Why promising drugs are shelved and barriers and facilitators to re-purposing them: A systematic literature review

Background: Despite enthusiasm on the role of repurposing in drug development, enhanced by the Covid-19 pandemic with the FDA granting emergency use authorization of several repurposed drugs to treat Covid-19, there remain knowledge gaps on why pharmaceutical companies abandon the development of promising drug candidates as well as facilitators and barriers to moving them back into development, a process often referred to as drug repurposing. Method: This systematic literature review used a combination of controlled vocabulary and free text terms related to the de-prioritization, shelving, abandonment and repurposing of promising experimental drugs unapproved by the FDA for any indication, to search ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases. The main outcomes of interest were the characteristics and reasons for the phenomenon of companies deprioritizing or abandoning development of promising drugs, facilitators and successful examples of advancing development of promising abandoned or deprioritized drugs (often referred to as drug repositioning or re-purposing), and barriers to advancing development of promising abandoned or de-prioritized drugs. Study inclusion was not limited by publication date or type. Data extracted included article type, article title, journal title, first author, publication date, extraction and analysis of terminology used to describe abandoned investigational drugs and moving them back into research and development, reason(s) and methods for drug de-prioritization or abandonment, conditions treated, examples of deprioritized or repurposed drugs, as well as barriers and facilitators to drug repurposing. Risk of bias was not performed due to the varying study designs included in this study. Instead, Oxford Centre for Evidence-Based Medicine: Levels of Evidence was used to grade the level of evidence included in this study. Results: We identified 11,814 articles, screening 5,976 for relevance, finding 437 eligible for full text review, 115 of which were included in full analysis. Most articles (66%, 76/115) provided reasons for why drug development may be abandoned, with lack of efficacy, or superiority to other therapies, for the studied indication (n=59), strategic business reasons (n=35), safety problems (n=28), research design decisions (n=12), the complex nature of a studied disease or drug (n=7) and regulatory bodies requiring more information (n=2) among the top. Inadequate resources (n=42) including expertise (n=11), intellectual property challenges (n=26), poor data access (n=20), and uncertainty about the value of repurposing (n=13) along with liability risks (n=5) are key barriers to repurposing. The most common facilitators of drug repurposing were multi-partner collaborations (n=38), access to comprehensive compound databases and corresponding screening tools (n=32), regulatory modifications (n=5) and tax incentives (n=2). Conclusion: More research is needed on the current value of repurposing in drug development, as there remain uncertainties, as well as on how to better facilitate access to resources to support it, where valuable. Financial barriers, insufficient staffing focused on out-licensing shelved products, and challenges negotiating IP agreements in multi-partner collaborations were discussed as barriers to repurposing without clear solutions, suggesting more research is needed in this area. Registration: The protocol was registered on Open Science Framework (https://osf.io/f634k/) as it was not eligible for registration on PROSPERO.