E-DRUG: RFI: Bioequivalence and generics registration (4)
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Dear E-Druggers,
As a pharmacist working part-time for the Dutch Medicines Evaluation Board
assessment of bioequivalence of generic products is part of my work. A note
for guidance on assessing bioequivalence of generic products is issued by
the European Regulatory Authority: EMEA and can be found at their website.
Follow this URL: http://www.emea.eu.int/pdfs/human/ewp/140198en.pdf
These regulations apply to the whole European Union.
Indeed the first two issues raised by the anonymous E- drugger apply in the
EC as well. i.e.
1) Dissolution Time in vitro;
2) Quantative analysis of the active ingredients;
but further issues of course apply.
As for point three for tablets it has to be shown in a clinical trial
(usually a randomized two-way crossover study) that rate and
extent of absorption are essentially similar. This is usually defined as
(sorry it gets technical here): the ratio's of AUC 0-inf (from time 0 to
infinite) and Cmax of test and reference product (innovator product) their
logarithmic transformed 90% Confidence intervals have to fall within a 80%
to 125% range.
So not specifically t1/2 has to be defined in-vivo, but is calculated as
well (as part of the AUC estimation). Even when half-life is similar this
does not necessarily mean rate and extent of absorption of two products are
similar and therefore bioequivalent!
Thus in-vivo tests are still considered necessary. However, in cooperation
with WHO there is a lot of work done looking for a waiver
of in-vivo bioequivalence studies for certain products. The
Biopharmaceutical Classification System (BCS) has been developed to
classify products according to their expected problems regarding
bioequivalence. The above mentioned note for guidance also goes into this
issue.
Having worked myself in a developing country I realise that it will be
difficult to assess whether such studies have performed
adequately. Probably the focus should be at having a reliable supplier,
securing that also further batches (thus not only the test- batch) comply
with the required or registration specifications.
So unfortunately I cannot completely agree with you. However I understand
this procedure does form a hurdle to register generics in
developing countries. Nevertheless, generics should also be of good
quality. Some products are really substandard (Of course MOST are not).
Further based on the BCS certain less problematic products possibly not
requiring in-vivo studies can be identified.
Alternatively you might be inclined to widen the acceptance range we have
set in the industrialized world (80-125%) but some proof of
quality of the generic product is probably still warranted.
Hope this contributes to the discussion. And please you can download the
note for guidance that applies to 25 countries in Europe
at the above mentioned site.
With regards,
Peter
Peter GM Mol, MScPharm
department of Clinical Pharmacology University Groningen
P.O. Box 196
9700 AD Groningen
The Netherlands
+31 (0)50 3638313
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