NLM Title Abbreviation
J Clin Pharmacol
Journal of clinical pharmacology
DOI of Published Version
Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3-by-1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration-recommended 3-by-1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3-by-1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 μg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 μg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 μg yielded little benefit (less than 10% cost reduction), whereas adding 720 μg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90-μg test dose and a 720-μg reference dose (42% cost reduction). Combining a 180-μg test dose and a 720-μg reference dose produced an estimated 36% cost reduction.
Emax model, Monte Carlo simulation, asthma, cost analysis, pharmacodynamics, pediatrics
Journal Article Version
Version of Record
Published Article/Book Citation
J Clin Pharmacol. 2018 Apr;58(4):457-465. doi: 10.1002/jcph.1045. Epub 2017 Dec 27.
© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.