Overall survival (OS) analyses in clinical trials provide not only valuable efficacy data, but also safety data for assessing the risk-benefit profile of a treatment. OS has long been considered the gold standard for oncology clinical trials, but its utility is sometimes limited by the length of time needed to measure it. With the advances in oncology treatments made in recent years, the time needed to measure OS has increased. Therefore, early endpoints such as progression-free survival (PFS) are increasingly used for novel agents to expedite their approval, although PFS results do not always align with OS. In some cases, treatment has even led to worse OS despite promising PFS results. Additionally, certain considerations may affect interpretation of OS, such as unequal randomization, crossover between trial arms, subsequent lines of therapy, subgroup considerations, and adverse effects.
A workshop with drug development stakeholders was held in July 2023 to discuss and address the challenges of OS evaluations and was summarized a year later in an article in Clinical Cancer Research, which is published by the American Association for Cancer Research (AACR). The article was coauthored by researchers, clinicians, statisticians, industry representatives, patient advocates, and experts from the AACR, the American Statistical Association, and the US Food and Drug Administration (FDA). Below are some highlights from the article
- Trials with registrational intent should be designed to collect and assess OS to inform patient safety, regardless of its role in evaluating efficacy
- A measure of harm including OS and other safety endpoints should be prespecified to rule out specific safety concerns when OS is not the primary efficacy endpoint
- Although crossover elements and unequal randomization could complicate analysis of OS, they may be appropriate in some situations
- Plans for adequate follow-up time should be informed by factors such as disease setting, patient population, and expected survival time
- Independent data monitoring committees should have access to OS data for futility and safety analyses
High level
In addition to the above recommendations for OS analyses in clinical trials, robust assessments of OS as a safety measure are critical to reinforce the FDA’s use of earlier endpoints to support drug approvals. Continued cross-disciplinary collaborations such as this one will ultimately improve the quality of cancer research and lead to better patient care.
Ground level
Prespecified OS analyses in clinical trials as a safety endpoint provide valuable information on a treatment’s benefit-risk profile. When reviewing clinical trial data, clinicians should look for studies with an OS endpoint to support individualized treatment decisions.
