Justifying the lack of incurred sample reproducibility in a study Perspective
The intra subject coefficient of variation (CV) An approximated intra subject CV based on in-house data and/or literature is usually already stated in the study protocol. If the intra subject CV obtained during the study is close to the intra subject CV mentioned in the protocol, it demonstrates that the results are similar to those observed in previous studies and/or described in the literature. This is a good indication that the assay is not highly variable and should have a good reproducibility.
Conclusion In addition to the points discussed above, a good prac- tice in ISR testing is investigating the results to delin- eate possible biases in the original data. Indeed, failing or not, the percent difference calculated between the first values and their repeats may indicate an issue with one of the two analyses or with the method itself. For example, a high quantity of biases on the same side of the mean (e.g., all negative or all positive) can indi- cate an issue beyond the expected analytical variabil- ity such as a significant technical difference between the two analyses or a stability issue in study samples. Failing ISRs can be due to a poor execution or a poor method [7]. In justifying the lack of ISR in a study per- formed before the ISR requirement came into place, it is therefore appropriate to evaluate if such a bias could have changed the study outcome. The investigation process detailed in this paper
may reveal that the assay used at the time of the study did not perform in a way that would, with today’s
References
1 Viswanathan CT, Bansal S, Booth B et al. Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Pharm. Res. 24(10), 1962–1973 (2007).
2
Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation. US Department of Health and Human Services, DC, USA (2001).
3 European Medicine Agency. Guideline on Bioanalytical Method Validation. Committee for Human Medicinal Products, London, UK (2011).
4 European Medicine Agency. Questions & Answers: Positions on Specific Questions Addressed to the Pharmacokinetics
5
knowledge, ensure the full integrity of the data. In these rare occasions, we recommend a transparent approach with both the sponsor and the agency who has issued the deficiency.
Future perspective With its Q&A paper, the EMA has provided a useful back-bone for the justification of the lack of ISR in a study. As of now, the justifications that were written based on these outlines seem to have been successfully accepted by agencies. However, will the regulators con- tinue to accept studies that were performed sometimes more than 10 years ago? Only time will tell. In the meantime, in order to provide the best impact assess- ment possible, it is pivotal to look at every aspect of the study, from the chemistry of the drug itself to every bioanalytical and statistical data available. No rock must be left unturned and a certain level of creativity is a plus; sound arguments of the reliability of the data can sometimes be found in areas less traveled.
Financial & competing interests disclosure The authors have no relevant affiliations or financial in- volvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employ- ment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this
manuscript.
Working Party. Committee for Human Medicinal Products, London, UK (2012).
Lowes S, Jersey J, Shoup R et al. Recommendations on: Internal standard criteria, stability, incurred sample reanalysis and recent 483s by the Global CRO Council for Bioanalysis. Bioanalysis 3(12), 1323–1332 (2011).
6 European Medicine Agency. Guideline on the Investigation of Bioeqivalence. Committee for Medicinal Products for Human Use. Committee for Human Medicinal Products, London, UK (2010).
7 Timmerman P, Luedtke S, van Amsterdam et al. Incurred sample reproducibility: Views and recommendations by the European Bioanalysis Forum. Bioanalysis 1(6), 1049–1056 (2009).
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