New research published by Shen et al in JNCCN—Journal of the National Comprehensive Cancer Network has found that more than 80% of therapies tested in phase III oncology trials did not achieve meaningful clinical benefit in prolonging survival.
The researchers analyzed 362 industry-sponsored phase III randomized trials from 2008 to 2017 and found that 87% were either false-positive or true-negative for meeting overall survival goals. More than half of the initially reported positive trials were found to be false-positive (58.4%) for overall survival, while the majority of negative results were determined to be true-negative (with only 0.9% false-negative).
“Our study highlights the need to more efficiently identify which new therapies merit phase III testing,” said lead researcher Changyu Shen, PhD, Associate Professor at Harvard Medical School at the time this study was conducted. “In order to sustain the rate of innovation in cancer therapeutics and ensure that our patients have access to effective yet affordable therapies, the clinical trial pipeline in oncology must be efficient and accurate. Our work shows that in the past 10, years, this has not been the case.”
Dr. Shen continued, “Our study shows that reducing false-positive errors by imposing [a] more stringent statistical threshold in phase III trials is not likely to be practically feasible. A better strategy is to rethink the process that leads to the decision of moving a new therapy to phase III testing to begin with. More research is needed in this regard.”
Most of the trials in this novel study focused on treatments for lung, breast, gastrointestinal, and hematologic cancers; trials with fewer than 100 participants were excluded, meaning rare cancer types were less likely to be included. The phase III trials were predominantly two-arm studies of an interventional regimen compared with a control treatment.
“This paper shows that a lot of drugs with ‘positive’ phase III trials may have a smaller ultimate benefit than was expected, and that changing the threshold for statistical significance is not a quick fix,” said Elizabeth A. Handorf, PhD, Associate Research Professor at Fox Chase Cancer Center, who was not involved in this research. “I think it highlights the need for more efficient study designs, like adaptive trials, and clear definitions of what makes an effect clinically meaningful.”
The study authors concluded, “Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.”
Disclosure: For full disclosures of the study authors, visit jnccn.org.
