Safety and Transparency of Pediatric Drug Trials

Benjamin, Daniel K.; Smith, P. Brian; Sun, Meng; Murphy, M. Dianne; Avant, Debbie; Mathis, Lisa L.; Rodríguez, William J.; Califf, Robert M.; Li, Jennifer S.

doi:10.1001/archpediatrics.2009.229

Cited by 59 publications

(40 citation statements)

References 15 publications

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“…In addition, mechanisms for evaluation of longer-term outcomes, particularly safety-related outcomes that may be affected by the dynamic processes of growth and development, are needed because most of the current trials are of relatively short duration. 24 Finally, our data support earlier reports demonstrating the globalization of clinical trials. 2,25 We have shown previously that 65% of studies conducted under the Pediatric Exclusivity Provision enrolled patients in at least 1 country outside the United States.…”

Section: Discussionsupporting

confidence: 90%

Status of the Pediatric Clinical Trials Enterprise: An Analysis of the US ClinicalTrials.gov Registry

et al. 2012

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WHAT'S KNOWN ON THIS SUBJECT: There are limited data regarding the current status of the pediatric clinical trial enterprise. WHAT THIS STUDY ADDS: Evaluation of the ClinicalTrials.gov data set allows description of the overall portfolio of clinical trials relevant to US children, which was previously not possible. abstract BACKGROUND AND OBJECTIVES: Clinical trials are the gold standard for generating evidence-based knowledge in medicine. Recent legislation requiring trials to be registered at ClinicalTrials.gov has enabled evaluation of the clinical trial enterprise as a whole, which was previously not possible. The purpose of this study was to create a snapshot of the pediatric clinical trial portfolio. METHODS: All interventional trials registered at ClinicalTrials.gov from July 2005 to September 2010 were included. Pediatric (ie, enrolling patients aged 0-18 years) trial characteristics, therapeutic area, location , and funding were described. Secondary objectives included describing pediatric trials over time and comparison with nonpedi-atric trials.

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Section: Discussionsupporting

confidence: 90%

Status of the Pediatric Clinical Trials Enterprise: An Analysis of the US ClinicalTrials.gov Registry

et al. 2012

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“…One analysis of 33 drugs with safety concerns identified in FDA-requested pediatric studies found that only 16 (48%) of these trials were reported in peer-reviewed publications, and many reports did not accurately reflect the findings presented in the FDA reviews. 7 Consequently,thesevaluablepediatricdatamayfailtoinform treatment decisions at the point of care and may not be reflected in guidelines, meta-analyses, or other clinical reviews. Policy makers should consider modifying the statute to define full compliance with PREA requirements as public dissemination of study results, ideally not only on ClinicalTrials.gov but also through a peer-reviewed publication.…”

Section: Improving Transparency and Communicationmentioning

confidence: 99%

The Pediatric Research Equity Act Moves Into Adolescence

Bourgeois

Hwang

2017

JAMA

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Children continue to be underrepresented as participants in clinical trials, limiting the evidence available to guide treatment decisions. Among new interventional trials registered on ClinicalTrials.gov in 2015, only 6% of 19 239 trials focused on children from birth to 17 years of age, even though this age group comprises about a quarter of the US population. As a result, clinicians frequently use medications tested in adults for the treatment of children and adolescents. In one study, rates of off-label prescribing were estimated to involve 85% of 57 000 hospitalized children nationally. 1 Without adequate evidence to support these interventions, children may be exposed to serious unintended harms. Notable examples include the off-label use of verapamil to treat children with supraventricular tachycardia (associated with hypotension and death) and the antimicrobial chloramphenicol administered to infants (leading to fatal circulatory collapse).To improve the clinical study of medications in children, Congress passed in 2002 the Best Pharmaceuticals for Children Act, which grants sponsors an additional 6 months of market exclusivity in return for voluntarily performing US Food and Drug Administration (FDA)requested studies in children. The Pediatric Research Equity Act (PREA), passed in 2003, is a complementary, mandatoryprogramthatauthorizestheFDAtorequirethe studyofanewdrugorbiologicinpediatricpopulations(defined as <17 years of age). Under PREA, sponsors must submit data that assess the safety and effectiveness of a product in children or that justify the extrapolation of adult data torelevantpediatricsubpopulationsfortheindicationsunder review in adults. The act's requirements apply to new drug applications and biologics license applications, as well assupplementstothese,includingnewindicationsandformulations. Although these studies are ordinarily required before approval, sponsors can request that the FDA de-ferorwaivetheirPREArequirementsincertaincases(Box).The Pediatric Research Equity Act has the potential to provide pediatric labeling data at the time of entry of a new product to the market, thereby helping to prevent nonevidence-based use of new therapeutics in children. However, several reports, including from the Institute of Medicine (now the National Academy of Medicine), 2 have suggested that the goals of the program have been diluted by exemptions, frequent study delays, and inadequate results reporting. Since its last reauthorization in 2012 through the end of 2015, 53 of the 137 novel drugs approved by the FDA required pediatric studies under the act. 3 Only 7 of these 53 products had completed pediatric studies at the time of approval and entered the market with pediatric-specific labeling information. 3 Policy makers are currently negotiating the reauthorization of the Prescription Drug User Fee Act, due to expire in September 2017, which governs the FDA's drug ap-

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“…4 New safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program in the United States confirms that adverse events differ in children compared with adults, and availability of additional information about children led to safety labeling changes in 26% of drugs reviewed. 5 Postapproval reporting of adverse events for 1 year in children, which has occurred in the United States because of the Best Pharmaceuticals for Children Act, led to changes in recommendation for .30% of drugs, and several of the adverse events revealed were rare and life-threatening. 6 It is well known that children' s rapid growth and development provide a unique context for health care delivery.…”

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confidence: 99%

Standard 6: Age Groups for Pediatric Trials

et al. 2012

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DILEMMAIt has long been an axiom in clinical pediatrics that "children are not just little adults." It has also been recognized that there are many changes from birth through childhood and the adolescent years. However, the full implications of pediatric age groupings for health care and research are still not adequately understood. There is still much to be discovered about children' s biological and psychological development and how these processes affect the effectiveness and efficacy of interventions. Trial design that accounts for age differences and promotes consistency in reporting of age-related data is essential to ensure the validity and clinical usefulness of pediatric trial data.A recent study highlighted variable treatment efficacy in children versus adults. In this study, 128 meta-analyses from Cochrane reviews, containing data on at least 1 adult and 1 pediatric randomized controlled trial (RCT) with a binary primary efficacy outcome, were reviewed. 1 The authors found that in all except 1 case, the 95% confidence intervals could not exclude a relative difference in treatment efficacy between adults and children of .20%; in two-thirds of these cases, the relative difference in observed point estimates was .50%. The study also highlighted the paucity of RCTs in pediatrics; the median number of children per metaanalysis was 2.5 times smaller than the number of adults.Children and adults seem to have distinctive responses to treatments. For example, administration of phenobarbitones is useful for adults with cerebral malaria and is associated with decreased convulsions. However, in children, this drug is associated with increased 6-month mortality. Similarly, corticosteroids may offer survival benefit for adults with bacterial meningitis but not for children with the same condition. In acute traumatic brain injury, corticosteroids did not decrease mortality in adults, but there was a trend for increased mortality in children. 1 In asthma, long-acting b2-agonists decreased exacerbations in adults but tended to increase exacerbations in children. 1 Intravenous lorazepam, when compared with diazepam in status epilepticus, led to significantly more discontinuations of status in adults but not in children. It is not surprising then that although using an algorithm for extrapolation of adult data for use in pediatric drug licensing and development was found to be useful for streamlining drug development and approvals for pediatric use, complete extrapolation from adult data were only appropriate for 6% of drugs reviewed. 2 Beyond the stark contrast in the efficacy of pharmacologic interventions between children and adults, considerable variation of adverse events and morbidity can be anticipated across the pediatric age range. Authors of a recent study of pediatric drug surveillance and adverse event reporting concluded that "suspect drugs and adverse events should be evaluated in the context of age groups" because both drug utilization and the ability to report adverse events vary by age. 3 For example, t...

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Safety and Transparency of Pediatric Drug Trials

Cited by 59 publications

References 15 publications

Status of the Pediatric Clinical Trials Enterprise: An Analysis of the US ClinicalTrials.gov Registry

Status of the Pediatric Clinical Trials Enterprise: An Analysis of the US ClinicalTrials.gov Registry

The Pediatric Research Equity Act Moves Into Adolescence

Standard 6: Age Groups for Pediatric Trials

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