Table 6.5 Decision criteria at the interim analysis and final analysis in the proposed design scenarios. Decision Criteria Interim Interim Final Final Success Futility Success Futility Pr(|RED90 > 0) >95% <20% –Ctrl| Pr(|RED90 > 0.95) >70% –Ctrl| Pr(|Rdmax > 0) > 0.95 or Pr(|RED90 > 0) Yes No –Ctrl| –Ctrl| >95% Pr(|RED90 > 0): The probability of dose response near ED90 dose level achieves a drug effect greater than the control or –Ctrl| placebo. Pr(|RED90 > 0.95): The probability of dose response near ED90 dose level achieves a drug effect greater than the control –Ctrl| or placebo and 0.95 is the clinical significant difference. Pr(|Rdmax > 0): The probability of any dose with maximal effect achieves a drug effect greater than the control or placebo. –Ctrl| Only final success and futility are accessed in fixed design. When there is truly is no effect or a placebo like effect, the Type I error rate is calculated based on the chance of rejecting the null hypothesis (when it is true). In the context of this simulation it would also be the chance of incorrectly accepting that the drug has a dose response - or the false positive rate. Simulation Results Scenario 1 is non-adaptive, therefore the study allocates 8 patients to receive doses of GSK123456 (0.03, 0.3, 3, 10, 20 and 30 mg/kg) and 16 patients to receive placebo. All doses including placebo are top of standard first-line therapy, therefore a placebo like response is a -0.5 as a measure of DAS28 change from baseline. Figure 6.5 is the subject allocation for the proposed fixed design, the subject allocations are the same for all four types of dose response model. When there is no effect or a placebo like effect, the type I error rates are 6% and 17% when analysed using the model and the NDLM model respectively (Table 6.6). A type I error rate Emax
Table 6.5 Decision criteria at the interim analysis and final analysis in the proposed design scenarios. Decision Criteria Interim Success Interim Futility Final Success Final Futility Pr(|RED90 –Ctrl| > 0) >95% <20% Pr(|RED90 –Ctrl| > 0.95) >70% Pr(|Rdmax –Ctrl| > 0) > 0.95 or Pr(|RED90 –Ctrl| > 0) >95% Yes No Pr(|RED90 –Ctrl| > 0): The probability of dose response near ED90 dose level achieves a drug effect greater than the control or placebo. Pr(|RED90 –Ctrl| > 0.95): The probability of dose response near ED90 dose level achieves a drug effect greater than the control or placebo and 0.95 is the clinical significant difference. Pr(|Rdmax –Ctrl| > 0): The probability of any dose with maximal effect achieves a drug effect greater than the control or placebo. Only final success and futility are accessed in fixed design. When there is truly is no effect or a placebo like effect, the Type I error rate is calculated based on the chance of rejecting the null hypothesis (when it is true). In the context of this simulation it would also be the chance of incorrectly accepting that the drug has a dose response - or the false positive rate. Simulation Results Scenario 1 is non-adaptive, therefore the study allocates 8 patients to receive doses of GSK123456 (0.03, 0.3, 3, 10, 20 and 30 mg/kg) and 16 patients to receive placebo. All doses including placebo are top of standard first-line therapy, therefore a placebo like response is a -0.5 as a measure of DAS28 change from baseline. Figure 6.5 is the subject allocation for the proposed fixed design, the subject allocations are the same for all four types of dose response model. When there is no effect or a placebo like effect, the type I error rates are 6% and 17% when analysed using the Emax model and the NDLM model respectively (Table 6.6). A type I error rate