FDA Draft Guidance Could Change Designs of Future Oncology Clinical Trials

The FDA recently issued a draft document titled “Approaches to Assessment of Overall Survival in Oncology Clinical Trials: Guidance for Industry,”¹ which recommends modifications to the design of randomized trials in oncology. Although the document contains more advice than I will include in this column, I will highlight 3 important points from the document, as follows:

1. “Overall survival should be prioritized as the primary end point when feasible...[particularly] in randomized trials of oncologic diseases with a short natural history (eg, metastatic pancreatic cancer), late-line disease settings, or in disease settings where there are other therapeutics known to prolong overall survival.”
2. “All randomized oncology clinical trials should be designed to assess overall survival in order to adequately evaluate the potential for harm…. The assessment of overall survival can be [included] as a primary or secondary efficacy end point.”
3. Because crossover can “confound treatment effect estimates…, its use should be limited.”

It is worth considering how these principles might affect future trial design and how changes in trial design could affect the cost of studies and the rate of drug development in general.

For example, consider the BRUIN CLL-321 trial (NCT04666038).² This randomized, phase 3 trial of patients with relapsed chronic lymphocytic leukemia (CLL) compared pirtobrutinib (Jaypirca), a novel, noncovalent inhibitor of Bruton tyrosine kinase, with the investigators’ choice of chemoimmunotherapy or idelalisib (Zydelig) plus rituximab (Rituxan). The study was designed as a confirmatory trial to gain a full approval for pirtobrutinib, which had already achieved an accelerated approval based on a previous trial demonstrating a significant response rate and high degree of safety. The primary end point was progression-free survival (PFS); overall survival (OS) was a secondary end point. Crossover from the control arm to pirtobrutinib was allowed for patients whose disease progressed on the control arm. The study demonstrated that pirtobrutinib led to improved PFS and had a more favorable toxicity profile, but there was no significant difference in OS.

How might the trial have differed if it had been designed using the new principles put forth by the FDA? Perhaps OS would be the primary end point, rather than a secondary one. If that were the case, the trial would have required many more patients and a longer duration of follow-up, both of which would have led to a higher cost to the sponsor. Crossover would not have been allowed, which would have made the study less attractive to participants, who would have been more likely to decline enrollment so they could receive pirtobrutinib off study, since pirtobrutinib had already received an accelerated approval. In fact, investigators would have found it more difficult to enroll participants in countries like the US, where pirtobrutinib was already available. Even if OS had remained a secondary end point, crossover likely would not have been allowed, and the duration of follow-up would have been extended, thereby increasing the cost of drug development to the sponsor.

In this study, pirtobrutinib was shown to be less toxic than the control. However, there are many other examples in which a novel drug or combination might achieve similar efficacy results—improved PFS and no change in OS—but cause more adverse effects. In such cases, it seems possible that the FDA would deny full approval.

In my opinion, the FDA is trying to do the right thing by improving clinical trial design in oncology to ensure that trials correctly determine the risk-benefit ratio of novel agents. That said, we should be cognizant of the risks of higher costs to sponsors, impaired ability to enroll participants in trials, delayed read-outs on clinical trial results, delayed drug development, and higher barriers to innovation.

REFERENCES:

1. Approaches to assessment of overall survival in oncology clinical trials: guidance for industry. US Department of Health and Human Services. August 14, 2025. https://www.fda.gov/media/188274/download

2. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol 2025; 43(22):2538-2549. doi:10.1200/JCO-25-00166