Bioequivalence and Bioavailability Forum • Dasatinib EMA, April 2020

ElMaestro
★★★

Denmark,
2020-06-21 13:49
(1785 d 05:09 ago)

Posting: # 21554
Views: 3,964

Dasatinib EMA, April 2020 [BE/BA News]

Hi all,

check this out.

"In order to avoid the bias introduced by the randomly occurring low-lier values under fasting conditions, it is considered acceptable that low-lier profiles can be excluded from statistical analysis of the fasted state study if they occur with the same or lower frequency in the test product compared to the reference product. The low-lier profiles are defined as those profiles with dasatinib AUC exposures < 10% of the geometric mean AUC obtained in the rest of the profiles. This should be predefined in the protocol."

Just think about it. It marks a novel and much needed way by which you can take the variability of the reference into consideration when deciding whether or not your Test product is BE to the Ref.

Technically, it could get a little involved: If you have n observations, of which m may be less than 10% of the (n-m) rest of observations, then identifying those m observations is computationally very different from anything else we usually encounter in BE. The approach can rightfully be called a kind of m'th order jackknife but we do not need to traverse all permutations to find the m observations.

I think it is a brave and much needed leap forward on the part of the regulators that they allow it. Dasatinib has caused lots of headaches and peptic ulcers at Sponsors and CROs globally. Those days may be gone. :-)

—
Pass or fail!
ElMaestro

Helmut
★★★

Vienna, Austria,
2020-06-21 16:12
(1785 d 02:46 ago)

@ ElMaestro
Posting: # 21556
Views: 3,012

What a relief!

Post reply

Hi ElMaestro,

❝ check this out.

THX for that one!

❝ "[…] it is considered acceptable that low-lier profiles can be excluded from statistical analysis […] if they occur with the same or lower frequency in the test product compared to the reference product."

(my emphasis)
One-sided Fisher’s exact test or gut feeling? See this post.

❝ Technically, it could get a little involved: If you have n observations, of which m may be less than 10% of the (n-m) rest of observations, then identifying those m observations is computationally very different from anything else we usually encounter in BE. The approach can rightfully be called a kind of m'th order jackknife but we do not need to traverse all permutations to find the m observations.

Correct. Little bit tricky.

❝ I think it is a brave and much needed leap forward on the part of the regulators that they allow it. Dasatinib has caused lots of headaches and peptic ulcers at Sponsors and CROs globally. Those days may be gone. :-)

Yep. What surprises me is the footnote (as in many product-specific guidances of the EMA).

As intra-subject variability of the reference product has not been reviewed to elaborate this product-specific bioequivalence guideline, it is not possible to recommend at this stage the use of a replicate design to demonstrate high intra-subject variability and widen the acceptance range of C_max. If high intraindividual variability (CV_intra > 30 %) is expected, the applicants might follow respective guideline recommendations.
(my emphases)

Well, we know that the CHMP’s PKWP reviewed a lot of studies. The ones I’m aware of showed – without an exception – highly variable C_max.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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