Seamless Phase IIa/IIb and enhanced dose-finding adaptive design

ABSTRACT

In drug development, when the drug class has a relatively well-defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This article considers combining a proof of concept (POC) study and a dose-finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for Phase III trials. This article seeks more efficient DF strategies that allow the economical testing of more doses. Hypothetical examples are simulated to compare the proposed adaptive design vs. the conventional design based on different models of the overall quantitative representation of efficacy, safety, and tolerability. The results show that the proposed adaptive design tests more active doses with higher power and comparable or smaller sample size in a shorter overall study duration for POC and DF, compared with a conventional design.

KEYWORDS:

• Adaptive design
• dose finding
• proof of concept
• seamless design
• utility

Acknowledgments

We thank Dr. Heinz Schmidli for his review and comments on an earlier version of this article, which have been incorporated into this version. The authors thank the editor, the associate editor, and three referees for their constructive comments that led to a substantial improvement of the article.

Funding

This work was partially supported by the National Institutes of Health (grant P01CA142538).

Additional information

Funding

This work was partially supported by the National Institutes of Health (grant P01CA142538).