Tanja Obradovic: Assessment of Cancer Drug Effect on OS

Tanja Obradovic, Oncology Medical Strategy Advisor at Mercurial AI, shared on LinkedIn:

“Assessment of cancer drug effect on overall survival – strategy implications of the latest guidance from FDA

We continue to witness lack of data readiness to describe novel cancer drug effect upon overall survival (OS) of patients in submitted dossiers or planned programs of trials supporting initial study filing. The US Food and Drug Administration (FDA) is bringing clarity by just issuing yesterday on August 18th Draft Guidance on ‘Approaches to Assessment of Overall Survival in Oncology Clinical Trials’

OS is reflective of both efficacy and safety of the new cancer treatment and FDA is especially emphasizing that aspect as new therapy can positively affect OS while toxicity can also negatively affect OS and therefore it is a critical end point that “should be prioritized as the primary endpoint when feasible”.

FDA specifically described that ‘It is most appropriate for consideration in randomized trials of oncologic diseases with a short natural history (e.g., metastatic pancreatic cancer), late-line disease settings, or in disease settings where there are other therapeutics known to prolong overall survival and it is important to demonstrate retention or improvement of this survival advantage.’

Point on explorations of novel treatments building upon already existing beneficial backbone is critical especially in light of several very recent issues on combinations of standard of care drug with novel drug where contribution of the novel drug addition could not be established due to insufficient strategic approach either in leading study or in the follow-up trials.

Another very important aspect of the just issued Draft Guidance is comments from FDA on situations when OS determination is not feasible such as cases where the drug can be highly efficacious with very long survival times or not appropriate as primary objective based on trial design such as in single-arm trials because time-to-event endpoints are generally challenging to interpret without a randomized control arm.

Guidance lists approaches such that ‘when OS is not the primary endpoint and other endpoints such as response rate, progression-free survival, or event-free survival are the primary endpoint in an oncology randomized trial, FDA recommends collection and submission of OS data,’ and ‘in some situations, overall survival may be a secondary endpoint included in a pre-specified hypothesis testing plan to permit a formal statistical test for an efficacy evaluation, which includes control of the overall study-wise Type I error rate.’

FDA also provided clarifications on statistical analysis considerations when designing trials and approach to data including importance of the statistical analysis in the trial protocol and the statistical analysis plan (SAP). Several aspects of the design are highlighted such as inclusion of OS interim analysis for futility or harm and approach to allowing cross-over on arms.

Considering criticality of demonstrating OS benefit of the new therapy option that is expected by patients, providers and coverage bodies this new FDA Guidance is truly useful resource for Pharma and Biotech community. Community can comment on the draft guidance on www.regulations.gov under docket no. FDA-2024-D-5850 by 20th of October.”

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