Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data.

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Development and Implementation of the Military Treatment Facility Engagement Committee (MTFEC) to Support Pragmatic Clinical Trials in the Military Health System.

INTRODUCTION: Within the population of military service members and veterans, chronic pain is highly prevalent, often complex, and frequently related to traumatic experiences that are more likely to occur to members of this demographic, such as individuals with traumatic brain injury or limb loss. In September 2017, the National Institutes of Health (NIH), Department of Defense (DOD), and Department of Veterans Affairs (VA) Pain Management Collaboratory (PMC) was formed as a significant and innovative inter-government agency partnership to support a multicomponent research initiative focusing on nonpharmacological approaches for pain management addressing the needs of service members, their dependents, and veterans. METHODS: A Pain Management Collaboratory Coordinating Center (PMC3) was also established to facilitate collective learning across 11 individually funded pragmatic clinical trials (PCTs) designed to optimize the impact of the PMC as an integrated whole. Although the DOD and VA health care systems are ideal sites for the enactment of PCTs, executing these trials within the local context of DOD military treatment facilities (MTFs) can present unique challenges. The Military Treatment Facility Engagement Committee (MTFEC) was created to support the efforts of the PMC3 in its role as a national resource for development and refinement of innovative tools, best practices, and other resources in the conduct of high impact PCTs. RESULTS: The MTFEC is composed of experts from each service who bring experiences in executing clinical pain management trials that can enhance the planning and execution of the PCTs. It provides expertise and leadership in the execution of research studies at within MTFs and within the DOD health care system, with guidance from PMC3 Directors and in collaboration with NIH, DOD, and VA program and scientific officers. DISCUSSION/CONCLUSION: Considering the importance of enacting large-scale, pragmatic studies to implement effective strategies in clinical practice for chronic pain management, the MTFEC has begun to actualize its purpose by identifying potential barriers and challenges to study implementation and exploring how the PMC can support and aid in the execution of PCTs by applying similar approaches to stakeholder and subject matter engagement for their research.

Strategy for addressing research-site overlap in pragmatic clinical trials: lessons learned from the NIH-DOD-VA Pain Management Collaboratory (PMC).

BACKGROUND: The Pain Management Collaboratory (PMC) is a multi-site network of pragmatic clinical trials (PCTs) focused on nonpharmacological approaches to pain management, conducted in health care systems of the US Department of Defense (DoD) and Department of Veterans Affairs (VA) and co-funded by the National Institutes of Health (NIH). Concerns about potential research-site overlap prompted the PMC investigator community to consider strategies to avert this problem that could negatively affect recruitment and contaminate interventions and thus pose a threat to trial integrity. METHODS: We developed a two-step strategy to identify and remediate research-site overlap by obtaining detailed recruitment plans across all PMC PCTs that addressed eligibility criteria, recruitment methods, trial settings, and timeframes. The first, information-gathering phase consisted of a 2-month period for data collection from PIs, stakeholders, and ClinicalTrials.gov . The second, remediation phase consisted of a series of moderated conference calls over a 1-month time period to develop plans to address overlap. Remediation efforts focused on exclusion criteria and recruitment strategies, and they involved collaboration with sponsors and stakeholder groups such as the Military Treatment Facility Engagement Committee (MTFEC). The MTFEC is comprised of collaborating DoD and university-affiliated PIs, clinicians, and educators devoted to facilitating successful pragmatic trials in DoD settings. RESULTS: Of 61 recruitment sites for the 11 PMC PCTs, 17 (28%) overlapped. Four PCTs had five overlapping Military Treatment Facilities (MTFs), and eight PCTs had 12 overlapping VA Medical Centers (VAMCs). We developed three general strategies to avoid research-site overlap: (i) modify exclusion criteria, (ii) coordinate recruitment efforts, and/or (iii) replace or avoid any overlapping sites. Potential overlap from competing studies outside of the PMC was apparent at 26 sites, but we were not able to confirm them as true conflicts. CONCLUSION: Proactive strategies can be used to resolve the issue of overlapping research sites in the PMC. These strategies, combined with open and impartial mediation approaches that include researchers, sponsors, and stakeholders, provide lessons learned from this large and complex pragmatic research effort.