## Deep shit [RSABE / ABEL]

HI Mikalai,

» […] we do not use RR for the ref drug in our calculations and should not control TIE if we initially go by the ABE approach and reach bioequivalence within 125-80% interval (alpha at 0.05).

Read my last post again. And again. You do not know beforehand whether or not you will pass ABE. If not, you continue with the calculation CVwR and ABEL. If that happens, you will evaluate the data twice. That’s a textbook-example of multiplicity. Just by that the TIE will be $$1-(1-\alpha)^k=1-(1-0.05)^2=0.0975$$. That’s not rocket science and already higher than with the usual framework, where we calculate the 90% CI only once. Add the potential bias of CVwR and you are in deep shit. Excuse my French.

» Also, it seems the only reason that we should calculate RR for the ref drug first is to calculate and control TIE latter if the CV is higher than 30%.

No. It prevents us from potentially assessing the CI twice. See above.

» If it turns out that it is lower than 30% then we simply use the ABE and no control TIE. However, if we do not plan to do this (control TIE), then it is not important to calculate the RR ref first.

See above. If you continue with this appraoch (IMHO, a bad idea), please use at least a 95% CI.

» As you mentioned there Post and there post no regulatory agency issued a formal guideline on TIE in replicate studies, and FDA and EMA do not require and accept replicate studies without controlling TIE.

Unfortunately regulations science.

In bioequivalence we must not forget the
only important – the patient! He/she is a living
person, not just α 0.05.
Dirk Marteen Barends

IMHO, it is a cowardly excuse to rely on an approach ‘because a guideline says so’ and the agencies accepts studies (quote of a European assessor: I don’t have enough time to read all those papers…).
There are almost twenty published showing an increased patient’s risk by re­fe­rence-scaling and not a single one (‼) showing the opposite. Even with the FDA’s ‘desired consumer risk model’ – called by some hocus pocus – there is a substantial inflation of the TIE. Your approach is worse.

» In this case (no control TIE), we can calculate the RR only when we fail in Cmax. We do not recalculate our new CI we just use that from ABE to compare with a new or the standard CI if CV less than 30. In the latter case, we basically fail the study.

See above.

» I would not like to discuss whether we should or not control TIE in replicate studies in this branch. In my view, probably we should not, …

Well, that’s like my niece being afraid of monsters in the nursery. Her solution: Close the eyes and cover the ears with her hands.

» … and it is also probably that leading agencies won't do anything with this issue unless a safety signal occurs.

Forget pharmacovigilance. It is terribly insensitive. There are some HVD(P)s where the concentrations vary tenfold day-to-day. Seriously. Yep, even the maximum expansion is too conservative. Furthermore, we are not worried about drugs / drug products with a true CVwR of ~45% and higher. The troublesome are the borderline cases.

PS: Waiting for a guideline takes quite some perseverance. Grizzle’s concept of testing for a sequence effect (unequal carry-over) of 1965 was proven false by Freeman in 1989. Took another 21 years to make it to the EMA’s GL.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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