Bioequivalence and Bioavailability Forum

Hi ElMaestro and all,

I’ve read the Q&A again. Here the last paragraph in all of its beauty:

Any approach based upon confidence intervals for ƒ₂ would, however, be considered appropriate whether the validity criteria outlined in CHMP guidance are met or not [CPMP/EWP/QWP/1401/98 Rev. 1/Corr**]. Similarity could then be declared if the confidence interval for ƒ₂ were entirely above 50. However, regardless of whether the conditions to adequately apply ƒ₂ in a dissolution experiment are fulfilled or not, the properties of the ƒ₂ sampling distribution do not allow the derivation of exact confidence intervals to adequately quantify the uncertainty of the ƒ₂ estimate. To address this, bootstrap methodology could be used to derive confidence intervals for ƒ₂ based on quantiles of re-sampling distributions, and this approach could actually be considered the preferred method over ƒ₂ and MD.

(my emphases)

Do I get this right? Bootstrapping is preferred over ƒ₂ even if the validity criteria* are met?
I expect ‘regulatory creep’. Preferred will turn into mandatory. Will it be required retrospectively? I know some minor variations supported by ƒ₂, where it was say, only 53 in one pH. Will not pass the lower confidence limit.
IMHO, the only way to decrease the CV – and hence, the width of the bootstrapped CI – is to substantially increase the number of units.

CV units
────────
♫    12
¾    21
⅔    27
½    48
⅓   108

No risk, no fun.

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• ≥12 units of T and R, CV ≤20% at ≤15 minutes, CV ≤10% at >15 minutes, not more than one mean value of >85% dissolved for each formulation.