1

Introduction

In the late 1990s, the federal government enacted policies to expand the study of drugs in children and thereby to begin to correct a serious deficit in the data on drug safety and efficacy for young patients. In one case, it offered marketplace incentives for the completion of pediatric drug studies. In the other case, it required such studies in specific situations. The objectives of these policies were to expand information for clinicians who prescribe drugs to children and, as a consequence, to improve pediatric clinical care and child health outcomes. 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 Administration (FDA), which must approve new drugs before they can be legally marketed in the United States. Drugs that have been approved and labeled on the basis of the results of studies conducted with adults may be legally prescribed by health care professionals (as part of the practice of medicine) for children.1 Clinicians who treat young patients often have had to prescribe medications without specific, scientific information on their safe and effective use by children of different ages and sizes. This “off-label” prescribing may be guided by the personal experience as well as the accumulated experience of clinicians. This experience may be published in the

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1 Manufacturers may not promote and are limited in their ability to disseminate information about product uses for which they have not obtained FDA approval.



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1 Introduction I n the late 1990s, the federal government enacted policies to expand the study of drugs in children and thereby to begin to correct a serious deficit in the data on drug safety and efficacy for young patients. In one case, it offered marketplace incentives for the completion of pediatric drug studies. In the other case, it required such studies in specific situations. The objectives of these policies were to expand information for clinicians who prescribe drugs to children and, as a consequence, to improve pediatric clinical care and child health outcomes. 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 Adminis- tration (FDA), which must approve new drugs before they can be legally marketed in the United States. Drugs that have been approved and labeled on the basis of the results of studies conducted with adults may be legally prescribed by health care professionals (as part of the practice of medi- cine) for children.1 Clinicians who treat young patients often have had to prescribe medications without specific, scientific information on their safe and effective use by children of different ages and sizes. This “off-label” prescribing may be guided by the personal experience as well as the accu- mulated experience of clinicians. This experience may be published in the 1Manufacturers may not promote and are limited in their ability to disseminate information about product uses for which they have not obtained FDA approval. 19

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20 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN medical literature as case series reports or codified in consensus guidelines. Although recent years have seen increasing emphasis on evidence-based practice guidelines, neither guideline developers nor practitioners can use evidence that does not exist or is not public. The use of medications by chil- dren without guidance from pediatric studies of safety and efficacy raises ethical issues that underscore the importance of such studies. In some cases, high-quality clinical trials sponsored by government agencies or nonprofit groups are available but are not reflected in product labeling. In the years preceding the adoption of BPCA and PREA and their pre- decessor policies, several analyses documented the lack of information on the safety and efficacy of FDA-approved medications that are prescribed for children. Table 1-1 summarizes several of these. The frustration of many clinicians with the lack of pediatric prescribing information was expressed decades ago in a 1968 editorial in the Journal of Pediatrics that referred to children as “therapeutic orphans” (Shirkey, 1968). This oft-used description of children appeared years later in the Senate report (Senate Report 105-43, 1997) that accompanied the Food and Drug Administration Modernization and Accountability Act of 1997 (FDAMA; PL 105-115). FDAMA first established the incentives for pediat- ric research, which were reauthorized in 2002 and 2007. The 1997 Senate report also stated that less than 20 percent of prescription medications available in the United States were labeled for pediatric use. For drugs that may be used by children as well as adults, evidence from pediatric studies is important for several reasons (see, e.g., IOM, 2000, TABLE 1-1 Historical Data on Drugs Without Adequate Labeling for Pediatric Use Year Extent of Pediatric Drug Labeling 1973 78% of drugs listed in the Physicians’ Desk Reference (PDR) lacked sufficient pediatric drug labeling 1984-1989 80% of new molecular entities (NMEs) approved by FDA lacked pediatric drug labeling 1991 81% of drugs in PDR had disclaimers or age restrictions 1991 44% of NMEs with potential pediatric usefulness had no pediatric labeling when approved 1992 79% of NMEs were not approved for potential pediatric use 1991-1994 71% of NMEs lacked pediatric drug labeling 1996 37% of NMEs with potential pediatric usefulness had some pediatric labeling when approved SOURCE: Adapted from Wilson (1999), with additional information from FDA (1998).

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21 INTRODUCTION 2008; Kearns et al., 2003, Reed and Gal, 2004; Ward and Lugo, 2005; Rakhmanina and van den Anker, 2009). These include the need to 1. understand age- and development-related variations in the way that the body affects a drug (pharmacokinetics, including absorption, distribution, metabolism, and excretion); 2. identify age- and development-related variations in how a drug affects the body (pharmacodynamics); 3. develop evidence about age- and development-related variations in a drug’s short- and long-term benefits and harms (efficacy and safety); and 4. provide the basis for creating developmentally suitable formula- tions of a drug (e.g., an oral solution for a toddler who cannot swallow a pill or capsule). Several factors, notably economic disincentives, explain the historical shortage of pediatric drug studies and the need for BPCA and PREA (see, e.g., IOM, 2000, 2008; Milne, 2009). Children, who account for approxi- mately 25 percent of the nation’s population, are usually healthy (FIFCFS, 2009). They provide a far smaller market for most medications than do adults, especially older adults. Even for the common childhood condition of asthma, individuals age 18 years or older account for 75 percent of those with the condition (Akinbami, 2006). Drug studies with adults thus typi- cally offer companies a better economic return on their research investment than do pediatric studies. Even when pediatric studies result in positive find- ings and labeling of a drug for pediatric use, companies may not recover the costs of the research. Moreover, the study of a drug in children may be more challenging than the study of the same drug in adults. Recruitment of a sufficient number of children may require more study sites. That difficulty is multiplied to the extent that studies need to include sufficient numbers of children in differ- ent age groups to support credible conclusions about safety, efficacy, and dosing across the developmental spectrum. Although pediatric studies may include a smaller total number of participants, sponsors still incur many of the same fixed research costs that they do for larger adult studies. Even with multiple sites, pediatric studies sometimes cannot be com- pleted because investigators are unable to secure an acceptable sample size in a reasonable period of time. Also, if FDA is requesting or requiring stud- ies of several drugs in the same class or for the same condition, companies may be competing with each other for the same pool of potential child research participants. In addition, as noted above, once a drug is approved for use by adults, clinicians can legally prescribe it for children. This avail-

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22 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN ability may discourage physicians and parents from enrolling children in a trial of the drug. Companies thus benefit from sales of the drug without the necessity of conducting studies to demonstrate the safety and efficacy of pediatric use. Beyond limited numbers, companies and investigators may encounter other problems of practicality or feasibility. Young children may lack the developmental maturity to cooperate with certain research procedures or measurements. For children too young to reliably swallow existing tablet or capsule forms, a new formulation may be required, and development of such a formulation adds time and costs to pediatric studies. Ethical considerations also complicate pediatric research. Reflecting concerns that date back to the 1960s and before, the federal government in 1983 added special protections for children to federal regulations on the BOX 1-1 Knowledge Contributed by Pediatric Drug Studies Conducted Under BPCA and PREA Pediatric studies support safety and efficacy Insulin glulisine (Apidra), a recombinant, rapid-acting human insulin analog, was approved in 2004 for treatment of type 1 diabetes mellitus in adults, with a re- quirement for a study with children ages 5 to 17 years (Meyer, 2004). In 2008, on the basis of the findings of one previously submitted pharmacokinetic/pharmaco- dynamic study and one new safety and efficacy study, FDA approved use of the product by children ages 4 to 17 years, the period of peak onset for this disease (Gabry and Joffe, 2008). Safe and effective dosing in children differs from expectations for youngest children Gabapentin (Neurontin) was first approved in 1993. FDA requested studies under BPCA in 1999, and the drug was approved in 2000 as adjunctive treatment of partial seizures in children ages 3 years and older (Katz, 2000). Based on staff analyses of pharmacokinetic data, FDA concluded that children under 5 years of age required higher than anticipated doses (Feeney, 2000). Findings from the study for the 3- to 12-year-old age group also led to a warning on the product’s label about adverse neuropsychiatric events, such as concentration problems, hostility, and hyperactivity. Drug affects growth and development Pegylated interferon alfa 2b (PegIntron) in combination with ribavirin (Rebetol) was approved in June 2008 for the treatment of chronic hepatitis C virus infec- tion in patients ages 18 years or older, with deferral of PREA-required studies for children ages 3 years or older. In December 2008, after the required studies

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23 INTRODUCTION ethical conduct of human research (45 CFR 46, Subpart D; see also IOM, 2004). For example, parents normally must give their permission for their child’s participation in research. As discussed further in Chapter 4, certain studies that are required to support approval of a drug for adult use—no- tably, early studies with healthy individuals to understand a drug’s pharma- cokinetics—may be unethical to undertake with healthy children and also impermissible under federal regulations, except under limited conditions. Notwithstanding these complexities, the study of drugs in children is essential because children’s growth and development affect their responses to medicines. Fortunately, public officials, investigators, and manufactur- ers have demonstrated a commitment to expanding research on the safety and efficacy of drugs in children. Such research has contributed important information to guide the prescribing of drugs for children (Box 1-1). were submitted, FDA approved labeling for use by that age group. The clinical review noted that “growth inhibition and hypothyroidism were two notable adverse reactions” and that they were being further evaluated in a 5-year follow-up study (Crewalk, 2008, p. 4). The review also noted that these adverse reactions pre- sented less risk than the risk of untreated hepatitis C. The revised label included warnings about the impact of pediatric use on growth of the child. Studies support different dosing calculation Nevirapine (Viramune), which was first approved in 1996, was approved in 1998 for treatment of HIV infection in children ages 2 months of age to 16 years, with additional information submitted in 2002. The 2002 approval letter specified re- quired studies to determine dosing for younger groups. The information submitted by the sponsor in 2007 provided for dosing down to age 15 days and also provided data to support calculation of pediatric dosing based on body surface area rather than weight (Belew, 2008). Risk-benefit assessment does not support pediatric use Omalizumab (Xolair) was approved in 2003 for treatment of moderate to severe persistent asthma in individuals 12 years of age or older. Although this approval occurred during a period when pediatric study requirements were not in effect, FDA encouraged further pediatric studies and noted that pending legislation might require such studies (Risso, 2003). The sponsor submitted studies for the 6-to-11 age group in 2008. After the data were reviewed by FDA staff and considered in a meeting of the joint Pulmonary-Allergy, Pediatric, and Drug Safety and Risk Management Advisory Committee, the product’s labeling was revised to include the statement “Considering the risk of anaphylaxis and malignancy seen in Xolair- treated patients ≥12 years old and the modest efficacy of Xolair in the pivotal pediatric study, the risk-benefit assessment does not support the use of Xolair in patients 6 to <12 years of age” (Starke, 2009; Genentech, 2010b).

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24 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN STUDY ORIGINS AND OVERVIEW Charge to the Committee In late 2009, FDA approached the IOM about an examination of pediatric studies of drugs and biologics conducted under the provisions of BPCA and PREA (and their predecessor policies). This examination was called for in the 2007 reauthorizations of these policies as part of the Food and Drug Administration Amendments Act of 2007 (FDAAA; PL 110-85). While planning for the study was under way, Congress passed the Patient Protection and Affordable Care Act (PL 111-148) in March 2010, which included the Biologics Price Competition and Innovation Act. That legisla- tion changed the study specifications related to biologic products, and the FDA altered the Statement of Task accordingly. The tasks for the study 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 subpopulations; (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.

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25 INTRODUCTION 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. Unlike many other IOM committees, this committee was not asked to make recommendations except with respect to recently enacted policies to provide incentives for pediatric studies of biologics. This report does, how- ever, include conclusions and suggestions or options for consideration by Congress and FDA. The report is written for a diverse audience, including not only policy makers but also companies that develop pharmaceutical and biologic products subject to the incentives and requirements of BPCA and PREA, researchers who study drugs and biologics in pediatric populations, professional societies and child health advocacy groups that promote pedi- atric research, and others interested in better information to guide clinical care for children. For the most part, the committee examined studies intended to sup- port initial labeling of a drug or biologic for use in pediatric age groups as approved by FDA. It did not investigate policies and activities to monitor the safety and effectiveness of products after they have been approved for pediatric use. The committee did, however, consult the postapproval (1- year) safety reviews that FDA’s Pediatric Advisory Committee is required to conduct following a labeling change under BPCA or PREA. Such monitor- ing is important because the use of approved products in real-world clinical practice may reveal safety problems or shortfalls in effectiveness that are not evident in the relatively short-term controlled studies that FDA typically requires to support product approvals. The absence of information about pediatric use or pediatric studies in the labeling of a medication does not mean that there have been no well- controlled studies of a drug’s safety or efficacy. The committee could not, however, systematically evaluate either the extent of off-label use of medica- tions with children or the extent to which there are controlled studies (other than those reflected in product labeling) to support or contradict such use for specific drugs and indications. FDA did not ask the IOM to assess the impact of BPCA and PREA on clinical practice or child health, for example, the extent to which off-label use of a product decreased following labeling changes that described studies with negative safety or efficacy findings. The study committee recognizes that clinical practice is not always consistent with scientific evidence and also that many other factors such as nutrition and environmental hazards affect the health and well-being of children.

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26 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Overview of Conclusions In the course of its work, the committee reached several conclusions that are discussed in later chapters. Summarized, the conclusions are as follows: • 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. The information from pediatric studies sometimes supports and sometimes challenges expectations and assumptions about the ef- ficacy, safety, and pharmacokinetics of drugs in children of different ages. The timely conduct of studies with children can discourage potentially unsafe off-label use of drugs approved for adults and encourage the timely incorporation of safe and effective drugs into pediatric care. • 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 product labeling. More careful specification of requested and required studies combined with ad- vances in the science of clinical trials would increase the likelihood that studies will provide uniformly high-quality information for clinicians who care for children. • More timely planning, initiation, and completion of pediatric stud- ies would benefit children. European requirements for the submis- sion of plans for pediatric studies apply somewhat early in the drug development process, whereas U.S. requirements apply later than is needed for access to credible safety and efficacy data for adults that are sufficient to support the planning and initiation of pediat- ric studies. Delays in sponsor completion of some studies required under PREA is also a concern. • 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 is a general concern, but it is a special worry for developing children. Questions about long-term safety exist both for drugs that may be used for decades for chronic conditions and for drugs for which relatively short-term use may have adverse consequences

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27 INTRODUCTION on a child’s development months or years later. Many drugs com- monly used to treat premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulner- able age group. • Congress has significantly expanded professional and public ac- cess to information from pediatric studies conducted under BPCA and PREA and has thereby enhanced the value of these studies. Although the addition of information to product labeling is im- portant, other valuable information is included in FDA clinical and clinical pharmacology reviews of the pediatric studies submitted to support a labeling change. Access to such information from studies associated with labeling changes prior to September 2007 remains limited, especially for studies conducted under PREA. • The reauthorization processes for BPCA and PREA have improved the policies in both acts, but the short term of reauthorizations cre- ates uncertainties for industry and for FDA. Since 1997, Congress has strengthened the application of expertise in pediatrics to the development of requests and requirements for pediatric studies and to the review of submitted studies. It has directed the inclu- sion of information from pediatric studies in product labeling in most cases and required a follow-up assessment of safety informa- tion from the first year following a pediatric labeling change. At the same time, frequent reauthorizations of the policies—every 5 years—create uncertainties for sponsors, given the long lead time for planning, conducting, analyzing, and submitting studies, and they may discourage FDA from developing final and updated guid- ance on BPCA and PREA. • Pediatric studies of biologics conducted under PREA have gener- ated valuable information. The 2010 expansion of BPCA to cover biologics has the potential to expand knowledge further, but it is too early to assess its effects. Almost 90 percent of biologics inves- tigated by the committee are labeled for use with children or have been the subject of some study with children. Most of the remain- ing 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 the broad range of existing pediatric research on biologics, BPCA may have a valuable but more modest effect in encouraging studies of biologics than was the case for small- molecule drugs.

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28 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Report Structure The rest of this chapter provides historical context and defines key terms. In this and subsequent chapters, unless otherwise indicated, refer- ences to studies conducted under BPCA and PREA also encompass studies undertaken as result of predecessor policies (e.g., the 1998 Pediatric Rule) that are described below. Chapter 2 briefly reviews how children’s develop- ment affects their response to drugs and discusses ways in which pediatric drug research must take children’s growth and development into account. Chapter 3 describes key features of BPCA and PREA in the broader context of U.S. regulatory policies to ensure drug safety and efficacy. Public policy is also the focus of Chapter 4, which discusses policies for the protection of human research participants, including special protections for children. This chapter also describes some of the ethical issues that the committee encountered in its assessments of studies conducted under BPCA and PREA (Task 3d). Chapter 5 examines elements of safety and efficacy determinations in studies conducted under BPCA and PREA. It considers FDA conclusions about the safety profile of a drug or biologic based on judgments about the source and importance of adverse events reported by study sponsors (Task 4). It also considers the use of alternative endpoints and extrapolation in determinations about efficacy (Tasks 3a and 3b). Chapter 6 discusses the complexities of assessing the safety and efficacy of drugs in neonates and describes the relatively small number of BPCA- and PREA-related labeling changes for this age group (Task 3c). Chapter 7 builds on the preceding chapters to consider the types and outcomes of studies conducted under BPCA and PREA and the information added (or not added) to product labeling as a result of these studies (Tasks 1 and 2). Chapter 8 looks at incentives and requirements for pediatric studies of biologics and identifies and discusses the small number of biologics that have not been evaluated in studies with children (Tasks 5, 6, and 7). Appendix A describes committee activities and explains the methods the committee used to select the representative sample referred to in the Statement of Task. Appendix B discusses the dissemination of informa- tion from FDA-approved drug labeling to professionals through various intermediary resources. Appendix C presents additional information about the use of biologics in pediatric populations, and Appendix D summarizes data on pediatric labeling and pediatric studies of nearly 100 biologics that were approved by FDA between 1997 and 2010. Appendix E summarizes changes in the specifications of written requests for pediatric studies of drugs for hypertension. Appendix F provides brief biographies of committee members and project staff.

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29 INTRODUCTION EVOLUTION OF POLICIES TO PROMOTE PEDIATRIC STUDIES OF DRUGS AND BIOLOGICS Harm to Children as a Spur to Regulation of Drug Safety and Efficacy FDA, the agency responsible for administering BPCA and PREA, owes its existence and modern responsibilities, in some measure, to public reac- tion to the injuries, illnesses, and deaths of children that were caused by un- safe and unregulated medical products. For example, the federal regulation of vaccines and other biologics dates to the Biologics Control Act of 1902 (PL 57-244), a year after more than a dozen children died from tainted diphtheria antitoxin and other children died from contaminated smallpox vaccine (Junod, 2002). The law assigned responsibility for regulation of vaccines and antitoxins to the Hygenic Laboratory (which eventually be- came the National Institutes of Health [NIH]) (NIH, 2011b). Four years later, in 1906, Congress passed the Pure Food and Drugs Act (PL 59-384). It set certain standards for the labeling and lawful interstate transport of drugs and created the foundation for what later became the FDA. Although drugs could be removed from the market under the law, the law did not require drug testing or government approval. The deaths in 1937 of more than 30 children from a product called Elixir Sulfanilamide contributed to the passage of the Federal Food, Drug, and Cosmetic (FDC) Act of 1938 (PL 75-540). Ironically, the development of this deadly product resulted from the manufacturer’s effort to create a form of the drug—an early antimicrobial—that was suitable for young children and others who could not swallow pills (Ballentine, 1981; Wax, 1995). The formulation, which was tested for palatability and appearance but not safety, unfortunately included diethylene glycol, a toxic substance found in antifreeze. Among other provisions, the FDC Act required govern- ment approval of new drugs prior to marketing on the basis of evidence of safety and also required that drug labels include information on how to use the products safely. It did not require evidence of efficacy. Further legislation came after women who took the drug thalidomide in the 1950s and early 1960s gave birth to thousands of children with limb and other deformities. An FDA medical officer is credited with keeping the drug off the market in the United States, and the tragedy itself is credited with mobilizing support for passage of the Kefauver-Harris Amendments to the FDC Act (PL 87-781) (Kuehn, 2010). These 1962 amendments required that FDA approval of drugs be based on evidence not only of safety but also of efficacy as demonstrated in well-controlled clinical trials. Yet another tragedy—deaths and permanent paralysis linked to a con- taminated polio vaccine—prompted a strengthening of the oversight of biologics and the creation in 1955 of an independent Division of Biolog-

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32 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN a 6-year period between 1991 and 1996, drug sponsors promised to com- plete 71 postmarketing pediatric studies. Only 11 were completed” (FDA, 2001b, p. 8).3 In 1998, to justify new regulations, the agency made this case: The response to the 1994 rule has not substantially addressed the lack of adequate pediatric use information for marketed drugs and biological products. Pediatric labeling supplements were submitted for approximately 430 drugs and biologics, a small fraction of the thousands of prescription drug and biological products on the market. Of the supplements submit- ted, approximately 75 percent did not significantly improve pediatric use information. Over half of the total supplements submitted simply requested the addition of the statement “Safety and effectiveness in pedi- atric patients have not been established.” (63 FR 66631) (emphasis added) Policies to Promote Pediatric Drug Research, 1997 to 2010 The response to the limited effects of previous efforts to encourage pediatric drug studies and increase pediatric drug labeling was twofold. One response involved the creation through legislation of incentives for pediatric drug studies; the other relied on the creation through regulations of requirements for such studies. The discussion below briefly summarizes the policies; Chapter 3 provides more details. Incentives for Pediatric Studies and Pediatric Exclusivity: FDAMA and BPCA Among many other provisions, FDAMA provided companies with market protections—pediatric exclusivity—when they undertook pediatric studies of a drug in response to formal written requests from FDA. As passed in 1997, the relevant section of the law was not entitled “Best Phar- maceuticals for Children,” although it incorporated proposed legislation that had been first introduced in 1992 under the title “Better Pharmaceuti- cals for Children” (AAP, 2008). Pediatric exclusivity extends for 6 months beyond any existing period of exclusivity and patent protection, which means that products that have no remaining patent life or exclusivity are usually not eligible for the ex- clusivity incentive. Exclusivity applies to all forms of a company’s drug that contain the same active moiety (in essence, the active ingredient in the 3 In November 1996, the agency sent letters to 250 manufacturers asking if and when they intended to file applications; by December 30, it had received 40 responses. In addition, it received a request from the Pharmaceutical Research and Manufacturers of America that the compliance date be extended because “some companies with large numbers of products had encountered unexpected problems in gathering the required information” (61 FR 68623).

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33 INTRODUCTION drug). For a drug with a lucrative market in adults, this incentive can be significant, producing net economic returns in the hundreds of millions of dollars (see, e.g., Li et al., 2007; Baker-Smith et al., 2008). Congress reauthorized the exclusivity provisions of the 1997 legislation in BPCA of 2002 (PL 107-109) and again in 2007 as part of FDAAA. BPCA is once more up for reauthorization by October 1, 2012. FDA issued guidance for industry on pediatric exclusivity in 1998 and subsequently revised the guidance in 1999 (CDER/CBER, 1999a). That guidance has not been updated or reissued to reflect subsequent legislative changes in 2002 and 2003. For companies considering or planning studies under BPCA, FDA will advise about current requirements and expectations. Requirements for Pediatric Studies The same year that Congress created the pediatric exclusivity incentive for pediatric drug studies, FDA on its own initiative proposed regulations— the Pediatric Rule—that required companies to undertake pediatric studies of drugs and biologics under certain conditions. It issued the revised, final regulations in 1998 with an effective date of April 1, 1999 (63 FR 66631; 21 CFR 314.55(a) and 601.27(a)). Except when FDA waived or deferred its application, the rule required that the submission of a drug or biologics marketing application contain a pediatric assessment if the submissions involved a new active ingredient, indication, drug form, dosing regimen, or route of administration. The FDA issued draft guidance on the application of the Pediatric Rule in November 2000 (FDA, 2000). In December 2000, groups opposing the regulations filed suit claiming that FDA exceeded its authority in issuing them. In 2002, a U.S. district court agreed and enjoined their enforcement (Association of Am. Physicians & Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204 (D.D.C. 2002)). Supporters of the regulations went to Congress, which codified the key features of the Pediatric Rule in the PREA of 2003 (PL 108-155). In 2005, FDA published draft guidance for industry on compliance with PREA (70 FR 53233). That guidance has not been updated or made final.4 Like BPCA, PREA was reauthorized in 2007 as part of FDAAA. It, too, is due for reauthorization by October 1, 2012. 4 Early in 2012, FDA announced plans to issue a new guidance document, Pediatric Stud- ies: How to Comply with the Pediatric Research Equity Act, Title IV of the Food and Drug Administration Amendments Act of 2007 (FDA, 2012).

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34 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN PREA Compared with and in Conjunction with BPCA Following the precedent of the Pediatric Rule, PREA applies not only to drugs but also to biologics and, under certain circumstances, to generic products. The incentives established by BPCA did not extend to biolog- ics until the passage of the Patient Protection and Affordable Care Act of 2010 (see Chapter 8). Under PREA, FDA can require pediatric studies only for the indications specified in an application for FDA approval, whereas requests under BPCA can cover studies for other indications, including indications that were approved before the adoption of either policy. Drugs with designation under the Orphan Drug Act are exempt under PREA but can be the subject of written requests. The incentives of BPCA and the requirements for PREA can operate in tandem for the same product and sponsor. That is, FDA can require pedi- atric studies and also request them to give an incentive for the companies to conduct the required studies in a timely fashion. Congress has made the BPCA and PREA more consistent in certain respects over the years, par- ticularly with respect to public access to information developed through requested or required pediatric studies. As described further in Chapter 7, from July 1998 through October 2011, FDA approved more than 425 labeling changes associated with stud- ies requested under BPCA or required under PREA. More than 380 of these changes involved the submission of information from new pediatric studies. During the same time period, FDA • issued more than 330 written requests under BPCA, nearly half of them in the first 2 years of the program; • approved 145 labeling changes related solely to such requests and granted exclusivity to 174 active moieties; • approved at least 179 labeling changes related solely to PREA requirements; • approved 49 labeling changes related to both BPCA requests and PREA requirements; and • made public clinical and other reviews associated with 139 labeling changes (since September 2007). Other Activities and Policies at FDA FDA supports other policies and initiatives not directly related to BPCA or PREA that may encourage the study of drugs in children. As discussed in Chapter 8, the Orphan Drug Act has promoted the study and approval of drugs for rare diseases, many of which affect children. Products with

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35 INTRODUCTION orphan drug designations are exempt from PREA requirements, but many orphan drugs are approved for pediatric use. In addition, through its initiative on unapproved drugs, the agency has sought to get sponsors of such drugs, generally older products, to provide information sufficient to support their approval, including for use by relevant pediatric populations (FDA, 2006a). After announcing in 2007 that sponsors of three previously unapproved pancreatic enzyme products had until April 2010 to secure agency approval, FDA approved the three products by that date (FDA, 2010d). All are labeled for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions in all pediatric age groups. National Institutes of Health NIH supports pediatric clinical research on a wide range of specific diseases and conditions and likewise funds basic research in many areas that may eventually translate into products that benefit children. In 1998, in response to congressional directives, NIH issued policies and guidelines to increase the participation of children in agency-funded research. The goal is “that adequate data will be developed to support the treatment modalities for disorders and conditions that affect adults and may also affect children” (NIH, 1998, unpaged). As described in Chapter 2, NIH has recently an- nounced an initiative to investigate new strategies for creating and testing drug formulations suitable for children. In addition, because pediatric exclusivity is generally not relevant to drugs that have no existing exclusivity or remaining patent life, Congress, as part of BPCA of 2002, directed NIH to create a pediatric drug develop- ment program and to set priorities for pediatric studies of off-patent drugs. (The priority-setting process now extends to pediatric therapeutics more broadly.) Under certain circumstances, FDA may also refer to NIH a writ- ten request for studies of an on-patent drug if the sponsor has declined the request and the agency determines that the requested information is still needed. (See Chapters 3, 6, and 7 for further discussion of the role of NIH under BPCA.) International Activities and Policies Pharmaceutical research is global. Many pediatric studies conducted under BPCA or PREA include foreign study sites, and some (e.g., those for prevention of HIV transmission from mother to child) may be undertaken entirely outside the United States. These activities are subject to the laws and regulations of many countries.

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36 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN FDA is involved in a number of efforts to harmonize national policies and otherwise try to limit some of the problems caused by different policies. These efforts include frequent communication with agency counterparts in the European Medicines Agency, which has somewhat different poli- cies to require or encourage pediatric drug studies. Oversimplified, a key difference is that European policies require the submission of a pediatric study plan earlier in the process of drug development. Other differences in these policies—and efforts to harmonize policies—are briefly described in Chapter 3. Chapter 4 discusses ethical aspects of studies conducted outside the United States. In addition, the World Health Organization (WHO), which also pro- vides guidance and encourages consensus on national regulation of medica- tions, has the Make Medicines Child Size initiative that includes working in partnerships with governments, researchers, industry, and others to promote the development of medicines for children (WHO, 2011b). As part of a broader program to identify drugs to meet priority health needs of the majority of the world’s population, WHO has developed a list of what it describes as essential medicines for children (WHO, 2011a). SELECTED DEFINITIONS This section discusses a number of terms used in the committee’s State- ment of Task and defines several other key terms used in the report. The terms drug, biologic, and active moiety are defined in Chapter 3. Additional terms are defined in later chapters. Pediatric Age Group, Children Neither BPCA nor PREA defines the age range covered by the term pediatric population and pediatric age group. Federal regulations on drug labeling define the pediatric population as the age group from “birth to 16 years, including age groups often called neonates, infants, children, and adolescents” (21 CFR 201.57(f)(9)). Elsewhere, FDA has described the age ranges for pediatric subpopulations as follows: “neonate—birth to up to one month; infant—one month up to 2 years of age; child—2 years up to 12 years; and adolescent—12 years up to 16 years” (see, e.g., FDA, 1996).5 5 In contrast, FDA guidance on pediatric studies of medical devices (which are not covered by PREA and BPCA) includes as adolescents individuals “up to the age of 21” (CDRH, 2004, p. 4). Other federal agencies may also use different definitions. For example, in infant mortal- ity and other statistics, the Centers for Disease Control and Prevention define infancy as the period from birth up to 1 year of age. To cite a different example, under NIH policies, an 18-year-old might be an adult for purposes of consenting to participation in research but a child under a policy on the inclusion of children (up to age 21 years) in research (NIH, 1998).

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37 INTRODUCTION It is not always clear when a particular FDA document refers, for example, to the “6- to 12-year” age group whether it is referring to children from the ages of 6 years up to but not including 12 years or to children from the ages of 6 years to 12 years inclusive. In practice, when it specifies the age groups for which pediatric stud- ies may be requested or required, FDA is not tied to fixed age categories. It typically relies on knowledge of the drug and condition to be studied as the basis for identifying appropriate pediatric age ranges and often specifies ranges that differ from those described above. When specifying studies for the youngest age groups, FDA may distinguish between term and preterm infants and may consider gestational age (usually calculated as the number of weeks from the start date of the mother’s last menstrual period). Among older children, FDA sometimes defines a study population based on extent of pubertal development. In general discussions, this report uses the terms pediatric population and children interchangeably. Pediatric Studies, Clinical Studies As defined in BPCA, the term pediatric studies refers to clinical inves- tigations with pediatric age groups in which use of a drug is anticipated (21 § USC 355a(1)). The term is most clearly applied to studies that include only pediatric populations. However, studies submitted in support of label- ing for a pediatric age group occasionally include children in a larger study group that includes adults. For example, when omalizumab (Xolair) was originally approved in 2003 for use in patients ages 12 years and older, the critical clinical efficacy studies included participants ages 12 to 74 years in one trial and 12 to 76 years in the other (Kaiser, 2003). (Adolescents comprised approximately 6.5 percent of participants in one trial and ap- proximately 8 percent in the other.) Sponsor submissions to FDA are not public. Thus, when this report refers to assessments of studies, it means assessments of studies as they are described in FDA staff reviews, primarily the clinical, clinical pharmacol- ogy, and statistical reviews. For the initial approval of a new drug or biologic, FDA typically re- quires an extensive range of preclinical and clinical studies. The assessments in this report focus on clinical studies or trials, that is, studies with humans. FDA recently made a distinction between studies and trials as follows: “Clinical trials are any prospective investigations in which the applicant or investigator determines the method of assigning the drug product(s) or other interventions to one or more human subjects. Studies are all other investigations, such as investigations with humans that are not clinical trials as defined above (e.g., observational epidemiologic studies), animal studies,

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38 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN and laboratory experiments” (CDER/CBER, 2011). In this report, a trial is one type of clinical study. When FDA defers the submission of pediatric studies that are required under PREA to a later date because the product is ready for approval for adults (see Chapter 3), these studies are referred to as postmarket study commitments. Although they are postmarket studies in the sense that they occur after a drug has been approved for marketing for use by adults (or another pediatric age group), the pediatric studies submitted at a later date will usually include one or more Phase I, II, or III trials (see Box 1-2). Thus, this report generally does not refer to pediatric studies requested under BPCA or required under PREA as Phase IV trials. BOX 1-2 Types of Clinical Trials Phase I trials initiate the study of candidate drugs and biologics in humans. Such trials typically assess the safety and tolerability of a drug, routes of administration and safe dose ranges, and the way in which the body processes the drug (e.g., how it is absorbed, distributed, metabolized, and excreted). They usually involve less than 100 individuals, often healthy volunteers (in adult trials). Phase II trials continue the assessment of a drug’s safety and dosing but also begin to test efficacy in people with the target disease, including children. These studies may include a range of controls for potential bias, including use of a con- trol group that receives standard treatment or a placebo, the random assignment of research participants to the experimental and control groups, and the conceal- ment (blinding) from participants and researchers of a participant’s assignment. The studies may involve hundreds of participants, although pediatric trials are usually smaller. Phase III trials are expanded, usually well-controlled investigations of safety and efficacy that are intended to allow a fuller assessment of a drug’s benefits and harms and to provide information sufficient to prepare labeling or instructions for the use of the drug. These studies may involve hundreds to thousands of research participants and multiple sites. Phase IV studies occur after a new product or a new indication, drug form, dosing regimen, or similar change is approved for marketing. They are highly variable in their designs and purposes. Scientifically focused studies are typically intended to provide further information about outcomes in clinical practice, for example, when the drug is used over periods longer than those studied in the trials used to support FDA approval. SOURCES: Adapted from FDA (2010a) and IOM (2010).

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39 INTRODUCTION Benefit, Harm, Risk The public health goal of drug development is to create drugs that pro- duce desired health benefits and avoid or minimize harm insofar as possible. A benefit is a valued and helpful outcome from an intervention; a harm is an unwanted and hurtful outcome. Risk refers to the potential for harm. Few medical interventions are without risks. The challenge for those evaluating studies submitted in sup- port of a drug’s approval is to weigh the projected benefits against the risks. Adverse Event, Safety Signal, Efficacy, Effectiveness In the context of clinical studies being undertaken to support the ap- proval of a drug or biologic, an adverse experience (adverse event is used in this report) is defined in federal regulations as “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related” (21 CFR 312.32(a)). The regulations use the term adverse reaction to describe an adverse event caused by a drug. In addition to lengthy descriptions and analyses of adverse events, FDA reviewers usu- ally provide an overall assessment of a product’s safety profile, specifically, whether the profile was similar to or different from that found in adults (unless the product has not been evaluated in adults) and whether it identi- fied serious drug-related adverse events. Efficacy refers to the achievement of desired results in controlled clini- cal studies. Effectiveness refers to the achievement of desired results in actual clinical practice. Results in clinical practice may differ significantly from results in carefully controlled clinical trials. Although the FDC Act uses the term effectiveness to describe positive results reported in clinical trials (21 USC 355), FDA clinical reviews and other documents use the term efficacy rather than effectiveness in discussing such data. Alternative Endpoint, Extrapolation This report uses the term alternative endpoint to refer to a measure of efficacy in a pediatric clinical trial that takes pediatric development into ac- count and thus differs from endpoints for adult studies for the condition be- ing investigated. For example, in studies with adults, investigators may rely on self-reports of symptoms, whereas in studies with children, particularly young children, they may rely on reports from parents or on investigator assessments based on such physical expressions as crying or grimacing or behaviors such as loss of appetite. For conditions that are found solely or primarily in children, the pediatric endpoint may be unique. In the context of pediatric studies conducted under BPCA or PREA,

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40 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN extrapolation refers to FDA’s acceptance of clinical trial and other infor- mation developed in studies with adults to support decisions about the approval of a product for pediatric use. As discussed in Chapters 3 and 5, FDA also may accept extrapolation of data from one pediatric age group to another. Label, Labeling Under the FDC Act, the drug label refers to “written, printed, or graphic matter upon the immediate container of any article,” whereas the term labeling refers to “all labels and other written, printed, or graphic matters” accompanying a product (whether affixed or not) (21 USC 321(k) and (m)). The former term is popularly applied to the short label affixed to prescription drug containers. Consistent with FDA usage, this report uses the term labeling to refer to the longer and more detailed prescribing information (sometimes called package inserts) that FDA approves to accompany prescription drugs. Also, because labeling changes require FDA authorization, this report sometimes uses the terms labeling change and approval interchangeably, including when a product is approved for the first time and thus has no previous labeling to change. As a shorthand expression, this report may use the term pediatric label- ing to describe a product that is explicitly labeled for use by all or some pediatric age groups. Many products do not have pediatric labeling but do have some information in the labeling from pediatric studies, for example, brief reports of clinical trials that did not show safety and efficacy. Indications, On-Label Use, Off-Label Use FDA approves drugs and biologics for specific indications. An indica- tion describes a particular use of a product, for example, for acute treat- ment of schizophrenia or long-term control of asthma symptoms. FDA may approve use of a drug for an indication for a medically relevant subset of people with a condition, for example, those with severe disease or those with disease that is not responsive to commonly used or less risky treat- ments. Labeling, particularly if it has not recently been updated, is not always explicit about the age groups to which the approved indication applies. On-label use refers to clinical use that is covered by a product’s label- ing, primarily the indication(s) and age group(s) described in the labeling. Physicians may legally prescribe drugs off-label for uses that are not ap- proved and included in a product’s labeling. Companies may not explicitly promote such uses.

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41 INTRODUCTION Applicant, Sponsor, Company, Manufacturer In FDA terminology, an applicant or drug sponsor is “the person or entity who assumes responsibility for the marketing of a new drug, includ- ing responsibility for compliance with applicable provisions of the Federal Food, Drug, and Cosmetic Act and related regulations” (FDA, 2010a). The sponsor of an application for FDA approval of a drug or biologic is typi- cally a pharmaceutical or biotechnology company. Rarely, applications come from public or nonprofit agencies. For ex- ample, the California Department of Health Services developed, tested, and received FDA approval for botulism immune globulin (BabyBIG) for the treatment of infant botulism (Arnon, 2007). Notwithstanding such examples, this report uses the terms sponsor, applicant, company, and manufacturer interchangeably. As companies consider the planning and conduct of pediatric studies, they must consider the particular scientific, ethical, legal, practical, and economic aspects of such studies. The next chapter provides an overview of developmental pharmacology and adaptations in research strategies to accommodate the ways in which children of different ages differ from adults and each other.

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