Positive and negative AIT trials: What makes the difference?
Abstract: Background Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical trials may unexpectedly fail. The purpose of this review is to discuss the possible factors that may contribute to a successful or unsuccessful study. Methods Descriptive review exploring the possible causes of negative outcomes in allergen immunotherapy trials. Results A series of factors may lead to negative results. Among of these a… Show more
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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.
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.
Background Repurposing is a drug development strategy receiving heightened attention after the Food and Drug Administration granted emergency use authorization of several repurposed drugs to treat Covid-19. There remain knowledge gaps on the root causes, facilitators and barriers for repurposing. Method This systematic review used controlled vocabulary and free text terms 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 for the characteristics, reasons and example of companies deprioritizing development of promising drugs and barriers, facilitators and examples of successful re-purposing. Results We identified 11,814 articles, screened 5,976 for relevance, found 437 eligible for full text review, 115 of which were included in full analysis. Most articles (66%, 76/115) discussed why promising drugs are abandoned, with lack of efficacy or superiority to other therapies (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 top reasons. Key barriers to repurposing include inadequate resources (n = 42), trial data access and transparency around abandoned compounds (n = 20) and expertise (n = 11). Additional barriers include uncertainty about the value of repurposing (n = 13), liability risks (n = 5) and intellectual property (IP) challenges (n = 26). Facilitators include the ability to form multi-partner collaborations (n = 38), access to compound databases and database screening tools (n = 32), regulatory modifications (n = 5) and tax incentives (n = 2). Conclusion Promising drugs are commonly shelved due to insufficient efficacy or superiority to alternate therapies, poor market prospects, and industry consolidation. Inadequate resources and data access and challenges negotiating IP are key barriers to repurposing reaching its full potential as a core approach in drug development. Multi-partner collaborations and the availability and use of compound databases and tax incentives are key facilitators for repurposing. More research is needed on the current value of repurposing in drug development and how to better facilitate resources to support it, where valuable, especially financial, staffing for out-licensing shelved products, and legal expertise to negotiate IP agreements in multi-partner collaborations. Trial registration The protocol was registered on Open Science Framework (https://osf.io/f634k/) as it was not eligible for registration on PROSPERO as the review did not focus on a health-related outcome.
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