Safe and Effective Medicines for Children Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (2012) / Chapter Skim
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8 Pediatric Studies of Biologics
8 Pediatric Studies of Biologics
Pages 207-230
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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 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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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 (biosimilar)
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. That meant, for example, 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.
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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)
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Beyond the incentives potentially provided by BPCIA and BPCA, the committee identified two other relevant policies that are not aimed narrowly at pediatric studies. They are the Orphan Drug Act and, potentially, priority review vouchers.
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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 communication, 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)
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(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)
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Pediatric Rule and PREA In the absence of incentives under BPCA and in addition to the incentives provided by the Orphan Drug Act, PREA and its predecessor, the Pediatric Rule, have helped to ensure pediatric studies of biologics. Unfortunately, their contributions are not as clear as they might be.
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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.
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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)
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(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)
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and the current labeling is ambiguous and does not cite pediatric studies or describe pediatric dosing, the product is categorized as not labeled for use by children and not studied in children.10 (Changing this categorization would not affect the committee's conclusions.) Approval Letters and Postmarket Study Requirements Database In addition to consulting the product labeling, the committee reviewed FDA approval letters in the public domain for references to studies required under the Pediatric Rule or PREA.
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Including the product's 12 In 1997, FDAMA required the creation of the clinical trials database to provide information about certain interventional studies of drugs, biologics, and devices (Phases II through IV) for which FDA has issued an IND Application or an Investigational Device Exemption or for which there was at least one U.S.
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For products not labeled for pediatric use, the labeling may report pharmacokinetic 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., clotting factors and enzyme replacement therapies)
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Biologics with orphan drug exemptions or waivers of pediatric study requirements may still be evaluated in studies with children (Box 8-1)
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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.
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The product was exempt from pediatric study requirements because it had an orphan drug designation for the indication (Pazdur, 2008)
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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.
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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.
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Becaplermin (Regranex) , a topical platelet-derived growth factor that is approved for treatment of diabetic foot ulcers (with a waiver of required pediatric studies)
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For the four products listed in Box 8-2 for which the committee identified 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)
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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 conditions 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 incentive in 1997 (effective in July 1998)
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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.
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