## Great post! [Outliers]

Hi Zizou,

at a first look your arguments are convincing indeed.

A basic assumption in BE is that what we observe in the study is an

Observations:

at a first look your arguments are convincing indeed.

A basic assumption in BE is that what we observe in the study is an

*unbiased*sample of the population,*i.e.*, the true (but unknown) distributions of the sample and the population are identical. Only then we can extrapolate the study’s result to the patient population (BE as a substitute for therapeutic equivalence). As stated in HC’s guidance parametric methods are not robust against extreme values. My example:` n method PE 90% CI CV`

(negative variance component)_{intra} CV_{inter}

12 LME 110.15% 77.60–156.36% 50.1% NA

`12 ANOVA 110.15% 77.60–156.36% 50.1% NA`

(note: 91.78% CI)

11 LME 92.45% 78.34–109.11% 21.3% 22.2%

12 nonparametric 98.95% 76.24–130.06% NA NA

Observations:

- The mixed effects model (according to the guidance) converged but with a negative variance for the random effect. Tweaks weren’t successful (singularity tolerance ↓, convergence criterion ↓, maximum number of iterations ↑).

- Excluding the outlier I got a pretty narrow CI (which is similar to the other PK metrics). However, the one in the nonparametric method of the full dataset is much wider. Is the distribution of n=11 really close to the true one?

- In a strict sense the nonparametric method gives only a correct measurement of shift if distributions are similar. Duno whether this is the case here. Haven’t tried the Brunner-Munzel test* yet (which doesn’t require this assumption).

- Brunner E, Munzel U. (2000).
*The Nonparametric Behrens-Fisher Problem: Asymptotic Theory and a Small Sample Approximation.*Biometr. J. 2000;42(1):17–25. doi:10.1002/(SICI)1521-4036(200001)42:1<17::AID-BIMJ17>3.0.CO;2-U.

—

Cheers,

Helmut Schütz

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

Science Quotes

Cheers,

Helmut Schütz

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

Science Quotes

### Complete thread:

- Rules acc. to Health Canada - Helmut, 2019-02-05 15:04 [Outliers]
- Rules acc. to Health Canada - ElMaestro, 2019-02-05 15:30
- Rules acc. to Health Canada - Helmut, 2019-02-05 16:24
- Rules acc. to Health Canada - ElMaestro, 2019-02-05 17:33

- Rules acc. to Health Canada - Helmut, 2019-02-05 16:24
- Rules acc. to Health Canada - Ohlbe, 2019-02-05 15:54
- Rules acc. to Health Canada - Helmut, 2019-02-05 17:52

- for either the test or reference product? - mittyri, 2019-02-05 15:58
- Discordant outliers - Helmut, 2019-02-05 17:42

- Rules acc. to Health Canada - Shuanghe, 2019-02-06 11:48
- Rules acc. to Health Canada - ElMaestro, 2019-02-06 12:20

- Rules acc. to Health Canada - zizou, 2019-02-06 20:52
- Great post! - Helmut, 2019-02-07 10:37

- Rules acc. to Health Canada - ElMaestro, 2019-02-05 15:30