Bioequivalence and Bioavailability Forum • Murky waters

Murky waters [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2019-08-13 16:40 (894 d 20:04 ago) – Posting: # 20496
Views: 1,654

Hi Abhimanyu,

first of all I agree with ElMaestro.

» How can we find outlier? which one will be appropriate scenario for any regulatory point of view?

EMA and others following its ABEL method:
An outlier test is not acceptable. Have to justify that the estimated CV_wR (driving the expanded limits) is not caused by outliers. Aha. Can be explored by box plots of studentized residuals of the EMA’s model. Some people set the limits to 2×IQR. If outliers are detected, remove them and recalculate CV_wR. However, the analysis has still to be done with the complete data set (the outlier is not removed). Since the expanded limits will be narrower you shoot yourself in the foot.
FDA:
No way.
Health Canada:
See the guidance (Sections 2.3.5 and 2.7.4.1). Outliers can be completely removed from the data set if
- identification is performed before the BE assessment (i.e., no CIs calculated already),
- the studentized model residual is outside {–3, +3} (irrespective whether T or R),
- identified for all PK metrics (that’s a big obstacle, especially if one has to deal with partial AUCs of multiphasic products),
- not more than 5% of subjects (or only one subject if the sample size is 20 or lower),
- the procedure is stated unambiguously in the protocol.

—
Dif-tor heh smusma 🖖
Helmut Schütz

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Complete thread:

Outlier test for reference replicate crossover study design abhimanyu 2019-08-13 15:11 [Regulatives / Guidelines]
- Outlier test for reference replicate crossover study design ElMaestro 2019-08-13 15:28
- Murky watersHelmut 2019-08-13 16:40