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A synthetic control arm for refractory metastatic colorectal cancer: the no placebo initiative

Nature Medicine volume 29, pages 2389–2390 (2023)Cite this article

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Randomized placebo-controlled trials are the preferred design for clinical development. For trials of refractory cancers without any treatment options, all patients usually receive best supportive care — with one standard arm receiving a placebo and the experimental arm receiving a new treatment (single or combination drugs). Randomized clinical trials provide the best evidence for the effects of a new treatment as randomization reduces bias and provides a rigorous tool to examine cause-and-effect relationships between interventions and outcomes. This is commonly required for drug approval by regulatory agencies. However, in the field of oncology, use of a placebo may present practical and ethical concerns for both enrolled patients and the treating physicians, such as the difficulty for physicians to obtain informed consent for a patient to spend time without treatment with active drugs. For the sponsors, the inclusion of a placebo group adds extra costs and requires more participants, leading to longer enrollment periods1.

The analysis and research in metastatic colorectal cancer (mCRC) of the ARCAD (Aide et Recherche en Cancérologie Digestive) Foundation is an international collaboration of CRC specialists. The CRC ARCAD global database project has been developed as a historical individual participant data database, including data from more than 43,488 patients and 59 studies worldwide, and is still growing. These trials were sponsored by industry, governments or academic groups with high-quality clinical data and will allow use of individual participant data from 1,673 patients treated with placebo plus best supportive care in a salvage-line setting for refractory mCRC. This can be used as a synthetic control arm, from pooled placebo data, for clinical trials.

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Fig. 1: Three-step analysis for no-placebo initiative.

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Authors and Affiliations

  1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Takayuki Yoshino & Hideaki Bando

  2. Department of Data Science, National Cancer Center Hospital East, Chiba, Japan

    Takayuki Yoshino, Toshihiro Misumi, Hideaki Bando & Masashi Wakabayashi

  3. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Qian Shi

  4. Fondation A.R.CA.D, Aide et Recherche en CAncérologie Digestive, Levallois-Perret, France

    Morteza Raeisi, Thierry Andre & Aimery de Gramont

  5. Sorbonne University and Department of Medical Oncology, Saint-Antoine Hospital, Paris, France

    Thierry Andre

  6. Department of Medical Oncology, Franco-British Hospital, Levallois-Perret, France

    Aimery de Gramont

Authors
  1. Takayuki Yoshino
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  2. Qian Shi
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  3. Toshihiro Misumi
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  4. Hideaki Bando
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Corresponding author

Correspondence to Takayuki Yoshino.

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Competing interests

T.Y. reports honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono and Takeda; research funding from Taiho, Sumitomo Dainippon, Ono, Chugai, Amgen, Parexel International, MSD, Daiichi-Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health, Nippon Boehringer Ingelheim, Pfizer, Roche Diagnostics, Sysmex and Sanofi. Q.S. reports a consulting and advisory role from Yiviva, Boehringer Ingelheim Pharmaceuticals, Regeneron Pharmaceuticals, Hoosier Cancer Research Network, Kronos Bio and Mirati Therapeutics; an honorarium and speaker role from Chugai Pharmaceutical Co. (directly to Q.S.); research funds from Celgene/BMS, Roche/Genentech, Janssen and Novartis (to Q.S.’s institution). T.M. reports honoraria from Chugai and AstraZeneca. H.B. reports a grant from Ono; honoraria from Taiho, Eli Lilly Japan and Ono. M.W. reports honoraria from Nihon Medi-Physics. T.A. reports attending advisory board meetings and receiving consulting fees from Aptitude Health, Astellas, Bristol Myers Squibb, Gilead, Gritstone Oncology, GamaMabs Pharma SA, GSK, Kaleido Oncology, Merck & Co., Seagen, Servier and Transgène; honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Squibb, Gritstone Oncology, GSK, Merck & Co., Merck Serono, Pierre Fabre, Roche, Seagen and Servier; support for attending meetings and/or travel from Servier and Merck & Co.; and is President of the ARCAD Foundation. M.R. and A.G. have no competing interests to declare.

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Yoshino, T., Shi, Q., Misumi, T. et al. A synthetic control arm for refractory metastatic colorectal cancer: the no placebo initiative. Nat Med 29, 2389–2390 (2023). https://doi.org/10.1038/s41591-023-02488-0

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