Summary1

Decades of research have demonstrated that children do not respond to medications in the same way as adults. Differences between children and adults in the metabolism, renal clearance, other drug disposition mechanisms, and overall response to medications are due to profound anatomical, physiological, and developmental differences. Substantial variation also exists among children of different ages in the ability to metabolize, absorb, excrete, and transform medications. Although few would argue that children should receive medications that have not been adequately tested for safety and efficacy, the majority of drugs prescribed for children—50 to 75 percent—have not been tested in pediatric populations. The younger the age group, the less information is available.

Product labels provide important information to clinicians and consumers on the risks and appropriate use of drugs, and are based on the results of controlled clinical studies. The limited amount of testing of drugs in pediatric patients is reflected in the lack of pediatric-specific information on the product labels for many drugs used to treat children. Without adequate data from such testing, prescribing drugs appropriately becomes challenging for clinicians treating children, from infancy through adolescence.

Current laws employ both incentives and mandates to spur drug makers to test their products in pediatric populations and to enhance the

1

The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.



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Summary1 D ecades of research have demonstrated that children do not respond to medications in the same way as adults. Differences between children and adults in the metabolism, renal clearance, other drug disposition mechanisms, and overall response to medications are due to profound anatomical, physiological, and developmental differences. Sub- stantial variation also exists among children of different ages in the ability to metabolize, absorb, excrete, and transform medications. Although few would argue that children should receive medications that have not been adequately tested for safety and efficacy, the majority of drugs prescribed for children—50 to 75 percent—have not been tested in pediatric popula- tions. The younger the age group, the less information is available. Product labels provide important information to clinicians and con- sumers on the risks and appropriate use of drugs, and are based on the results of controlled clinical studies. The limited amount of testing of drugs in pediatric patients is reflected in the lack of pediatric-specific information on the product labels for many drugs used to treat children. Without adequate data from such testing, prescribing drugs appropriately becomes challenging for clinicians treating children, from infancy through adolescence. Current laws employ both incentives and mandates to spur drug makers to test their products in pediatric populations and to enhance the 1The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT pediatric information provided on drug labels. The result has been a sub- stantial increase in pediatric drug trials, with corresponding information being added to the labels for 115 drugs. Nonetheless, a pressing need for more study remains. Although incentives exist for the study of new, on- patent drugs, some argue that additional incentives are needed, especially to encourage testing of older, off-patent drugs. The two existing laws that address the need to study drugs in pediatric populations—the Best Phar- maceuticals for Children Act (BPCA)2 and the Pediatric Research Equity Act (PREA)3—will sunset in October 2007 without congressional action.4 In this context, and given the urgency of addressing the current gap in pediatric drug safety, the Institute of Medicine’s Forum on Drug Dis- covery, Development, and Translation held a 1-day workshop, Addressing the Barriers to Pediatric Drug Development, on June 13, 2006. The purpose of the workshop was to identify barriers to the development and testing of drugs for pediatric populations, as well as ways in which the system can be improved to facilitate better treatments for children. The Forum invited representatives from the U.S. Food and Drug Administration (FDA), the National Institutes of Health, the American Academy of Pediatrics, the pharmaceutical industry, academia, and several patient advocacy groups to discuss • the current regulatory framework, • current challenges in prescribing and developing drugs for children, • models for enhancing pediatric drug development, and • challenges and opportunities for the future. REGULATORY FRAMEWORK Regulatory efforts to protect children from harmful medications began in the early part of the twentieth century. Many of the initial laws were established in response to specific incidents involving products that caused harm, especially to children; according to Dr. Lisa Mathis of the FDA, however, the resulting laws benefited adults disproportionately. Information on the use of drugs in children was limited and remained insufficient for decades. 2Best Pharmaceuticals for Children Act. Public Law 107–109. http://www.fda.gov/opacom/ laws/pharmkids/pharmkids.html (2002). 3Pediatric Research Equity Act. Public Law 108–155. http://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=108_cong_public_laws&docid=f:publ155.108 (2003). 4Subsequent to this workshop, both BPCA and PREA were reauthorized by Congress as part of the Food and Drug Administration Amendments Act of 2007, Public Law 110-85, which was signed by the President in September 2007.

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 SUMMARY Workshop participants gave an overview of the current regulatory framework for pediatric drug development and testing. BPCA, passed in 2002, provides 6 months of additional marketing exclusivity and pat- ent protection when studies are performed in children as requested by the FDA. The act also specifies a process by which the FDA can request studies of older, off-patent drugs. PREA was passed in 2003 as a comple- ment to the incentives offered by BPCA. Under this act, the FDA can require pediatric studies of a product for which a New Drug Application is submitted if the agency determines the product is likely to be used in a substantial number of pediatric patients or would provide meaningful benefits for children over existing treatments. Workshop participants described the positive impact of these laws on the development of therapies for children. Since 2002, in addition to the labeling changes for 115 pediatric drugs noted above, 12 new pediatric formulations and 8 extemporaneous formulations have been devised; in addition, adverse events have been reported for 54 pediatric drugs. Yet many participants agreed that, while the incentives and mandates in these laws are working, more could be done. Suggestions included adding a requirement to new iterations of BPCA and PREA that product labels provide information on the results of pediatric trials regardless of the product’s approval status, and securing additional funding for studies of off-patent, older agents, as the Foundation for the National Institutes of Health lacks sufficient resources to conduct the needed pediatric studies of these drugs. CURRENT CHALLENGES IN DEVELOPING AND PRESCRIBING DRUGS FOR CHILDREN Challenges in developing and prescribing pediatric drugs were a central theme of the workshop. Barriers to the development of medica- tions for children were discussed, including ethical, economic, logistical and technical barriers, as well as the industry perspective of these bar- riers. Ethical barriers cited include clinicians who prescribe drugs off label absent sufficient pediatric data, which results in delays in needed research; drug sponsors who pursue pediatric clinical trials late in a drug’s life cycle, with more objectives and procedures included than may be appropriate for the study design; academic institutions that fail to reward investigators for participating in clinical trials; and a clinical research enterprise that lacks transparency at all levels. An additional barrier is a reluctance to alter existing practices and focus on the goal of finding efficient and effective ways to develop adequately studied drugs for the treatment of children. Economic barriers were outlined as well. One such barrier is the dif-

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT ficulty of stimulating investment in pediatric drugs by pharmaceutical companies. For one thing, the market is relatively small, thereby reduc- ing financial incentives. For another, pediatric trials involve many special considerations relative to adult studies. For example, different endpoints may be required; the volume of samples that can be taken may necessitate a more innovative statistical design or require multisite or even global studies to accrue sufficient patients; and additional safety concerns must be taken into account, such as issues of growth and development. Logistical and technical barriers also exist. They include a deficient U.S. infrastructure for pediatric drug studies, limited availability of base- line information on frequency of disease and treatments of choice, and a lack of accepted endpoints and validated pediatric assessment tools. Participants also described problems with drug formulations that are not suitable for children and with extemporaneous formulations that may be unsafe because of a lack of quality control. They also discussed dosing issues, including imprecise measuring instruments, problems with taste and palatability (which can affect adherence), and the need for alterna- tives to oral liquid formulations. In addition, participants emphasized the lack of information noted above, and suggested that moving from dose guessing to informed prescribing will require additional study. Also stressed was the need to improve the dissemination of information to physicians so they can make the best choices in prescribing medications for individual pediatric patients. MODELS FOR ENHANCING PEDIATRIC DRUG DEVELOPMENT Workshop participants cited creative solutions from the vaccine development arena that might be applied to pediatric drugs: the no-fault compensation system for patients (or their families) who suffer serious adverse reactions from required childhood vaccines, and the two-page public information fact sheets on each vaccine. Participants were also encouraged by promising regulatory approaches that have been adopted by the European Union and appear to be more cohesive than current U.S. regulations. These include a new Pediatric Committee working at the European Agency for the Evaluation of Medicinal Products; new incentives for patent-protected and off-patent medicinal products; and the Pediatric Investigation Plan, a document describing proposed stud- ies of a drug in pediatric populations, which must be approved by the Pediatric Committee if the associated incentives are to be received. Also discussed was a model used by St. Jude Children’s Research Hospital to develop innovative public–private partnerships for the production of new molecularly targeted drugs for pediatric oncology patients.

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 SUMMARY CHALLENGES AND OPPORTUNITIES FOR THE FUTURE Workshop participants suggested many critical needs and opportuni- ties for further progress, addressing both systemic solutions and potential means of eliminating the economic barriers discussed previously. Sugges- tions included • improving the postmarket safety surveillance system; • combining incentives and requirements for the conduct of pediatric research into one process; • increasing transparency throughout the clinical research enterprise; • increasing training for the next generation of clinical pharmacolo- gists and pediatric researchers; • exploring practice-based research networks to expand the pool of pediatric patients; • providing additional funding and incentives for pediatric drug development; and • implementing lessons learned from models such as U.S. vaccine development, European Union regulations, and St. Jude’s efforts to develop public–private partnerships for the discovery and development of pediatric cancer drugs.

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