8

Pediatric Studies of Biologics

Until recently, the incentives of the Best Pharmaceuticals for Children Act (BPCA) were not available to sponsors of products defined as biologics. These products have, however, been subject to the requirements for pediatric studies of the Pediatric Research Equity Act (PREA) and its predecessor, the Pediatric Rule. The Biologics Price Competition and Innovation Act (BPCIA), which was included in the Patient Protection and Affordable Care Act of 2010 (PL 111-148), substantially reshaped the regulation of biologics. Among other changes, it made products regulated under the Public Health Service (PHS) Act eligible for the incentive of pediatric exclusivity.

BPCIA also replaced certain provisions for this Institute of Medicine (IOM) study that had been included in the Food and Drug Administration Amendments Act of 2007 (FDAAA).1 One of the new provisions called for the IOM to “review and assess the number and importance of biological products for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 and the importance for children, health care providers, parents, and others of labeling changes made as a result of such testing.” A second provision called for the review and assessment of “the number, importance, and prioritization of any biological products that are not being tested for pediatric use.” Under the third new provision, IOM was to “offer recommendations for

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1 The 2007 provisions had called for the IOM to review and assess pediatric studies of biological products required under PREA and to make recommendations about incentives to encourage pediatric studies of biologics.



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8 Pediatric Studies of Biologics U ntil recently, the incentives of the Best Pharmaceuticals for Children Act (BPCA) were not available to sponsors of products defined as biologics. These products have, however, been subject to the requirements for pediatric studies of the Pediatric Research Equity Act (PREA) and its predecessor, the Pediatric Rule. The Biologics Price Com- petition and Innovation Act (BPCIA), which was included in the Patient Protection and Affordable Care Act of 2010 (PL 111-148), substantially reshaped the regulation of biologics. Among other changes, it made prod- ucts regulated under the Public Health Service (PHS) Act eligible for the incentive of pediatric exclusivity. BPCIA also replaced certain provisions for this Institute of Medicine (IOM) study that had been included in the Food and Drug Administration Amendments Act of 2007 (FDAAA).1 One of the new provisions called for the IOM to “review and assess the number and importance of biological products for children that are being tested as a result of the amendments made by the Biologics Price Competition and Innovation Act of 2009 and the importance for children, health care providers, parents, and others of la- beling changes made as a result of such testing.” A second provision called for the review and assessment of “the number, importance, and prioritiza- tion of any biological products that are not being tested for pediatric use.” Under the third new provision, IOM was to “offer recommendations for 1 The 2007 provisions had called for the IOM to review and assess pediatric studies of biological products required under PREA and to make recommendations about incentives to encourage pediatric studies of biologics. 207

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208 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN ensuring pediatric testing of biological products, including consideration of any incentives, such as those provided under this section or section 351(m) of the Public Health Service Act.”2 This chapter outlines the incentives for pediatric studies included in BPCIA and explains why it is too early to assess the impact of these in- centives or offer recommendations. It also summarizes information about biological products that have been studied, are being studied, or are pend- ing study with children and then identifies a small number of products that appear not to have been the subject of pediatric studies. As context for this chapter, Appendix C describes some differences between small-molecule drugs and biologics and reviews information about the use of biologics by children. Appendix D includes tables listing 96 biological products with summary information about pediatric studies identified in each product’s labeling or in a public database of clinical trials. ENSURING PEDIATRIC STUDIES OF BIOLOGICS Biologics Price Competition and Innovation Act The primary objective of BPCIA was to create a pathway to licensure for biological products that are demonstrated to be biologically similar (bi- osimilar) to and, in some cases, interchangeable with a previously licensed biologic.3 In 1984, when Congress created a pathway for the approval of less expensive generic versions of drugs regulated under the Food, Drug, and Cosmetic (FDC) Act, no analogous pathway was created for products regulated under the PHS Act. At the time, modern biotechnology was in its early days, so the lack of such a pathway was not a particularly pressing issue. Congress has defined the terms biosimilar and interchangeable. As sum- marized by FDA in 2010, A biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to the reference product notwithstand- ing minor differences in clinically inactive components and there are no 2 Section 351(m) covers incentives for pediatric studies of biologics added to the PHS Act by BPCIA. 3 As described in Chapter 3, for regulatory purposes, a biologic is “a virus, therapeutic se- rum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, pro- tein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of a disease or condition of human beings” (42 USC 262(i)). A few older products that were originally derived from human or other animal sources (e.g., insulin, human growth hormone, and certain enzymes) are regulated under the FDC Act rather than the PHS Act and were covered by BPCA from the outset.

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209 PEDIATRIC STUDIES OF BIOLOGICS clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency. (75 FR 61497) To meet the higher standard of “interchangeability,” a product must dem- onstrate that it can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider. (75 FR 61497 at 61498) BPCIA provides for a 12-year period of exclusivity for an innovative (reference) biological product following its approval. During that period, the Food and Drug Administration (FDA) cannot approve a biosimilar product. In addition, the sponsor of an application for a biosimilar product cannot submit its Biologics License Application (BLA) to FDA until 4 years after the date on which the reference product was first licensed. By creating the new periods of exclusivity for biologics, the 2010 legislation provided the basis for the key incentive of BPCA: the 6-month extension of exclusivity for sponsors that conduct pediatric studies of a product in response to a written request from FDA. Thus, to the 12-year and 4-year periods of exclusivity created by the 2010 law, a grant of pedi- atric exclusivity for the completion of requested studies would provide 6 further months of marketing protection. In addition, the 2010 law included explicit provisions for the application of the BPCA incentive to both new and previously marketed biologics (42 USC 262(m)). That meant, for ex- ample, that although the incentives of the Orphan Drug Act already applied to biologics, sponsors that completed studies requested under BPCA could now qualify for 6 months of pediatric exclusivity to be added to the 7-year period of orphan drug exclusivity. However, as explained in Chapter 3, by statute, patents on products with BLAs cannot be extended by pediatric exclusivity. Moreover, supple- mental BLAs involving a nonstructural change (such as the approval of a new indication) or a structural change that does not change the product’s safety, potency, or purity are not eligible for an additional period of ex- clusivity. Although sponsors of small-molecule drugs are eligible for such exclusivity for certain supplemental NDAs, the periods of exclusivity for drugs described in Chapter 3 (5 years for NDAs for new molecular entities and 3 years for qualifying supplemental NDAs) are relatively short com- pared to the 12-year exclusivity provided for biologics. BPCIA presents a host of complicated issues and questions for FDA to consider in developing regulatory guidance and otherwise implementing the

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210 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN legislation. In November 2010, the agency held a public meeting to obtain views on a number of these issues (75 FR 61497). For example, the agency noted that the legislation had altered the definition of biologic by extending it expressly to proteins (excluding chemically synthesized polypeptides).4 After explaining that there was an “absence of scientific consensus on the distinction between the categories of ‘protein’ and ‘polypeptide’ or ‘pep- tide’” (75 FR at 61499), FDA asked for comments on the scientific and technical factors that it should take into account if it develops definitions of these new elements in the definition of biologics. Among several other questions, the agency also asked for comments on factors to consider in determining when a product is highly similar and in deciding what clinical and other studies would be needed to assess differences between a reference product and a proposed biosimilar product.5 In the public notice for the meeting, FDA did not ask for comments on pediatric exclusivity. However, in response to a question, a presenter for the American Academy of Pediatrics noted that the sponsor of an existing biological product would have no incentive to respond to a written request if the standard for approval of a biosimilar product was so high that no approval (and thus no competition) would be expected (Bromberg, 2010). In an August 2011 commentary on the challenges of reconciling law and science, senior FDA officials indicated that FDA was still considering what data would be needed to make the assessments required under the law and to develop regulatory standards (Kozlowski et al., 2011). Aside from clarifying issues related to biosimilar products, which may affect the strength of the pediatric exclusivity incentive, it is important for FDA to clarify how the exclusivity provision of BPCIA will be applied to biologics that were already approved or under review when the law was passed. In a presentation to IOM in December 2010, agency staff indicated that they did not expect that many, possibly any, products would soon be candidates for written requests (Ross, 2010). As of December 2011, no re- quests for studies of biologics had been issued. At that time, FDA was still 4 The legislation specifies that products in this class must now be approved under the PHS Act rather than the FDC Act. An exception provides that certain products that had previously been approved under the FDC Act could still be approved under that act (through March 2020), unless a product in the same class had been approved under the PHS Act and could be considered a reference product. 5 As this report was being completed in February 2012, FDA issued three draft guidance documents on biosimilars: Scientific Considerations in Demonstrating Biosimilarity to a Refer- ence Product; Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product; and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (see FDA news release at http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm291232.htm).

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211 PEDIATRIC STUDIES OF BIOLOGICS considering how to implement the exclusivity provisions of BPCIA and was unable to discuss with the committee the law’s application to previously approved or submitted products. For example, would a biologic approved a year before passage of the law, be considered to have 4- and 12-year exclusivities dating from that approval? Would such a product be eligible for a written request and cor- responding pediatric exclusivity? The relevance of BPCIA as an incentive for pediatric studies will clearly depend on how the agency interprets the law’s provisions. Even if FDA had determined early on that the incentives of pediatric exclusivity were available to previously marketed biologics, it would still be premature to assess the impact of the law on pediatric studies of biolog- ics. For example, if FDA had quickly issued and sponsors had promptly accepted written requests for pediatric studies of biologics under BPCIA, it would take time for such studies to be planned, completed, analyzed, and submitted to FDA and for FDA to evaluate the studies and make its decision public. For most pediatric studies of safety and effectiveness, this process normally takes several years (except when requested studies have been completed or are under way at the time that the request was issued). Thus, it is highly unlikely that this process for a biologic could have oc- curred within the period of the IOM study, which was required to start by September 2010. In sum, given the combination of the legislation’s recent adoption, its complexity, the lack of guidance from FDA about the application of pediatric exclusivity to previously approved products, and the typical time horizon for conducting requested studies, the timetable for this IOM study did not allow an assessment either of the number and importance of bio- logical products for children being tested as a result of BPCIA or of the labeling changes made as a result of such testing. Likewise, it is too early to assess the incentives of BPCIA and make recommendations that take into account the law’s effectiveness as one means of ensuring pediatric testing of biologics. Beyond the incentives potentially provided by BPCIA and BPCA, the committee identified two other relevant policies that are not aimed nar- rowly at pediatric studies. They are the Orphan Drug Act and, potentially, priority review vouchers. As discussed below, the former has encouraged pediatric studies of drugs and biologics for rare diseases. In addition, al- though PREA establishes requirements rather than providing incentives for pediatric studies, its provisions are important to any consideration of strategies for ensuring that such studies are conducted when appropriate.

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212 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Orphan Drug Act As described in Chapters 1 and 3, the Orphan Drug Act provides incen- tives for studies of rare diseases. The law defines a rare condition as one that affects less than 200,000 individuals in the United States. The orphan drug incentives, which include 7 years of exclusivity following the approval of a product for an indication with an orphan designation, are intended to encourage development of new therapeutics. The incentives of BPCA focus on encouraging pediatric studies of products that are already approved for use by adults or for which approval for adult use is the primary develop- ment objective. Unlike pediatric exclusivity, the incentives of the Orphan Drug Act are available even for products that have no remaining patent life or other exclusivity.6 According to FDA, of the 358 products with orphan drug approvals as of July 2010, almost 20 percent of the approvals involve conditions that exclusively affect children and more than 55 percent involve conditions that affect both children and adults (Goodman, 2010b; personal commu- nication, Catherine Lee, Office of Pediatric Therapeutics, FDA, August 12, 2011).7 Overall, from 1984 through 2008, biologics approved with orphan designations accounted for about 31 percent of all original BLAs, whereas drugs so designated accounted for 21 percent of approved new molecular entities (calculated from data of Coté, 2009). Products with orphan designations are exempt from PREA require- ments. Thus, when FDA approved factor XIII concentrate (human) (Corifact) in 2011 for routine prophylactic treatment of congenital factor XIII deficiency in adult and pediatric patients, the labeling change for this orphan-designated indication was appropriately not attributed to PREA (Vanco, 2011). When products with orphan designations receive FDA approval, spon- sors may agree to conduct postmarket pediatric studies that are not re- lated to requirements under PREA. For example, when alglucosidase alfa (Myozyme) was approved in 2006 for treatment of infantile-onset Pompe disease (a rare enzyme deficiency disease with an orphan designation), the sponsor agreed to complete a postmarket safety and efficacy study with patients with juvenile- and adult-onset disease (Beitz, 2006a). 6 In addition to exclusivity incentive, the Orphan Drug Act also provides grants to support research on rare conditions. For example, under this program, FDA joined with NIH and the sponsor to fund a pediatric study of peginterferon alfa-2a (Pegasys)/ribavirin (Copegus) combination for treatment of hepatitis C (http://www.accessdata.fda.gov/scripts/opdlisting/ oopdgrants/OOPD_Grants_Results_2.cfm). In 2011, FDA approved extension of labeling for the product to cover children ages 5 to 17 years (Birnkrant, 2011b). 7 By November 2011, FDA listed 390 orphan drug approvals at its orphan drug website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm).

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213 PEDIATRIC STUDIES OF BIOLOGICS FDA has sometimes shown considerable flexibility in accepting evidence of efficacy for products to treat rare diseases (Kesselheim et al., 2011). In the case of the just-mentioned alglucosidase alfa, for example, the pri- mary evidence of efficacy was from a randomized, open-label, historically controlled trial involving 18 children with infantile-onset disease (Beitz, 2006a). Although the number of participants was small, the differences in outcome were substantial. For the treated infants, the ventilator-free survival rate was 83 percent at 18 months, whereas the rate was 2 percent for the 61 patients in the comparison group. The sponsor also agreed to conduct long-term studies to collect growth and development data for chil- dren with the condition. (This product is listed in the tables in Appendix D.) FDA staff have described some concerns about the evidence submitted in support of orphan drug approvals (Pariser, 2010). These concerns include inadequate early-phase dosing and safety studies as a basis for Phase III tri- als (an issue also identified in this report) and failure to plan and design Na- tional Institutes of Health (NIH)-funded therapeutic trials for products for rare diseases so that they would meet FDA criteria for marketing approval. In 2010, another IOM committee recommended that NIH and FDA cooper- ate on steps to ensure that NIH-supported studies of the pharmacokinetics, safety, or efficacy of drugs for rare diseases are designed and conducted to meet FDA standards (IOM, 2010). Similar cooperation is important when NIH supports other relevant clinical studies of drugs for pediatric use, in- cluding studies conducted outside the NIH BPCA program (see Chapter 3). Priority Review Vouchers Priority review vouchers, which were authorized under FDAAA, entitle a company that secures FDA approval of a product to treat or prevent specified tropical diseases to obtain expedited FDA review of another prod- uct. A company may use the voucher or transfer it to another company. The goal for a priority review is the completion of FDA’s review of the New Drug Application or BLA submission within 6 months rather than the standard 10 months (CDER/CBER, 2008). Somewhat offsetting the value of savings in time, FDA charges a fee for priority review, in addition to other fees that sponsors pay. Congress is considering a proposal to make priority review vouchers available for studies of rare pediatric diseases (S. 606, Creating Hope Act of 2011; see also BVGH, 2011). Among other features, the proposal would remove current limits on the transfer or trading of vouchers. As of November 2011, only one priority review voucher had been re- deemed, and that was for a product that clearly had been in development before the creation of the voucher incentive (Hughes, 2011). The product, artemether/lumefantrine (Coartem), was approved for treatment of acute,

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214 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN uncomplicated malaria in adults and children who weigh 5 kilograms or more (Cox, 2009). Until additional experience with this program accumu- lates, it is difficult to judge its potential as another incentive for pediatric studies for either drugs or biologics. Pediatric Rule and PREA In the absence of incentives under BPCA and in addition to the incen- tives provided by the Orphan Drug Act, PREA and its predecessor, the Pediatric Rule, have helped to ensure pediatric studies of biologics. Unfor- tunately, their contributions are not as clear as they might be. Despite a committee request, FDA could not identify all labeling changes for biolog- ics that were associated with studies required under PREA or the Pediatric Rule (which took effect April 1, 1999). (As explained in Appendix A, FDA’s posted table of labeling changes associated with BPCA and PREA did not, until recently, note that it did not include some biologics approved before September 27, 2007.) The committee also could not identify the percent- age of biologics approved since 1999 for which either the requirements for pediatric studies were fulfilled from the outset or for which pediatric studies were deferred.8 In addition, given the incomplete documentation, particu- larly for biologics approved before 2003, it is possible that some waived or deferred studies that were to have been conducted under the Pediatric Rule or PREA were not identified. For the two dozen new and supplemental BLAs that the committee reviewed for the period from 2008 through 2010, all but one of the letters approving a new indication or other covered label- ing change included a statement about pediatric study requirements (e.g., that they had been fulfilled or were deferred). In the other case (Golding, 2008a), the committee found that the sponsor had an orphan drug desig- nation for the approved indication (chronic inflammatory demyelinating polyneuropathy, for intravenous immune globulin [Gamunex-C]) and thus was exempt from PREA requirements. The discussion below documents a considerable pursuit of pediatric investigations of biologics. The incentives of the Orphan Drug Act have likely motivated some of the completed and ongoing studies, and the re- quirements of PREA or the Pediatric Rule account for others. Undoubtedly, the promise of many biologics to treat or prevent illness in children is a key motivation for many of the pediatric studies. Under the circumstances, it seems unlikely that the incentives provided by BPCIA (if applied to previously marketed as well as new biologics) would lead to a surge of written requests for pediatric studies of biolog- 8 Of the 97 biologics that the committee examined, 16 were approved before the Pediatric Rule became effective.

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215 PEDIATRIC STUDIES OF BIOLOGICS ics similar to the surge in requests for pediatric drug studies that followed the creation of the pediatric exclusivity incentive in 1997 (see Chapter 7). Nonetheless, the incentives would likely encourage further studies of some biologics and lead to the addition of information (and an indication) to product labeling. It is reasonable for Congress to continue the incentives until they can be systematically evaluated. IDENTIFYING BIOLOGICS NOT STUDIED WITH CHILDREN Defining the Universe of Products Before the committee could review and assess “the number, importance, and prioritization of any biological products that are not being tested for pediatric use,” it had to define the universe of such products for its inves- tigation. Identification of all biologics, including those that are under de- velopment but that are not approved by FDA, was not feasible. Although FDA may have received Investigational New Drug (IND) applications for products under development, FDA does not make INDs public. For older products approved by FDA before about 1997, relevant clinical reviews, product labels, and other documents that might identify or describe pedi- atric studies are rarely public. At the suggestion of FDA, the committee’s review targeted products with BLAs approved by FDA from January 1, 1997, through December 31, 2010.9 From this group of biologics, the committee excluded non- therapeutic products such as assays and reagents (e.g., products used for blood testing or blood grouping) and allergenics. It also excluded preventive vaccines, which are often intended primarily or entirely for use by children. Vaccines are the subject of other government policies and programs (e.g., the National Vaccine Program and the Advisory Committee on Immuniza- tion Practices) that promote and monitor the development, testing, and im- provement of vaccines for both children and adults. Appendix D provides summary information on pediatric labeling and a brief review of pediatric labeling and studies of vaccines. With FDA’s agreement, the committee concluded that it did not make sense to identify only products that are currently being tested for pediatric use. Rather, the conclusion was that the committee should also attempt to identify biologics for which pediatric studies are either completed or pend- ing. Completed studies might have been submitted for FDA approval and have led to the labeling of a product for children or, at least, to the inclusion 9 Because the biologics included are limited to those with BLAs, they exclude certain animal- derived or recombinant products that were approved under the NDA rather than the BLA process (see footnote 3 earlier in this chapter).

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216 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN of some information from the studies in the labeling. Pending studies might include PREA-required or NIH-supported studies that have not yet started enrolling children. Thus, by identifying completed, ongoing, or pending pediatric studies of biologics, the committee would, by elimination, identify biologics approved since 1997 that (1) had not been studied with children, (2) were not currently under study with children, and (3) were not pending the start of a pediatric study. Sources of Data For biologics that are now reviewed and approved by the Center for Drug Evaluation and Research (CDER), FDA staff created and supplied a list of products that were approved from 1997 through 2010. The Center for Biologics Evaluation and Research (CBER) originally approved some of these products before FDA transferred the responsibility for certain categories of therapeutic biologics to CDER in 2003. For biologics that are still under the jurisdiction of CBER, the committee compiled a list of products that had BLAs that were approved from 1997 through 2010 and for which CBER had posted some supporting documents (e.g., approval letters). CBER staff were consulted to help the committee identify relevant omitted products and exclude products that were approved under new drug applications (NDAs), were not on the market, or were not new products. The final list included 96 biologics, 57 of which are now regulated by CDER, and 39 of which are now regulated by CBER. To identify biologics that had been studied, were being studied, or were planned for study with children, the committee consulted several sources of information, including • the current product labeling; • the product approval letter(s), if available; • the FDA database that tracks various kinds of postmarket study re- quirements or commitments, including those required under PREA; and • ClinicalTrials.gov, a registry of publicly and privately supported clinical trials administered by NIH. For products for which no pediatric studies were identified in the sources described above, the committee searched further for pediatric studies in PubMed, the National Library of Medicine’s database of bio- medical literature citations and abstracts. It also consulted with CBER staff.

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217 PEDIATRIC STUDIES OF BIOLOGICS Current Product Labeling The first step in identifying completed pediatric studies was a search of a product’s current labeling for approved pediatric indications; references to pediatric pharmacokinetic, safety, or efficacy studies; or statements indicat- ing that the product had not been studied with children. According to FDA, the statement in the labeling of a CBER-regulated product that “safety and efficacy have not been established in pediatric patients” means that the products had not been studied with children (personal communication, Catherine Lee, Office of Pediatric Therapeutics, FDA, August 8, 2011). The committee also searched for warnings or recommendations against use with children that were based on analyses of adverse event reports. In most cases, the labeling consulted was that posted by the sponsor; FDA did not always have the current label posted. Some product labeling is ambiguous about pediatric studies. For ex- ample, the label for crotalidae polyvalent immune Fab (ovine) (CroFab) states that “specific studies” of pediatric patients have not been conducted, but the label also describes two clinical trials conducted with individuals 11 years old or older (Protherics, Inc., 2010, unpaged). The pediatric use section of the labeling for antithymocyte globulin (rabbit) (Thymoglobulin) states that “safety and efficacy have not been established in controlled trials” but goes on to state that dose, efficacy, and adverse event profile “are thought to be similar to adults” on the basis of limited (presumably uncontrolled) European studies and other data (Genzyme, 2008, unpaged). Because studies of both products are listed in the clinical trials database discussed below, they are categorized to have been studied with children. Labeling is also ambiguous for Rho(D) immune globulin intravenous (Rhophylac). It is labeled for suppression of Rhesus (Rh) isoimmunization in pregnancy and obstetric conditions and in incompatible transfusions in Rho(D)-negative individuals and also for raising platelet counts in Rho(D)- positive, nonsplenectomized adults with chronic idiopathic thrombocytope- nic purpura (ITP). The use of the term “individuals” for one indication and “adults” for another indication could reasonably be interpreted as implying that the term individuals referred to individuals of all ages. However, the labeling later states that the safety and effectiveness of the product have not been established in pediatric subjects being treated for an incompatible transfusion; it then goes on to state that the physician should weigh the potential risks against the benefits of treatment, particularly for girls whose later pregnancies might be affected by Rh isoimmunization. The 2007 label- ing posted by CBER includes a statement that “studies have demonstrated the safe and effective use of Rho(D) Immune Globulin in children with ITP” (CBER, 2007, unpaged). The latest manufacturer’s labeling, which has not been posted by CBER, does not include that statement (CSL Behring, 2010).

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220 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN sponsor as a search term may exclude studies of competitors’ products but may also exclude potentially relevant studies of the product funded by other entities. For example, restricting the search for IVIG products to studies of a product’s sponsor would have excluded the National Institute of Mental Health study of the IVIG product (Gamunex) for treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infec- tions (ClinicalTrials.gov identifier: NCT01281969). Given the difficulty of identifying these kinds of individual products in the database, the analysis of the trials database grouped a few classes of biologics together for analysis (see Appendix D).13 The tables in Appendix D may understate the extent of pediatric studies for some products because the committee did not attempt a comprehensive search of the broader scientific literature for all products. Such a search might have identified older studies that predate the clinical trials registry and that were not pursued to support labeling in the United States. Results: Products Studied with Children Table 8-1 summarizes the primary results of the committee’s search. Tables D-1 and D-2 in Appendix D provide more detailed information. In general, Table 8-1 presents a positive picture. For approximately 60 percent (59) of the 96 biological products examined, the labeling includes a pediatric indication for at least one pediatric age group or information from pediatric studies, or both, or it includes a specific warning about a lack of safety on the basis of FDA analysis of adverse event reports or other data. Of these 59 products, 47 were considered to be labeled for pediatric use, although the labeling, particularly for older biologics, is not always clear. For products not labeled for pediatric use, the labeling may report pharma- cokinetic or safety information from pediatric studies, including studies that did not demonstrate safety or efficacy, or the labeling may include pediatric safety warnings based on analysis of adverse event reports. Products with pediatric study information in the labeling may have been intended from the outset to be approved for use by children (e.g., clot- ting factors and enzyme replacement therapies), or studies of the products may have been conducted in response to PREA requirements or orphan drug incentives. Some products with no information about pediatric studies in the current label may have information added in the future, for example, 13 FDA does not treat these products as interchangeable for purposes of marketing approval, but hospital formularies, clinicians, and health plans may. The committee did not examine or take a position on this practice. Differences in IVIG products that may be clinically relevant include their purification processes, concentration, stabilizing agents, and pH (http://www. ashp.org/s_ashp/docs/files/DShort_IVIGsidebysideupdatedDec07.pdf).

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221 PEDIATRIC STUDIES OF BIOLOGICS TABLE 8-1 Summary Information on Biologics Studied in Children No. (%) of Biologics Labeling or trial status All (n = 96) CDER (n = 57) CBER (n = 39) Products with pediatric information 59 (61) 30 (53) 29 (74) in most recent labelinga Products with registered pediatric 81 (84) 51 (88) 30 (79) trialsb Overall: Products with pediatric 85 (89) 50 (88) 35 (90) information in labeling or registered pediatric trials or both NOTE: Biologics included were originally approved by FDA from 1997 through 2010. See Appendix D for more details. a Labeling (generally as of July or August 2011) (1) included a pediatric indication or men- tions results of pediatric studies or both or (2) included an explicit warning about lack of pediatric safety based on analysis of adverse event reports. b Data at ClinicalTrials.gov were consulted between August and December 2011 for plau- sible listings of pediatric studies. Plausible listing means that the description of the study, even if it did not mention the product by name, suggests that it is likely to be a study of the product, for example, because the company funding or sponsoring the study is the company that sponsored the BLA (or its successor company). SOURCE: Tables D-1 and D-2, Appendix D. as a result of studies now under way or planned. For other products, studies now planned or under may be stopped or not pursued further on the basis of safety findings or results showing a lack of activity or efficacy. For studies not required under PREA, such negative safety or efficacy results might not be added to the product’s labeling. In some cases, changes in the priorities of sponsors may affect their pediatric research program. Biologics with orphan drug exemptions or waivers of pediatric study requirements may still be evaluated in studies with children (Box 8-1). Some products may have exemptions or waivers of study requirement for one indication but not another, and as noted earlier, a majority of orphan drugs are approved for conditions that affect children. The committee did not systematically examine pediatric labeling, PREA requirements, or registered studies of biologics by pediatric subgroup. For some products, it is possible that a public health benefit might accrue from investigations with individuals in age groups not yet studied. For example, in 2009, after the 1-year safety review for a fibrin sealant (Artiss), the Pedi- atric Advisory Committee recommended that the product, which is labeled for use with older children, be studied in infants less than 1 year of age (PAC, 2009). FDA had previously waived studies related to skin grafts for burns for that age group (Epstein, 2008).

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222 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN BOX 8-1 Examples of Products with PREA Waivers or Orphan Designation Exemptions for Which Pediatric Studies Are Listed at ClinicalTrials.gov Alpha1-Proteinase Inhibitor (Human) (GLASSIA) (BLA 125325): approved in 2010, one of several products approved for treatment of emphysema due to a con- genital deficiency of α1-proteinase inhibitor. The CBER approval letter waived the requirement for pediatric studies because this deficiency “is not known to cause emphysema in pediatric subjects” (Malarkey and Epstein, 2010). The sponsor has registered a randomized, placebo-controlled, Phase II study of the safety and ef- ficacy of an investigational inhaled formulation of the product in individuals (ages 5 years and older) with cystic fibrosis (ClinicalTrials.gov identifier: NCT00499837). In 2004, the sponsor received orphan designation for this indication, and in 2009, the sponsor of another product in this class (trade name not specified) likewise obtained such a designation, although no apparently related studies are registered for the latter sponsor. In addition, the sponsor of GLASSIA has registered a Phase I/II trial of the product as a possible disease-modifying agent in type 1 diabetes mellitus; enrollment criteria specify ages 10 to 25 years inclusive (ClinicalTrials. gov identifier: NCT01304537). In 2011, the sponsor obtained an orphan designa- tion for treatment of recent-onset type 1A diabetes mellitus with residual beta-cell function in children less than 15 years of age. Pediatric studies of diabetes have been registered for at least one other similar biologic (Aralast NP) (see, e.g., ClinicalTrials.gov identifier: NCT01183455). Antithrombin (Recombinant) (ATryn) (BLA 125248): approved in 2009 for the prevention of perioperative and peripartum thromboembolic events in patients Results: Products Not Studied with Children Overall Although a sizable majority of biologics have been studied, are be- ing studied, or are planned for study with children, the resources that the committee consulted showed no indication that pediatric studies had been completed, are under way, or are pending recruitment for a few products. Box 8-2 lists the 11 products that are not labeled for pediatric use and for which no pediatric studies were identified in the product labeling or the clinical trials registry. The table also indicates whether the committee found citations relevant to pediatric study of the product in PubMed. As discussed below, the first product listed in Box 8-2 appears to be a possible candidate for consideration for study with children. Most of the products listed in Box 8-2 were approved for treatment

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223 PEDIATRIC STUDIES OF BIOLOGICS with hereditary antithrombin deficiency. FDA determined that it was exempt from pediatric study requirements based on the orphan designation of that indication (Malarkey and Epstein, 2009). The sponsor has a Phase I study registered to investigate the use of the products with neonates scheduled for surgery involving cardiopulmonary bypass (ClinicalTrials.gov identifier: NCT01158729). RimabotulinumtoxinB (Myobloc) (BLA 103846): approved in 2000 for treatment of cervical dystonia in adults. That indication has an orphan drug designation dating to 1992. In 2005, the sponsor registered a Phase I/II trial to investigate whether the product could improve hand functioning for children with upper-extremity hy- pertonia (stiffness of the arm) related to cerebral palsy (ClinicalTrials.gov identifier: NCT00238641). The study, which is listed as completed but without posted results, was to have enrolled 10 children from the ages of 2 up to 18 years. Romiplostim (Nplate) (BLA 125268): approved in 2008 for treatment of thrombo- cytopenia in patients with chronic immune thrombocytopenic purpura who have had an insufficient response to certain other treatments. The product was exempt from pediatric study requirements because it had an orphan drug designation for the indication (Pazdur, 2008). The sponsor conducted a Phase I/II randomized, double-blind safety and efficacy study of the drug for treatment of thrombocytope- nia in pediatric subjects ages 12 months up to 18 years with immune (idiopathic) thrombocytopenic purpura (ClinicalTrials.gov identifier: NCT00515203). Reports on the completed study stated that the product was well tolerated and effective (Buchanan et al., 2009; Bussel et al., 2011). SOURCES: Tables D-1 and D-2 in Appendix D and ClinicalTrials.gov. Information about or- phan drug designations and approvals can be found at http://www.accessdata.fda.gov/scripts/ opdlisting/oopd/index.cfm. of conditions that are not found or are rare in children. FDA has waived pediatric study requirements for some of these indications (e.g., prostate cancer and diabetic foot ulcers) and exempted studies for others that have an orphan designation (e.g., Depuytren’s contracture and chronic gout). For four products for which no pediatric studies were identified, similar products have been the subject of pediatric studies or are labeled for pediat- ric use or both. In some cases, the studies of the other product involve the indication for which the listed product is approved for use with adults. In other cases, the studies involve a different indication. Three products were approved before the Pediatric Rule took effect; one of these products had no subsequent labeling changes. Two products were first approved during the hiatus between the overturning of the Pe- diatric Rule and the passage of PREA and had no subsequent labeling changes. Four of the products listed in Box 8-2 were approved in 2010.

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224 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN BOX 8-2 Products with No Indication of Pediatric Studies in Labeling, FDA Approval Letters, or Clinical Trials Registry (ClinicalTrials.gov) Possible Candidate for Pediatric Study Becaplermin (Regranex) (BLA 03691): approved in December 1997 for treatment of lower extremity diabetic ulcers. A 2005 labeling change added information about stud- ies with adults that did not demonstrate efficacy for treatment of for pressure ulcers and venous stasis ulcers. At that time of that change, FDA granted a waiver of required pediatric studies for all age groups (the rationale was not stated). PubMed lists a report of a retrospective case series analysis of use of the product to treat ulcerated heman- giomas of infancy (Metz et al., 2004). Products with No Pediatric Studies Identified but Closely Related Products Are Labeled or Studied for Pediatric Use Alpha1-Proteinase Inhibitor (Human) (Zemaira) (BLA 125078): approved in July 2003 for treatment of individuals with alpha1-proteinase inhibitor deficiency and evidence of emphysema. No pediatric studies are listed at ClinicalTrials.gov, but pediatric studies involving similar products are listed in that database, including studies of cystic fibrosis and type 1 diabetes (see the first entry in Box 8-1). Incobotulinumtoxin A (Xeomin) (BLA 125360): approved in July 2010 for treatment of cervical dystonia and blepharospasm (eyelid twitch). FDA waived pediatric study requirements for all age groups for both indications because too few children were available for study participation. Other botulinum products have been studied with children. One product, onabotulinumtoxin A (Botox) is approved for pediatric use for blepharospasm or strabismus for patients 12 years of age and older. According to FDA’s database of postmarket study requirements and commitment, this product is also the subject of PREA requirements for upper limb spasticity (ages 2 up to 17 years), severe axillary hyperhidrosis (ages 12 to 16 years), prophylaxis of headaches with chronic migraine (in adolescents ages 12 to 17 years), and urinary incontinence due to detrusor overactivity associated with a neurologic condition (ages 10 to 17 years). Pediatric trials involving the product are registered for additional conditions, including cerebral palsy and clubfoot. A second product, abobotulinumtoxin A (Dysport) is not labeled for pediatric use, but trials are registered for studies with children with lower limb spasticity and possibly other conditions. The labeling for all three products includes a boxed warning of the risk that the effect of the toxin could spread from the injection site and cause swallowing and breathing difficulties and death. The symptom reports that prompted the warning mostly involved children with cerebral palsy (FDA, 2009d). Ranibizumab (Lucentis) (BLA 125156): approved in June 2006 for treatment of neovas- cular (wet) age-related macular degeneration and in June 2010 for treatment of macular edema following retinal vein occlusion. FDA waived required pediatric studies without explanation for the first indication and waived required pediatric studies for the second indication because studies would be impossible or highly impracticable as too few pediatric patients with macular edema following a retinal vein occlusion exist. Another antivascular endothelial growth factor product (bevacizumab [Avastin], approved in February 2004) from the same sponsor is registered for a study of treatment of retinop- athy of prematurity and for several pediatric cancer studies. Ranibizumab is a fragment of the bevacizumab antibody. Case reports of the use of ranibizumab listed in PubMed describe use of the product with children for treatment of choroidal neovascularization of various origins (Benevento et al., 2008; Goodwin et al., 2009; Gregory-Evans, 2009; Kohly et al., 2011). Bevacizumab, which is approved for treatment of several types of cancer, is widely used off-label and at lower cost for neovascular age-releated macular degeneration; preliminary results from a controlled trial for this indication show similar outcomes for both products according to a recent government report (OIG/HHS, 2011).

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225 PEDIATRIC STUDIES OF BIOLOGICS Rho(D) Immune Globulin Intravenous (Rhophylac) (BLA 125070): approved in February 2004 for suppression of rhesus (Rh) isoimmunization in Rho(D)-negative individuals transfused with Rho(D)-positive red blood cells or blood components and in 2007 for adults with immune thrombocytopenic purpura (ITP). The labeling of this product is ambiguous as described elsewhere in this chapter. The FDA posted label (2007) states that studies have demonstrated safety and efficacy of Rho(D) Immune Globulin in children with ITP but the manufacturer’s posted label (2010) does not include that statement. FDA waived required pediatric studies for the ITP indication (Golding, 2004). The 2007 approval letter is not public, but no postmarket study requirements are listed for this product in FDA’s tracking database. Several pediatric studies of this type of product (also called anti-D immune globulin) are registered at ClinicalTrials.gov or listed in PubMed, but none are listed under the brand name Rhophylac. Another Rho(D) immune globulin intravenous (human) product, WinRho, which was originally approved in 1995, is labeled for use for idiopathic thrombocytopenic purpura in adults and children and for suppression of Rh isoimmunization (including in girls and women) (Cangene, 2010). ClinicalTrials.gov lists a pilot study of this product for dengue fever (ClinicalTrials.gov identifier: NCT01443247), and a study listed at PubMed shows in- terim results from a study in adults and children for thrombocytopenia in dengue fever (de Castro et al., 2007). A listing of registered studies for “anti-D” (with no brand identi- fied) included a completed Phase II pediatric study for idiopathic thrombocytopenic purpura (ClinicalTrials.gov identifier: NCT00128882), and a report on this study cites favorable results (Kjaersgaard et al., 2009). Other Biologics Not Identified to Have Been Studied with Children Autologous Cultured Chondrocytes (Carticel) (BLA 103661): approved in August 1997 for repair of cartilage defects of the femoral condyle caused by acute or repetitive trauma in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure. No pediatric studies were identified at ClinicalTrials. gov or PubMed. Collagenase Clostridium Histolyticum (Xiaflex) (BLA 125338): approved in February 2010 for treatment of Dupuytren’s contracture with an orphan designation for that indi- cation and an exemption from PREA requirements. No pediatric studies were identified at ClinicalTrials.gov or PubMed. Interferon Alfacon-1 (Infergen) (BLA 103663): approved in October 1997 for treatment of chronic hepatitis C and in 2010 for use in combination therapy for the same condi- tion. In 2010 FDA waived required pediatric studies on grounds that the product does not offer a meaningful therapeutic benefit over current therapies and is unlikely to be used by a substantial number of pediatric patients. No pediatric studies were identified at ClinicalTrials.gov or PubMed. Pegloticase (Krystexxa) (BLA 125293): approved in September 2010 for treatment of chronic gout refractory to conventional treatment. The sponsor has an orphan drug designation for this indication and is thus exempt from PREA requirements. No pediatric studies were identified at ClinicalTrials.gov or PubMed. Sipuleucel T (Provenge) (BLA 125197): approved in April 2010 for treatment of prostate cancer with a PREA waiver because the condition is unlikely to occur in the pediatric population. No pediatric studies were identified at ClinicalTrials.gov or PubMed. Tositumomab and Iodine I 131 Tositumomab (Bexxar) (BLA 125011): approved for treatment of non-Hodgkin lymphoma in June 2003. The sponsor has an orphan des- ignation for this indication and is thus exempt from PREA requirements. No pediatric studies were identified at ClinicalTrials.gov or PubMed. SOURCES: Tables D-1 and D-2 in Appendix D.

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226 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Possible pediatric applications may emerge as more experience with these products develops. Product with Possible Promise for Pediatric Study For FDA, the issuing of a request for a pediatric study under BPCA is to be based on the agency’s determination that information about the use of a product by the pediatric population may yield health benefits. Becaplermin (Regranex), a topical platelet-derived growth factor that is approved for treatment of diabetic foot ulcers (with a waiver of required pediatric stud- ies), might yield benefits for a different condition found in children.14 The product is the subject of a case series report of eight infants treated with the product for ulcerated perineal hemangiomas of infancy (Metz et al., 2004). Other sources suggest that the product is viewed as an effective off-label option for short-term treatment of refractory infantile hemangiomas when other treatments, including other products (e.g., beta blockers and corti- costeroids) used off-label, have failed (see, e.g., Cohen, 2007; Children’s Hospital of Wisconsin, 2010; NOVA, 2010). FDA or NIH could take several criteria into account in considering whether becaplermin has sufficient potential health benefits (taking risks and alternative treatments into account) to warrant encouraging or sup- porting controlled pediatric trials. For example, the National Institute of Child Health and Human Development (NICHD) has identified criteria that may be used to guide the setting of priorities for pediatric therapeutics as required under BPCA (see Chapters 1 and 3) (NICHD, 2011; see also Goodman, 2010a). The criteria for evaluating candidate therapies include • relevance to NICHD’s BPCA mission and goals (which primarily involve off-patent products); • possible disqualifying ethical concerns (e.g., a boxed warning in current labeling); • gaps in existing evidence; • potential effects on children (e.g., taking into account preva- lence and burden of a condition and the availability of alternative therapies); • potential effects on society and the delivery of medical care (e.g., taking into account costs and health disparities); 14 According to the European Medicines Agency, the company that distributes the product in Europe announced in 2011 that for commercial reasons (i.e., low demand and availability of alternative treatments) it would cease supplying it as of June 30, 2011 (EMA, 2011). In the United States, a company that makes other wound care products acquired rights to the product in 2011 (Robertson, 2011).

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227 PEDIATRIC STUDIES OF BIOLOGICS • different populations that might benefit from research; and • availability of resources (e.g., from private sources) to fund research. The committee did not attempt a formal assessment of becaplermin against these criteria, for example, by seeking public input. It did identify some information relevant to the above-mentioned criteria that might in- form an FDA or NIH decision. First, in 2008, FDA approved the addition of a boxed warning to the product’s labeling (FDA, 2008; see also Frieden, 2008). The warning, which was based on data from adults with diabetes who used the product repeatedly for foot ulcers, cited an increased risk of mortality secondary to malignancy and recommended caution in the use of the product for patients with known malignancy. Second, although FDA has not approved any products for treatment of infantile hemangiomas, other products are also being tested for the condition.15 These medica- tions (primarily corticosteroids and beta-blockers) are not biologics and have generic versions, and FDA and clinicians have extensive experience with the safety profiles of these products, including their risks to children. Third, if these other products were found to be safe and effective for treat- ment of refractory hemangiomas, they would likely be less expensive than becaplermin. Fourth, with respect to the condition, infantile hemangiomas of various degrees of severity may be relatively common (e.g., an estimated incidence of 4 to 5 percent overall) (Children’s Hospital of Wisconsin, 2010). Depending on where the hemoganioma is located (e.g., the eye or the anal region), it can, if ulcerated, take years to resolve and cause pain, scarring, and other serious problems. Fifth, as described above, becaplermin is being used off-label to treat infants in the absence of controlled studies to evaluate its safety and efficacy. For the four products listed in Box 8-2 for which the committee iden- tified pediatric studies of similar products, FDA or NIH consideration of pediatric studies of the listed product might take into account (1) whether the similar product has pediatric labeling and, if yes, what the risk-benefit profile is for this use and (2) whether evidence of off-label use of the unstud- ied version of the product suggests a possible health benefit from pediatric studies. If the similar product is not labeled for pediatric use and does not have an IND application, FDA or NIH might investigate the status of the pediatric studies of the products to assess its promise as a possible higher- priority candidate for FDA or NIH consideration. 15 See, for example, trials with the following ClinicalTrials.gov identifiers: NCT01074437, NCT00967226, NCT01056341, NCT01072045, and NCT01010308.

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228 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN CONCLUSIONS Whether as a result of Orphan Drug Act incentives, requirements under PREA, or other reasons, approximately 60 percent of the 96 still-marketed biologics approved by FDA since 1997 are labeled for pediatric use or have information about pediatric use in the labeling. Most of the remaining products have been studied, are being studied, or are planned for studies with children. This is not to say that no further opportunities or needs for pediatric studies of these products exist. Such opportunities might, for example, involve studies that pursue promising findings from early-phase studies, studies for additional indications or for individuals in additional pe- diatric age groups, or long-term studies of safety and effectiveness. If FDA has determined that already labeled or studied products would be eligible for pediatric exclusivity, it might then make written requests to encourage additional pediatric studies of some products. The priority-setting criteria described in this chapter may help with decision making. Of the small number of products that have not been studied with chil- dren, most appear to have limited potential for pediatric use. It is possible that future research on the mechanism of action of one or more of these products will suggest promising lines of investigation involving pediatric conditions. At this time, on the basis of experience with off-label use, one product may have sufficient promise that FDA or NIH, or both, might con- sider encouraging or supporting controlled pediatric trials, whether through requests under BPCA or otherwise. Given the timing of BPCIA and its early stage of implementation, the committee could not practically assess its impact as an incentive for pedi- atric studies of biologics or make recommendations about its effectiveness. Other policies have, however, had an impact. Since it became effective in 1984, the Orphan Drug Act has encouraged pediatric studies of drugs for rare conditions. Although overall data on PREA-related labeling changes for biologics are not available from FDA, PREA and its predecessor, the Pediatric Rule, have prompted pediatric studies of biologics for condi- tions that are found in children and are not covered by an orphan drug designation. As described in Chapter 7, the creation of the pediatric exclusivity in- centive in 1997 (effective in July 1998) led to a surge of written requests for pediatric drug studies that peaked in 1999. A peak in exclusivity determi- nations followed in 2008. It seems unlikely that BPCIA will have a similar impact for biologics. Older biologics have been eligible for the incentives of the Orphan Drug Act, and newer biologics have also been subject to PREA determinations. A substantial majority of biologics approved since 1997 have already been the subject of some type of pediatric study, and some information about these studies is included in the labeling of most of

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229 PEDIATRIC STUDIES OF BIOLOGICS these products. Nonetheless, it is reasonable to expect that the incentives of BPCIA may encourage further studies of some biologics to the benefit of children. Thus, it is reasonable for Congress to continue these incentives until they can be systematically evaluated 3 to 5 years after FDA issues implementing regulations.

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