We examined 119 discontinued projects at Phase3 and a comparison group of 544 projects that led to drug approval in 2011-2015 to identify discontinuation reasons including differences in Phase2 and Phase3 protocols. Though most projects were discontinued due to lack of efficacy, many were discontinued for strategic reasons. The discontinuation reason in each therapeutic area differed and varied over time along with changes in indications. By comparing the E/S ratio (number of failures due to efficacy/due to strategy), we found that failures in Oncology and Cardiovascular area were relatively more often than those in Endocrine/Metabolism and Infection areas due to efficacy. Protocol changes between Phase2 and Phase3 negatively impacted success rates; changes in endpoint exerted the greatest negative impact, followed by evaluation period, target subjects, control, and design. Protocol changes in both endpoint and evaluation period were associated with a high risk of impact on the result. By comparing the D/A ratio (ratio of percentages of discontinued/approved projects), it is also supported protocol changes resulted in negative impacts on success rate. Additionally, protocol changes were found more often with new chemical entities than reformulations. More frequent changes in Oncology projects appeared to be the cause of higher failure rates than those in Infection project. The E/S and D/A metrics would provide insights into why drugs fail during late-stage development and why failure rates are different for different therapeutic areas. Drug developers should guard against late-stage protocol changes and should be particularly careful in setting their strategy in therapeutic areas.
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