Bioequivalence and Bioavailability Forum

Hello ElMaestro,

Thank you for your quick reply.

The kind of oral powder I meant is something like that (http://www.sanaplus.com/product/powder-shots/powder-shot-vitamin-c-500-mg/), not the kind that is meant to be mixed with food for toddlers or elderly. That's why a claim "without water" would have been preferred, but it's not a no-go to specify water in the SmPC.
We are targeting OTC only, reimbursement is not an issue for us.

Regulatory environment: EU only, decentralised procedure, definitely Germany and Austria, probably additional CMS, free choice of RMS, 10(1) generic application (or probably 10(3) hybrid)

Study results
C_max: 82,70%, CI 77,08%-88,74%, CV 15,81%
AUC_0-tlast: 98,22%, CI 95,26%-101,28%, CV 6,84%
t_max(test): 2,70h
t_max(ref): 1,85h

sample size: 29 (30-1 dropout)
power for 15% CV and 10% product difference: 90%
necessary sample size for observed difference (17%): 280 for 80%, which is a no-go

Study design
single centre, open-label, randomised order of treatments, balanced, 3-period, 6-sequence, single dose change-over trial, administration under fasting conditions, separated by washout period >= 2 days
(Two reference products were used, one for BE, the other for marketing reasons...)

Food/liquid intake:
(Fasted state is the recommended condition for this substance.)
standardized dinner on evening before treatment, >8h fasting (no food, no beverages) before administration
standardized meals at 4, 8 and 12h p.a.
no fluid intake for 1h p.a., standardized fluid intake at 1-10h p.a. (150ml non-carbonated water per hour)

Administration of oral powder: wet mouth by swallowing 20ml tap water before administration, oral cavity examined after swallowing
Administration of reference: tablet taken with 240ml water

Our conclusion: We missed C_max due to slower absorption, most likely because of slower gastric passage (no resorption in the stomach). Administration with water would most likely solve the problem, i.e. result in a lower CI above 80.00%.

Therefore our main question is:
If BE is shown for administration with water, but not shown for administration without water, would the regulatory authorities accept a restriction "only with water" in the product information, or would they consider it a "potential serious risk to public health" and refuse the marketing authorisation, arguing that a patient might take the powder without water?

The situation is similar to the guideline for ODTs, where a comparative study ODT with water vs ODT without water vs reference with water is recommended, but the consequences of "failing BE without water" are not clear to me.

Thanks again,
Christian

P.S.: The statistics are all calculated by the CRO, not in-house.