Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Methodol. Jun 26, 2014; 4(2): 109-122
Published online Jun 26, 2014. doi: 10.5662/wjm.v4.i2.109
Choosing inclusion criteria that minimize the time and cost of clinical trials
Charles F Babbs
Charles F Babbs, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States
Author contributions: Babbs CF was the sole author and contributor to this paper.
Correspondence to: Charles F Babbs, MD, PhD, Weldon School of Biomedical Engineering, Purdue University, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, United States. babbs@purdue.edu
Telephone: +1-765-4942995 Fax: +1-765-4941193
Received: November 14, 2013
Revised: February 13, 2014
Accepted: April 16, 2014
Published online: June 26, 2014
Processing time: 279 Days and 17.8 Hours
Abstract

AIM: To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria.

METHODS: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design.

RESULTS: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on a representative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial.

CONCLUSION: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors.

Keywords: Adaptive trial designs; Biomarkers; Clinical trials; Device; Drug therapy; Ethics; Methodology; Optimal allocation; Personalized medicine; Sequential design

Core tip: This paper presents statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria. The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist for many realistic scenarios. Potential cost savings for typical trial scenarios range in millions of dollars. Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of type II errors.