Bioequivalence and Bioavailability Forum

Tóthfalusi L, Endrényi L and A García-Arieta
Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence
Clin Pharmacokinet 48(11), 725–43 (2009)
online Abstract

  The EMEA began discussion of this topic by issuing a concept paper on it. The concept paper was later withdrawn from the EMEA website, although it is still available on other websites, such as http://bebac.at/Guidelines.htm#EU.
  The recently published new draft of the European guideline on the investigation of bioequivalence suggests a very conservative approach to solving the problem of HVDs. It abandons the concept of widening bioequivalence limits based only on clinical grounds. It suggests a single alternative limit of 0.75–1.33 for HVDs, but only if the applicant can demonstrate, by using a replicate design, that the within-subject variability of the reference drug is >30%. A further restriction is that this widened limit is allowed only for the C_max. However, the draft guideline is certainly not the final version. Numerous comments were submitted on the draft document during the consultation period, suggesting the need to follow the SABE approach. Thus, several aspects of the new guideline, including SABE to establish bioequivalence of HVDs, are still being discussed intensively in Europe.