A clinical trial simulation study to investigate and compare efficacy and toxicity findings in parallel and titration designs
Chao Chen, Shan Pan
CPMS, GlaxoSmithKline, Stevenage, UK
Background & Objectives: Dose-ranging studies are designed to understand the efficacy and toxicity of an investigational compound, aiming to maximise its benefit-risk ratio. Both parallel and titration designs are commonly used to evaluate population and individual dose-response relationships [1]. In this work, we used computer simulation to investigate treatment success level, as well as efficacy and toxicity profiles, for these two designs.
Methods: Clinical trials with both designs were simulated and analysed using the MSToolkit package in R. The dose-response relationships for efficacy and toxicity were defined as a simple Emax model; the mean doses producing 50% of maximum efficacy (ED50) and 50% of maximum toxicity (TD50) were set at 1 and 8 respectively [2].
Three active doses (0.5, 1 and 2) were given to parallel groups. In the titration study, the dose for each patient increased step-wise until at least 90% of maximum efficacy or at least 20% of maximum toxicity was observed. The placebo effect was not separated from active treatments due to its questionable nature in titration designs [3, 4].
In total 10,000 patients were simulated. Three levels of between-subject variability in ED50 and TD50 (25%, 45% and 75%) and three levels of measurement error (10%, 30% and 60%) were considered. Both low and high correlations between ED50 and TD50 were investigated. A dropout rate of 10% was assumed for each treatment period.
The responder rate and distributions of efficacy, toxicity and efficacy-toxicity ratio (reflecting benefit-risk ratio) among responders were compared between the two designs.
Results: For all evaluated scenarios, the responder rate in the titration trials was consistently higher; it was up to 75% higher than that at the high dose in the parallel trials. The efficacy profile for the titration trials was similar to that at the high dose of the parallel trials. Both toxicity and the efficacy-toxicity ratio profiles in the titration trials were similar to that at the middle dose of the parallel trials.
Conclusion: The current exploration study suggests that titration design is likely to be more effective than parallel design. Compared to the parallel design, it results in higher responder rate with optimal benefit-risk profile. The placebo effect and interaction between dose-response and time for this design remain to be further assessed.
References:
[1] ICH E4 Dose-response information to support drug registration.
[2] Chen C. PAGE 19 (2010) Abstr 1897 [www.page-meeting.org/?abstract=1897]
[3] Meno-Tetang et al. PAGE 17 (2008) Abstr 1409 [www.page-meeting.org/?abstract=1409]
[4] Enck et al. The placebo response in clinical trials: more questions than answers. Philosophical Transactions of the Royal Society B: Biological Sciences. 2011;366(1572):1889-95.