使用非信息贝叶斯程序 (BEST) 的ANDA数据与两种单面t-test (TOST) 相比具有生物等价性
Jing Wang1, Gregory Campbell2,3, Jae H Lee1
1Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
传统的两种单面t测试 (TOST) 对生物等价性 (BE) 可能过于保守,具有极端的数据. 贝叶斯替代方案 (BayesT) 提供了更可靠的BE评估,特别是当数据偏离逻辑正常时.
科学领域:
- 药物动力学和生物制药学
- 药物开发中的统计方法
- 监管科学 监管科学
背景情况:
- 两种单面t测试 (TOST) 是评估平均生物等价性 (BE) 的标准统计方法.
- 对仿制药的监管评估,配方桥接和505b2药物比较依赖于BE评估.
- 与逻辑正常度和极端值的偏差可能会影响TOST用于BE确定的可靠性.
研究的目的:
- 为了比较TOST和贝叶斯程序 (BayesT) 的生物等价性评估的性能.
- 为了评估从逻辑正常度和极端值的偏差对BE确定的影响.
- 评估统计推断程序的可靠性,以准确和公平地对生物等价性和非生物等价性进行监管评估.
主要方法:
- 进行了对TOST和基于t分布的贝叶斯程序 (BayesT) 的比较分析.
- 从678个匿名缩写新药申请 (ANDA) 中分析了2341个药理学参数数据集.
- 两种方法的BE标准是90%的置信度 (CI) 或贝叶斯可信度 (CrI) 间隔的日志测试/参考比在0.80-1.25.5之间.
主要成果:
- 在98.9%的分析数据集中,TOST和BayesT同意了BE的结论.
- 在20个不同意的案例中,TOST拒绝了BE,而BayesT则结论BE,所有失败的lognormality和17个包含极端值.
- 在极端值时,TOST可能过于保守,并且从逻辑正常度的偏差可能导致错误的BE推断.
结论:
- 贝叶斯方法 (BayesT) 提供了一个可靠的替代TOST生物等价性评估.
- 贝叶斯测试可以在从逻辑正常度和极端值偏差的场景中提供更强大的结果.
- 贝叶斯测试的预先规定的应用可能会提高生物等价性监管评估的可靠性.
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