Kaur Paramjeet, Jiang Xiaojian, Stier Ethan
Division of Bioequivalence II, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
J Pharm Pharm Sci. 2017;20(0):252-257. doi: 10.18433/J39S6Z.
The US FDA's rule on "Requirements for Submission of Bioequivalence Data" requiring submission of all bioequivalence (BE) studies conducted on the same formulation of the drug product submitted for approval was published in Federal Register in January 2009. With the publication of this rule, we evaluated the impact of data from non-pivotal BE studies in assessing BE and identified the reasons for failed in vivo BE studies for generic oral delayed-release (DR) drug products only. We searched the Agency databases from January 2009 toDecember 2016 to identify Abbreviated New Drug Applications (ANDAs) submitted for DR drug products containing non-pivotal BE studies. Out of 202 ANDAs, 43 ANDAs contained 102 non-pivotal BE studies. Forty-nine non-pivotal BE studies were conducted on the to-be-marketed (TBM) formulation and 53 were conducted on formulations different from the TBM formulation. These experimental formulations primarily differed in the ratio of components of the enteric coating layer and/or amount (i.e., %w/w) of enteric coating layer. Of the 49 non-pivotal BE studies conducted on the TBM formulation, 41 failed to meet the BE acceptance criteria. The majority of failed non-pivotal BE studies on the TBM DR generic products had insufficient power, which was expected as these studies are exploratory in nature and not designed to have adequate power to pass the BE statistical criteria. In addition, among the failed non-pivotal BE studies on the TBM DR generic products, the most commonly failing pharmacokinetic parameter was Cmax. The data from these non-pivotal BE studies indicate that inadequate BE study design can lead to failure of the BE on the same formulation. Also, the non-pivotal BE studies on formulations different from the TBM formulation help us link the formulation design to the product performance in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
美国食品药品监督管理局（FDA）关于“生物等效性数据提交要求”的规定要求，对于提交批准的药品同一剂型，需提交所有进行过的生物等效性（BE）研究。该规定于2009年1月在《联邦公报》上发布。随着此规定的发布，我们评估了非关键BE研究数据在评估生物等效性方面的影响，并仅针对仿制口服缓释（DR）药品确定了体内BE研究失败的原因。我们检索了2009年1月至2016年12月期间该机构的数据库，以识别提交了包含非关键BE研究的DR药品的简略新药申请（ANDA）。在202份ANDA中，43份ANDA包含102项非关键BE研究。49项非关键BE研究是针对待上市（TBM）剂型进行的，53项是针对与TBM剂型不同的剂型进行的。这些实验剂型主要在肠溶包衣层成分比例和/或肠溶包衣层量（即%w/w）方面存在差异。在针对TBM剂型进行的49项非关键BE研究中，4项未达到BE接受标准。TBM DR仿制药非关键BE研究失败的大多数情况是检验效能不足，鉴于这些研究本质上是探索性的，并非设计用于具备足够检验效能以通过BE统计标准，这是意料之中的。此外，在TBM DR仿制药非关键BE研究失败的案例中，最常未达标的药代动力学参数是Cmax。这些非关键BE研究的数据表明，BE研究设计不当会导致同一剂型的BE研究失败。而且，针对与TBM剂型不同的剂型进行的非关键BE研究有助于我们将剂型设计与体内产品性能联系起来。本文接受发表后审查。注册读者（见“致读者”）可通过点击本期目录页面上的摘要进行评论。
