Abstract
Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)—one of the tools used to validate a method—is included in the bioanalytical regulatory recommendations. The methodology of this test is well established, but the estimation of the sample size is still commented on and contested. We have applied the hypergeometric distribution to evaluate ISR test passing rates in different clinical study sizes. We have tested both fixed rates of the clinical samples—as currently recommended by FDA and EMA—and a fixed number of ISRs. Our study revealed that the passing rate using the current sample size calculation is related to the clinical study size. However, the passing rate is much less dependent on the clinical study size when a fixed number of ISRs is used. Thus, we suggest using a fixed number of ISRs, e.g., 30 samples, for all studies. We found the hypergeometric distribution to be an adequate model for the assessment of similarities in original and repeated data. This model may be further used to optimize the sample size needed for the ISR test as well as to bridge data from different methods. This paper provides a basis to re-consider current ISR recommendations and implement a more statistically rationalized and risk-controlled approach.
Highlights
Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development
This is in line with the current regulatory practice which uses a two-step fixed ratio depending on the clinical study size: n/N = 10% up to 1000 clinical samples and n/N = 5% [5,7]
This paper provides a basis to re-consider the current incurred samples reanalysis (ISR) sample size calculation based on the clinical study size (N)
Summary
Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. The American Association of Pharmaceutical Scientists (AAPS) and the US Food and Drug Administration (FDA) were the driving forces behind discussions on the bioanalytical method validation in the 1990s [1]. Both AAPS and FDA are constantly involved in the evolution of bioanalytical requirements, including incurred samples reanalysis (ISR) [2,3]. The ISR was included in the bioanalytical regulatory recommendations by the European Medicines Agency (EMA) [5], the Health Canada [6], and the FDA [7]. The ISR is part of the regulatory documents, the topic is still under much discussion in the bioanalytical and pharmaceutical community [8,9,10,11,12,13,14,15,16]
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