BEBAC   Ing. Helmut Schütz

Recommendation on the Need for Revision of (CHMP) <Note for Guidance on the Investigation of Bioavailability and Bioequivalence> CPMP/EWP/QWP/1401/98

EU – EMEA

On 24 May 2007 a Recommendation to update the current European NfG on BA/BE was published by the Efficacy Working Party (EWP).

An overview of the document is given below:

  1. Introduction

    Discussion during mutual recognition procedures (MRP) and decentralised (DC) procedures revealed that several issues in the NfG may be differently interpreted by Member States. Better clarity on these issues should improve the understanding of the Guideline, and as a result may increase the consensus between Member States. Better clarity on these issues should improve the understanding of the Guideline, and as a result may increase the consensus between Member States during the MRP and DC procedures.

  2. Problem Statement
    • The NfG is outdated in some aspects, since the coming into force of the new pharmaceutical legislation with the new amendment of Directive 2001/83/EC.
    • BA and BE are two different topics that need to be distinguished and each deserves specific attention.
    • Regulatory experience has shown that guidance on BE needs further harmonisation within the European Union (see the article on the Questions & Answers Document).
    • Update on guidance and requirements on the analytes to be measured.
    • Further recommendations on biowaivers based on the Biopharmaceutics Classification System (BCS).
  3. Discussion Points
    • Specific recommendations on BA will be given. Requirements on exploratory and confirmatory BA and BE studies will be differentiated in separate sections of the guidance document.
    • Recommendations on BE in the current guidance will be updated with regard to:
      • the concept of essential similarity which has changed since the new legislation with reference to the recent Directive amendment (Directive 2004/27/EC) and relevant guidelines
      • under which circumstances a parallel design may be used
      • under which circumstances a sequential design may be used
      • the study design for drugs with dose and time dependent pharmacokinetics
      • the acceptability of steady state designs
      • the analytes to be measured and to be taken into account in the assessment of bioequivalence
      • 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 of compositions
    • Incorporation and adaptation of other topics discussed in the recent Question and Answer document:
      • the assessment of Cmax in bioequivalence studies
      • whether the acceptance range of BE limits (90% CIs) can be extended
      • requirements on how to handle outliers
      • inclusion of the borders of the 90% CI
      • the use of a non-parametric statistical method
      • in which cases metabolites have to be measured and to be taken into account in the bioequivalence assessment
      • the definition of highly variable drugs
      • the selection of the strength to be measured
      • standardisation with regard to food intake for studies under fed conditions
      • the use of urinary data for bioequivalence assessment
    • BCS concepts and biowaiver requirements will be revised and expanded in a separate Annex/section

It is proposed to revise the current Note for Guidance on the Investigation of BA/BE (CHMP/EWP/QWP/1401/98) to provide an updated NfG on the above-mentioned issues.

It is anticipated that a draft CHMP document may be released 12 months after adoption of the Concept Paper. The preparation of this document will involve the EWP Therapeutic Subgroup on Pharmacokinetics and the QWP.

End of consultation (deadline for comments) by interested parties (academia and international scientific societies related to bioavailability, bioequivalence, pharmacokinetics and in vitro dissolution) was 31 August 2007.
Comments should by provided to EWPSecretariat@emea.europa.eu
Fax: +44 20 74 18 86 13