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Bayesian dose finding by jointly modelling toxicity and efficacy as time-to-event outcomes


  • Ying Yuan
  • Guosheng Yin


In traditional phase I and II clinical trial designs, toxicity and efficacy are often modelled as binary outcomes. Such methods ignore information on when the outcome event occurs, such as experiencing toxicity or achieving cure or remission. They also have difficulty accommodating a high accrual rate under which toxicity and efficacy outcomes cannot be observed in a timely manner, and thus delay treatment assignment. To address these issues, we propose a Bayesian adaptive phase I-II design that jointly models toxicity and efficacy as time-to-event outcomes. At each decision-making time, patients who have not experienced toxicity or efficacy are naturally censored. We apply the marginal cure rate model to account explicitly for those patients who are insusceptible to efficacy owing to drug resistance. The correlation between the bivariate time-to-toxicity and time-to-efficacy outcomes is properly adjusted through the Clayton model. After screening out the excessively toxic or futile doses, we adaptively assign each new patient to the most appropriate dose on the basis of the ratio of the areas under the predicted survival curves corresponding to toxicity and efficacy. We conducted extensive simulation studies to examine the operating characteristics of the method proposed, and we illustrate the application of the method in a clinical trial in prostate cancer. Our design selects the target dose with a high probability, treats most patients at the desirable dose and potentially shortens the duration of a trial. Copyright (c) 2009 Royal Statistical Society.

Suggested Citation

  • Ying Yuan & Guosheng Yin, 2009. "Bayesian dose finding by jointly modelling toxicity and efficacy as time-to-event outcomes," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 58(5), pages 719-736.
  • Handle: RePEc:bla:jorssc:v:58:y:2009:i:5:p:719-736

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    References listed on IDEAS

    1. Nilanjan Chatterjee & Joanna Shih, 2001. "A Bivariate Cure-Mixture Approach for Modeling Familial Association in Diseases," Biometrics, The International Biometric Society, vol. 57(3), pages 779-786, September.
    2. Peter F. Thall & John D. Cook, 2004. "Dose-Finding Based on Efficacy–Toxicity Trade-Offs," Biometrics, The International Biometric Society, vol. 60(3), pages 684-693, September.
    3. Mauro Gasparini & Jeffrey Eisele, 2000. "A Curve-Free Method for Phase I Clinical Trials," Biometrics, The International Biometric Society, vol. 56(2), pages 609-615, June.
    4. Ying Kuen Cheung & Rick Chappell, 2000. "Sequential Designs for Phase I Clinical Trials with Late-Onset Toxicities," Biometrics, The International Biometric Society, vol. 56(4), pages 1177-1182, December.
    5. Saurabh Mukhopadhyay, 2000. "Bayesian Nonparametric Inference on the Dose Level with Specified Response Rate," Biometrics, The International Biometric Society, vol. 56(1), pages 220-226, March.
    6. Guosheng Yin & Yisheng Li & Yuan Ji, 2006. "Bayesian Dose-Finding in Phase I/II Clinical Trials Using Toxicity and Efficacy Odds Ratios," Biometrics, The International Biometric Society, vol. 62(3), pages 777-787, September.
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    1. repec:bla:jorssc:v:66:y:2017:i:5:p:979-996 is not listed on IDEAS
    2. Peter F. Thall & Hoang Q. Nguyen & Thomas M. Braun & Muzaffar H. Qazilbash, 2013. "Using Joint Utilities of the Times to Response and Toxicity to Adaptively Optimize Schedule–Dose Regimes," Biometrics, The International Biometric Society, vol. 69(3), pages 673-682, September.
    3. Peter F. Thall & Aniko Szabo & Hoang Q. Nguyen & Catherine M. Amlie-Lefond & Osama O. Zaidat, 2011. "Optimizing the Concentration and Bolus of a Drug Delivered by Continuous Infusion," Biometrics, The International Biometric Society, vol. 67(4), pages 1638-1646, December.

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