Inefficiency of two-stage designs in phase II oncology clinical trials with high proportion of inevaluable patients

Background: Two-stage designs are commonly used for oncology Phase II clinical trials with a binary response endpoint. An issue that has not gained sufficient attention is the potential inefficiency in the usage of two-stage designs due to multiple enrollment suspensions when the proportion of patients inevaluable for response is high. Methods: Simulation studies were used to assess the performance of Simon's two-stage designs, two-stage designs with a proposed modification, and a single-stage design in the context of Phase II clinical trials with a high proportion of patients inevaluable for response. Results: Two-stage designs can require multiple enrollment disruptions when the inevaluable proportion is high, which can result in unacceptable inefficiency. The proposed modification provides a practical solution to this issue by enrolling an extra number of patients towards the end of the 1st stage, anticipating that a proportion of the patients pending response evaluation could be inevaluable. Single-stage designs with interim monitoring of futility that require no interim accrual suspension can be more efficient than two-stage designs, especially when the accrual and inevaluable rates are high. Conclusions: Planning of Phase II trials should consider the issue of inefficiency of the two-stage designs, especially for trials with a high inevaluable proportion. Designs with monitoring rules that do not require accrual suspensions may be given more considerations, especially in trials of agents that have already had some evidence for safety and efficacy in other populations.