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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7 Outcomes of Written Requests, Requirements, Studies, and Labeling Changes
7 Outcomes of Written Requests, Requirements, Studies, and Labeling Changes
Pages 177-206
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approved 425 labeling changes attributed to studies or analyses requested under BPCA or required under PREA.1 FDA attributed approximately half (54 percent) of the changes to studies required under PREA and approximately one third (35 percent)
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Thus, the list provided to the committee understates to an unknown extent the number of labeling changes made as a result of studies of biologics that were required under PREA or the Pediatric Rule. Figure 7-1 shows the time trend of labeling changes attributed by FDA to BPCA and PREA through October 25, 2011.
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Since 2005, pediatric studies required under PREA have accounted for most labeling changes. Some of these changes are for products studied from the outset in at least one pediatric age group.
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The rest of this chapter starts with a discussion of written requests and PREA requirements. Later sections discuss the committee's assessment of pediatric studies (as reviewed by FDA staff)
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More grants of exclusivity and labeling changes can therefore be expected for previously issued written requests. Figure 7-2 shows trends in the issuing of written requests and the granting of exclusivity.
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The high rate of requests related to sponsor proposals may explain why almost 90 percent of written requests issued since January 1, 2008, have been accepted by sponsors (personal communication, Catherine Lee, Office of Pediatric Therapeutics, FDA, November 30, 2011)
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. Although FDA's letters that describe amendments in particular written requests often do not explain the reason for changes, subsequent clinical reviews of submitted studies suggest that some changes have come after a sponsor encountered difficulties with conducting the studies as requested.
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The amended written request in February 2005 dropped the request for the pharmacokinetic study and decreased the sample size of the third study to 200 participants. Inclusion criteria for the ef ficacy trial did not change between the original and the amended request.
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Box 7-2 provides examples. To focus on one therapeutic area, details of the written requests for pediatric studies of a number of drugs used to treat hypertension in adults -- and the resulting trials -- have been criticized for a number of reasons.
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If the initial run-in phase effectively heals erosive esophagitis, withdrawal is not likely to show a significant difference between the placebo treatment and the proton pump inhibitor treatment. An amendment to the written request eliminated the efficacy study, although the drug is widely used by infants.
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Six months of exclusivity is the reward whether the requested studies primarily involve small pharmacokinetic, pharmacodynamic, and safety studies or larger, well-controlled studies of safety and efficacy. These concerns do not imply the need to change the current policy that allows the granting of exclusivity for both studies with positive results and studies with negative results, as long as they meet the terms of the written request.
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.5 The results of at least five NIH-funded studies have been submitted to FDA. Application of PREA Requirements As described above, PREA requirements have become increasingly important as a source of pediatric studies.
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Recent letters are generally specific about the applicability of PREA requirements and the rationale for determinations. In an analysis required by Congress in 2007, FDA's PeRC analyzed the extent to which FDA approval letters or other documents were citing appropriate rationales for waiving or deferring pediatric studies under PREA (PeRC, 2010)
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The report concluded that a more detailed pediatric plan or more specific recommendations from the review division might have avoided the problems. Specifications for Types of Studies Required As noted above, some approval letters, particularly early letters, did not mention PREA requirements, whereas others noted a requirement for deferred studies but provided no specifics beyond those for the age group involved.
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, the pediatric research plan was approximately as detailed as many of the written requests that the committee reviewed. It included a proposed clinical study approach with a description of the proposed design, the age groups to be studied and number in each group to be studied, the entry criteria, the primary and secondary efficacy endpoints, the safety variables, the timing of various assessments, and the general types of statistical analyses to be provided.
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provides some perspective. It found that PREA studies accounted for a somewhat larger share of delayed studies than of total studies in the backlog (Booz Allen Hamilton, 2010)
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. Chapter 4 of this report suggests that Congress ask for an independent assessment of the extent to which redactions in reviews of pediatric studies are appropriate.
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Types of Studies Supporting Labeling Changes In 2007, Congress required FDA to begin reporting certain characteristics of studies conducted under BPCA and PREA, including the types of studies submitted by sponsors to support labeling changes or pediatric exclusivity determinations. Of the requested or required studies reported since then, FDA has classified two-thirds (229 of 346)
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Examples of informative labeling changes resulting from these studies are discussed in the next section. This section focuses on studies that did not reach their potential.
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Some pharmacokinetic information was added to the labeling. FDA judged the sponsor to have made diligent effort to fulfill PREA requirements and noted that the Children's Oncology Group (COG; which is centrally involved in the conduct of most pediatric cancer trials in the United States)
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. PEDIATRIC STUDIES AND CHANGES IN LABELING Types of Labeling Changes All but one of the products in the committee's sample had labeling changes that resulted from the studies conducted under BPCA or PREA.
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In requested studies of leflunomide (Arava) , children with juvenile rheumatoid arthritis receiving this drug showed less im provement than children in the active comparator (methotrexate)
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. It is not clear what prompted that change, which is not recorded in FDA's overview table of BPCA- and PREA-related labeling changes.
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Some changes reflected safety findings for children that differed from findings for adults. As discussed in Chapter 5, FDA sometimes requests only pharmacokinetic and safety information and expects to extrapolate efficacy on the basis BOX 7-4 Examples of Informative Labeling Changes Vinorelbine tartrate injection (Navelbine)
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. Box 7-5 presents examples of committee concerns about the labeling changes that followed pediatric studies.
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The pediatric use section of the labeling for olmesartan (Benicar) notes that it was studied in children ages 1 to 16 years and that it was generally well tolerated and had an adverse experience profile similar to that for adults.
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In the old format, the indications and usage section did not explicitly state that it was not recommended for the latter use. Although the committee was not asked to evaluate the efforts by FDA or others to disseminate information from pediatric studies and labeling changes, it recognized that these efforts are important.
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If FDA creates a formal system for tracking pediatric drug applications through the submission and review process as recommended by GAO, it would be helpful for the system to track pediatric studies by age group, including neonates specifically. The organization and highlighting of key information in the current structured labeling format are substantial improvements over the previous version.
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205 OUTCOMES of pediatric studies of analgesic medication and other pain prevention and alleviation strategies described in Chapter 6. To improve pediatric studies of drugs and biologics and their evaluation, it is important for FDA to continue and expand initiatives to strengthen the science base for its work, analyze shortcomings in pediatric studies, and develop innovative strategies to meet the specific challenges of pediatric trials.
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