Are Too Many Phase III Cancer Clinical Trials Set Up to Fail?

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New research in JNCCN finds four out of five cancer therapies tested in Phase III trials do not achieve clinically-meaningful benefit in prolonging survival, and is the first study to quantify the number of false-positive, false-negative, and true-negative trial results.

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National Comprehensive Cancer Network

Sep 23, 2021, 09:17 ET

PLYMOUTH MEETING, Pa., Sept. 23, 2021 /PRNewswire/ -- New research in the September 2021 issue of JNCCN—Journal of the National Comprehensive Cancer Network finds 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 in oncology 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 overwhelming 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 ten years, this has not been the case."

Dr. Shen continued: "Our study shows that reducing false positive errors by imposing 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 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 predominately 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, 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."

To read the entire study, visit JNCCN.org. Complimentary access to "Underperformance of Contemporary Phase III Oncology Trials and Strategies for Improvement" is available until December 10, 2021.

About JNCCN—Journal of the National Comprehensive Cancer Network
More than 25,000 oncologists and other cancer care professionals across the United States read JNCCN—Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about innovation in translational medicine, and scientific studies related to oncology health services research, including quality care and value, bioethics, comparative and cost effectiveness, public policy, and interventional research on supportive care and survivorship. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside. Visit JNCCN.org. To inquire if you are eligible for a FREE subscription to JNCCN, visit NCCN.org/jnccn/subscribe. Follow JNCCN on Twitter @JNCCN.

About the National Comprehensive Cancer Network
The National Comprehensive Cancer Network^® (NCCN^®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients^® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation^®. NCCN also advances continuing education, global initiatives, policy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.