Fuglsang Anders, Dogra Anshul, Sharma Naveen
Fuglsang Pharma, Aastrupvej 11E, 1.Th, 6100, Haderslev, Denmark.
Cliantha Research, Cliantha Corporate, TP 86, FP 28/1, Off S.P. Ring Road, Sarkhej, Ahmedabad, 382210, Gujarat, India.
AAPS J. 2024 Dec 16;27(1):15. doi: 10.1208/s12248-024-01000-x.
Duplicate pharmacokinetic profiles in bioequivalence trials is an issue which has caused hundreds of retracted marketing authorizations. No formal test for profile duplication exists in spite of the existence of profile comparison algorithms, so defining a threshold that distinguishes a naturally occurring pair from a duplication remains difficult. An idea called ISPR (incurred subject period analysis) was aired in 2023 and is evaluated in this paper along with three new profile comparison methods. ISPR involves analysis of entire PK-profiles within a study. It is shown that when ISPR is combined with appropriate PK-profile comparison methods, the duplicate pairs display a lower score (better similarity) than pair that do not arise out of duplication. Therefore, ISPR may help establish a threshold that distinguishes fraudulent profile pairs from non-fraudulent profile pairs. ISPR therefore may be used as QA tool, serves as a method by which a CRO can -to some extent- show that their studies do not contain duplicates in the primary analysis, and thus also may be a means by which sponsor can argue that their studies are trustworthy, in case the suspicion about duplication arises. This paper does not introduce a formal test for this type of fraud; rather the authors see it as a first moderate step in that direction. Hopefully, if or when ISPR data is submitted to authorities as part of general dossier submission, data will accumulate to the extent that they may be able to develop models that allow formal testing for profile duplication.
生物等效性试验中的重复药代动力学特征是一个已导致数百项上市许可被撤回的问题。尽管存在特征比较算法，但目前尚无针对特征重复的正式测试，因此，要确定一个能区分自然出现的配对与重复配对的阈值仍然很困难。一种名为ISPR（受试者用药期分析）的方法于2023年被提出，并在本文中与三种新的特征比较方法一同进行评估。ISPR涉及对一项研究中整个药代动力学特征的分析。结果表明，当ISPR与适当的药代动力学特征比较方法相结合时，重复配对的得分（相似度更高）低于非重复产生的配对。因此，ISPR可能有助于建立一个区分欺诈性特征配对与非欺诈性特征配对的阈值。因此，ISPR可用作质量保证工具，作为一种方法，合同研究组织（CRO）可以在一定程度上表明其研究在初步分析中不包含重复数据，因此，在出现重复嫌疑的情况下，它也可能是申办者证明其研究可信的一种手段。本文并未针对此类欺诈行为引入正式测试；相反，作者将其视为朝着该方向迈出的适度的第一步。希望当ISPR数据作为通用档案提交的一部分提交给当局时，数据能够积累到一定程度，使他们能够开发出允许对特征重复进行正式测试的模型。
