Advancing Therapeutic Development for Pulmonary Morbidities Associated with Preterm Birth.

Chronic pulmonary and respiratory conditions associated with preterm birth are incompletely characterized, complicating long-term treatment and development of more effective therapies. Stakeholders face challenges in the development of validated, clinically meaningful endpoints that adequately measure morbidities and predict or represent health outcomes for preterm neonates. We propose in this paper a research agenda, informed by the input of experts from a 2018 workshop we convened on this topic, to advance endpoint and treatment development. We discuss the necessity of further evaluation of existing endpoints and the improved characterization of disease endotypes. We also discuss key steps to the development of optimized short- and long-term endpoints that can be linked to meaningful health outcomes. Finally, we discuss the importance of limiting variability in data collection and the application of new clinical trial endpoints as well as the critical nature of multi-stakeholder collaboration to advancing therapeutic development for this vulnerable patient population.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

NGF reprograms metastatic melanoma to a bipotent glial-melanocyte neural crest-like precursor.

Melanoma pathogenesis from normal neural crest-derived melanocytes is often fatal due to aggressive cell invasion throughout the body. The identification of signals that reprogram de-differentiated, metastatic melanoma cells to a less aggressive and stable phenotype would provide a novel strategy to limit disease progression. In this study, we identify and test the function of developmental signals within the chick embryonic neural crest microenvironment to reprogram and sustain the transition of human metastatic melanoma to a neural crest cell-like phenotype. Results reveal that co-culture of the highly aggressive and metastatic human melanoma cell line C8161 upregulate a marker of melanosome formation (Mart-1) in the presence of embryonic day 3.5 chick trunk dorsal root ganglia. We identify nerve growth factor (NGF) as the signal within this tissue driving Mart-1 re-expression and show that NGF receptors trkA and p75 cooperate to induce Mart-1 re-expression. Furthermore, Mart-1 expressing C8161 cells acquire a gene signature of poorly aggressive C81-61 cells. These data suggest that targeting NGF signaling may yield a novel strategy to reprogram metastatic melanoma toward a benign cell type.

Building a drug development database: challenges in reliable data availability.

CONTEXT: Policy and legislative efforts to improve the biomedical innovation process must rely on a detailed and thorough analysis of drug development and industry output. OBJECTIVE: As part of our efforts to build a publicly-available database on the characteristics of drug development, we present work undertaken to test methods for compiling data from public sources. These initial steps are designed to explore challenges in data extraction, completeness and reliability. Specifically, filing dates for Investigational New Drugs (IND) applications with the U.S. Food and Drug Administration (FDA) were chosen as the initial objective data element to be collected. MATERIALS AND METHODS: FDA's Drugs@FDA database and the Federal Register (FR) were used to collect IND dates for the 587 New Molecular Entities (NMEs) approved between 1994 and 2014. When available, the following data were captured: approval date, IND number, IND date and source of information. RESULTS: At least one IND date was available for 445 (75.8%) of the 587 NMEs. The Drugs@FDA database provided IND dates for 303 (51.6%) NMEs and the FR contributed with 297 (50.6%) IND dates. Out of the 445 NMEs for which an IND date was obtained, 274 (61.6%) had more than one date reported. DISCUSSION: Key finding of this paper is a considerable inconsistency in reliably available or reported data elements, in this particular case, IND application filing dates as assembled from publicly-available sources. CONCLUSION: Our team will continue to focus on finding ways to collect relevant information to measure impact of drug innovation.

Improving pharmaceutical innovation by building a more comprehensive database on drug development and use.

New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation.

CXCR4 controls ventral migration of sympathetic precursor cells.

The molecular mechanisms that sort migrating neural crest cells (NCCs) along a shared pathway into two functionally discrete structures, the dorsal root ganglia and sympathetic ganglia (SGs), are unknown. We report here that this patterning is attributable in part to differential expression of the chemokine receptor, CXCR4. We show that (1) a distinct subset of ventrally migrating NCCs express CXCR4 and this subset is destined to form the neural core of the sympathetic ganglia, and (2) the CXCR4 ligand, SDF-1, is a chemoattractant for NCCs in vivo and is expressed adjacent to the future SGs. Reduction of CXCR4 expression in NCCs disrupts their migration toward the future SGs, whereas overexpression of CXCR4 in non-SG-destined NCCs induces them to migrate aberrantly toward the SGs. These data are the first to demonstrate a major role for chemotaxis in the patterning of NCC migration and demonstrate the neural crest is composed of molecularly heterogeneous cell populations.

Vascular endothelial growth factor (VEGF) regulates cranial neural crest migration in vivo.

The neural crest is an excellent model to study embryonic cell migration, since cell behaviors can be studied in vivo with advanced optical imaging and molecular intervention. What is unclear is how molecular signals direct neural crest cell (NCC) migration through multiple microenvironments and into specific targets. Here, we tested the hypothesis that the invasion of cranial NCCs, specifically the rhombomere 4 (r4) migratory stream into branchial arch 2 (ba2), is due to chemoattraction through neuropilin-1-vascular endothelial growth factor (VEGF) interactions. We found that the spatio-temporal expression pattern of VEGF in the ectoderm correlated with the NCC migratory front. RT-PCR analysis of the r4 migratory stream showed that ba2 tissue expressed VEGF and r4 NCCs expressed VEGF receptor 2. When soluble VEGF receptor 1 (sVEGFR1) was injected distal to the r4 migratory front, to bind up endogenous VEGF, NCCs failed to completely invade ba2. Time-lapse imaging revealed that cranial NCCs were attracted to ba2 tissue or VEGF sources in vitro. VEGF-soaked beads or VEGF-expressing cells placed adjacent to the r4 migratory stream caused NCCs to divert from stereotypical pathways and move towards an ectopic VEGF source. Our results suggest a model in which NCC entry and invasion of ba2 is dependent on chemoattractive signaling through neuropilin-1-VEGF interactions.