Critical Path Institute Proposal for RFA-FD-20-030 ABSTRACT Historically, FDA has utilized real-world evidence (RWE) as a key component of its efforts to assure post-marketing surveillance and evaluation of medical product safety. The 21st Century Cures Act mandates FDA to develop a framework that expands the use of RWD and RWE to support approvals of a new indications for an already approved drug. By leveraging data generated through the normal practice of medicine, signals of safety and efficacy for new indications can be identified in already approved therapies. However, as most existing RWD was generated without the regulatory standards in mind, significant challenges exist to ensure RWD is fit-for-purpose to generate RWE capable of informing regulatory decisions. Efforts to use existing RWD to answer regulatory questions can identify these challenges and corresponding solutions, but this endeavor requires a significant amount of data and regulatory science expertise to fully optimize the use of RWD to extract actionable RWE. The Critical Path Institute (C-Path) has that data expertise and will execute a pilot project to facilitate the use of RWD to generate RWE in neonates, with learnings being broadly applicable to other therapeutic areas. Each year in the U.S., 10% of neonates are born preterm and there is an urgent need to improve survival and outcome. However, there is minimal new drug development and most existing drugs have insufficient evidence to support safety, efficacy, and dosage in this high-risk population. C-path will leverage its Data Collaboration Center processes and infrastructure to develop an RWD Analytics Platform. RWD will be accessed through collaborations with investigators and data scientists. Specific algorithms and mechanisms will be implemented to extract RWD from relevant sources (aggregated databases and EMRs), curate and standardize data, and enable analyses to generate actionable RWE. When data are analyzed remotely, C-Path will validate processing workflows for quality assurance. Data thus extracted will address two key unmet needs in the neonatal population: 1) current lack of actionable reference values for routine laboratory tests (as a function of gestational/postnatal age) and 2) lack of disease progression model for bronchopulmonary dysplasia. A gaps analysis will identify key lessons specific to neonates relating to the access, quality, extraction, curation, standardization, and analysis of RWD, and potential solutions to optimally generate actionable RWE identified, and shared with key stakeholders in the neonatal community. Lessons learned with this high-risk population can then be generalized to other therapeutic areas.

Critical Path Institute Proposal for RFA-FD-20-030 NARRATIVE The 21st Century Cures Act mandates FDA develop a framework that expands the use of Real-World Data (RWD) and Real-World Evidence (RWE) to support approval of new and existing drugs. This is particularly important for preterm neonates where most drugs are used off-label and there is an urgent unmet need to improve survival and outcome. This project will greatly accelerate neonatal drug development by collecting, extracting, curating, standardizing, and analysing RWD to generate RWE to address major challenges in neonatal drug development.