Bioequivalence and Bioavailability Forum

Hi rocky,


Wow, 10.1 for the high strength and 10.3 for the others, that's creative thinking from your side

❝ My question is whether a three arm bio study (2.5mg x 4 vs 10mg (Test) vs 10mg (Ref) is acceptable on the above case and whether authorities allow to use two reference products (RMP & ERP) on the same DCP procedure?

That is likely your best try but you really are in a situation that is not covered in detail by EU guidelines. I imagine you are now in your clock-stop without time for a sc. advice? If authorities requested a biostudy then I guess you may have to do one unless you have very compelling reasons to believe they will back down. You could also just do 10 mg vs 10 mg initially, get approval for that and then do a line extension for the other strengths once you have thmbs up for the high strength. I think this would be a safer approach although I am sure your marketing folks will punch you in the face and tell you they want approval for everything here and now if you suggest that.
If you can then please give more details: API, reasons for other strengths, proposed 4.1 and 4.2 for the lower strengths, RMS, CMSs.
As regards the ERP/RMP issue I haven't understood it. Why is the ERP different from the RMP in your case?

Dear Rocky
for a reasonable reply I would need some further information. First why did you think, that a bio study was not required? A BCS class I or III biowaiver does not apply (non-linearity, variable absorption).
According to CPMP/QWP/EWP/1401/98 Rev. 1 bioequivalence should in most cases be established both at the highest strength and at the lowest strength for drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose range. However you have the problem, that for the lowest strength you have no reference product. Testing of 2.5mg x 4 vs 10mg x 1 would be of no help if the non-linearity is not caused by limited solubility but is due to e.g. saturation of uptake transporters. A line extension (additional strength) would only be possible within the therapeutic dose range (strengths) covered by the originator. For additional strengths outside the originatorś dose range you need to submit clinical data.
BTW what does RMP & ERP mean?
Kind regards
Dan

❝ My question is whether a three arm bio study (2.5mg x 4 vs 10mg (Test) vs 10mg (Ref) is acceptable on the above case and whether authorities allow to use two reference products (RMP & ERP) on the same DCP procedure?

I guess you mean that the RMP is the Reference Medicinal Product in the country of application and that the ERP is the European Reference Product (another reference product available within EU/EEA).

Authorities normally do not accept different reference products for the same DCP, unless you can prove that there is a link between the reference products (that they belong to the same global MA).