The continual reassessment method is a model-based procedure, described in the literature, used to determine the maximum tolerated dose in phase I clinical trials. The maximum tolerated dose can also be found under the framework of D-optimum design, where information is gathered in such a way so that asymptotic variability in the parameter estimates in minimised. This paper investigates the two methods under some realistic settings to explore any potential differences between them. Simulation studies for six plausible dose-response scenarios show that D-optimum design can work well in comparison with the continual reassessment method in many cases. The D-optimum design is also found to allocate doses from the extremes of the design region to the patients in a trial.
If the inline PDF is not rendering correctly, you can download the PDF file here.
Atkinson A.C. Fedorov V.V. Herzberg A.M. Zhang R. (2014): Elemental information matrices and optimal experimental design for generalized regression models. Journal of Statistical Planning and Inference 144(1): 81–91.
Babb J. Rogatko A. Zacks S. (1998): Cancer phase I clinical trials: Efficient dose escalation with overdose control. Statistics in Medicine 17(10): 1103–1120.
Chernoff H. (1953): Locally optimal designs for estimating parameters. The Annals of Mathematical Statistics 24(4): 586–602.
Collins J.M. Grieshaber C.K. Chabner B.A. (1990): Pharmacologically guided phase I clinical trials based upon preclinical drug development. Journal of the National Cancer Institute 82(16): 1321–1326.
Dixon W.J. Mood A.M. (1948): A method for obtaining and analyzing sensitivity data. Journal of the American Statistical Association 43(241): 109–126.
Goodman S.N. Zahurak M.L. Piantadosi S. (1995): Some practical improvements in the continual reassessment method for phase I studies. Statistics in Medicine 14(11): 1149–1161.
Korn E.L. Midthune D. Chen T.T. Rubinstein L.V. Christian M.C. Simon R.M. (1994): A comparison of two phase I trial designs. Statistics in Medicine 13(18): 1799–1806.
Le Tourneau C. Lee J.J. Siu L.L. (2009): Dose escalation methods in phase I cancer clinical trials. Journal of the National Cancer Institute 101(10): 708–720.
Leung D.H.Y. Wang Y.G. (2001): Isotonic designs for phase I trials. Controlled Clinical Trials 22(2): 126–138.
Lévy V. Zohar S. Porcher R. Chevret S. (2001): Alternate designs for conduct and analysis of phase I cancer trials. Blood 98(4): 1275–1275.
O’Quigley J. Pepe M. Fisher L. (1990): Continual reassessment method: A practical design for phase I clinical trials in cancer. Biometrics 46(1): 33–48.
O’Quigley J. Shen L.Z. (1996): Continual reassessment method: A likelihood approach. Biometrics 52(2): 673–684.
O’Quigley J. Zohar S. (2006): Experimental designs for phase I and phase I/II dose-finding studies. British Journal of Cancer 94(5): 609–613.
Reiner E. Paoletti X. O’Quigley J. (1999): Operating characteristics of the standard phase I clinical trial design. Computational Statistics and Data Analysis 30(3): 303–315.
Simon R. Rubinstein L. Arbuck S.G. Christian M.C. Freidlin B. Collins J. (1997): Accelerated titration designs for phase I clinical trials in oncology. Journal of the National Cancer Institute 89(15): 1138–1147.
Storer B.E. (1989): Design and analysis of phase I clinical trials. Biometrics 45(3): 925–937.