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Complicated regulatory decision-making following inconsistent trial results: the issue with ibrutinib for mantle cell lymphoma

Nature Reviews Clinical Oncology (2023)Cite this article

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In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

The US FDA’s Accelerated Approval pathway facilitates early access to promising novel therapies in areas of unmet medical need, based on surrogate measures that are — in the view of the FDA — “reasonably likely” to predict clinical benefit. To validate these predicted clinical outcomes, confirmatory trials for drugs that receive Accelerated Approval require completion in a timely fashion1. Since 2020, the FDA has focused on the growing problem of delayed or incomplete confirmatory trials, which has prompted the withdrawal of more than 20 Accelerated Approval indications in which confirmatory trials did not substantiate the anticipated clinical benefit2. In nearly all of these cases, the withdrawals were appropriate, but one — the withdrawal of the Accelerated Approval of ibrutinib for mantle cell lymphoma (MCL) — is worth deeper reflection, because it highlights the challenges that can arise when confirmatory trials have mixed results.

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Acknowledgements

The research of E.R.S.C. and A.S.K. is funded by Arnold Ventures. The funders had no role in the design and conduct of the study, collection, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. The authors thank N. Mehta-Shah for discussions regarding romidepsin.

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Authors and Affiliations

  1. Program On Regulation, Therapeutics And Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Edward R. Scheffer Cliff & Aaron S. Kesselheim

  2. Harvard Medical School, Boston, MA, USA

    Edward R. Scheffer Cliff & Aaron S. Kesselheim

  3. Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA

    Talal Hilal

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  1. Edward R. Scheffer Cliff
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Correspondence to Edward R. Scheffer Cliff.

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Competing interests

A.S.K. reports having served as an expert witness on behalf of the Leukemia and Lymphoma Society in litigation relating to royalties on venetoclax (2021–2022). E.R.S.C. and T.H. have no competing interests to declare.

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Cliff, E.R.S., Hilal, T. & Kesselheim, A.S. Complicated regulatory decision-making following inconsistent trial results: the issue with ibrutinib for mantle cell lymphoma. Nat Rev Clin Oncol (2023). https://doi.org/10.1038/s41571-023-00821-7

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  • DOI: https://doi.org/10.1038/s41571-023-00821-7

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