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EMA issues new Q & A document for Pharmacokinetics. 

EMA has issued a new Q & A document titled “Positions on specific questions addressed to the pharmacokinetics working party”. In the context of assessment procedures, the Pharmacokinetics Working Party (PKWP), or its predecessor the Therapeutic Subgroup on Pharmacokinetics of the Efficacy Working Party (EWP-PK subgroup), is occasionally consulted by the CHMP or, following CHMP’s agreement, by other Committees, Working parties or the CMD(h). The objective is to address specific questions in relation to pharmacokinetic evaluations and particularly the requirements and assessment of bioequivalence studies. The positions, which are being elaborated by the PKWP in response to such questions, are being forwarded to the enquiring party for consideration in their assessment. 

It is understood that such position will be reflected in the procedure-related assessment reports if applicable. In some cases however, these position might also be of more general interest as they interpret a very specific aspect that would not necessarily be covered by guidelines. This paper summarises these positions which have been identified as being within this scope. In addition, general clarifications related to guidelines authored by the PKWP are subject to specific positions in this paper. 

It should be noted that these positions are based on the current scientific knowledge as well as regulatory precedents. They should be read in conjunction with the applicable guidelines on bioequivalence in their current version. If the questions have initially been raised in the context of specific assessment procedures, details of these procedures have been redacted for reasons of confidentiality. The positions in this document are addressing very specific aspects. They should not be quoted as product-specific advice on a particular matter as this may require reflection of specific data available for this product. By no means should these positions be understood as being legally enforceable. 

The new topic added in this document is “Number of subjects in a two-stage bioequivalence study design”. According to the Guideline on the Investigation of Bioequivalence (CPMP/QWP/EWP/1401/98 Rev.1), it  is acceptable to use a two-stage approach when attempting to demonstrate bioequivalence. The question was raised whether there was a minimum number of subjects that should be included in the second stage of such a design. The conclusion for this is summarized below: 

1) The expected analysis for the combined data in a two-stage design is ANOVA with terms for stage, sequence, sequence*stage, subject (sequence*stage), period (stage), formulation.

2) This model can be fitted provided that in each stage, there is at least one subject randomised to each sequence. This does not supersede the requirement for at least 12 subjects overall.

3) A term for a formulation*stage interaction should not be fitted.