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A Change in Course: FDA Requires Randomized Data to Support PI3K Inhibitor Approvals in Hematologic Malignancies

The Oncologic Drugs Advisory Committee (ODAC) convened a meeting on April 21, 2022, to review the data used to support phosphatidylinositol 3-kinase (PI3K – a class of medical drugs that are used mainly to treat advanced cancers) inhibitor approvals in hematologic malignancies. ODAC unanimously voted (16-0 with one abstention) that future approvals of PI3K inhibitors are to be supported by randomized controlled trials (RCTs) in which subjects are randomized to an active arm with the PI3K inhibitor or a comparator arm consisting of standard of care therapy, for example. Single-arm trials, where there is no direct comparator arm, will no longer be accepted as pivotal registration trials for PI3k inhibitors in hematologic malignancies.

This vote may bring frustration and trepidation to some sponsors and investors as this will dramatically increase spend and lengthen recruitment and enrollment timelines, as well as raise the bar for their PI3K inhibitor to demonstrate substantial evidence of effectiveness and safety when directly compared to a control arm. However, this decision gets at the core of our shared mission to impact human health by providing meaningful safe effective therapies to patients in need.

Overview of PI3K Inhibitor Approvals in Hematologic Malignancies

PI3K inhibitors have been approved under both traditional approval and accelerated approval pathways. Those approved under the accelerated approval pathway had to conduct post-approval confirmatory trials to confirm efficacy and safety. PI3K inhibitors have been approved in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) and are being developed in patients with B-cell and T-cell non-Hodgkin lymphoma (NHL). The initial approval pathway and endpoints, along with post-approval trials and outcomes, are outlined in Table 1.

Table 1: Status of FDA-Approved PI3K Inhibitors for Hematologic Malignancies

Source: U.S. Food and Drug Administration, ODAC Briefing Document, April 21, 2022, P. 12-13.

Core Issues Raised and Discussed at the FDA ODAC Meeting

The FDA has identified key issues with the development of PI3K inhibitors concerning endpoints, safety profile of PI3K inhibitors, inadequate dose optimization, and trial design. It was evident the FDA has the patient’s welfare at the center of the argument when Nicole Gormley, MD, Acting Division Director of Hematology products for the FDA stated: “While we definitely want to expedite drug development and make sure there are new therapies available to patients as soon as possible, it’s imperative, in our view, that we ensure those products are safe and effective.” Three core issues discussed during the ODAC meeting were the endpoint of Overall Survival (OS), the toxicity profile of PI3K inhibitors, and dosing evaluation.

Overall Survival as both an efficacy and safety endpoint:

Toxicity Profile of PI3K:


Impacts to Future PI3K Inhibitor Development

While it is important that potentially lifesaving therapies make it into the hands of patients, it is also critical that those same therapies are both safe and effective. The exhibited toxicity of the PI3K inhibitors draws into question not only the benefit: risk ratio of those therapies, appropriate trial design, primary endpoints, and dose optimization.

Historically, PI3K Inhibitor drugs were approved based on single arm studies and intermediate primary end points (PFS, ORR). Due to the concerning toxicities of FDA approved PI3K Inhibitor class drugs, it is FDA’s view that randomized, controlled trials with a primary end point of OS may better support both safety and efficacy of these therapies. Additionally, optimizing dose range may greatly reduce toxicity concerns in the relevant patient population.

The ODAC decision will undoubtably cause frustration for investors and sponsors alike due to the increase spend, extension of timelines and recruitment, as well as increase data-based evidence requirements to support both safety and effectiveness of potential PI3K Inhibitor therapies. It will become incredibly important that sponsors consider FDA’s view on PI3K Inhibitor class drugs indicated to treat Hematologic Malignancies while designing their proposed clinical studies, selection of primary endpoints, and determining evidence-based dose selection. Determining benefit of risk ratio of PI3K inhibitors can only be done within the setting of randomized, controlled trials in which OS is both the efficacy and safety endpoint.


If you have any questions about this regulatory update and want to further the discussion, please be in contact with the authors:

Our regulatory team will also be releasing insights on FDA’s Project Optimus (as referenced in this blog post) in the near future. Please check here for an update.


Phillips TJ, Michot JM, Ribrag V. Can next-generation PI3K inhibitors unlock the full potential of the class in patients with B-cell lymphoma? Clin Lymphoma Myeloma Leuk 2021; 21(1): 8-20 e3.

U.S. Food and Drug Administration, Oncological Drugs Advisory Committee Meeting (ODAC) Briefing Document. (April 21, 2022). Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies, pgs. 12-13.