Editor's Summary

Sumner Yaffe, M.D., Editor

The development of rational therapeutics for infants and children has recently received much attention from the academic community, industry, the U.S. Congress, and the federal government. The members of the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices recognized that a variety of interesting and challenging issues are being raised, from several different perspectives, among a diverse group of interested and affected parties. Consequently, they requested that a workshop be held to explore such issues in depth. This report summarizes the proceedings of that workshop.

The U.S. Food and Drug Administration (FDA), the federal regulatory body involved during the development, preclinical studies, and clinical trial phases of new drug discovery and testing with humans, requires that companies provide evidence of the safety and effectiveness of a product before marketing of that product. The protocols used to meet this requirement have been in effect for the last three decades and have historically been primarily confined to studies with adult populations. For many years, however, it was considered to be unethical to enroll children in clinical studies.

However, over time it became increasingly recognized that children are not small adults and that special considerations for this population are critical. In 1977, the American Academy of Pediatrics declared that it was unethical to ex-

The content of this summary reflects the views of the editor, which are not those of the Roundtable. It is based solely on the presentations and the discussions that took place during the workshop.



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Rational Therapeutics for Infants and Children: Workshop Summary Editor's Summary Sumner Yaffe, M.D., Editor The development of rational therapeutics for infants and children has recently received much attention from the academic community, industry, the U.S. Congress, and the federal government. The members of the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices recognized that a variety of interesting and challenging issues are being raised, from several different perspectives, among a diverse group of interested and affected parties. Consequently, they requested that a workshop be held to explore such issues in depth. This report summarizes the proceedings of that workshop. The U.S. Food and Drug Administration (FDA), the federal regulatory body involved during the development, preclinical studies, and clinical trial phases of new drug discovery and testing with humans, requires that companies provide evidence of the safety and effectiveness of a product before marketing of that product. The protocols used to meet this requirement have been in effect for the last three decades and have historically been primarily confined to studies with adult populations. For many years, however, it was considered to be unethical to enroll children in clinical studies. However, over time it became increasingly recognized that children are not small adults and that special considerations for this population are critical. In 1977, the American Academy of Pediatrics declared that it was unethical to ex- The content of this summary reflects the views of the editor, which are not those of the Roundtable. It is based solely on the presentations and the discussions that took place during the workshop.

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Rational Therapeutics for Infants and Children: Workshop Summary pect physicians to prescribe therapeutic agents to children in the absence of specific evidence on how children responded to such agents; to do so amounted to conducting an uncontrolled experiment when dispensing a prescription to a child. FDA regulations published in 1994, 1997, and 1998 significantly changed the circumstances under which therapeutics are prescribed for pediatric patients. Manufacturers, for example, are now required to evaluate the safety and effectiveness of certain new and marketed drugs and biologic products in pediatric patients. In addition, the Food and Drug Administration Modernization Act, enacted in 1997, provides a financial incentive, in the form of a 6-month extension of patent exclusivity, for manufacturers to undertake studies on the safety and efficacy of drugs prescribed for children. Thus, through the regulatory process, financial incentives are now provided to pharmaceutical sponsors who investigate drugs and biologics in children and who present such information in their new drug application submissions. However, the exact relationship among these provisions remains to be determined. Although the main directions for undertaking the requisite studies on the proper use of therapeutics in children are in place, many challenges and issues remain. The term pediatric population, for instance, does not encompass one homogeneous group of patients; instead, it consists of a collection of highly variable subgroups, from neonates, to infants, to teenagers. Recruitment of subjects for a clinical trial is another challenge that involves complicated issues of informed consent of children and parents. Another critical variable in this equation involves consideration of the growth and developmental changes that occur through infancy, childhood, and adolescence, which in turn complicates determination of appropriate surrogate endpoints and drug dosages. Completing clinical trials in children is yet another challenge, given the required long-term follow-up studies. Although the regulatory process encourages pharmaceutical sponsors to investigate drugs and biologics in studies with children and rewards them for doing so, until now the primary emphasis has been on the collection of data concerning drug kinetics and, to a lesser extent, dynamics in pediatric and aged individuals. Little emphasis has been placed on understanding the mechanistic basis for the differences and the similarities that are observed. Consequently, there is a dearth of information on the basic mechanisms responsible for the pharmacokinetic and pharmacodynamic behaviors of major classes of drugs in these special populations. Although maturation is one area of investigation known to influence drug disposition in children, information on other processes, such as ontogeny of drug biotransformation pathways, drug transport systems, and pharmacologic receptor functions and their regulation and gene expression, is generally lacking or is at best rudimentary. Advances in molecular biology have resulted in an unprecedented surge in the number of new therapeutic agents available for testing in studies with children. There is a concern, however, that a shortage of trained clinical pharma-

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Rational Therapeutics for Infants and Children: Workshop Summary cologists (particularly those who can integrate the field of molecular biology with clinical investigation), the increasing number of drugs available for testing, and the limited capacity to conduct clinical trials with children may still result in the prescription of too many drugs for children in the absence of good evidence for their safety and efficacy in that population. Additionally, on the basis of a lack of experience, there are concerns about the new FDA regulations that permit a drug to be prescribed for a pediatric patient on the basis of adequate and well-controlled studies with adults if the course of the disease and the effects of the drug are sufficiently similar in the pediatric and adult populations. Comparison of the pediatric and adult populations needs to take several factors into account, including pathophysiology and natural history of diseases common to both groups and the host reactions to disease and therapeutic agents (including pharmacodynamics and toxic reactions). The workshop summarized in this report explored how scientists in industry, academia, and the government can develop a research strategy to gather the needed information to facilitate the development process for therapeutic drugs and biologics designed for use in the pediatric population. The workshop focused on four major areas of importance for improving understanding of the development and testing of drugs and biologics in studies with pediatric populations, as well as facilitating future planning in this area: how children are similar or dissimilar to adults with regard to physiology, drug metabolism, immunology, cognitive effects, and response to disease states and therapy; the identification of new advances in biomedical science that are uniquely applicable to children and that could be applied to the development and testing of drugs and biologics in studies with children; the special requirements in evaluating drugs and biologics in studies with pediatric populations, including an assessment of when and how safety and efficacy data can be used for children; and an examination of the many legal and regulatory issues in evaluating new drugs and biologics in studies with pediatric populations, as well as interrelated social and ethical concerns. The following sections highlight major themes discussed in the workshop presentations. SIMILARITIES AND DISSIMILARITIES IN PHYSIOLOGY, METABOLISM, AND DISEASE STATES AND RESPONSES TO THERAPY IN CHILDREN AND ADULTS The pediatric population often responds to drugs and biologics differently than adults do. Generally, the drug prescription guidelines that practitioners use

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Rational Therapeutics for Infants and Children: Workshop Summary have not always been based on biologic or pharmacologic principles when they extrapolate the drug doses used for adults to infants and children. Not only have the guidelines tended to be simplistic, in that they assume a linear relationship between children and adults, but they have also not made allowances for the complex changes in growth and development that take place during childhood. A number of quantitative and qualitative differences in the anatomy and physiology of the infant and developing child can affect the absorption, distribution, metabolism, and excretion of various drugs and other xenobiotic compounds. Additionally, children differ from adults not only in anatomical and physiological ways but also in the types of diseases from which they suffer and in their manifestations of these diseases that they do have in common with adults. These factors can determine the types of therapies developed for children as well as the design of studies that evaluate new therapeutic agents. Adverse experiences to drugs that have been tolerated by adults have been observed in children when the drugs have not been adequately studied before their use in the pediatric population. A structured analysis of children's responses to drugs that are tolerated by adults could strengthen the safety component of the study design. The ontogeny of drug-metabolizing enzymes in humans, for instance, may explain several differences in the responses to drugs by adult and pediatric populations. Understanding the relative role of absorption in drug biotransformation may also lead to better understanding of the drug-metabolizing abilities of the different populations. Phenotyping studies of drug biotransformation could also help explain differential responses to drugs. The results of studies with adults may not always be extrapolated to children because growth and development issues add a range of complicated variables to the already intricate realm of drug metabolism and pharmacodynamics. Studies of drugs for use in children must be designed to account for the complex developmental changes that can affect drug biodisposition and pharmacodynamics. PHARMACOKINETICS AND PHARMACODYNAMICS IN CHILDREN VERSUS ADULTS Pharmacokinetics and pharmacodynamics are very different in children and adults. The pharmacokinetics of many drugs vary with age (Kearns, 1998). For instance, because of the rapid changes in size, body composition, and organ function that occur during the first year of life, clinicians as well as pharmacokineticists and toxicologists are presented with challenges in prescribing safe and effective doses of therapeutic agents (Milsap and Jusko, 1994). Studies with adolescents reveal even more complexity in drug metabolism and differences in drug metabolism between the sexes. The therapeutic value of understanding differences in pharmacokinetics because of developmental factors thus relies on an ability to understand better the dose versus concentration versus effect profile for a specific drug in patients of

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Rational Therapeutics for Infants and Children: Workshop Summary various ages (Kearns, 1998). In turn, recognition of differences in pharmacokinetics because of developmental factors can be invaluable for interpretation of data and improving and guiding the design of clinical thais on drug disposition and efficacy. EXTRAPOLATION OF SAFETY AND EFFICACY DATA TO CHILDREN Extrapolation to children of safety and efficacy data generated for adults requires careful attention to potentially important differences between these two populations. The safety of drugs, for instance, needs to be supported by appropriate research with the targeted age group. Some medications that are completely safe for adults may produce toxic effects in children. An assessment of pharmacokinetic-pharmacodynamic relationships, however, by use of a surrogate and comparison of those results with those for adults may suffice as a basis for approval of the drug for use in the pediatric population or help determine the doses to be used in clinical trial. Unlike drugs, the majority of which are for oral administration, the majority of therapeutic biologics are for parenteral use only. Thus, many of the formulation issues for biologics to be used in the pediatric population are similar to the formulation issues for parenteral drugs to be used in the adult population. Because of their distinctive properties, the use of biologics results in unique safety concerns that require different types of monitoring, such as for adventitious agents that occur as a result of treatment with the biologic, or for reactogenicity. There is some concern about therapeutic biologics because little is known about the long-term effects of treatment with such agents, especially their effects on developing children. Many questions about the evaluation of biologics in the pediatric population need to be addressed; no simple approach is available. The requirements for the safety and efficacy of medical devices are different from those for the safety and efficacy of drugs and biologics. Not only can the size of a device pose engineering problems, but also hormonal influences and the activity levels of patients need to be factored into the design of devices. Obtaining approval for use of a device in the pediatric population is also not an easy undertaking; ample evidence indicating that it has been properly designed for children and that the safety and efficacy are demonstrated rather than presumed must be made available. RAISING AWARENESS OF REGULATORY, LEGAL, AND ETHICAL ISSUES Every year, information necessary for the proper use of drugs and biologics in infants and children is lacking for more than half of newly approved drugs and biologics that are likely to be used by children. This is often because chil-

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Rational Therapeutics for Infants and Children: Workshop Summary dren are not sufficiently included in research studies. Pediatric clinical trials involve many logistical challenges as well as legal and regulatory considerations. For instance, a special consideration is informed consent and whether parental consent, the assent of the child, or both are required. FDA's new Pediatric Rule makes it more likely that children will receive improved treatment, because physicians will have more complete information on how drugs affect children and the appropriate doses for each age group (FDA, 1998e). The rule also allows FDA to require industry to test already marketed products in studies with pediatric populations in certain compelling circumstances, such as when a drug is commonly prescribed for use in children and the absence of adequate testing and labeling could pose significant risks. OPPORTUNITIES FOR IMPROVING THE PROCESS To conduct the necessary studies of drugs with pediatric populations, adequate numbers of patients and researchers are needed. New laboratory methodologies need to be developed to make drug testing more applicable to children. It will be important to address the lack of appropriate formulations and commercial incentives for some drugs that are important for the pediatric population. Recent efforts to grant exclusivity to sponsors of pediatric drugs are aimed at achieving a societal good. It has been a tool previously used by the U.S. Congress to promote the development of orphan and generic drugs. Now, the Congress is again using this tool to encourage the development of drugs for use in infants and children. This financial incentive carries with it a serious scientific responsibility. It is likely to result in changes in attitudes about the feasibility of studies with children and, as a result, a larger infrastructure for studying drugs in children. Hopefully, this will result in better drug labeling for the pediatric population, more appropriate formulations, better dosing guidelines for more age ranges, and better information about efficacy and toxicity. It will be important to carefully evaluate, over the next several years, how well this financial incentive achieved its stated objectives. Doing so poses several challenges: Industry, government, and academia must together develop some good metrics to determine if the goals of the new incentive programs have been met. If heavy reliance is placed on extrapolation of data for adult populations, there must be a way of evaluating, over the long-term, whether it is working well. A means of long-term monitoring must be developed, financed, and conducted to assess the effects of drugs on children's growth and their neuronal, psychosocial, and endocrinologic maturation.

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Rational Therapeutics for Infants and Children: Workshop Summary If it is concluded that this incentive program does work for the pediatric population and is worth the cost, it may encourage its application to other populations, such as pregnant women, elderly people, or minority groups. If it is applicable to these other groups, will it be at the expense of maintaining the program for children?