Experts from the American Association for Cancer Research (AACR), American Statistical Association (ASA), and U.S. Food and Drug Administration (FDA) have outlined considerations for clinical trial designs to enhance the collection and analysis of overall survival data in the context of modern-day treatments. Their work was published by Rodriguez et al in Clinical Cancer Research.
Background
Overall survival—measuring how long a patient survives following treatment—is an important metric of a drug’s safety and efficacy and has long been considered the gold standard for oncology clinical trials.
“Although overall survival has been a good endpoint in the past for new drug approval, its utility has become difficult in recent decades,” explained senior study author Kenneth C. Anderson, MD, FAACR, Co-Chair of the FDA-AACR-ASA Workshop on Overall Survival in Oncology Clinical Trials. “It quite simply takes too long to measure now due to the remarkable progress we’ve made in the treatment of many cancers,” he added.
While early endpoints, such as progression-free survival, can offer early insight into a drug’s efficacy, these measures do not always align with overall survival. In some instances, the study treatment led to worse overall survival, despite promising progression-free survival results.
“There are examples where patients who received the study treatment had longer progression-free survival than patients in the control arm, but subsequent overall survival in larger trials was not any different between the arms,” Dr. Anderson revealed. “The questions surrounding overall survival measures must be addressed in order to continue with new drug development and approvals at such a rapid pace,” he emphasized.
Study Methods and Results
The study—involving a team of researchers; clinicians; statisticians; industry representatives; patient advocates; and experts from the AACR, ASA, and FDA—built on discussions from the FDA-AACR-ASA Workshop on Overall Survival in Oncology Clinical Trials in July 2023. The workshop convened stakeholders in drug development to explore how to overcome hurdles associated with traditional analyses of overall survival.
Attendees of the July 2023 workshop discussed how unequal randomization, crossover from one trial arm to another, subsequent lines of therapy, subgroup considerations, and adverse effects might impact the interpretation of overall survival.
The recent study consolidated discussions from workshop attendees and session working groups to provide:
- Best practices in clinical trial design and planning, including considerations for when overall survival should be a primary efficacy endpoint
- A recommendation that all trials with registrational intent should be designed to collect and assess overall survival to inform patient safety, regardless of its role in evaluating efficacy
- A recommendation to prespecify a measure of harm including overall survival and other safety endpoints to rule out specific safety concerns when overall survival is not the primary efficacy endpoint
- Acknowledgement that trials with crossover elements could complicate the analysis of overall survival but, in certain cases, may be appropriate
- Acknowledgement that unequal randomization may reduce the statistical power of overall survival analyses but may be used in certain situations
- The importance of planning adequate follow-up time informed by disease setting, patient population, and expected survival time—among other factors
- A recommendation that independent Data Monitoring Committees have access to overall survival data for futility and safety analyses
- Considerations for prespecified analyses of overall survival, post hoc analyses of overall survival, and subgroup planning and analyses
- Considerations and regulatory implications for incorporating early or limited overall survival results into benefit-risk assessments for drug reviews and approvals.
Conclusions
“The focus on [overall survival] is often as an efficacy endpoint in oncology clinical trials, but [overall survival] is also an important safety endpoint. Prespecified statistical analyses of [overall survival] as a safety endpoint provide valuable information on a product’s benefit-risk profile when relying on earlier endpoints such as progression-free survival or overall response rates,” highlighted co–study author Nicole Gormley, MD, Associate Director of Endpoint Development in the Oncology Center of Excellence at the FDA. “Robust assessments of [overall survival]as a safety measure are critical for the FDA’s use of earlier endpoints to support approval,” she continued.
“The significant efforts showcased in the article and throughout the workshop exemplify a successful cross-disciplinary collaboration. These endeavors will ultimately improve the quality of cancer research and lead to better patient care,” underscored co–study author Ruixiao Lu, PhD, FASA, Co-Chair of the FDA-AACR-ASA Workshop on Overall Survival in Oncology Clinical Trials and Chair of the ASA’s Partnership for Clinical Research and Statistics.
“I extend my sincere appreciation to all involved for their dedication to promoting scientific excellence and advancing public health outcomes,” stated Ron Wasserstein, PhD, Executive Director of the ASA. “We look forward to the continued dialogues in driving innovations in the field of oncology and beyond,” he concluded.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
