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Drug approval based on randomized phase 3 trials for relapsed malignancy: analysis of oncologic drugs granted accelerated approval, publications and clinical trial databases

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Summary

Background As relapsed disease is frequently the first target of newly developed therapies, it is vital to address the difficulty in demonstrating the efficacy of new drugs for relapsed malignancy in randomized phase 3 trials. Methods We analyzed the approved indications, target populations, and development status of post-marketing confirmatory trials of all oncology-related drugs that were granted accelerated approval for both hematological and solid malignancies. Furthermore, we searched for randomized phase 3 trials for adult patients with relapsed lymphoid malignancy, other than chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Results Thirty-one (81.6%) of the 38 hematological indications and 23 (53.5%) of the 43 solid malignancy indications were in the relapsed settings. The target population of post-marketing studies was different from the approved indication in 18 (47.4%) of 38 hematological indications and 11 (25.6%) of 43 solid malignancy indications; all 18 hematological indications involved relapsed settings. Improved time-to-event outcome for relapsed patients was the primary endpoint in 6 (19.3%) of the 31 relapsed hematological indications. In 4 published studies of relapsed lymphoid malignancy, the medication significantly improved outcomes. From 33 trials listed at Clinicaltrials.gov, 2 were positive and 13 were negative. Five out of the 13 negative trials were terminated due to poor accrual. Conclusion Our analysis indicates that drug approval based on phase 3 trials is more challenging for relapsed hematological malignancies than for solid malignancies. Therefore, determining proper evaluation methods for the efficacy and safety of drugs for relapsed malignancy, without randomized trials, is important.

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Acknowledgements

This manuscript was professionally edited by a native English speaker at Editage, a supplier of English editing service.

Authorship contributions

SN designed the study; collected, analyzed, and interpreted the data; and wrote the manuscript. KO interpreted the data, supervised the research and wrote the manuscript.

Funding

This study was funded by JSPS KAKENHI Grant Number 15 K20967.

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Authors and Affiliations

  1. Division of Genetic Therapeutics, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 1088639, Japan

    Sumimasa Nagai & Keiya Ozawa

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  1. Sumimasa Nagai
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  2. Keiya Ozawa
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Correspondence to Sumimasa Nagai.

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Conflict of interest

Dr. Nagai was paid as a consultant at Takara Bio Inc. Dr. Ozawa received research funding from Takara Bio Inc. and was paid as a consultant at Celgene Japan. These were not related to this work.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Nagai, S., Ozawa, K. Drug approval based on randomized phase 3 trials for relapsed malignancy: analysis of oncologic drugs granted accelerated approval, publications and clinical trial databases. Invest New Drugs 36, 487–495 (2018). https://doi.org/10.1007/s10637-018-0572-2

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  • DOI: https://doi.org/10.1007/s10637-018-0572-2

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