Bioequivalence of ANDA Data using a Non-Informative Bayesian Procedure (BEST) Compared with the Two One‑Sided t‑Tests (TOST).

IF 5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Jing Wang, Gregory Campbell, Jae H Lee, Meng Hu, Kairui Feng, Somesh Chattopadhyay, Liang Zhao, Carl C Peck
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引用次数: 0

Abstract

The regulatory statistical standard for evaluating average bioequivalence (BE) in generic drug testing, formulation bridging, and 505b2 drug comparisons has traditionally employed the two one-sided t-tests (TOST) procedure. A comparison of BE determinations of TOST and a t-distribution-based, non-informative Bayesian procedure (BayesT) was conducted on 2341 pharmacokinetic parameter datasets in 678 anonymized abbreviated new drug applications (ANDAs) to assess the influence of deviations from lognormality and the presence of extreme values. This research has been motivated to assess reliability of statistical inference procedures for accurate and fair regulatory assessments of BE and non-BE (NBE). The BE criterion of 90% confidence (CI) or Bayesian credible (CrI) intervals of log test/reference ratios for TOST and BayesT was 0.80-1.25. TOST. BayesT agreed on BE conclusions in 98.9% of cases. There were 20 disagreed cases in which TOST rejected BE and BayesT concluded BE, wherein all cases failed the lognormality test and 17 of which contained extreme values (4.2% of 409 cases that contained extreme values). In this circumstance, TOST can be overly conservative in the presence of extreme values. There were 7 cases in which TOST concluded BE at outer BE bounds, while BayesT marginally rejected BE, despite these cases successfully passing the lognormality test. While TOST remains a widely accepted method for BE assessment, the presence of extreme values and deviations from lognormality may lead to faulty inference of BE. The BayesT methodology offers an alternative approach to TOST that can be prespecified to assess BE in such scenarios. Pre-specified application of the BayesT procedure may ensure more reliable outcomes in regulatory assessments of BE.

使用非信息贝叶斯程序(BEST)与双单侧t检验(TOST)比较ANDA数据的生物等效性
在仿制药测试、配方桥接和505b2药物比较中,评估平均生物等效性(BE)的监管统计标准传统上采用了两个单侧t检验(TOST)程序。对678个匿名简化新药申请(anda)的2341个药代动力学参数数据集进行了TOST的BE测定与基于t分布的非信息贝叶斯方法(BayesT)的比较,以评估偏离对数正态性和极值存在的影响。本研究的动机是评估统计推断程序的可靠性,以准确和公平地对BE和非BE (NBE)进行监管评估。TOST和BayesT的对数检验/参考比的90%置信(CI)或贝叶斯可信(CrI)区间的BE标准为0.80-1.25。烤面包。在98.9%的案例中,BayesT同意BE的结论。有20例TOST拒绝BE, BayesT推断BE,其中所有病例均未通过对数正态性检验,其中17例包含极值(409例包含极值的4.2%)。在这种情况下,TOST在存在极端值时可能过于保守。有7例TOST在BE边界外推断BE,而BayesT在边际上拒绝BE,尽管这些病例成功地通过了对数正态性检验。虽然TOST仍然是一种被广泛接受的BE评估方法,但极值和偏离对数正态性的存在可能导致错误的BE推断。BayesT方法提供了一种替代TOST的方法,可以预先指定以评估这种情况下的be。预先指定BayesT程序的应用可以确保在BE的监管评估中获得更可靠的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
AAPS Journal
AAPS Journal 医学-药学
CiteScore
7.80
自引率
4.40%
发文量
109
审稿时长
1 months
期刊介绍: The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists (AAPS), publishes novel and significant findings in the various areas of pharmaceutical sciences impacting human and veterinary therapeutics, including: · Drug Design and Discovery · Pharmaceutical Biotechnology · Biopharmaceutics, Formulation, and Drug Delivery · Metabolism and Transport · Pharmacokinetics, Pharmacodynamics, and Pharmacometrics · Translational Research · Clinical Evaluations and Therapeutic Outcomes · Regulatory Science We invite submissions under the following article types: · Original Research Articles · Reviews and Mini-reviews · White Papers, Commentaries, and Editorials · Meeting Reports · Brief/Technical Reports and Rapid Communications · Regulatory Notes · Tutorials · Protocols in the Pharmaceutical Sciences In addition, The AAPS Journal publishes themes, organized by guest editors, which are focused on particular areas of current interest to our field.
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