Monitoring overall survival in pivotal trials in indolent cancers

TL;DR

This paper develops guidelines for monitoring overall survival in clinical trials for indolent cancers, where long survival times make traditional assessment challenging, aiming to improve regulatory decision-making.

Contribution

It introduces tailored OS monitoring guidelines for indolent cancers, inspired by cardiovascular trial methods, with practical examples and case studies.

Findings

Proposed pragmatic OS monitoring approach for indolent cancers

Illustrated guidelines with real case studies

Enhanced support for regulatory decisions on OS risks

Abstract

Indolent cancers are characterized by long overall survival (OS) times. Therefore, powering a clinical trial to provide definitive assessment of the effects of an experimental intervention on OS in a reasonable timeframe is generally infeasible. Instead, the primary outcome in many pivotal trials is an intermediate clinical response such as progression-free survival (PFS). In several recently reported pivotal trials of interventions for indolent cancers that yielded promising results on an intermediate outcome, however, more mature data or post-approval trials showed concerning OS trends. These problematic results have prompted a keen interest in quantitative approaches for monitoring OS that can support regulatory decision-making related to the risk of an unacceptably large detrimental effect on OS. For example, the US Food and Drug Administration, the American Association for Cancer Research, and the American Statistical Association recently organized a one-day multi-stakeholder workshop entitled 'Overall Survival in Oncology Clinical Trials'. In this paper, we propose OS monitoring guidelines tailored for the setting of indolent cancers. Our pragmatic approach is modeled, in part, on the monitoring guidelines the FDA has used in cardiovascular safety trials conducted in Type 2 Diabetes Mellitus. We illustrate proposals through application to several examples informed by actual case studies.