Patient recruitment strategies for adaptive enrichment designs with time-to-event endpoints.

BACKGROUND

Adaptive enrichment designs for clinical trials have great potential for the development of targeted therapies. They enable researchers to stop the recruitment process for a certain population in mid-course based on an interim analysis. However, adaptive enrichment designs increase the total trial period owing to the stoppage in patient recruitment to make interim decisions. This is a major drawback; it results in delays in the submission of clinical trial reports and the appearance of drugs on the market. Here, we explore three types of patient recruitment strategy for the development of targeted therapies based on the adaptive enrichment design.

METHODS

We consider recruitment methods which provide an option to continue recruiting patients from the overall population or only from the biomarker-positive population even during the interim decision period. A simulation study was performed to investigate the operating characteristics by comparing an adaptive enrichment design using the recruitment methods with a non-enriched design.

RESULTS

The number of patients was similar for both recruitment methods. Nevertheless, the adaptive enrichment design was beneficial in settings in which the recruitment period is expected to be longer than the follow-up period. In these cases, the adaptive enrichment design with continued recruitment from the overall population or only from the biomarker-positive population even during the interim decision period conferred a major advantage, since the total trial period did not differ substantially from that of trials employing the non-enriched design. By contrast, the non-enriched design should be used in settings in which the follow-up period is expected to be longer than the recruitment period, since the total trial period was notably shorter than that of the adaptive enrichment design. Furthermore, the utmost care is needed when the distribution of patient recruitment is concave, i.e., when patient recruitment is slow during the early period, since the total trial period is extended.

CONCLUSIONS

Adaptive enrichment designs that entail continued recruitment methods are beneficial owing to the shorter total trial period than expected in settings in which the recruitment period is expected to be longer than the follow-up period and the biomarker-positive population is promising.