An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials

Abstract

Background Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD design already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and if we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample size re-estimation, up to 25% power was recovered from underestimated sample size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study’s results are limited to situations described by the parameters that were used, and may not generalize to all possible scenarios. Furthermore, drop-out of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.

Criticisms of drugs in early development for the treatment of depression: what can be improved?

“…A number of possible contributing factors have been identified, but further studies are needed. The sequential parallel comparison design has been proposed to address this issue and its ability to minimize the placebo effect has been demonstrated [35][36][37]. Statistical modeling has demonstrated that sequential parallel design reduces sample size by 20 --25% relative to traditional parallel design, while retaining similar power, leading to financial savings and shortening total study length by reducing the enrollment period [35][36][37].…”

“…The sequential parallel comparison design has been proposed to address this issue and its ability to minimize the placebo effect has been demonstrated [35][36][37]. Statistical modeling has demonstrated that sequential parallel design reduces sample size by 20 --25% relative to traditional parallel design, while retaining similar power, leading to financial savings and shortening total study length by reducing the enrollment period [35][36][37]. Adaptive design (e.g., treatment algorithms) and equipoise-stratified design (e.g., flexibility in randomization by allowing participants and investigators to choose among groups) will also improve design issues [35][36][37].…”

Establishing an evaluation mode with multiple primary outcomes based on combination of diseases and symptoms in TCM clinical trials

“…An adaptive design is defined as a clinical trial design that uses accumulating data to decide on how to modify trial and/or statistical aspects of the study as it continues, without undermining the validity and integrity of the trial (30,31).…”