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Back to the forum  Query: 2017-04-29 01:33 CEST (UTC+2h)
 
VStus
Regular

Poland,
2017-03-21 14:06

Posting: # 17175
Views: 544
 

 Fixed combination product – clinical study instead of BE? [Regulatives / Guidelines]

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
javier
Junior

Spain,
2017-03-30 13:31

@ VStus
Posting: # 17211
Views: 265
 

 Fixed combination product – clinical study instead of BE?

» 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.

Hello

In my opinion Cmax is important BE studies if the RMP is administraded by specific route, (like subcutaneous) or has an clinical impact in this case mayors guideline like EMA and FDA demands it as a coprimary endpoints (toguether with AUC)

the regulatory authorithies demands a mean value for both product or demonstrade one primary endpoint is enough for bioequivalence (like intravenous infusion when F=100%)

I hope this explanation help you a little

best regards
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