Critical Path Institute (C-Path) is a non-profit organization created to improve the drug development process; its consortia include more than 1,600 scientists from government regulatory and research agencies, academia, patient organizations, and bio-pharmaceutical companies.
The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren’t sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated.
Introduction:To support the development of the National Trauma Research Repository (NTRR), a multidisciplinary workgroup used a consensus-driven approach to review established epidemiologic data elements and recommend basic common data elements (CDEs) for inclusion in the NTRR data dictionary. Methods:A 10-member workgroup of military and civilian trauma researchers and data scientists located and reviewed databases, codebooks, data collection forms, and published articles for data elements relevant to trauma epidemiology. Identified data elements were reviewed in a three-round Delphi survey, and monthly meetings with the workgroup were conducted. Consensus during the Delphi survey was analyzed with an 80% agreement threshold. Results:13 sources were reviewed for epidemiology data elements. After the three survey rounds and workgroup discussions, 33 elements (80%) reached consensus for inclusion, 3 elements (7%) were excluded, and 5 elements (12%) did not reach consensus. Discussion:The Delphi process proved effective in achieving expert consensus on basic CDEs for trauma epidemiologic research. The resulting standardized basic CDEs will improve data harmonization and support consistent data collection in the NTRR. These CDEs represent an initial framework and serve as a foundational starting point for epidemiological data collection within the NTRR. As researchers use the NTRR, the list of CDEs will grow and evolve with the needs of the trauma research community. CDE standardization not only supports interoperable research but also enhances research quality, efficiency, and translation into clinical practice. Level of Evidence:Level VII.
Transformation in the neurosciences in biomarkers is enabling novel therapeutic strategies targeting earlier stages of disease prior to onset of clinical symptoms. Emerging progress in the area of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have significant implications for clinical trials. Misfolded α-synuclein aggregates (syn-seeds) propagate by templated misfolding of native α-synuclein, driving disease spread. The advent of the α-synuclein seed amplification assay (syn SAA) now enables highly sensitive and specific detection of syn-seeds in cerebrospinal fluid (CSF), allowing in vivo identification of underlying α-synuclein pathology, including in individuals prior to the onset of motor symptoms. To support regulatory alignment, the Critical Path Institute's Critical Path for Parkinson's (CPP) consortium compiled and evaluated the totality of scientific evidence in the area of syn SAA as an in vivo measure of misfolded alpha synuclein in CSF and submitted it to the U.S. Food and Drug Administration (FDA) in a request for a Biomarker Letter of Support (LoS). Within three months of submission, the FDA issued a LoS endorsing CSF syn SAA as a susceptibility and risk biomarker for use in clinical trials targeting α-synuclein–related neurodegenerative diseases, enabling enrichment of participants with underlying pathology and reducing trial risk. These data have enabled the development of biological classification frameworks for synucleinopathies that define disease based on molecular pathology rather than clinical symptoms alone. This review summarizes the regulatory-grade evidence supporting syn SAA and discusses its implications for biologically driven clinical trial design and early-intervention strategies.
Transparent reporting of how patient-reported outcomes (PROs) are collected is essential to ensure reproducible and interpretable data. Different modes of assessment may affect data quality and feasibility, yet their use in cancer trials is poorly described. Electronic PRO (ePRO) assessment may improve data quality and enable active review, but it is unclear how often different modes of assessment like ePRO assessment are used and in which trials. We systematically searched PubMed for randomized controlled trials (published 2019–2023) that used cancer-specific PRO measures in patients with the six most common solid cancers. Trial characteristics, PRO reporting practices, and evidence of active review of PRO data were summarized descriptively. Univariate logistic regression was used to examine predictors of (1) reporting the mode of PRO assessment and (2) use of ePROs exclusively. Of 9331 references screened, 296 trials were included in the analysis. 135 (45.6
ABSTRACT Evaluating the benefit–risk profile of a medical product requires comprehensive evidence that integrates information across development stages. Technological advances and broader use of real‐world data are enabling innovative quantitative paradigms characterized by greater efficiency, patient centricity, and sustainability. Despite regulatory recognition of model‐informed drug development, disease progression modeling (DPM) remains underutilized compared with more established pharmacokinetic/pharmacodynamic modeling and simulation approaches. To inform adoption decisions by clinical, regulatory, and portfolio leaders, the Clinical Trials Transformation Initiative (CTTI) developed evidence‐based, cross‐sector recommendations that describe when and how to use DPM in medical product development and how to effectively communicate its impactful implementation across functions. In this article, we (i) define DPM and summarize its unique value in clinical development, (ii) describe CTTI's collaborative process to generate a set of nine DPM recommendations and a practical considerations framework, and (iii) present examples of strategic development questions showing how DPM can answer high‐value questions about indication, population, endpoints, and dose selection. By providing a shared vocabulary and structured questions for decision makers and modelers, these recommendations may lower barriers to DPM implementation, support fit‐for‐purpose use of existing and new models, and enable more efficient, patient‐focused, and sustainable clinical development.
