Success rates in Phase II clinical trials are lower than at other stage of drug development, and they are getting markedly worse, an analysis by the UK’s Centre for Medicines Research (CMR) has found.

“As the current likelihood of a drug successfully progressing through Phase III to launch is 50%, the overall attrition of late-stage drug development seems to be unsustainably high,” comments John Arrowsmith, scientific director at Thomson Reuters (which acquired the CMR in April 2006) in an article for Nature Reviews Drug Discovery.

The Centre reviewed drug development projects undertaken by 16 companies included in the CMR International Global R&D database and representing around 60% of global R&D spending.

The analysis revealed that Phase II success rates for new development projects had fallen from 28% in 2006–2007 to 18% in 2008–2009, although these rates did vary between therapeutic categories as well as between small molecules and biologics.

2008-2010 failures

To throw some light on these trends, Thomson Reuters Life Science Consulting took a closer look at 108 reported Phase II failures for new drugs and major new indications of existing drugs in the period 2008 to 2010.

Out of this total, reasons for failure were reported for 87 of the projects. Specifically, 51% (44 out of 87) were due to insufficient efficacy, 29% (25) for strategic reasons and 19% (17) for preclinical safety reasons.

Of the 25 projects terminated for strategic reasons, 16 involved validated targets such as peroxisome proliferator activated receptor-_ (PPAR_) or factor Xa, thus “suggesting that some of these failures were due to inadequate differentiation from more advanced drugs in the same class or from drugs with similar indications in another mechanistic class”, Arrowsmith notes.

Of the 21 failures for which no reasons were reported, 17 involved validated targets, “although not always in an approved indication for drugs affecting that target”, Arrowsmith observes.

“Again,” he adds, “it would seem reasonable to conclude that some of these failures were due to insufficient evidence of an efficacy advantage over a more advanced drug; however, it is important not to rule out that failure could be due to the change in the benefit–risk balance of a known target in a new patient population.”

Therapeutic areas

In terms of therapeutic categories, the data for 2008 to 2010 show that 68% (73 out of 108) failures were in four therapeutic areas: alimentary/metabolism (23 failures), cancer (21), neuroscience (17) and cardiovascular (12). Notably, 61% (14 out of 23) of the failures in the alimentary/metabolism category were for diabetes.

“Although it is difficult to draw conclusions from these data, the finding that a substantial proportion of Phase II failures were due to strategic reasons suggests that one important underlying factor could be overlapping R&D activity between companies with drugs in Phase II trials,” Arrowsmith suggests.

“This raises the question of whether an increase in collaborative efforts between companies up to the point of proof-of-concept for novel targets or mechanisms might be more cost-and time-effective.”

Standard of care

Industry commentator Derek Lowe teases out these issues on his In the Pipeline blog for Corante. The “best guess”, he says, is that compounds “seem to have been targeting areas where there was already competition, and they didn’t differentiate themselves enough from the standard of care to be worth continuing”.

The relatively high failure rates in neuroscience and oncology are in keeping with the traditional sharp degree of risk associated with these categories, Lowe suggests, while diabetes is “a tough field – big market, but pretty well-served, making efficacy versus the standard of care a high bar to clear, and this while the FDA’s [US Food and Drug Administration’s] safety requirements have gotten very stiff indeed”.

Cardiovascular disease, though, has traditionally enjoyed one of the better success rates in clinical trials, Lowe notes.

“Perhaps that one is also suffering from the standard of care being pretty good (and often generic, or soon to be),” he comments. “So the high-success-rate mechanisms of the old days are well covered, leaving you to try your luck in the riskier ideas, while still trying to beat some pretty good (and pretty cheap) drugs.”