Success rates doubled for cancer drugs that entered clinical trials in the early 1990s and those that entered the clinic a decade later, even as the number of such compounds increased by 50 percent over the period, according to a new analysis by the Tufts Center for the Study of Drug Development (CSDD).

Clinical success rates – the percentage of investigational compounds that eventually obtain FDA approval – for cancer therapeutics rose from 9.9 percent for drugs that entered the clinic in the mid-1990s to 19.8 percent for those that entered human studies in the early 2000s, with an overall success rate of 13 percent across the study period.

"While drug development remains highly complex, drug companies are making headway in improving the development process," said Joseph A. DiMasi, director of economic analysis at Tufts CSDD, who served as principal investigator of the study.

DiMasi cited a variety of factors, including a focus on targets with validated pathways, the design of novel drug formats and improved trial design.

"Both industry and the FDA have learned more, over the years, about targeted therapies, and that has facilitated development and review," DiMasi told BioWorld Today.

Over the past 20 years, scientists also have gained greater understanding about the disease process, he added.

"I would expect these findings to carry forward," he said, noting that progress in cancer drug development is accelerating, with 10 FDA approvals of cancer drugs in 2012 and four related approvals in cancer diagnostics and in the treatment of precancerous indications and conditions related to cancer. The FDA approved eight cancer compounds in 2011 , DiMasi added.

Improved clinical success rates were due, in part, to the share of investigational drug pipelines devoted to cancer during the study period. The number of cancer compounds entering clinical studies increased from 250 between 1993 and 1998 to 375 between 1999 and 2004, according to the Tufts CSDD study. The number of new biologics entering clinical studies grew by 59 percent between the first and second six-year periods in the study, compared to 47 percent for small-molecule drugs during the same periods. However, small molecules dominated as a percentage of cancer drugs entering clinical trials, representing 73 percent of compounds during 1993 to 1998 and 71 percent in 1999 to 2004.

Small-molecule drugs also had a higher overall success rate, at 14.3 percent, than biologics, at 11 .5 percent, over the 12-year study period – a finding mirrored in other drug categories, DiMasi said.

The findings were based on data obtained from Tufts CSDD industry surveys, commercial pipeline databases, clinicaltrials.gov, FDA websites and published company pipeline information. Cancer compounds included those where clinical studies were sponsored, at least in part, by commercial firms, focusing on therapeutics directed primarily against cancerous cells or functioning secondarily to affect cancerous cells.

Carlo Toniatti, head of research at the Institute for Applied Cancer Science and the Center for Co-Clinical Trials at the University of Texas MD Anderson Cancer Center, was "not entirely surprised" by the findings, adding that he expects clinical success rates for cancer drugs to continue to improve as targeted therapies multiply in the cancer development pipeline.

"If you look just at targeted therapies and compare them with classical chemotherapeutics, you can see clearly that they have a higher approval rate," Toniatti told BioWorld Today. "These success rates can only get better."

Early Trial Design Key to Success

Investigational compounds studied only in solid tumor indications constituted nearly three-quarters of molecules initiated during the study period, while one in five investigational molecules were studied in both solid tumor and hematological indications. However, drugs focused solely on hematologic tumors had a 36 percent success rate over the study period, compared to just 10 percent for drugs focused only on solid tumors. The approval success rate also was higher for the hematological group, at 32 percent, compared to 6 percent for solid tumors.

The difference is due, in part, to the success of certain pharmacologic classes, such as kinase inhibitors, in hematologic targets, DiMasi pointed out. But solid tumors also represent a vastly more complicated set of challenges with many more potential mutations, Toniatti added.

The transition from Phase II to Phase III in cancer drugs was lower than for drugs in development across other therapeutic categories, according to DiMasi, based on a previous CSDD analysis. However, cancer drugs that filed for regulatory approval mostly succeeded, with 92 percent that submitted a new drug application or biologics license application gaining the FDA's endorsement. The willingness of biotechs and pharmas to halt programs that did not meet early development goals likely improved success rates of late-stage candidates.

"Termination of less promising candidates early on helps improve later transition rates," DiMasi said.

For drug developers, the findings validate the economic premise that early failure – and the willingness to yank a suboptimal candidate – enables companies to steer resources into more promising compounds.

"The economics dictate that it's prudent to be as objective as possible as early on as possible," DiMasi said.

Long term, the key to sustained improvement in clinical success rates is to strengthen trial design, especially in Phase I studies, said Toniatti, noting that cancer trials, increasingly, are structured to seek signs of early efficacy in Phase I.

"You need to do very good Phase I and Phase II trials," he said, recommending greater collaboration among biotechs, pharmas and academic institutions in initial trial design. "If you raise the bar in the clinic, the number of Phase III trials that fail will dramatically decrease."