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Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective

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Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.

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Acknowledgements

The authors would like to thank the following individuals for their feedback on the manuscript, John Scott (FDA), Larissa Lapteva (FDA), Xiaofei Wang (FDA), James McBane (MHRA), and Evgeny Degtyarev (Novartis).

Disclaimer

The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. The findings and conclusions in this article have not been formally disseminated by Medicine and Healthcare products Regulatory Agency and should not be construed to represent any Agency determination or policy.

Funding

The authors did not receive any funding in relation to the work described in the article.

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Authors and Affiliations

  1. Bristol Myers Squibb, Seattle, WA, USA

    Daniel Li

  2. US Food and Drug Administration, Silver Spring, MD, USA

    Zhenzhen Xu

  3. Novartis Pharmaceuticals, East Hanover, NJ, USA

    Shihua Wen

  4. Bristol Myers Squibb, Summit, NJ, USA

    Revathi Ananthakrishnan

  5. Lyell Immunopharma, Seattle, WA, USA

    Yeonhee Kim & Alan Chiang

  6. Medicines and Healthcare Products Regulatory Agency, London, UK

    Khadija Rerhou Rantell

  7. ICON Centre for Cell and Gene Therapy, Houston, TX, USA

    Patricia Anderson

  8. Kite, Santa Monica, CA, USA

    James Whitmore

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Correspondence to Daniel Li.

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Conflict of interest

Daniel Li is an employee of BMS and owns stocks; Zhenzhen Xu has no relevant conflict of interest to disclose; Shihua Wen is an employee of Novartis and owns stocks; Revathi Ananthakrishnan is an employee of BMS and owns stocks; Yeonhee Kim is an employee of Lyell and owns stocks; Khadija Rerhou Rantell has no relevant conflict of interest to disclose; Patricia Anderson is an employee of ICON; James Whitmore is an employee of Kite, a Gilead Company, and owns stock; Alan Chiang is an employee of Lyell and owns stocks.

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Li, D., Xu, Z., Wen, S. et al. Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective. Ther Innov Regul Sci (2024). https://doi.org/10.1007/s43441-024-00652-3

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