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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1 Introduction
1 Introduction
Pages 19-42
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From page 19... ...
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)
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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)
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. 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)
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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)
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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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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.
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This report does, however, 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 pediatric research, and others interested in better information to guide clinical care for children.
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• 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.
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• 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.
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Appendix B discusses the dissemination of information 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.
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. 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.
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.2 Policies to Promote Pediatric Research Adopted Before 1997 Although the 1938 FDC Act provided the first requirements that drugs be found safe and the 1962 legislation required demonstration of efficacy, that regulatory framework did little to ensure that safety and efficacy studies would, in fact, extend to children for whom FDA-approved drugs were being prescribed off-label but legally. Drugs or elements of drugs that prove safe for adults may harm children.
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. One of the first policies aimed directly at improving pediatric prescribing information came in 1979, when FDA issued regulations requiring that the precautions section of drug labeling include a subsection on pediatric drug use (44 FR 37434; see also 71 FR 3922 and 21 CFR 201.57(f)
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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.
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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.
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As described further in Chapter 7, from July 1998 through October 2011, FDA approved more than 425 labeling changes associated with studies requested under BPCA or required under PREA. More than 380 of these changes involved the submission of information from new pediatric studies.
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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 development program and to set priorities for pediatric studies of off-patent drugs. (The priority-setting process now extends to pediatric therapeutics more broadly.)
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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)
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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 investigations with pediatric age groups in which use of a drug is anticipated (21 § USC 355a(1)
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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)
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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)
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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 labeling to describe a product that is explicitly labeled for use by all or some pediatric age groups.
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Rarely, applications come from public or nonprofit agencies. For example, the California Department of Health Services developed, tested, and received FDA approval for botulism immune globulin (BabyBIG)
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