Keynote abstract
Since January 2002 a new version of the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence (NfG on BA/BE) has been into operation.
The application of this new version, has led to divergence of interpretation on some sections. This is a consequence of the new EU regulations (Directive 2001/83 as amended by Directive 2004/27). Not only the number of generic medicinal products has increased enormously, but the stricter rules have left less room for individual decisions among the member states as well. These divergent opinions are referred to the EMEA committees (CMDh and CHMP) with the consequent work load and decisions which are more of a regulatory rather than a scientific nature.
The need to revise the NfG has been identified and a “Questions and Answers” document has been approved trying to clarify some of the most controversial issues. However it is the NfG itself that has to be revised, since clarifications cannot modify its contents.
A NfG is not a static set of rules.The input resulting from its use in new cases has to be taken into account and incorporated, should it be the case, as modifications to the current text, even if this implies a major revision.
The following subjects have been the object of doubts and been subject to misinterpretations:
- Dose proportionality rules
- Use of metabolite data
- Steady state studies
- Reference Medicinal Products
- Concept of Highly Variable Drugs
- Tolerance intervals for parameters of interest
- Use of exemption criteria
Therefore a substantial revision is in order covering the following topics on the basis of sound scientific principles and data.
- the concept of essential similarity, which has been changed in the new legislation
- references to recent directives and guidelines
- need/use of parallel and sequential designs
- steady state and dose and time dependent pharmacokinetics designs
- analytes to be measured and to be taken into account in the assessment ofbioequivalence.
- the need of enantiomeric bioanalytical methods
- requirements for potency correction of Test and Reference products.
- study design/dosing instructions for particular dosage forms (e.g. orodispersible tablets)
- dissolution test conditions
- proportionality rules and the selection of the strength to be measured
- the assessment of Cmax in bioequivalence studies and whether the acceptance range of BE limits (90% CIs) can be extended
- requirements on how to handle outliers and the inclusion of the borders of the 90% CI
- the use of a non-parametric statistical method
- the definition and handling of highly variable drugs
- standardisation in food effect studies
- the use of urinary data for bioequivalence assessment
- BCS concepts and biowaiver requirements to be revised and expanded.
