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Can Clinical Trial Changes Increase Drug Approvals



By Allison Proffitt  
 
January 13, 2014 | An article published last week in Nature Biotechnology* summarized the state of drug approvals from 2003 to 2012, and it’s not terribly encouraging. 
 
The research, funded by Sagient Research Systems and the Biotechnology Industry Organization (BIO), looked at likelihood of approval rates for drugs from 835 drug developers including big pharma, small biotechs, and specialty companies. The authors analyzed success rates for over 7,300 independent drug paths. If one drug was developed for two indications, they considered them both, but did highlight lead indications.
 
They found the likelihood of approval (LOA) from Phase 1 to be about 10% for all indications, and 15% for lead indications. From Phase 1 to Phase 2 success rates are about 65%; from Phase 3 to new drug applications success rates fall again between 60% and 68%. The biggest drop off comes moving from Phase 2 to Phase 3, with only 32% of all indications advancing. 
 
The numbers are somewhat less encouraging than previous studies. DiMasi et al. and Kola et al. found higher LOA rates from Phase 1 (19% over 50 years and 11% over 10 years respectively), but both studies looked at far fewer companies, and the current study purposefully considered the success of all indications, rather than just a lead indication. 
 
But for an industry pumping $5 billion into each approved drug, and with clinical trial costs climbing, why are we seeing just one in ten programs result in a new drug? And how sustainable is that trajectory?
 
The study authors acknowledge the large number of small biotech companies represented in the data and a more recent time frame (2003–2011) as two reasons for what seems to be a gradual slowdown. 
 
“Small biotech companies tend to develop riskier, less validated drug classes and targets, and are more likely to have less experienced development teams and fewer resources than large pharmaceutical corporations,” they posit. 
 
But possibly the bigger reasons are higher regulatory hurdles for new drugs, and challenges around designing clinical trials. In the wake of the 2004 Vioxx recall, the FDA cracked down on safety. Drug standards, they argue, are higher. 
 
“The past nine-year period has been a time of increased clinical trial cost and complexity for all drug development sponsors, and this likely contributes to the lower success rates than previous periods,” they write. “An increasing number of diseases have higher scientific and regulatory hurdles as the standard of care has improved over the past decade. More clinical studies are comparative in nature and published data show clinical trials are more complex today than in previous decades.”
 
A point of particular concern for authors was Phase 3 success rates. On the whole, drugs advanced out of Phase 3 60%-68% of the time. For oncology and cardiology, that number was only around 50%. 
 
“Such low phase 3 success rates for these diseases are concerning as 35% of all R&D spending is now spent on phase 3 development, and phase 3 trials account for 60% of all clinical trial costs,” the authors said. 
 
They believe that changing trial design—especially communication with regulators at the end of Phase 2— could help improve rates. The authors point out that heterogeneous trials are far more likely to fail than trials built on specific biomarkers. 
“The adoption of adaptive trial design may facilitate the identification of targeted subsets of patient populations before study completion,” they suggest. “Greater flexibility with alternative surrogate endpoints,… and improved methodologies for assessing patient benefit-to-risk are some areas where improvements can be made.” 
 
*Michael Hay, David W Thomas, John L Craighead, Celia Economides, and Jesse Rosenthal. (2014). Clinical development success rates for investigational drugs. Nature Biotechnology. doi:10.1038/nbt.2786
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