Bioequivalence and Bioavailability Forum

Dear bioequa!

❝ Thank You for Your prompt answer. What would You suggest?

Without further information – nothing.
When it comes to highly variable drugs, countries’ regulations are very different (see this post). The only European public assessment report I could find was on Tevas’ issued by the Hungarian authority (RMS) back in 2009 (CMSs: AT, BE, BG, CZ, DE, DK, EE, EL, ES, FR, IE, IT, LT, LU, LV, NL, NO, PL, PT, RO, SI, SK, UK). According to this report in a scientific advice (October 2008) it was suggested to give an acceptance range for AUC and C_max of 2-OH atorvastatin. It’s unclear to me whether bioequivalence was shown for parent, metabolite, or both (BTW, 4-OH was also measured).

EMA has no intentions to come up with a list of highly variable drugs and/or product-specific guidelines (which would end the parent/metabolite discussions). The only tool we have are the public assessment reports – which lag behind. The guideline is in force for only five months right no now. I don’t expect that there’s a single PAR according to the new GL already available at the European Product Index.

In your original post you asked about the acceptability of parent/metabolite and widening of the acceptance range in different countries. As already said – points of view are different. If you plan a study for one region (EU, US, ), your chances to get an approval in another region can be rated from likely to nil. Examples:

• Australia follows EU’s 2001 GL, but you have to use the Australian reference product. EMA’s 2010 GL is currently in the evaluation phase. Outcome unclear.
  
• RSA has their own guidelines and require the South African reference product – unless you can show that the reference in the study is similar in vitro to RSA’s reference.
  
• Whilst it is possible to run a conventional BE study for US and EU (6-sequence, 3-period) with both a European reference and US’ RLD - if you think about scaling: no way.
  
• And so on and so forth…

Any submission of a dossier which was planned to follow closely one region’s guidelines to another region is more or less risky. The worst I have seen was the application of a HVDP to Saudi Arabia 19 years after the study was performed in Germany. At that time it was state of the art to run a study only in steady state in order to reduce variability. And the validation of the analytical method was, well… Took ages, deficiency letters and answers went to and fro and finally the dossier was retracted.
See also ElMaestro’s observations.