If numbers tell a story, then the numbers pertaining to Phase II clinical trials offer a sobering tale. A new analysis finds that Phase II success rates fell from 28 percent in 2006 and 2007 to just 18 percent in 2008 and 2009, according to the Centre for Medicines Research, which examined trials undertaken by 16 drugmakers.
The upshot? Phase II success rates are lower than at any other phase of development, although success rates do vary between therapeutic areas and between small molecules and biologics. Nonetheless, the implication is that the overall attrition of late-stage drug development seems to be unsustainably high. The findings appear in Nature Reviews Drug Discovery.
Specifically, the analysis looked at 108 reported Phase II failures from 2008 to 2010 for new drugs and major new indications of existing drugs. Of these, 87 reported the reasons for failure. The breakdown? Well, 51 percent, or 44 of 87, were due to insufficient efficacy; 29 percent, or 25 of 87, were due to strategic reasons and 19 percent, or 17 of 87, were due to clinical or preclinical safety.
Of the 25 failures, 16 involved validated targets, suggesting some failures can be blamed on inadequate differentiation from more advanced drugs in the same class or from drugs with similar indications in another mechanistic class, the journal writes. Of 21 failures for which reasons were not reported, 17 involved validated targets, although not always in an approved indication for drugs affecting that target.
Meanwhile, 68 percent, or 73 of 108 failures fell into four therapeutic areas: alimentary/metabolism, cancer, cardiovascular, and neuroscience. And 61 percent, or 14 of 23 failures in alimentary/metabolism, were for diabetes.
“Strategic failures result from too many companies chasing the same targets or because the drug was a long shot (and) wishful thinking,” study author John Arrowsmith, scientific director at Thomson Reuters, which owns CMR, tells Outsourcing Pharma. "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 a change in the benefit-risk balance of a known target in a new patient population” he added. “The increased losses from Phase II have probably been catalysed by recent M&A activity and the need to manage R&D costs.” The increase in focus on rare disease and patient stratification will open up the opportunity space but as change is driven by the emerging science then the problem will not go away completely...There will also be an increase in consortia and partnering so this should also temper the strategic failures.
pic thx to austinsdkeyscouter on flickr
6 Comments
You state that Phase II success rates are lower than at any other phase of development. Martine PIccart-Gebhart of the Jules Bordet Institute, a Keynote Speaker at the 2009 ASCO Breast Cancer Symposium, made the point that only 8% of new drugs entering Phase I trials ever make it to marketing and that this percentage is even lower for cancer drugs, because current drug testing is inefficient, with many drugs failing late in development, owing in large measure to ineffective drugs, and poor patient selection, like the lack of prognostic and predictive markers for response to therapy. Gebhart noted that little progress had been made in identifying which therapeutic strategies are likely to be effective for individual patients. He concluded that identifying markers that can predict response to a particular drug remains a great challenge.
So much for reliance on biomarkers and proof of concept. At Merck and other companies they used to use a very unsophisticated shotgun type of approach Basically they kept looking for indications that would work, then when they forund one or two they would drill down like a laser beam in Phase III, usually with about a 95% probability of success.
Lack of time, money and marketing pressures are contributing largely to Phase II failure these days. It's a massive paradigm shift. Merck and others would spend at least 2-3 years in Phase II before even considering a candidate for Phase III. Noawadays one year for Phase II is pretty much the norm, ergo the higher failure rate.
I really think that PHRMA should be advertising this. People have no idea what the failure rate is for pharma R&D. By the time something gets to PhaseII, researchers have already invested 4-8 years in the project! After 4-8 years of research, we have an 80% failure rate. THIS is why drugs are so expensive. PHRMA needs to do some public education around this fact.
I'd have to agree with so much for reliance on biomarkers. Ninety percent of biomarkers studies are total crap. And this is so, even if the logistical, study conduct issues are carried out flawlessly. Sloppiness a la Potti/Nevins leads to 100 percent crap. But it's not just Potti/Nevins. The whole concept of using molecular signatures of any kind to do anything beyond the most straightforward of cases is so flawed that everyone should have seen the problems at the beginning. A beautiful biological technology is no different than a beautiful computer technology. It's not worth much without some very good apps, and personalized molecular medicine is still waiting for its first killer app.
Thanks, Greg. In fact I would go further and say that many of the animal models are also worthless. Nevertheless, we keep relying on models such as the "learned helplessness" model, or the electric grid to zap rats' feet as animals of depression, then wonder why so many potential antidepressants fail in the clinic.
Here are some animal models for depression and anxiety. My favorites are forced swimming and intracranial self-stimulation.
http://en.wikipedia.org/wiki/Animal_model_of_depression
A lot of compounds have died in recent years even in phase III due to pharmacoeconomical considerations. As the reimbursment rules have changed a lot, even effective drugs are killed, as the "benefit to the healthcare system" will not warrant a price sufficient to bring in costs.
A new mechanism of action in a therapeutic area with established pharmacotherapeutic option will not warrant "adequate" princing in the future.