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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5 Safety and Efficacy Assessments in Studies Conducted Under BPCA and PREA
5 Safety and Efficacy Assessments in Studies Conducted Under BPCA and PREA
Pages 111-140
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From page 111... ...
. Beyond FDA, the system for ensuring safety and efficacy extends to the organizations and individuals responsible for conducting drug studies and protecting research participants and research integrity.
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From page 112... ...
For efficacy, the discussion focuses on the use of alternative endpoints and extrapolation. SOURCES OF INFORMATION ABOUT SAFETY AND EFFICACY RESULTS IN PEDIATRIC DRUG STUDIES The most comprehensive perspective on the pediatric study data submitted by sponsors and evaluated by FDA is provided in the clinical reviews prepared by staff of the Center for Drug Evaluation and Research (CDER)
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From page 113... ...
who may be included as needed. As described in the desk reference guide, the primary audience for the clinical review includes the review team (i.e., those with responsibility for BOX 5-1 CDER Template for Clinical Reviews (2010)
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From page 114... ...
As noted in Chapter 7, almost 10 percent of labeling changes attributed to studies requested under BPCA or required under PREA involved no information from new pediatric studies. During the course of a clinical trial, the sponsor is responsible for trial monitoring.
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From page 115... ...
CDER Template for Review of Safety in Drug Studies The CDER template for clinical reviews outlines a comprehensive evaluation and discussion of safety that covers key topics and data sources in a systematic order (Box 5-2)
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Special Safety Studies/Clinical Trials Immunogenicity Other Safety Explorations Dose Dependency for Adverse Events Time Dependency for Adverse Events Drug-Demographic Interactions Drug-Disease Interactions Drug-Drug Interactions Additional Safety Explorations Human Carcinogenicity Human Reproduction and Pregnancy Data Pediatrics and Assessment of Effects on Growth Overdose, Drug Abuse Potential, Withdrawal, and Rebound Additional Submissions/Safety Issues SOURCE: CDER Manual of Policies and Procedures (Section 7 of Clinical Review Template) , 6010.3R (issued December 14, 2010)
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From page 117... ...
This broader scope provided additional context for understanding FDA's evaluation of safety findings in pediatric drug studies. Unfortunately, the FDA clinical reviews examined by the committee were completed before FDA's shift to the new, more targeted strategy for reporting adverse events.
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From page 118... ...
(FDA may disapprove the labeling of a product for pediatric use but provide for the addition of safety or other information from pediatric studies to the product labeling for already marketed products.) In assessing clinical reviews, the committee looked for a risk-benefit assessment (to use FDA's language)
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From page 119... ...
Because one objective of FDA's evaluation of adverse events in pediatric studies is to determine whether a product's labeling needs to be revised, reviewers sometimes explicitly noted whether the findings about treatmentrelated adverse events in children were reflected in the existing labeling (for previously approved products) or whether some revisions were needed.
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From page 120... ...
for treatment of schizophrenia. "Based on a comparison of the results of five short-term adult studies in schizophrenia with the results of this pediatric schizophrenia study, the safety profile of aripiprazole in adolescents with the diagnosis of schizophrenia is comparable to the adult schizophrenia population, with the exception of dose-related occurrence of higher frequency of somnolence and extrapyramidal symptoms observed in the pediatric population" (Zhang, 2008, p.
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From page 121... ...
For example, in an assessment of irinotecan hydrochloride (Camptosar) for refractory solid tumors, a clinical reviewer concluded that the pediatric studies provided no meaningful new safety information (Ibrahim, 2003)
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From page 122... ...
Few (7 of 46) of the clinical reviews in the committee's sample included fairly explicit summary risk-benefit statements.4 An example of an explicit positive assessment is found in the review of tenofovir disoproxil fumarate (TDF; Viread)
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From page 123... ...
. A framework based on sound regulatory science could make an important contribution to FDA's assessments of pediatric drug studies.
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Long-Term or Other Studies or Safety Reporting After a Pediatric Labeling Change As it reviewed the safety findings in its sample, the committee identified concerns about long-term product-related adverse events -- including neurological and growth-related events -- that would not be evident in the submitted studies. As discussed in Chapter 2, results of medication use in actual practice may differ from results in carefully controlled clinical trials that involve selected populations and strict protocols for product use and monitoring.
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From page 125... ...
Congress and FDA clearly recognize the problem and have taken some steps to address it. The 1-year safety reviews described below provide examples specific to products with labeling changes resulting from studies conducted under BPCA or PREA.
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From page 126... ...
In its sample of 45 labeling changes, the committee found that nine approval letters included postmarket study requirements not required under PREA. The required studies included • an analysis of already collected data (example: for salmeterol xin afoate and fluticasone propionate [Advair]
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From page 127... ...
ASSESSING AND REPORTING EFFICACY IN PEDIATRIC DRUG STUDIES: SELECTED ISSUES Efficacy refers to the achievement of desired results in controlled clinical studies. In its statement of task, IOM was specifically asked to assess the use of alternative endpoints and the use of extrapolation for pediatric
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From page 128... ...
CDER Template for Review of Efficacy in Drug Studies Box 5-4 presents the efficacy review section of CDER's clinical review template. As is the case for the safety review, this section of a review may include a discussion of sponsor- or reviewer-conducted literature searches and may also cite findings from clinical trials involving adults, in addition to results from trials involving children.
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From page 129... ...
For conditions such as attention deficit hyperactivity disorder and irritability associated with autism that may be first identified and studied with children but are subsequently diagnosed in adults, efficacy endpoints for pediatric drug studies are not considered alternative if they are defined prior to studies with adults. An alternative endpoint may also be a surrogate endpoint, that is, an
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From page 130... ...
Consultants from CDER's Study Endpoint and Labeling Development Group may be involved in consultations about pediatric endpoints without being cited in clinical reviews. The group is also involved in the process that FDA created to evaluate and qualify biomarkers, patient-reported outcome tools, and other measures that sponsors may use in specific drug development efforts so that the appropriateness of each such use does not have to be individually evaluated (CDER, 2010)
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From page 131... ...
For the sample of requested or required pediatric studies and labeling changes that the committee examined, almost half (23 of 49) used primary efficacy endpoints that were the same as those used in adult studies.
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Indication studied: attention deficit hyperactivity disorder (ages 6 up to 12 years) Primary efficacy endpoint: IOWA Conners Teacher Rating Scale (Inattention/ Overactivity Subscale)
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. Use of Extrapolation Chapter 1 described the FDA initiative in the early 1990s to increase pediatric studies.
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From page 134... ...
. Occasionally, the written requests or FDA clinical reviews that the 8 In addition to the FDA provisions for extrapolation that were explicitly directed at pediatric studies, FDA also has more general authority to determine effectiveness based on "data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation)
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From page 135... ...
Only rarely did a written request or FDA clinical review provide a more substantive explanation with references to the scientific literature to justify decisions to allow extrapolation. One example of a justification with explicit citation to the literature appears in the written request for a study of aripiprazole (Abilify)
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From page 136... ...
. Nonetheless, given the significance of the reliance on extrapolation, it would be desirable for requests and reviews to provide the public with a justification somewhat fuller than that now provided in each case in which the agency accepts full or partial extrapolation.
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From page 137... ...
The FDA analysis did not examine the use of extrapolation in studies required under PREA. For its sample, the committee examined FDA's acceptance of extrapolation to support labeling changes resulting both from studies requested under BPCA and studies required under PREA.
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. commitment to conduct two clinical trials for this indication, we do not believe that your new proposal to submit one completed clinical study and one completed pediatric pharmacokinetic study, as a substitute for submitting two completed clinical studies, would be sufficient to support the safety and effectiveness [of the drug]
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From page 139... ...
The 1-year safety reviews mandated by Congress appear to provide a useful opportunity for FDA to examine safety experience and to consider overall safety information after products have had labeling changes based on pediatric studies. In several instances, the reviews have led to revisions of safety information in product labeling or pending recommendations for such changes.
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From page 140... ...
For the most part, FDA's specification of efficacy endpoints appears to be reasonable, including the use of alternative endpoints when measures used for adults are not appropriate. Written requests and clinical reviews rarely discuss the rationale for endpoints, whether they are alternative or not.
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