Ensuring Safe and Effective Medications for Children

Pediatricians and other child health professionals routinely treat children with medications that have not been proven to be safe and effective for their patient population and that have labels that lack appropriate guidance from the manufacturer on how those drugs should be used for children. Shocking? Perhaps. But in reality those who provide medical care to children have little choice because, as noted in the article by Roberts et al¹ in this issue of THE JOURNAL, "only one third of drugs used to treat children have been studied adequately in the population in which they are being used and have appropriate use information on the product label. For the other two thirds of drugs, information regarding safety and efficacy for pediatric patients is insufficient or absent."

Under the Federal Food, Drug and Cosmetic Act,² the Food and Drug Administration (FDA) must approve new medications as safe and effective before they can be marketed. But approval is limited to specific indications that the manufacturers identify and for which they provide scientific evidence. Detailed information from the studies that provided the basis for approval is then incorporated into the drug's "label," which includes the package insert and most advertising. Once the drug is approved for any particular set of indications, physicians are free to use their clinical judgment as to the value of the drug for conditions, dosages, or populations other than those that have been approved. Such off-label prescribing is considered medical practice, which the FDA does not regulate, and is not part of the drug approval process.³ Physicians may incur malpractice liability for failing to obtain appropriate consent from patients or for making unsound choices or otherwise straying negligently from common practice in the use of pharmaceuticals, but clinicians are not precluded by the FDA from using approved drugs as they see fit.⁴

While off-label prescribing occurs with respect to medical care of adults, it is the cornerstone of pediatric medical therapeutics. If clinicians restricted their prescribing to medications specifically approved for children, they would have a relatively modest pharmacopoeia and children would not have access to many modern drugs. Of necessity, pediatric clinicians extrapolate from evidence and experience with adults and from fundamental principles of physiology and pharmacokinetics and try to make sound decisions with respect to dosage and usage of drugs for children.

The reasons for limited formal approval of drugs used for children include economic, legal, ethical, scientific, and practical challenges.⁵ Children consume a relatively small proportion of prescription medications and provide less financial incentive for pharmaceutical manufacturers to conduct studies in their age groups than in adults. Particularly for medications that will principally be used in older age groups, the likelihood of extensive off-label use in pediatrics further minimizes any economic incentive for manufacturers to evaluate the drug in children. In addition, there are serious ethical concerns related to obtaining proxy consent to conduct research in children, and questions about the propriety of providing financial incentives for parents to enroll minors in studies that will not be of immediate potential benefit to their child. Children span a wide age range, and separate studies may be needed for neonates, toddlers, and adolescents. While studies in adults can provide a basis for approval of a drug for use in children, substantial research is required to provide scientific justification for this approval pathway. Thus, there is little inherent motivation for addressing this problem, and many disincentives and barriers.

Is it harmful that most of the pharmaceuticals used to treat children have not been approved as safe and effective for their age group? It is clear that the preferred route would be for all medications used in children to be demonstrated to be safe and effective for that purpose. Prescribing medications for children based on clinical judgment—however well-informed and guided by experience and rational extrapolation—is nonetheless uncontrolled, undocumented, and unsystematic. Yet, because off-label prescribing is considered an accepted medical practice, it carries none of the protections afforded to participants in research studies, let alone the more restrictive ones applied when conducting research involving children. A few studies point to higher rates of adverse reactions from off-label use of drugs than from those specifically tested for use with children, but the evidence is limited.⁶

The article by Roberts et al¹ demonstrates how essential it is to conduct appropriate testing of drugs for use in children. "Highly important new information" related to dosing, safety, and (lack of) efficacy was discovered in more than one third of the drugs for which studies in children were conducted in response to a request from the FDA and led to new labeling. For the remaining drugs, "benefits included enhancement of our understanding of the safety and the pharmacokinetic profile of the drugs." This is critical information necessary to guide clinicians and ensure that children will benefit from the medications they are given.

What is being done about this problem? Action is taking place on several fronts, but more needs to be done to serve the best interests of children. Congress has passed 2 laws to encourage pharmaceutical manufacturers to test their products in the pediatric population, relying heavily on the financial incentives from extended marketplace exclusivity (delaying introduction of generic drugs).⁷ Since 1979, the FDA has made numerous efforts to cajole manufacturers to study the safety and efficacy of their drugs in children.^{8 - 9} Convinced that the modest results from voluntary measures were insufficient, the FDA moved to require extensive testing of drugs for children,¹⁰ but a federal court has ruled that Congress has not given the FDA authority to issue such a requirement.¹¹

The data presented by Roberts et al¹ demonstrate that the time has come to move forward to protect children from inadequately informed use of prescription drugs while ensuring that they have the benefits of the latest pharmaceuticals and biologicals. When manufacturers do submit information requested by the FDA, significant information on safety, effectiveness, and dosage is frequently obtained. Yet the current approach has yielded this critical information for only a fraction of the medications commonly used for children. For example, according to a 2001 FDA report, "10 drugs were identified in 1994 as the drugs most frequently prescribed for children that lack adequate labeling. Of these, the 6 without remaining exclusivity or patent life have not been studied under the pediatric exclusivity program and remain inadequately labeled."¹² Critics have noted that extending market exclusivity as the motivation for voluntary compliance can lead manufacturers to focus on drugs with large adult markets but only limited application in children.¹³ That approach also provides no incentive for pediatric studies of drugs with expired patents, and does not address the critical need for trials of drugs now predominantly used to treat relatively small numbers of children. Thus, although the exclusivity provisions have led to important information on some drugs, this approach has left large gaps.

Additional tools are needed to minimize the use of medications not specifically approved for children. The pharmaceutical industry, federal government, and pediatric clinicians should strive for a system that will collect the scientific data necessary to learn what works and what does not. Legislation that recently passed the Senate by unanimous consent¹⁴ would give the FDA authority to require studies for claimed indications for new drugs and for existing drugs that are or might well be used for approved indications in children. Working in synergy with the exclusivity provisions,¹⁵ this legislation would be one more step toward the too-long deferred goal of having adequate information on pharmaceuticals for children. The era of prescribing for children by trial and error¹ should come to an end.