Adding dose modifications into Phase II and Phase II/III seamless trials

Abstract

We present a technique for adding dose modifications into seamless Phase II and Phase II/III trials featuring dose selection at an interim analysis. The method is convenient to apply and can be used either in a fully prespecified, structured way or as a response to new considerations that emerge at interim. Strong control of the familywise error rate regarding false declarations of efficacy versus control is maintained. Two examples are given. One illustrates how the method could potentially “save” a trial performed in a Phase II context. The other is a seamless Phase II/III trial that uses an adaptive exploration strategy for an assumed nonmonotonic dose-response curve. It can result in greatly improved efficiency over a standard “promote the winner” rule.

Keywords

Adaptive design dose addition dose modification familywise error rate nonmonotonic dose response

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References

Cohen

Todd

Gregor

, et al. Adding a treatment arm to an ongoing clinical trial: A review of methodology and practice. Trials 2015; 16: 179.

Chang

Wang

. The add-arm design for unimodal response curve with unknown mode. J Biopharm Stat 2015; 25: 1039–1064.

Spivack

Cheng

Levin

. Limb-leaf designs with adaptive exploration of the dose response curve. Contemp Clin Trials 2018; 64: 210–218.

Kaufmann

, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009; 66(2): 235–244.

Responding to neglected patients' needs through innovation. Neglected diseases initiative, https://www.dndi.org/wp-content/uploads/2018/08/DNDi_AR_2017.pdf (2017, accessed 14 December 2018).

Genz A and Bretz F. Computation of multivariate normal and T probabilities. Lecture notes in statistics. Vol. 195. Heidelberg, Germany: Springer-Verlag, 2009.

Jennison C and Turnbull B. Group sequential methods with applications to clinical trials. New York, NY: CRC Press, 2000.

Černý

. A thermodynamical approach to the travelling salesman problem: An efficient simulation algorithm. J Optim Theory Appl 1985; 45: 41–51.

Thall

Simon

Ellenberg

. Two-stage selection and testing designs for comparative clinical trials. Biometrika 1988; 75: 303–310.

10.

Stallard

Todd

. Point estimates and confidence regions for sequential trials involving selection. J Stat Plan Inference 2005; 135: 402–419.

11.

Bretz

Schmidli

König

, et al. Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: General concepts. Biom J 2006; 48: 623–634.

12.

Jennison

Turnbull

. Adaptive seamless designs: Selection and prospective testing of hypotheses. J Biopharm Stat 2007; 17: 1135–1161.

13.

Liu

Proschan

Pledger

. A unifed theory of two-stage adaptive designs. J Am Stat Assoc 2002; 97: 1034–1041.

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