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# Panel Recommends Randomized Trials for PI3K Inhibitors
- URL: https://www.fdaweb.com/panel-recommends-randomized-trials-for-pi3k-inhibitors/
- Published: 2022-04-21T12:00:00.000Z
- Updated: 2026-09-14T17:41:33.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5151655

FDA’s Oncologic Drugs Advisory Committee 4/21 voted unanimously 16-0 (one abstention) to recommend that the agency require future approvals of phosphatidylinositol 3-kinase (PI3K) inhibitors be supported by randomized clinical trial data. Panel members agreed with FDA reviewers’ concerns about toxicity and using overall response rates in single-arm trials to support approvals, particularly in hematological malignancies.  

Most of FDA’s concerns were outlined in a recent [online *Lancet Oncology*](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2822%2900200-5/fulltext?ref=fdaweb.com#%20) article by FDA Oncology Center of Excellence director **Richard Pazdur** and other FDA officials ([see earlier story](https://www.fdaweb.com/pazdur-et-al-weigh-challenges-with-pi3k-inhibitors/)). A [briefing document](https://www.fda.gov/media/157762/download?ref=fdaweb.com) released in advance of the meeting also criticized current PI3K inhibitor development programs that did not perform adequate dose exploration which in some cases was further complicated by selecting a single-arm study design for initial registration. “The safety analysis of data from single-arm trials,” it says, “is confounded by the absence of a control, which can pose challenges in accurately attributing AEs \[adverse events\] to either drug or the underlying disease. Because sponsors may select a dose to achieve the highest ORR \[objective response rate\] without carefully considering a benefit-risk analysis, toxicities are compounded and may contribute to the worrisome OS \[overall survival\] results seen repeatedly in multiple RCTs \[randomized control trials\] of these agents.”

Additionally, the briefing document endorsed randomized trials as the “most effective method to control for confounding factors” and because they allow for assessing progression-free survival, overall survival (OS), and patient reported outcomes. It says that “OS data should be fully collected and analyzed, as OS is an important metric in the benefit-risk determination, especially for products with significant toxicity.”  

During the open discussion, some panel members were concerned that raising the approval bar on the drug class could stifle innovation and delay important products for patients. Pazdur weighed in to offer reassurance that if the agency saw early data from a PI3K inhibitor that had phenomenal response rates and was very non-toxic, ”then that’s a different story here and we always would demonstrate the appropriate degree of flexibility” to move the product through development.