Patient recruitment strategies for adaptive enrichment designs with time-to-event endpoints
Ryuji Uozumi1, Shinjo Yada2, Atsushi Kawaguchi3
1Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. uozumi@kuhp.kyoto-u.ac.jp.
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.
Insights
Adaptive enrichment designs can shorten clinical trial durations when patient recruitment outpaces follow-up. Continued recruitment strategies during interim analyses offer advantages for targeted therapy development, especially with promising biomarker-positive populations.
Area of Science:
- Clinical trial methodology
- Biostatistics
- Pharmacological research
Background:
- Adaptive enrichment designs offer potential for targeted therapy development by allowing mid-trial participant group adjustments.
- A key drawback is extended trial duration due to recruitment pauses for interim decision-making, delaying drug approvals.
Purpose of the Study:
- To investigate patient recruitment strategies within adaptive enrichment designs for targeted therapies.
- To compare the efficiency of adaptive enrichment designs with continued recruitment versus non-enriched designs.
Main Methods:
- Simulated clinical trials comparing adaptive enrichment designs with novel recruitment strategies against non-enriched designs.
- Evaluated operating characteristics, focusing on total trial period and patient numbers.
Main Results:
- Adaptive enrichment designs with continued recruitment (overall or biomarker-positive population) were advantageous when recruitment periods exceed follow-up periods.
- Non-enriched designs were more efficient when follow-up periods exceed recruitment periods.
- Concave recruitment distributions (slow early recruitment) significantly extend total trial duration.
Conclusions:
- Adaptive enrichment designs with continued recruitment methods shorten total trial periods in specific scenarios, particularly when recruitment outpaces follow-up.
- These strategies are beneficial for targeted therapy development when the biomarker-positive population shows promise.
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