Bioequivalence and Bioavailability Forum

Dear all,

at IBC's '5th annual Conference on Dissolution Testing, Bioavailability & Bioequivalence' which took place 22-24 May 2006 in Budapest/Hungary we had a little discussion about the generally applied method of average bioequivalence (ABE) in generic substitution.
Although conceptually ABE is designed to allow patients to enter a therapy on a generic drug ('Prescribability'), some European countries allow switching from one preparation to another one during therapy ('Switchability').

Formally ABE is not a correct method to assess switchability - which can be assessed by 'Individual BE' (IBE).

Interesting in this context is the statement of the Danish Authority (DKMA):
'The Danish Medicines Agency considers that the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed. Deviations may be accepted if they can be adequately justified not to have impact on either the overall therapeutic effect or safety profile of the product.'

The inclusion of 100% may be difficult to meet if a drug exhibits low variability (i.e., CV <10%), or the sample size is rather high ('to be on the safe side...'.
I had to deal with about one deficiency letter / month during the last half year (from Belgium and Germany).
Recommendation: don't overpower your study!

Another point stated (Table 1) is the narrower acceptance range (AUC, Cmax: 90%-111%) for a couple of drugs / drug classes, namely Aminophylline/Theophylline, Lithium, Thyroxine, Warfarin, Antiepileptics apart from benzodiazepines (Lamotrigine: 90%-110%), Immunosuppressives, Antiarrhythmics, Centrally acting anorectics, and Tricyclic antidepressants.