The Centre for Medicines Research International has noted that the average for the combined success rate at Phase III and submission has fallen to ∼50% in recent years. To learn more about the causes for Phase III and submission failures, Thomson Reuters Life Science Consulting analysed the reasons for these failures between 2007 and 2010. This analysis included failures across all therapeutic areas, initial indications and major new indications. Re-formulations and new claims closely related to already approved indications were excluded from the analysis.
There were 83 Phase III and submission failures between 2007 and 2010. As shown in Fig. 1a, the therapeutic areas in which the largest proportions of these failures occurred were: cancer (28%); nervous system, which includes neurodegeneration (18%); alimentary and/or metabolism, which includes diabetes and obesity (13%); and anti-infectives (13%). Almost 90% of the failures across all therapeutic areas were attributable to either lack of efficacy (66%) or safety issues (21%) (Fig. 1b). The efficacy failures can be further broken down into projects that failed to demonstrate a statistically significant improvement versus placebo (32%), an active control (5%) or as an add-on therapy (29%). Of the drugs that failed to show an improvement in efficacy as an add-on therapy, 58% were anticancer drugs, and of those that failed to show an improvement in efficacy versus placebo, 33% were nervous system drugs.
One conclusion from this analysis is that large numbers of failures are occurring with drugs that have novel mechanisms of action in areas of high unmet medical need: cancer and neurodegeneration, in particular. This could primarily be due to the challenging science in these areas, but is perhaps also a result of the pressure on companies to replenish pipelines with drugs that have high potential for approval and reimbursement, particularly in a period during which patent expiries for major products are threatening future revenues. Owing to this urgency, it seems that companies have progressed drugs into Phase III trials even though they only displayed marginal statistically significant efficacy in Phase II proof-of-concept studies; consequently, these drugs carry a greater than average risk of failure. There also seems to be a propensity to assume that success in one disease will translate into success in a new and significantly different disease. This is particularly apparent in oncology, for which it seems that success in one tumour type has been assumed to translate into success in a variety of other tumour types, without firm evidence that the mechanism of action remains relevant. This can be illustrated by the failures of sunitinib (Sutent; Pfizer) in hepatic cancer and of bevacizumab (Avastin; Genentech/Roche) in gastric cancer.
The way to improve Phase III success rates is to avoid wishful thinking and to rely on high-quality scientific evidence by fully testing mechanisms against each target indication, using well-defined end points in the right patient population in Phase II trials. Initially, this may lead to higher failure rates in Phase II trials, but some companies have already shown that good science can deliver a steady flow of robust positive proof-of-concept data.
The author declares no competing financial interests.
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Arrowsmith, J. Phase III and submission failures: 2007–2010. Nat Rev Drug Discov 10, 87 (2011). https://doi.org/10.1038/nrd3375
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