Design and Analysis of Sequential Clinical Trials using a Markov Chain Transition Rate Model with Conditional Power

Background: There are a plethora of potential statistical designs which can be used to evaluate efficacy of a novel cancer treatment in the phase II clinical trial setting. Unfortunately, there is no consensus as to which design one should prefer, nor even which definition of efficacy should be used and the primary endpoint conclusion can vary depending on which design is chosen. It would be useful if an all-encompassing methodology was possible which could evaluate all the different designs simultaneously and allow investigators an understanding of the trial results under the varying scenarios. Methods: Finite Markov chain imbedding is a method which can be used in the setting of phase II oncology clinical trials but never previously evaluated in this scenario. Simple variations to the transition matrix or end-state probability definitions can be performed which allow for evaluation of multiple designs and endpoints for a single trial. A computer program is written in R which allows for computation of p-values and conditional power, two common statistical measures used for evaluation of trial results. A simulation study is performed on data arising from an actual phase II clinical trial performed recently in which the study conclusion regarding the efficacy of the potential treatment was debatable. Results: Finite Markov chain imbedding is shown to be useful for evaluating phase II oncology clinical trial results. The R code written for evaluating the simulation study is demonstrated to be fast and useful for investigating different trial designs. Further detail regarding the clinical trial results are presented, including the potential prolongation of stable disease of the treatment, which is a potentially useful marker of efficacy for this cytostatic agent. Conclusions: This novel methodology may prove to be an useful investigative technique for the evaluation of phase II oncology clinical trial data. Future studies which have disputable conclusions might become less controversial with the aid of finite Markov chain imbedding and the possible multiple evaluations which is now viable. Better understanding of activity for a given treatment might expedite the drug development process or help distinguish active from inactive treatmentsPh