Perspective Gagnon-Carignan, Lachance, Saint-Laurent, Gendron & Lévesque
reference product, can be used for PK data compari- son. All attempts should be done to compare data from studies having the most appropriate study design. The standard deviation for all parameters is to be taken into account for comparison regardless of the source of the data. The criteria for bioequivalence are based on the
90% geometric confidence interval [6]. These criteria are usually defined a priori in the study proto- col. When assessing the impact of the lack of ISR in a study, the following can be examined:
The 90% confidence interval It is important to note that variability of the analyti- cal method will tend to widen the 90% confidence interval. Therefore, if the width of the 90% confidence intervals is narrow and well within the acceptance
Executive summary
In February 2012, the European Medicine Agency (EMA) made the incurred sample reanalysis (ISR) a requirement. The EMA published a paper entitled ‘Questions & Answers: Positions on specific questions addressed to the pharmacokinetics (PKs) working party’. The document separates the EMA’s expectation of the lack of ISR justification into five main topics. The metabolites back-conversion • Metabolites may interfere with the quantitation of an analyte and may back-convert into the analyte of interest. The justification for the lack of ISR should include an assessment of the extent of potential interference caused by these metabolites. In addition, each step of the bioanalysis must be assessed for the degradation of the metabolites into the parent drug.
The other ISR data obtained in the same laboratory • With the years, laboratories may have generated in-house ISR data for several compounds. This additional data can be used to demonstrate the reproducibility of the assay even if it was not generated for the same study. However, before using this data, certain considerations must be taken into account.
The data from repeat analysis • There can be three main types of repeats in a bioanalytical study that can prove the reproducibility of the analysis. For example: – Repeats that are generated when, for a multi-analyte assay, samples are repeated for one of the compounds only;
– Samples for which the initial analysis is deemed unacceptable due to measurable factors; – Samples for which the initial analysis is to be confirmed because of a doubt on its exactitude, for example, investigational repeats and PK repeats.
• The use of this repeat data to demonstrate that an assay is reproducible must however be done carefully and accompanied by a rationale.
The obtained PK data in the study • The PK data obtained in the study should be compared with the PK data available in-house or in the literature. The 90% confidence interval • The criteria for bioequivalence are based on the 90% geometric confidence interval. These criteria are usually defined a priori in the study protocol. When assessing the impact of the lack of ISR in a study, the following can be examined: – With the 90% confidence interval; – The ratio obtained; – The intra subject coefficient of variation (CV).
Conclusion • With its Q&A paper, the EMA has provided a useful back-bone for the justification of the lack or ISR in a study. Will the regulators continue to accept studies that were performed sometimes more than 10 years ago? In the meantime, in order to provide the best impact assessment possible, no rock must be left unturned and a certain level of creativity is necessary.
limits already planned by the study protocol, this can indicate the absence of the variations that would have been caused by potential ISR problem. The lack of ISR in such cases should therefore have no impact on the outcome of the study. However, in the cases where the 90% confidence
intervals obtained are close to the acceptance limits, an examination of the ratio and intra subject coeffi- cient of variation obtained can be done. In addition, the assessment of the impact of potential ISR problems on the outcome of the study should be conducted by evaluating the other topics discussed above.
The ratio obtained Again, if the ratios are near 100%, variations due to a potential ISR problem should have no impact on the outcome of the study.
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Bioanalysis (2015) 7(2)
future science group
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