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On Stopping a Randomized Clinical Trial for Futility

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Designs for Clinical Trials

Abstract

This chapter reviews the art and science of planned interim futility analyses in clinical trials that test a superiority hypothesis. Our goal is to recommend “best practices.” We briefly describe situations where we find terminating trials for futility advisable and not advisable. This chapter outlines four statistical methods of interim futility analysis – conditional power, predictive power, group sequential testing, and basing an interim futility analysis on a Phase 2 outcome or biomarker instead of on the primary efficacy variable. We distinguish between trials where the locus of control resides in the investigators from those where the commercial sponsor controls the trial. We provide guidance, based on our experience and opinion, as to types of trials where each method is preferable. We describe several practical issues that arise in the use of interim futility analysis, for example, lag in treatment effect, time patterns in development of evidence of efficacy, unreliability of early data, efficacy endpoints that take long follow-up to observe, and choice of timing of futility analysis. Finally, we consider the ethics of futility analyses including public disclosure of their results. A conclusion section summarizes our recommendations for the use of interim futility analysis.

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Acknowledgements

We thank Catherine Conlon for preparing Fig. 5.4. We are grateful to David Sackett for his insightful comments on an earlier version of this chapter.

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Authors and Affiliations

  1. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA

    Jay Herson

  2. IDDI Consultants, International Drug Development Institute, Louvain-la-Neuve, Belgium

    Marc Buyse

  3. Department of Biostatistics, Hasselt University, Diepenbeek, Belgium

    Marc Buyse

  4. Statistics Collaborative, Inc., Washington, DC, 20036, USA

    Janet Turk Wittes

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  1. Jay Herson
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  2. Marc Buyse
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Correspondence to Jay Herson .

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Editors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    David Harrington

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Herson, J., Buyse, M., Wittes, J.T. (2012). On Stopping a Randomized Clinical Trial for Futility. In: Harrington, D. (eds) Designs for Clinical Trials. Applied Bioinformatics and Biostatistics in Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0140-7_5

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