Probability monitoring procedures for sample size determination

ABSTRACT

In clinical research, power analysis is often performed for sample size calculation. The purpose is to achieve a desired power of correctly detecting a clinically meaningful difference at a pre-specified level of significance if such a difference truly exists. However, in some situations such as (i) clinical trials with extremely low incidence rates and (ii) for rare disease drug development clinical trials, power analysis for sample size calculation may not be feasible because (i) it may require a huge sample size for detecting a relatively small difference and (ii) eligible patients may not be available for a small target patient population. In these cases, other procedures for sample size determination with certain statistical assurance are needed. In this article, an innovative method based on a probability monitoring procedure is proposed for sample size determination. The concept is to select an appropriate sample size for controlling the probability of crossing safety and/or efficacy boundaries. For rare disease clinical development, an adaptive probability monitoring procedure may be applied if a multiple-stage adaptive trial design is used.

KEYWORDS:

• Rare disease
• power analysis
• precision analysis
• probability monitoring procedure

Disclaimer

The opinions and information in this manuscript are those of the authors, and do not represent the views and/or policies of the U.S. Food and Drug Administration.

Additional information

Funding

Huang’s work is partly supported through a grant from the U.S. Food and Drug Administration, and by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.