Data-Driven Approaches to Maximize the Impact of Pediatric Clinical Trials.

Abstract

In this issue of Pediatrics, Brewster et al1 present an analysis of pediatric clinical trials registered in ClinicalTrials.gov from 2007 to 2020. Focusing on interventional trials enrolling only children (up to 17 years), the authors examined rates of trial discontinuation and results reporting, including factors associated with these outcomes. Their analysis spans an extended period and encompasses a broad selection of trial designs and interventions, providing information on trends over time across the pediatric clinical trial enterprise. Their findings serve to highlight several key areas requiring continued focus and provide a benchmark for ongoing monitoring and assessment.The authors found that approximately 11% of trials were discontinued, with a modest reduction in this rate over the study period. Over one-third failed due to poor participant accrual, which was the most common reason for discontinuation irrespective of the type of trial sponsor. Prior studies have reported a wide range of rates for pediatric trial discontinuation and the current estimate is lower than previously reported. This is most likely related to the diverse types of trials examined in the current analysis, with prior evaluations focusing on more narrow trial selections, such as randomized pediatric clinical trials or pediatric drug trials conducted in the post-marketing phase.2,3 It is difficult to fully gauge the inefficiencies and loss this discontinuation rate represents without a better understanding of the resources invested in these trials or the number of participants enrolled in studies that failed to yield scientific findings. Nonetheless, it provides a reference across a broad cohort of pediatric trials and confirms the ongoing challenge of recruiting pediatric participants to clinical trials.The study also revealed that the timely dissemination of pediatric trial results through deposit in trial registries and publication in peer-reviewed journals, remains suboptimal. At 3 years since trial completion, only 23% of trials had results available in ClinicalTrials.gov and 39% had been published. Particularly notable is that compared with trials receiving funding from either industry or government entities, those sponsored by academic institutions were least likely to have results disseminated after trial completion (45% compared with 61% for trials with industry funding and 59% for those with government funding). This is consistent with prior studies demonstrating poor performance and marked variation in results reporting by academic medical centers across the US.4 While timely dissemination of research results represents a core mission of academic institutions, effective enforcement mechanisms are lacking. Closer monitoring of publication and reporting activities for pediatric clinical trials is warranted to reduce loss of scientific information and breaches in commitments to participating patients and families.5As we consider the persistent gap in generating clinical evidence and developing interventions for pediatric populations, we must consider not only ways to strengthen pediatric clinical trial infrastructure, but also methods to augment clinical trial data with other evidence types. Very few pediatric trials are large randomized controlled trials and the majority employ single-center designs.6 Leveraging collaborative networks and other multi-institutional endeavors should be the default approach whenever feasible to appropriately prioritize research questions, increase statistical power, and ensure study completion. Funding agencies can support ongoing development of such pediatric research infrastructure and encourage the use of multi-institutional study designs in research programs and funding opportunities. To supplement clinical trials, we must also maximize evidence generation from registries and real-world data, such as electronic heath records, pharmacy claims, and mobile technologies. Real-world data can be used in retrospective studies, for example by providing data for historical controls in the assessment of interventions used in small patient populations.7 These data can also support prospective, pragmatic randomized trials, where studies are embedded in routine clinical practice and longitudinal outcomes data are collected from electronic health records. Such studies hold tremendous promise in reducing costs and barriers to recruiting pediatric patients, enabling inclusion of diverse patient populations, and generating efficient and generalizable clinical evidence across pediatric healthcare settings.8The dissemination of trial results points to an additional area of consideration for maximizing the impact of pediatric clinical trials: data sharing and reuse. In clinical research, data sharing allows external investigators to augment and build on prior work by performing secondary analyses, meta-analyses of individual patient data, and method development. Since 2018, the International Committee of Medical Journal Editors (ICMJE) has required that a statement on plans for data sharing be included in publications of clinical trials, though the policy stopped short of making data sharing mandatory.9 The implementation of the current policy has been inconsistent, and it is estimated that less than a third of ICMJE-affiliated journals have adopted a data sharing policy.10 Beyond a commitment to share data, actual reuse of data requires additional resources and technical infrastructure, which may contribute to the low rates of data reuse seen in practice. Guiding principles have been established to facilitate sharing and effective data reuse, calling for all data to be FAIR: Findable, Accessible, Interoperable, and Reusable.11 Implementation of such a framework across pediatric clinical trials will require not only greater data transparency and incentivization in our research community, but also consistent use of standard pediatric terminologies and pediatric-specific data ontologies.To act on the findings reported by Brewster et al, we must build consensus across the pediatric clinical trial enterprise on key features and trial outcomes deemed essential to maximizing resources and advancing pediatric clinical care. These could include measures of trial discontinuation, results reporting, and data sharing and reuse. Using a standard set of metrics, a data-driven approach could be applied to monitoring activities and directing modification and strengthening of research infrastructures, governing policies, and investment strategies. Formalizing ongoing evaluation would provide the needed tools to efficiently advance pediatric clinical trial infrastructures and maximize benefits to child health.