Ask the Experts: Late Phase Oncology Trial Design

According to CROS NT’s expert biostatistician, how can adaptive trial design be a method for the future of cancer research?

During Phase III development, efficacy of the drug should be confirmed. Many new products have to find a very specific mechanism of effectiveness, so therefore subpopulations are necessary. Flexible study designs that allow for early termination and the use of fewer patients can be a successful solution for determining clinical efficacy. In oncology trials, we need to take into consideration differentiating factors such as slow patient recruitment, the importance of patient genotype, the use of various treatment combinations and the fact that the primary endpoint is overall survival time or time to progression.

Adaptive Designs in late phase cancer research offer the possibility to make modifications to a study while in progress on the basis of new information pulled from accumulated data. While it is well know that there is the possibility to re-estimate the number of patients needed for a study based on observational data in interim analysis, it is less known that design can allow objectives to be achieved in one study that would normally require the scheduling of two distinct studies, so called “seamless Phase II/III designs”.
Seamless Phase II/III designs combine two sequential and separate studies into one study and allows the use of collected information in the first stage to adapt the design in the second stage. The advantages of in this design are a reduction in overall time in the development of a drug, fewer patients required, and the early availability of long-term safety data.

Another interesting possibility of an adaptive design is to select the right target population for the drug. This is of special interest in the development of highly specific cancer drugs, which are only effective in selected patient populations – for example, monoclonal antibodies. An adaptive study in Phase II/III may allow for the selection of the most promising target population in the first stage for the second stage.

Based on CROS NT’s experience in oncology trials, our expert biostatisticians recommend the following for late phase adaptive trials:

– Budget more time for planning of an adaptive design as compared to a standard design
– Interact with regulatory authorities in the planning phase especially for Phase II/III studies
– Use simulations to calculate the power of the sample size and the probability of success
– Evaluate whether or not to stop the recruitment of patients for the interim analyses
– Schedule frequent monitoring visits in order to provide as much data as possible for the interim analyses

If you are interested in statistical consultancy with Thomas Zwingers, please send us an inquiry. Thomas consults on trial design, methodology and regulatory submissions and has particular expertise in adaptive trial design and oncology research.