Great post! [Outliers]
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 CVintra CVinter(negative variance component)
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
- 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.
The quality of responses received is directly proportional to the quality of the question asked. ☼
- 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 - 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 - zizou, 2019-02-06 20:52
- Great post! - Helmut, 2019-02-07 10:37