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Introduction

SCIENCE, CHALLENGES, AND CHILDREN

Presented by Jane Henney, M.D.

Commissioner, U.S. Food and Drug Administration

During recent years, the development of rational therapeutics for infants and children has received a great deal of attention from the academic community, the U.S. Congress, industry, and the federal government, particularly the U.S. Food and Drug Administration (FDA). Although FDA has been in existence for nearly 100 years, it had limited authority with respect to regulating drugs until the 1930s. During that time, however, it was charged with overseeing the evaluation of drug safety. It was not until the 1960s that FDA gained the regulatory authority to require companies to provide evidence that a product was effective before marketing of the product.

For the next three decades, demonstration of safety and effectiveness was largely confined to studies in adult populations. Children were not usually entered into clinical studies, with the exception of those for the development of vaccines, because it was considered unethical to enroll them in experiments. Although physicians and parents wanted adequate use information for products given to sick children, they feared that studies conducted with such children would be deleterious and perhaps unacceptable. These concerns still linger, although perhaps differently so for the parents of children affected by serious or life-threatening diseases and illnesses. Industry was also reluctant to study children because of concerns about liability and because of the large investments in drugs for potentially small markets.

FIRST STEPS

In 1977, the American Academy of Pediatrics made a first move to change the status quo. The Academy asserted that it was unethical to adhere to a system



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Rational Therapeutics for Infants and Children: Workshop Summary 1 Introduction SCIENCE, CHALLENGES, AND CHILDREN Presented by Jane Henney, M.D. Commissioner, U.S. Food and Drug Administration During recent years, the development of rational therapeutics for infants and children has received a great deal of attention from the academic community, the U.S. Congress, industry, and the federal government, particularly the U.S. Food and Drug Administration (FDA). Although FDA has been in existence for nearly 100 years, it had limited authority with respect to regulating drugs until the 1930s. During that time, however, it was charged with overseeing the evaluation of drug safety. It was not until the 1960s that FDA gained the regulatory authority to require companies to provide evidence that a product was effective before marketing of the product. For the next three decades, demonstration of safety and effectiveness was largely confined to studies in adult populations. Children were not usually entered into clinical studies, with the exception of those for the development of vaccines, because it was considered unethical to enroll them in experiments. Although physicians and parents wanted adequate use information for products given to sick children, they feared that studies conducted with such children would be deleterious and perhaps unacceptable. These concerns still linger, although perhaps differently so for the parents of children affected by serious or life-threatening diseases and illnesses. Industry was also reluctant to study children because of concerns about liability and because of the large investments in drugs for potentially small markets. FIRST STEPS In 1977, the American Academy of Pediatrics made a first move to change the status quo. The Academy asserted that it was unethical to adhere to a system

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Rational Therapeutics for Infants and Children: Workshop Summary that forces physicians to use therapeutic agents in essentially uncontrolled experiments every time that they write a prescription for a child. Furthermore, the Academy stated that it was imperative that new drugs intended for use in children be studied in children under controlled circumstances so that the benefits of therapeutic advances could become available to all who need them. These principles made a powerful, yet simple statement: children deserve and should have the same standard as adults when it comes to therapeutics. If adequate and well-controlled studies are needed to determine the efficacy of products used for adults, then the same should be true for products used for children. This statement of principle shifted everyone's thinking about clinical testing of medical products in the pediatric population. No longer were the experts focused on the dogma of how unethical it was to study the effects of drugs in children. It became unethical not to conduct such studies. In 1979, FDA confirmed the need to have information on how best to use a product in the pediatric population by issuing regulations. The position of the agency was that if statements were to be made regarding pediatric use of a drug for an indication approved for adults, such statements were required to be based on substantial evidence derived from adequate and well-controlled studies, unless the requirement was waived. Unfortunately, this particular regulation did not generate the intended response. Few clinical trials with the pediatric population were initiated. The regulation did not provide incentives for companies to conduct such studies, nor were there repercussions for not doing so. Thus, for two-thirds to three-quarters of all drugs used by the pediatric population, directions for use by children that were based on data from clinical trials were not available. More than a decade passed before the agency took a more assertive stance. In 1994, FDA issued a final rule requiring drug manufacturers to survey existing data and determine whether those data were sufficient to support the presentation of additional pediatric use information in a drug's labeling. The rule explicitly recognized that controlled clinical studies conducted to support pediatric use need not be carried out with a pediatric population if the course of the disease and the effects of the drug are sufficiently similar in children and adults. Extrapolation of adult effectiveness data to pediatric patients was permitted. In these cases, controlled clinical studies with adults, together with other information such as pharmacokinetics and adverse reaction data for pediatric patients, could be found to be sufficient to establish the safety and effectiveness of a drug in children. Under the 1994 role, if a manufacturer determined that existing data permitted modification of the label's pediatric use information, the manufacturer had to submit a supplemental new drug application to FDA to seek approval of these labeling changes. It is important to recognize that this rule did not impose a general requirement that manufacturers carry out studies if existing informa-

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Rational Therapeutics for Infants and Children: Workshop Summary tion was not sufficient to support pediatric use information. Instead, where there was insufficient information to support a pediatric indication or pediatric use statement, the rule allowed the manufacturer instead to include a statement in the drug's labeling which clarified that: ''Safety and effectiveness in pediatric patients have not been established." More than half of the responses to the role used the latter approach. Approximately 75 percent of the applications submitted did not show significant improvement in pediatric use information. The actions taken by FDA produced some gains in labeling for pediatric use, but did not substantially increase the number of drugs and biologic products for which there was adequate pediatric use information. Indeed, when the agency compared the number of new molecular entities approved in 1991 and 1996 with their potential usefulness in pediatric patients—using a specific process to assess the adequacy of labeling of those drugs for pediatric use—56 percent of the products approved in 1991 had some labeling for pediatric use at the time of approval. Yet in 1996 this number had fallen to only 37 percent. Of the seven new molecular entities that were approved in 1991 and for which postapproval pediatric studies were promised, only one had pediatric use labeling by 1997. Clearly, if the goal of ensuring the safety and effectiveness of drugs and biologic products for pediatric patients was to be met, additional steps needed to be taken. NEW RULE MAKING In August 1997, FDA proposed a rule with provisions that required the manufacturers of certain new and marketed drugs and biologic products to evaluate the safety and effectiveness of their products in pediatric patients. This included new drugs or biologic products that would provide a meaningful therapeutic benefit to pediatric patients over existing treatments, or that were likely to be used by a substantial number of pediatric patients. The proposed regulation also included certain marketed drugs or biologic products, such as those indicated for a very significant or life-threatening illness. In the preamble to the proposed rule, the agency noted that financial and other incentives to manufacturers, although largely beyond FDA's authority at that time, could further increase the number of drugs and biologics with adequate labeling for pediatric use. The incentive approach was provided by Congress in the Food and Drug Administration Modernization Act of 1997. The legislation includes "Section III," or the pediatric exclusivity provision. This provision created a financial incentive—an additional 6 months of market exclusivity to industry—for conducting studies of new drugs as well as drugs that were already on the market and for which the patent was still intact in the pediatric population (FDA, 1997b).

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Rational Therapeutics for Infants and Children: Workshop Summary FDA also initiated other actions to encourage the development of adequate pediatric use information. These included publication of guidance on clinical trial designs for the assessment of pediatric pharmacokinetics of drug and biologic products, development of an initial guidance document on clinical trials with pediatric subjects, and discussions with the pharmaceutical industry on a policy exempting user fees for pediatric supplements. In late 1998, FDA finalized its previously proposed regulations regarding studies in pediatric populations. Although no products found to be safe and effective in adults are to be—or have been—delayed or denied approval because of a lack of testing in the pediatric population, there is now a requirement for a manufacturer to conduct trials with children in an expeditious manner. The final rule and the pediatric exclusivity provisions are critical to ensuring needed and timely development of drugs for use by the pediatric population. From November 1997 to May 1999, FDA witnessed more interest and activity in this field than in the past several decades. Between June 1998 and May 1999, FDA received more than 115 proposals from sponsors requesting permission to perform various studies with pediatric populations. In comparison, there were 70 commitments for Phase 4 studies with pediatric subjects made from 1991 to 1997. CHALLENGES TO STUDIES WITH CHILDREN Since the new rule has been in effect, FDA has observed a needed shift in attitude toward clinical testing in pediatric populations on the part of all involved: the agency, industry, researchers, and parents. However, challenges remain. First, the term pediatric population does not refer to a homogeneous group of patients but really refers to a collection of highly variable subgroups from neonates, to infants, to teenagers. Neonates are often seen as one of the most difficult age groups to test because of the potential differences in how their bodies will metabolize and respond to a given drug. However, that group has the advantage of being highly monitored by a variety of devices and of being under the care of highly skilled hospital staff. Infants, on the other hand, do not receive the 24-hour monitoring given to neonates. If they do, it is often provided by their parents, who are not always the most unbiased observers. On the other end of the spectrum are adolescents. Although unlike the neonate or the infant, adolescents are able to communicate with providers and parents, they might not always be willing to do so. Recruitment of subjects for a clinical trial is also a challenge. It requires individuals who can understand parental concerns and communicate that understanding. Often, a number of family members need to be involved in this decision making activity. An investigator's ability to repeatedly explain the study to parents, grandparents, and other significant family members can be critical to a trial's success.

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Rational Therapeutics for Infants and Children: Workshop Summary Defining what benefit a child may derive from the additional discomforts of blood drawing, frequent hospital or clinic visits, or other inconveniences that the child may experience is an important aspect of ensuring the ethical implementation of such a study. Thai design issues, such as the requirement for hospitalization, the duration of a study, the number and timing of the evaluation visits, and the need to decrease or stop current therapy to initiate study therapy are all challenges that make study recruitment for the pediatric population different from that for the adult population. The parent, caretaker, or older child must weigh the benefits of the study to the patient or themselves versus the costs of the loss of work or school and the disruption to the family and daily living that may result from participation in a study. Another critical variable that must be considered for children involves growth and maturation and the expected changes that occur throughout infancy, childhood, and adolescence. It is difficult to define the effects of chronic therapy on children and to differentiate their positive effects or possible negative effects on the dynamic processes of childhood. Long-term follow-up over several years after the receipt of therapeutic interventions may be needed to assess neural development, behavior, and bone and joint growth. Another challenge that is simple in studies with adults but that is complex in studies with pediatric populations is determination of appropriate endpoints. Fundamental measurements, such as vital signs, height, and weight are dynamic measurements for children. Thus, outcome measures must be modified. For example, for children the important outcome measure is the rate of weight gain, not simply weight maintenance or weight gain, as it would be for adults. Another example is pain scales, which in studies with adults are represented by a bar with numerical options extending from one extreme to the other. The study subject selects his or her level of pain (e.g., 3 on a scale of 10). This concept is often not transferable as ordinal numbers to children; thus, a pain scale that depicts sad and happy faces is sometimes used in an attempt to capture the same endpoint measurement. Cost is also a challenge involved with completing clinical thais with children. Enrollment of children in clinical trials often requires long-term follow-up, which requires expertise, technology, and personnel, all of which are expensive. In addition, research is needed to assist those who conduct clinical trials with children to provide them with the technology and methods that allow studies to be conducted where it was not possible before. For example, innovations in such areas as blood sampling and diagnostic techniques are needed. THE ROLE OF FDA The days of reluctance to conduct clinical testing of new drugs in the pediatric population are past. FDA has the important task of defining what studies in

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Rational Therapeutics for Infants and Children: Workshop Summary pediatric populations are needed and requesting or requiring sponsors to perform such studies. The agency is committed to working with the scientific, professional, and consumer communities to improve this area of research and thus enhance the health of children.