Summary

ABSTRACT

Beginning in the 1990s and continuing into 2010, the federal government has acted to increase the study of drugs in children and thereby reduce a serious deficit in the data on drug safety and efficacy for young patients. One step was to offer economic incentives for the conduct of pediatric studies. A second step was to require such studies in specific situations. These policies—in their current form, the Best Pharmaceuticals for Children Act (BPCA; which provides the incentives) and the Pediatric Research Equity Act (PREA; which provides the requirements)—seek to expand the information available to clinicians who prescribe medications to children and, as a consequence, to improve clinical care and health outcomes for children of all ages.

Consistent with legislative provisions adopted in 2007 and 2010, the Food and Drug Administration (FDA) asked the Institute of Medicine (IOM) to examine pediatric studies requested under BPCA (or its predecessor policies) or required under PREA (or its predecessor policies) and to consider the incentives for pediatric studies of biologics. A committee appointed by the IOM reviewed and assessed a representative sample of labeling changes and other FDA actions related to requested or required studies for the period from July 1, 1998, through December 31, 2010. The assessments covered the use of extrapolation and alternative endpoints for pediatric populations, neonatal assessments, ethical issues, and safety



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Summary ABSTRACT Beginning in the 1990s and continuing into 2010, the federal government has acted to increase the study of drugs in children and thereby reduce a serious deficit in the data on drug safety and efficacy for young patients. One step was to offer economic incen- tives for the conduct of pediatric studies. A second step was to require such studies in specific situations. These policies—in their current form, the Best Pharmaceuticals for Children Act (BPCA; which provides the incentives) and the Pediatric Research Equity Act (PREA; which provides the requirements)—seek to expand the information available to clinicians who prescribe medications to children and, as a consequence, to improve clinical care and health outcomes for children of all ages. Consistent with legislative provisions adopted in 2007 and 2010, the Food and Drug Administration (FDA) asked the Institute of Medicine (IOM) to examine pediatric studies requested under BPCA (or its predecessor policies) or required under PREA (or its predecessor policies) and to consider the incentives for pediatric studies of biologics. A committee appointed by the IOM reviewed and assessed a representative sample of labeling changes and other FDA actions related to requested or required studies for the period from July 1, 1998, through December 31, 2010. The assessments covered the use of extrapolation and alternative endpoints for pe- diatric populations, neonatal assessments, ethical issues, and safety 1

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2 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN findings. The committee also examined the status of the incentives for pediatric studies of biologics created by the Biologics Price Competition and Innovation Act of 2009 (passed in 2010) and sought to identify and assess the importance of biological products that are not being tested for pediatric use. In the course of prepar- ing its report, the committee reached several broad conclusions: • ediatric studies conducted under BPCA and PREA are P yielding important information to guide clinical care for children. Information from pediatric studies sometimes sup- ports and sometimes runs counter to expectations about the efficacy, safety, and pharmacokinetics of a drug in children of different ages. • ome studies requested under BPCA or required under S PREA do not achieve their full potential. Reasons vary and may include the inability of sponsors to recruit sufficient numbers of children, the use of weak study designs and underpowered samples, the lack of dose-ranging studies to guide efficacy trials, and the omission of relevant study in- formation from a product’s labeling. FDA has taken steps to address many of these problems. • ore timely planning, initiation, and completion of pediatric M studies would benefit children. European requirements for the submission of plans for pediatric studies apply at a stage of drug development that may be somewhat premature, whereas U.S. requirements apply later than may be war- ranted. Delays in sponsor completion of required studies also warrant further attention. • ediatric drug studies remain particularly limited in certain P areas, including the use of medications with neonates and the long-term safety and effectiveness of drugs for all pe- diatric age groups. The frequent lack of information about the long-term safety of drugs used with children is a special worry—both for drugs that may be used for decades for chronic conditions and for drugs for which short-term use may have adverse consequences on a child’s development months or years later. Many drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group. • ongress has significantly expanded public access to infor- C mation from recent pediatric studies conducted under BPCA and PREA and has thereby enhanced the value of these stud-

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3 SUMMARY ies. Limitations still exist, however, particularly for products with PREA-related labeling changes that occurred prior to September 2007. • he reauthorization processes for BPCA and PREA have T improved policies promulgated under both acts, but frequent reauthorizations create uncertainties for industry and FDA. • ediatric studies of biologics conducted under PREA have P generated valuable information. The 2010 expansion of BPCA to cover biologics has the potential to expand knowl- edge further, but it is too early to assess its effects. Almost 90 percent of biologics that the committee investigated are labeled for use with children or have been the subject of some study with children. Most of the remaining products were approved for indications that are not diagnosed or very rarely diagnosed in children. Given the applicability to biologics of long-standing policies such as the 1984 Orphan Drug Act and PREA and given the range of existing pedi- atric research on many biologics, the incentives of BPCA may have a valuable but more modest effect in encouraging studies of biologics than they did for small-molecule drugs. The committee was not asked to make recommendations except with respect to pediatric studies of biologics. This report does, however, offer suggestions and options for Congress and FDA to • xpand public access to information from pediatric studies e conducted under BPCA and PREA; • mprove the timeliness of certain pediatric studies; i • trengthen pediatric studies requested under BPCA or re- s quired under PREA; • ddress areas of limited pediatric investigation under BPCA a and PREA, including neonatal studies and long-term safety studies; • ncrease the clarity and understanding of FDA judgments i about pediatric studies; and • ontinue to encourage pediatric studies of biologics. c I n the late 1990s, the federal government took steps to increase the study of drugs in children and thereby reduce a serious deficit in the data on drug safety and efficacy for young patients. One step was to offer eco- nomic incentives for the conduct of requested pediatric studies. Another was to require such studies in specific situations. The objectives were to expand the information available to clinicians who prescribe medications to chil-

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4 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN dren and, as a consequence, to improve clinical care and health outcomes for children. These policies—in their current form, the Best Pharmaceuticals for Children Act (BPCA; which provides the incentives) and the Pediatric Research Equity Act (PREA; which provides the requirements)—are the focus of this report from a committee of the Institute of Medicine (IOM). BPCA and PREA are implemented by the Food and Drug Administra- tion (FDA), which must approve drugs before they can be legally marketed in the United States. Drugs that have been approved and labeled on the basis of studies only with adults may be legally prescribed for children as part of the practice of medicine. For clinicians who prescribe drugs for children, evidence from pediatric studies is critical • to understand age- and development-related variations in the way that the body affects a drug (i.e., the drug’s pharmacokinetics, in- cluding absorption, distribution, metabolism, and excretion) and in the way that a drug affects the body (i.e., its pharmacodynamics); • to develop evidence about age- and development-related variations in a drug’s short- and long-term efficacy and safety; and • to evaluate, when necessary, a developmentally suitable formula- tion of a drug (e.g., an oral solution for toddlers who cannot swal- low tablets). The results of drug studies with children may differ from the results of studies with adults, revealing, for example, a different profile of drug- related adverse events. Studies may also guide dosing adjustments that are often more complicated than simply scaling down doses recommended for adults on the basis of a child’s age or weight. The shortage of pediatric drug studies that prompted passage of BPCA and PREA (and their predecessor policies) can be traced to many factors— in particular, the fact that children constitute a small market for medica- tions compared with the market constituted by adults. Moreover, pediatric drug studies are often challenging. Study strategies used with adults may require adaptations to accommodate both the small numbers of potential child research participants and the developmental differences between chil- dren and adults. If a product is already approved for marketing to adults and thus available for off-label use, study sponsors may find that clinicians and parents are reluctant to enroll a child in a trial, especially a placebo- controlled trial. In addition, studies must follow federal rules that limit the participation of children in certain types of studies that are considered ethical for adults. Both BPCA and PREA use the term pediatric, but neither the statute nor implementing regulations define the age range to which it applies. FDA definitions vary, but, in general, the pediatric population consists of chil-

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5 SUMMARY dren from birth up to 16 or 17 years of age. When requesting or requiring pediatric studies, FDA typically tailors the specification of included age groups to the characteristics of the condition and drug to be studied. STUDY ORIGINS AND FOCUS Consistent with provisions of the 2007 law reauthorizing BPCA and PREA and with provisions of the Biologics Price Competition and Innova- tion Act (BPCIA) enacted in 2010, FDA asked the IOM to examine pedi- atric studies requested under BPCA or required under PREA. The tasks for the committee appointed by the IOM were 1. Review and assess a representative sample of written requests is- sued by the Secretary [of the U.S. Department of Health and Hu- man Services] and studies conducted under BPCA since 1997, and labeling changes made as a result of such studies. 2. Review and assess a representative sample of studies conducted since 1997 under PREA or precursor regulations, and labeling changes made as a result of such studies. 3. Using a representative sample of written requests issued by the Sec- retary and studies conducted under BPCA since 1997 and studies conducted since 1997 under PREA or precursor regulations, review and assess (a) the use of extrapolation for pediatric subpopula- tions; (b) the use of alternative endpoints for pediatric populations; (c) neonatal assessment tools; and (d) ethical issues in pediatric clinical trials. 4. Using a representative sample of studies conducted since 1997 un- der PREA or precursor regulations, review and assess the number and type of pediatric adverse events. 5. Review and assess the number and importance of biological prod- ucts for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 (passed in 2010) and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing. 6. Review and assess the number, importance, and prioritization of any biological products that are not being tested for pediatric use. 7. Offer recommendations for ensuring pediatric testing of biological products, including consideration of any incentives, such as those provided under section 505A of the Federal Food, Drug, and Cos- metic Act or section 351(m) of the Public Health Service Act. Because BPCA did not take effect until July 1, 1998, and because docu- ments associated with drug approvals are not immediately made public by

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6 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN FDA, the committee’s sample of written requests and other documents and actions covered the period from July 1, 1998, to December 31, 2010. For this period, FDA supplied a master list of labeling changes categorized by major therapeutic area and policy origin (BPCA, PREA, or their predecessor policies). From this list, the committee selected a sample of 46 FDA actions (for 44 distinct products) representing these therapeutic and policy cat- egories. The committee excluded vaccines (which are subject to additional public oversight and needs assessments) and contraceptives (which are rou- tinely approved without new pediatric studies). With these exclusions, the universe included approximately 380 labeling changes. The committee also reviewed additional FDA actions involving written requests, studies with neonates, and, to the extent possible, required pediatric studies of biologics. FDA’s list of labeling changes excludes labeling changes for biologics (including vaccines) that were approved before September 27, 2007, and FDA was unable to supply the missing information. Therefore, the commit- tee’s sample underrepresents biologics to an unknown degree. For product approvals issued before September 2007, Congress has not required that relevant documents be made public. FDA did, however, agree to provide such documents for selected products after redaction of confidential information. Because the documents that companies submit to FDA are not public, the committee’s assessments relied primarily on FDA staff reviews of these materials. This report profiles the results of the committee’s analyses of requests, requirements, studies, and labeling changes associated with BPCA and PREA. In the course of preparing the report, the committee reached several broad conclusions: • Pediatric studies conducted under BPCA and PREA are yield- ing important information to guide clinical care for children. The yield varies by medical condition, type of product, and age group. Information from pediatric studies sometimes supports and some- times runs counter to expectations about the efficacy, safety, and pharmacokinetics of a drug in children of different ages. • Some studies requested under BPCA or required under PREA do not achieve their full potential. Reasons vary and may include the inability of sponsors to recruit sufficient numbers of children, the use of weak study designs and underpowered samples, the lack of dose-ranging studies to guide efficacy trials, and the omission of relevant study information from a product’s labeling. FDA has taken steps to address many of these problems. • More timely planning, initiation, and completion of pediatric stud- ies would benefit children. European requirements for the sub- mission of plans for pediatric studies apply at a stage of drug

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7 SUMMARY development that may be somewhat premature, whereas U.S. re- quirements apply later than is needed for access to safety and efficacy data from adult studies that are sufficient to support the planning and initiation of pediatric studies. Delays in sponsor completion of studies required under PREA also warrant further attention. • Pediatric drug studies remain particularly limited in certain areas, including the use of medications with neonates and the long-term safety and effectiveness of medications used for all pediatric age groups. The lack of information about the long-term safety of drugs prescribed for children is a special worry—both for drugs that may be used for decades for chronic conditions and for drugs for which short-term use may have adverse consequences on a child’s development months or years later. Many drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in this vulnerable age group. • Congress has significantly expanded public access to information from recent pediatric studies conducted under BPCA and PREA and has thereby enhanced the value of these studies. Limitations still exist, however, particularly for older pediatric studies and la- beling changes. • The reauthorization processes for BPCA and PREA have improved policies promulgated under both acts, but frequent reauthorizations create uncertainties for industry and FDA. Since 1997, Congress has strengthened the application of pediatric expertise to studies conducted under BPCA and PREA, has directed that information from pediatric studies be added to product labeling in most cases, and has required a follow-up assessment of adverse event reports for the first year following a labeling change. Nonetheless, the frequent reauthorizations of the two acts—every 5 years—create uncertainties for companies, given the typically long lead time re- quired to plan and conduct studies. • Requirements for pediatric studies of biologics conducted under PREA have generated valuable information. The 2010 expansion of BPCA to cover biologics has potential to expand knowledge further, but it is too early to assess its effects. Almost 90 percent of biologics that the committee investigated have been the subject of some study with children or are labeled for use with children.1 1 Somewhat simplified, a drug is a substance other than a food or medical device that is intended to affect the body’s structure or functioning or to diagnose, treat, or prevent disease. A biologic is a drug derived from human or animal sources or microorganisms. Examples of biologics include vaccines, blood or blood products, allergens, and recombinant therapeutic proteins (with certain exceptions).

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8 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Most of the remaining products were approved for conditions that are not diagnosed or very rarely diagnosed in children. Given the applicability of long-standing policies such as the 1984 Orphan Drug Act and PREA and given the range of existing pediatric research on many biologics, BPCA may have a valuable but more modest effect in encouraging studies of biologics than was the case for small-molecule drugs. Except with respect to recent incentives for pediatric studies of biolog- ics, the committee was not asked to make recommendations. This report does, however, include suggestions and options for Congress and FDA in several areas, as discussed below. POLICIES TO PROMOTE STUDIES OF DRUGS IN CHILDREN Beginning in the early 1900s with the deaths of children due to unsafe vaccines and continuing with more deaths due to unsafe anti-infectives in the 1930s and 1950s, public dismay about harms to children contributed to the passage of federal laws intended to promote drug safety and ef- ficacy. Ironically, these laws—which range from the Biologics Control Act of 1902 to the Food, Drug, and Cosmetic (FDC) Act of 1938 and the 1962 Kefauver-Harris amendments to the FDC Act—did not encourage or direct studies of medication safety and efficacy in children. Not until 1997 did Congress or FDA adopt incentives and requirements for such studies. Best Pharmaceuticals for Children Act Among other provisions, the Food and Drug Modernization and Ac- countability Act of 1997 offered companies pediatric exclusivity—a period of marketing protection from competitor (generic) drugs—when they un- dertook pediatric studies of a drug based on a written request from FDA. This exclusivity extends for 6 months beyond any existing period of mar- keting protection because of patents or other types of exclusivity. When granted, pediatric exclusivity applies to all forms of a company’s drug that contain the same active moiety or ingredient. For a drug with a lucrative market among adults, this added period of marketing protection is economically significant. Exclusivity is available when a company meets the terms of FDA’s request, whether or not the results support pediatric use, because information about a drug’s lack of efficacy or safety is as important as positive findings. Pediatric exclusivity is generally not relevant to drugs that have no existing exclusivity or remaining patent life. Thus, in 2002, Congress di- rected the National Institutes of Health (NIH) to create a pediatric drug

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9 SUMMARY development program under BPCA and to set priorities for pediatric studies of off-patent drugs (a task that has since been expanded to cover pediatric therapeutics broadly). Under this program, NIH has supported the study of several high-priority off-patent drugs. Congress reauthorized the exclusivity incentive in 2002 (under the BPCA title) and again in 2007. BPCA is due for reauthorization in October 2012.2 Pediatric Research Equity Act In 1998, FDA issued regulations generally referred to as the Pediatric Rule. Except when FDA waived or deferred its application, the rule re- quired that companies seeking approval of a New Drug Application (NDA) or Biologics License Application (BLA) include a pediatric assessment of the product if the submission involved a new active ingredient, indication, drug form, dosing regimen, or route of administration. The rule went into effect on April 1, 1999. After opponents successfully challenged the rule in court, Congress codified its key features in the Pediatric Research Equity Act of 2003. Like BPCA, PREA was reauthorized in 2007 and is next due for reauthorization in 2012. PREA does not cover drugs designated under the Orphan Drug Act and applies only to the indications approved for an NDA or BLA. It permits FDA to waive required studies with some or all pediatric age groups, for example, if studies would be infeasible because the indication in question does not occur in children or if evidence suggests that pediatric use of the drug would be unsafe. FDA often defers pediatric studies because the manufacturer has completed studies to support approval for use by adults. One concern for companies is variation between the United States and Europe in requirements for pediatric drug studies. Oversimplified, the European Medicines Agency requires submission of a pediatric study plan early during the clinical investigation of a drug in adults, whereas the United States requires the plan late in the drug approval process. Although harmonization of the policies would require action by both Congress and European authorities, Congress could act independently to require the more timely submission of pediatric plans in the United States after the comple- tion of Phase II studies with adults. Congress has made PREA and BPCA more consistent in certain re- spects. It has expanded public access to information from pediatric studies under both policies. In addition, an internal committee with pediatric ex- 2 After this report was released in February 2012, Congress reauthorized BPCA and PREA in June 2012.

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10 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN pertise (the Pediatric Review Committee) must now review written requests authorized under BPCA and deferrals and waivers of PREA requirements. ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES One broad ethical principle for the conduct of pediatric drug studies is that children should not be subjected to research that is not necessary to advance knowledge that is relevant to child health. Another is that children should not participate in studies that are designed or conducted in ways that predictably undermine the potential of the research to generate valid and useful information. In reviewing ethical issues in pediatric clinical trials conducted under BPCA and PREA, the committee recognized that a number of safeguards are in place to prevent unethical clinical studies with children. These safe- guards include federal regulations and international standards for research conduct and systems for research review and monitoring. The safeguards also provide for the application of pediatric expertise (including expertise in pediatric ethics) to FDA’s activities under BPCA and PREA. Most clinical reviews that the committee examined included brief com- ments on ethics, data integrity, and financial disclosures. Nonetheless, FDA clinical and other reviews generally do not provide details sufficient for the external assessment of certain important aspects of research conduct, for example, the adequacy of research protections at foreign research study sites or the processes for securing parental permission for or child assent to research participation. One issue identifiable in the committee’s sample involves placebo- controlled pediatric trials. Approximately half of the products were studied with a placebo control, and some of these studies involved conditions (e.g., asthma) for which effective therapies exist. Such trials do not necessarily present ethical problems, but the committee suggests that FDA’s written requests and clinical reviews describe the scientific and ethical rationales for the use of such trial designs. Another issue is that despite substantial improvements in public access to information, limitations continue, for example, as a result of the lack of access to reviews of older studies and the redaction of key sections of some clinical reviews. In addition, the lack of integration of FDA reviews of pediatric (and adult) studies into resources such as Medline means that these detailed evaluations and analyses may not be identified and incorpo- rated into evidence-based reviews of clinical therapeutics. Congress could further improve access by directing FDA to make public reviews for label- ing changes approved before September 2007 and to identify all PREA- related labeling changes for biologics. It could also request an independent evaluation of the extent and appropriateness of redactions in FDA reviews

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11 SUMMARY of pediatric studies and ask FDA to explore the integration of clinical and other reviews into databases such as PubMed and ClinicalTrials.gov. To obtain a better understanding of the dissemination of information, FDA could seek an analysis of third-party dissemination of labeling information from studies conducted under BPCA and PREA, including both the speed of dissemination and the accuracy and completeness of the information as disseminated. The committee recognized FDA’s limited resources. At the same time, it was concerned that rationales for ethically and scientifically sensitive decisions be clear and that the public have access to information in which sponsors, investigators, research participants, taxpayers and health insur- ance premium payers, and FDA staff have already invested—in different ways—considerable expense or effort. The task for IOM did not include evaluation of the ethics of pediat- ric marketing exclusivity itself, but the committee acknowledges that is- sues such as intergenerational justice (e.g., higher costs for drugs used by older adults during the period of marketing protection) warrant attention. Certainly, it is appropriate that written requests be accompanied by clear expectations that the requested studies are necessary, soundly designed and executed, and public in their results. SAFETY AND EFFICACY IN STUDIES CONDUCTED UNDER BPCA AND PREA IOM was asked to assess the number and type of pediatric adverse events in a sample of studies conducted under PREA or precursor regula- tions. FDA defines adverse events as any “untoward medical occurrence[s] associated with the use of a drug in humans, whether or not considered drug related.” FDA reviewers provide detailed assessments of adverse event data that sponsors submit and typically judge a substantial proportion of reported events to be unrelated to the study drug. Because adverse events often are not drug related, the IOM committee decided that it would not be productive to review and assess the number and type of adverse events in pediatric studies. Instead, the committee fo- cused on clinical reviewers’ more general and relevant conclusions about a product’s safety signal or profile, such as whether the safety issues identi- fied in pediatric studies were similar to those found in adult studies (for products that had been studied in adults) or to those identified for similar products. Because reviews of safety data are important for studies con- ducted under BPCA, the committee’s sample also included such reviews. Particularly for recent years, the committee found that FDA review- ers were generally thorough in evaluating adverse events, assessing their significance, and reaching conclusions about the safety profile of drugs

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12 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN studied with children. Summaries of conclusions about safety were usually accompanied by discussions of serious drug-related adverse events and the possible need for changes in the safety elements of a product’s labeling. To further improve the completeness, consistency, and clarity of safety assessments in clinical reviews, the committee suggests that FDA’s Center for Biologics Evaluation and Research explicitly adopt a template for clini- cal and other reviews similar to that used by the Center for Drug Evalu- ation and Research. Many reviews are long and detailed; readers benefit from clear summary conclusions about a product’s efficacy, safety profile, significant adverse events, and risks weighed against benefits. The 1-year reviews mandated by Congress provide useful opportuni- ties for FDA to examine safety information after labeling changes based on pediatric studies have been made and, in some cases, to recommend further analyses or inclusion of additional safety findings in product labeling. Given the limitations of the short-term studies typically used to support labeling changes and the limitations of the 1-year reviews, FDA might consider more frequent use of its authority to require sponsors to undertake long- term postmarket, follow-up studies of serious or potentially serious risks to patient safety. With respect to efficacy, IOM was asked to assess the use of alternative endpoints and extrapolation. The committee defined alternative endpoints in pediatric studies to be measures of efficacy that take children’s growth and development into account and thus differ from endpoints for the same or a highly similar condition in adult studies. Alternative endpoints may be used for a variety of reasons. For example, use of an endpoint consisting of a symptom self-report measure would not be appropriate for preverbal children. Approximately half of the primary efficacy endpoints used in the pe- diatric studies that the committee examined were the same as those used in adult studies, roughly one-fifth were alternative endpoints, and most of the remainder involved conditions found primarily or entirely in children. Although most alternative endpoints appear to be reasonable, it would be desirable for FDA to include an explicit discussion of their use (including whether they had been validated for use with the age groups to be studied) in written requests and clinical reviews. To approve the labeling of drugs for pediatric use, FDA and compa- nies have relied extensively on the extrapolation of efficacy from studies conducted with adults or, less often, other pediatric age groups. For almost half of the labeling changes in the committee’s sample resulting from stud- ies conducted under BPCA and PREA, the agency was prepared to accept what it terms partial extrapolation of efficacy based on submission of one controlled pediatric safety and efficacy study plus pharmacokinetic data. For almost 60 percent of such submissions, FDA approved labeling for

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13 SUMMARY pediatric use. For another third of the committee’s sample, the agency was not willing to accept extrapolation but required two well-controlled studies; it approved pediatric labeling for almost half of these submissions. In other cases, FDA was prepared to accept extrapolation with the submission of pharmacokinetic and safety data and limited data on efficacy. Compared with an agency staff analysis that was limited to studies requested under BPCA, the committee’s sample included a higher proportion of submissions for which no extrapolation was acceptable and a lower proportion of sub- missions for which complete extrapolation was acceptable (on the basis of additional pharmacokinetic and safety data only). FDA reviews typically provide limited rationales for the use of extrapo- lation, and the law requires only brief documentation. Given the extent and significance of FDA’s reliance on extrapolation of efficacy, it would be desirable for agency written requests and clinical reviews to offer the public a somewhat fuller justification than is now provided when the agency ac- cepts complete or partial extrapolation. Again, the committee recognized that presentation to the public of such justifications or explanations adds to the demands on agency staff. Overall, the committee believes that the significance of the judgments for which more explicit public rationales or justifications are suggested warrants the additional effort. NEONATAL ASSESSMENTS In considering how to interpret the term neonatal assessment tools as used but not defined in the statement of task, the committee decided to examine neonatal assessments, that is, clinical studies of drugs in neonates, generally. FDA provided the committee with a list of products for which information from studies with neonates had resulted in labeling changes or awards of exclusivity without labeling changes. From 1998 through 2010, only 23 of the more than 350 labeling changes resulting from new pediatric studies included information from studies with neonates. Another five prod- ucts had been studied in neonates and companies had received exclusivity, but no information from the neonatal studies was added to the labeling. For the determinations that the committee examined, the conditions covered by waivers, for example, asthma and autism, are either rare or not diagnosed in children less than 1 month of age. In addition, age groups covered by waivers typically were not limited to neonates but covered a broader age range, for example, children less than 3 years of age. Several factors appear to increase the likelihood that requests or re- quirements for studies with neonates will generate useful information. They include clarity about the nature of the condition to be studied, valid and reliable methods to diagnose it, and, for studies of response or efficacy, valid and reliable endpoints. In requesting or requiring studies with neonates, it

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14 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN is important that FDA consider the state of current knowledge about the diagnosis and the availability of valid and reliable endpoints for neonates, as well as the seriousness and frequency of the disease in question. A review of data on medications commonly used by neonates suggests that they are typically older, off-label products for which pediatric exclusiv - ity is not available. To promote more studies of drugs widely used but not adequately evaluated in neonates, one option is for Congress to provide additional resources for short- and long-term neonatal drug studies through the BPCA program at NIH. OUTCOMES OF WRITTEN REQUESTS AND PREA REQUIREMENTS Overall, from July 1998 through October 2011, FDA approved more than 420 labeling changes associated with studies requested under BPCA or required under PREA (or their predecessor policies). Some changes did not involve new pediatric trials, and FDA’s count omits labeling some changes for biologics that occurred before September 27, 2007. As of October 2011, FDA had also • issued more than 340 written requests under BPCA, nearly half of them in the first 2 years of the program; • approved nearly 150 labeling changes solely as a result of requested studies and granted exclusivity to more than 175 active moieties; • approved at least 180 labeling changes solely as a result of studies required under PREA; • approved 50 labeling changes as a result of studies both requested under BPCA and required under PREA; and • made public the clinical and other reviews associated with 139 labeling changes that had been made since September 2007. Most written requests that FDA has issued (approximately 80 percent) have been proposed by sponsors rather than initiated by FDA. Roughly half of written requests have led to the submission of pediatric studies for which exclusivity was granted, and more such studies will be submitted in the future. The number of written requests issued by year peaked at more than 90 in 1999 and then dropped sharply, with a more recent leveling off to ap- proximately a dozen requests per year. The number of grants of exclusivity rose fairly steadily for the first several years, reaching almost 60 in 2008 and then dropping steeply. Of the written requests that the committee ex- amined, the general pattern has been for the types of trial designs and sam- pling strategies described in requests to become more specific and rigorous

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15 SUMMARY over time. The health benefit expected from requested studies is, however, rarely described or justified. It would be desirable for FDA to more clearly articulate the health benefits expected of requested studies so that children do not participate in requested studies of minimal value. PREA has become increasingly important as a source of pediatric stud- ies. From 2008 through 2010, more than 60 percent of labeling changes were attributable solely to PREA requirements and another 22 percent were attributable to both BPCA and PREA. One concern is delays in studies required under PREA, and another is that FDA has limited practical ability to require their completion. An option for Congress is to provide FDA with more flexibility to impose sanctions, including monetary penalties, for unreasonably delayed studies. Most studies that the committee reviewed generated useful information about efficacy and safety, including information about products that were widely used off-label. The majority led to the labeling of a product for use by some pediatric age groups. Some studies, however, yielded unexpected findings about safety or efficacy and led to recommendations against use by children. Some studies had weaknesses in their design or their execution that modestly or significantly limited their value. Shortcomings involved the specification of endpoints inappropriate for some age groups, weak trial designs, inadequate sampling strategies, and inadequate investigations to identify an effective dose of a study drug. FDA has recognized the impor- tance of developing data to guide the selection of appropriate doses for efficacy studies, but the need for strict and consistent attention to dose selection for evaluation in pediatric drug studies remains. The committee’s review indicates that FDA has improved its specifica- tion of trial designs in requests and requirements for pediatric studies. In the future, its regulatory science initiatives should support further improve- ments, as should a number of activities that the agency has undertaken to evaluate specific challenges in pediatric trial design and propose innovative strategies to meet these challenges. To improve pediatric studies of drugs and biologics and their evaluation, it is important for FDA to continue to expand initiatives to strengthen the science base for its work, analyze shortcomings in pediatric studies, and develop innovative strategies to meet the specific challenges of pediatric trials. Just as most studies requested under BPCA or required under PREA yielded useful information, most labeling changes reflected this result. How- ever, labeling changes have sometimes excluded or downplayed important information, for example, information about certain adverse events. In a few cases, labeling changes were ambiguous or internally contradictory, recommending against pediatric use but also providing information to guide pediatric dosing. These situations may illustrate the dilemma that

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16 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN FDA faces when studies do not show efficacy but the agency expects off- label use to continue. It is important that FDA be clear that the provision of information about pediatric dosing in such situations does not constitute a recommendation for pediatric use. The agency can use transitions to the current, structured labeling format to clarify ambiguous, incomplete, or contradictory pediatric information in earlier labeling. PEDIATRIC STUDIES OF BIOLOGICS With some limitations, Congress extended the incentives of BPCA to biologics in 2010. FDA still has many complex questions to consider in implementing BPCIA. Even after it issues regulations, it will take time for the agency to prepare specific written requests, for willing sponsors to conduct and submit requested studies, and then for FDA to evaluate the submissions and make its judgments public. Given these constraints, the committee concluded that it was too early either to assess the impact of BPCIA on pediatric studies of biologics or to reach conclusions about its effectiveness or its limitations in ensuring pediatric studies of biologics. Thus, it is reasonable for Congress to continue the extension of BPCA to biologics until the results can be systematically evaluated 3 to 5 years after FDA issues implementing regulations. Barring surprises in their implementation, the incentives of BPCIA can be expected to encourage further pediatric studies of both older and newer biologics. Nonetheless, it seems unlikely that the law will lead to a surge of written requests for pediatric studies of biologics similar to the surge in requests for pediatric drug studies that followed the creation of the pedi- atric exclusivity incentive in 1997. Since 1999, biologics have been subject to PREA requirements (with exemptions for orphan-designated drugs). In addition, biologics have been eligible for the incentives of the Orphan Drug Act, which offer 7 years of exclusivity. Nearly three-quarters of the more than 350 approvals of orphan drugs since 1984 have involved rare condi- tions that affect children. Whether as a result of PREA, the Orphan Drug Act, the evident ther- apeutic promise of many biologics, or other factors, approximately 60 percent of the 96 still-marketed biologics (excluding vaccines, assays, and reagents) that FDA has approved between January 1, 1997, and December 31, 2010, are labeled for pediatric use, have some information about pedi- atric studies in the labeling, or have warnings against pediatric use based on analysis of postmarket safety reports. Further, an examination of stud- ies registered at the ClinicalTrials.gov database indicates that most of the remaining products have been studied, are being studied, or are planned for studies with children. Of the products that are neither labeled for pediatric use nor the subject of registered pediatric trials, most appear either to have

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17 SUMMARY limited potential to benefit children or to be in the same class as alternative products that are labeled for pediatric use. On the basis of case reports of off-label use and other information, the committee identified one product that may have sufficient promise for treating refractory infantile hemangio- mas that FDA or NIH, or both, might consider encouraging or supporting controlled pediatric trials of its safety and efficacy. The committee’s finding that most biologics have been studied with children does not mean that no further opportunities or needs for pediatric studies of these medications exist. Such opportunities could include studies that pursue promising findings in early-phase studies of specific biologics or studies of biologics for treatment of conditions that are now recognized to occur more frequently in children than previously thought.

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