Systematic Living Evidence for Clinical Trials (SyLECT): a data-driven framework for drug selection in clinical trials in motor neuron disease

Abstract Despite many promising preclinical studies and decades of clinical trials, there remains a paucity of effective disease-modifying drugs in motor neuron disease. We aimed to develop a systematic and structured data-driven framework to identify, evaluate and prioritise candidate drugs for clinical trials, specifically for the Motor Neuron Disease-Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART; NCT040302870). We developed the Systematic Living Evidence for Clinical Trials (SyLECT) platform as a modular framework integrating emerging data from different domains to inform prioritisation of candidate drugs. Current domains incorporated include published clinical, animal in vivo, and in vitro literature; in house in vitro high throughput drug screening; pathway and network analysis; and pharmacological, feasibility and clinical trial data from drug, chemical, and clinical trial databases. In this approach, we first identify a list of candidate drugs from these domains then select drugs for further consideration based on drug properties, feasibility, and expert opinion. For prioritised drugs we then generate, evaluate, and synthesise further evidence from across data domains. Using automated workflows and interactive web applications, we produce snapshot “living evidence summaries” to inform expert panel decisions on prioritisation of candidate drugs for MND-SMART. The third drug selected for MND-SMART and the first using this framework is amantadine. We demonstrated the feasibility of a systematic data-driven framework to inform prioritisation of candidate drugs for clinical trials in motor neuron disease, with potential for wider application across diseases where there is unmet clinical need. What is already known on this topic - Despite extensive preclinical research and clinical trials for disease-modifying treatments in motor neuron disease, translational success remains elusive. - Advances in research across biological domains presents a wealth of data to guide prioritisation of candidate drugs for clinical trials. What this study adds - This study demonstrates the feasibility of using a systematic, modular, data-driven framework to inform prioritisation of candidate drugs for an adaptive platform trial in motor neuron disease. How this study might affect research, practice or policy - The framework could be applied to inform prioritisation of drugs for clinical trials in other diseases, especially adaptive platform trials in neurodegenerative diseases. Competing Interest Statement In the last 3 years, J. Chataway has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche. Clinical Protocols Funding Statement MND-SMART is funded by grants from MND Scotland, My Name'5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. SC receives funding from UK Research and Innovation (Medical Research Council) (DRI-CORE-2017-EDI). The study funders have no role in study design, data collection, data analysis, data interpretation or writing of publications. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵^ Membership of the ReLiSyR-MND consortium is provided in the Acknowledgements Data Availability Data from systematic review components of the present study are available upon reasonable request to the authors. Data and methods for drug screening will be published separately.