Zeng Yaohui, Singh Sachinkumar, Wang Kai, Ahrens Richard C
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
J Clin Pharmacol. 2018 Apr;58(4):457-465. doi: 10.1002/jcph.1045. Epub 2017 Dec 27.
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.
使用乙酰甲胆碱激发试验来评估仿制药和创新药沙丁胺醇制剂生物等效性的药效学研究，通常是按照美国食品药品监督管理局发布的指南进行设计的，采用3个参比剂量和1个试验剂量（3×1设计）。这些研究实施起来具有挑战性且成本高昂，通常需要大样本量。我们提出了14种改良研究设计，作为美国食品药品监督管理局推荐的3×1设计的替代方案，假设增加参比和/或试验剂量会减少样本量和成本。我们使用蒙特卡洛模拟来估计样本量。模拟输入是根据已发表的研究以及我们自身对这类试验的经验来选择的。我们还估计了这些改良研究设计对研究成本的影响。相对于3×1设计，这些改变后的设计大多减少了样本量和成本，有些成本降低超过40%。最有效的单个添加试验剂量是180μg的试验制剂，估计成本相对降低30%。添加90μg的单个试验剂量效果较差，仅使成本降低13%。添加180μg、270μg或360μg的单个参比剂量益处不大（成本降低不到10%），而添加720μg导致成本降低19%。在我们评估的14种研究设计改良方案中，最有效的是同时添加90μg试验剂量和720μg参比剂量（成本降低42%）。将180μg试验剂量和720μg参比剂量相结合，估计成本降低36%。
