Bioequivalence and Bioavailability Forum

Dear Colleagues,

My understanding of the current BE paradigm is that bioequivalence trials are intended to (a) demonstrate pharmaceutical performance (quality) of Tested product versus some product of Reference quality and (b) help to link Tested product to the clinical efficacy/safety data generated for Reference product(s).

Previous paradigm was that bioequivalence trials were accepted as a reliable surrogate for clinical equivalence.

Fixed combination products follow current BE paradigm in case of substitution indications and it seems that bioequivalence is always required if we want to have a substitution indication.

Question:
Do you have experience about revercing this pattern: using clical equivalence data for substitution indications of new fixed combination product when bioequivalence has not been demonstrated?

Additional information:

• individual products are used broadly for a long time, including evidence of co-administration;
  
• there is no Reference FDC;
  
• SD fasting study has shown bioequivalence for AUC of both components, but failed for Cmax (PE outside of acceptance range, upper bounds of 90%CI partially within the acceptance range);

Section 4.5 of the current Draft FDC GL states: 'clinical efficacy/safety studies ... will not resque a failed bioequivalence study', but it is relevant only when Reference FDC is available.

What if we want to perform clinical trials to satisfy requirements of 'add-on' indications? Should we still reformulate our product to have bioequivalence for both Cmax and AUCt vs. individual components? We think that Cmax is not relevant for the clinical effect, as medications are taken continiously for a very long time periods.

We already initiated activities to get regulatory advice.

Thank you very much in advance!

Best regards, VStus