Bioequivalence and Bioavailability Forum

Dear D. Labes,

don’t want to interfer with your enthusiasm, but it seems that currently (anything?) except f₂ is not acceptable (in the EU). See HMA (XLS; tab ‘Finalised in 2008’, row 76 on Pantoprazole 20mg gastro-resistant, UK/H/1163/001/DC).

Grounds for referral to CMD(h)

The procedure was referred to CMD(h) due to potential serious risk to public health concerns raised on the absence of a bioequivalence study for the 20 mg strength. Concerns were raised that the justification for a biowaiver for the 20 mg strength based on similarity to the 40 mg strength was not acceptable due to differences in dissolution profiles. Although the applicant used statistical methods to prove similarity, these methods were not universally accepted.

Outcome

At the CMD(h) meeting, the RMS and CMS presented their view on the outstanding issue. The applicant had provided dissolution data to support the biowaiver for the 20 mg strength product, along with statistical assessment of these data. In order to confirm that the possible differences seen in the dissolution profile did not impact on the in vivo performance of the 20 mg product, the applicant would perform an additional bioequivalence study for the 20 mg strength within an agreed time frame. RMS and CMS agreed on this confirmatory study and consensus was reached that the procedure could be positively concluded. CMD(h) also considered that the issue of statistical methods used to show similarity of dissolution studies, should be referred to the QWP for further discussion and advice.

(my emphases)

The Mahanalobis distance was used in the application; for details see MHRA’s Public Assessment Report (pages 33-35).