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The Treatment Versus Experimentation Dilemma in Dose-finding Studies

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  • David Azriel
  • Micha Mandel
  • Yosef Rinott

Abstract

Phase I clinical trials are conducted in order to find the maximum tolerated dose (MTD) of a given drug from a finite set of doses. For ethical reasons, these studies are usually sequential, treating patients or group of patients with the best available dose according to the current knowledge. However, it is proved here that such designs, and, more generally, designs that concentrate on one dose from some time on, cannot provide consistent estimators for the MTD unless very strong parametric assumptions hold. We describe a family of sequential designs that treat individuals with one of the two closest doses to the estimated MTD, and prove that such designs, under general conditions, concentrate eventually on the two closest doses to the MTD and estimate the MTD consistently. It is shown that this family contains randomized designs that assign the MTD with probability that approaches 1 as the size of the experiment goes to infinity. We compare several designs by simulations, studying their performances in terms of correct estimation of the MTD and the proportion of individuals treated with the MTD.

Suggested Citation

  • David Azriel & Micha Mandel & Yosef Rinott, 2010. "The Treatment Versus Experimentation Dilemma in Dose-finding Studies," Discussion Paper Series dp559, The Federmann Center for the Study of Rationality, the Hebrew University, Jerusalem.
    • Handle: RePEc:huj:dispap:dp559
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    File URL: http://ratio.huji.ac.il/sites/default/files/publications/dp559.pdf
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    Cited by:

    1. Azriel, David, 2014. "Optimal sequential designs in phase I studies," Computational Statistics & Data Analysis, Elsevier, vol. 71(C), pages 288-297.
    2. Azriel, David, 2012. "A note on the robustness of the continual reassessment method," Statistics & Probability Letters, Elsevier, vol. 82(5), pages 902-906.
    3. Pavel Mozgunov & Thomas Jaki, 2020. "An information theoretic approach for selecting arms in clinical trials," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1223-1247, December.
    4. Peter F. Thall & Hoang Q. Nguyen & Sarah Zohar & Pierre Maton, 2014. "Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 109(507), pages 931-943, September.

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