, 1999. (21) The Rule required that manufacturers of certain new drugs and biological products conduct studies to provide adequate pediatric labeling. After the FDA issued the proposed Pediatric Rule, but before the rule was finalized, Congress enacted the Food and Drug Administration Modernization Act (FDAMA). (22) The Act provides economic incentives for conducting pediatric studies. According to a January 2001 status report to Congress, FDAMA has been highly effective in generating pediatric studies on many drugs, although some categories of drugs and some age groups remain inadequately studied. (23) The law, the Best Pharmaceutical for Children Act (BCPA), was reenacted in January 2002 for another five years. (24) The NIH also issued a new policy in 1998 to increase the enrollment of children in research studies. (25) All NIH-funded research must now include a plan for the inclusion of children, unless there is good justification to exclude them. To encourage compliance by researchers, the NIH clearly stated on the Frequently Asked Questions (FAQ) section of its website that the exclusion of children may affect the priority score given to determine grant funding. (26)

The emphasis of the new policies implemented by the FDA and NIH in the 1990s has shifted from protecting children from research risks to ensuring access for children. The policies of the last two years, however, suggest that the support is less robust than it may have seemed. The much-celebrated Children's Health Act of 2000 included the Pediatric Research Initiative Act of 1999. (27) The legislation was designed to make pediatric research, specifically research of children's illnesses and conditions, a high priority. Nevertheless, although funding for pediatric research is increasing, it is increasing at a slower rate than medical research generally, and pediatric research has slipped from 12.5% to about 12% of the NIH budget in recent years. (28)

Second, while the Pediatric Rule and FDAMA were seen as the stick and the carrot that would ensure pharmaceutical testing of all new drugs in children, (29) the Pediatric Rule was suspended in March 2002 in response to a lawsuit. (30) It was quickly reinstated in April 2002 "after members of Congress complained that the FDA was injuring children's health and introduced legislation to force the agency to reinstate the mandate." (31) In October 2002, the U.S. District Court for the District of Columbia struck down the Pediatric Rule on the ground that it exceeded the FDA's statutory authority. (32) Unless additional legislation is passed, only the carrot will remain, leaving pediatric drug testing to be determined by its economic profitability.

Although one of us has argued against a children-first approach in medical research, (33) we both acknowledge the need for and support the inclusion of children in research so that pediatric medicine continues to advance. Having said that, the question remains whether it matters which children participate. Specifically, does it matter if minority children participate?

III. THE MEANING OF RACE IN MEDICINE AND MEDICAL RESEARCH

In medical research, two reasons are given to demand greater participation of minorities: (1) to ensure access to experimental treatments to all who may benefit, particularly when no standard therapy exists; and (2) to ensure that the treatment is efficacious in a diverse subject population. The first rationale reflects a focus on fairness in access rather than fairness in distributing burdens. The focus on access was made poignant by the AIDS epidemic when only those in clinical trials had any chance of long-term survival. It is with sad irony then that recent publications show that minorities continue to remain significantly underrepresented in AIDS clinical research, (34) although HIV is one of the major contributors to disparities in mortality between blacks and whites. (35) The second rationale suggests that different populations may respond differently to a particular treatment. …

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