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Bong Sure,
4.1.8 (Stats):
"The assessment of bioequivalence is based upon 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration."
Population geometric means.. I am sure they will continue to mean LS Means although this is not what that sentence means. Business as usual.
"The terms to be used in the ANOVA model are usually sequence, subject within sequence, period and formulation. Fixed effects, rather than random effects, should be used for all terms."
Implies no more mixed effect modeling? Now, if we do a normal linear model on data from a replicated study then we are certain to violate some basic requirements (correlated errors; those that the Mixed Model intends to solve for us). That also implies that we will not be able to give unbiased or good estimates of the intra-subject variability. In 4.1.10 (HVD's):
"The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers."
The wording leaves anybody doing a replicated study in a dilemma. Either use a mixed model and violate 4.1.8 but get healthy withins, or using a fixed effects model as required and get toxic withins.
Next issue of course, is that if we comply with "Fixed effects, rather than random effects, should be used for all terms." then there will NOT be individual withins for Ref (or Test). The recommendation of using swr for scaling purposes does not make sense as long as no mixed effecs model is allowed.
I will stop here, but let me just quote John McEnroe:
"You cannot be serious!"
EM.
4.1.8 (Stats):
"The assessment of bioequivalence is based upon 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration."
Population geometric means.. I am sure they will continue to mean LS Means although this is not what that sentence means. Business as usual.
"The terms to be used in the ANOVA model are usually sequence, subject within sequence, period and formulation. Fixed effects, rather than random effects, should be used for all terms."
Implies no more mixed effect modeling? Now, if we do a normal linear model on data from a replicated study then we are certain to violate some basic requirements (correlated errors; those that the Mixed Model intends to solve for us). That also implies that we will not be able to give unbiased or good estimates of the intra-subject variability. In 4.1.10 (HVD's):
"The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers."
The wording leaves anybody doing a replicated study in a dilemma. Either use a mixed model and violate 4.1.8 but get healthy withins, or using a fixed effects model as required and get toxic withins.
Next issue of course, is that if we comply with "Fixed effects, rather than random effects, should be used for all terms." then there will NOT be individual withins for Ref (or Test). The recommendation of using swr for scaling purposes does not make sense as long as no mixed effecs model is allowed.
I will stop here, but let me just quote John McEnroe:
"You cannot be serious!"
EM.
Complete thread:
- EMA BE guideline - final version Ohlbe 2010-01-28 18:31 [Regulatives / Guidelines]
![[Mix]](https://static.bebac.at/img/mix.png "open in Mix view")
- Final version published Helmut 2010-01-29 14:29
- Final version publishedElMaestro 2010-01-29 17:02
- Statistix Helmut 2010-01-29 17:30
- Statistix ElMaestro 2010-01-29 18:11
- Calories ;-) Helmut 2010-01-29 19:22
- Calories ;-) ElMaestro 2010-01-29 20:43
- Calories ;-) Helmut 2010-01-29 21:08
- Variable calories d_labes 2010-02-01 12:05
- Calories ;-) ElMaestro 2010-01-29 20:43
- ANOVA only - no doubts Helmut 2010-02-10 23:41
- ANOVA only - no doubts ElMaestro 2010-02-12 21:09
- Statistix Helmut 2010-01-29 17:30
- Final EMA oracle d_labes 2010-02-01 11:53
- Final EMA oracle Helmut 2010-02-01 12:28
- Final EMA oracle ElMaestro 2010-02-01 12:50
- More then two EMA oracles d_labes 2010-02-01 13:30
- Less of an issue ElMaestro 2010-02-01 15:29
- Less or More of an issue d_labes 2010-02-01 16:53
- Less or More of an issue ElMaestro 2010-02-01 17:22
- Less or More of an issue d_labes 2010-02-01 16:53
- Effective with 1 Aug 2010 Helmut 2010-02-02 00:55
- Bias? ElMaestro 2010-02-04 11:27
- Less of an issue ElMaestro 2010-02-01 15:29
- Final EMA oracle Helmut 2010-02-01 13:43
- Final EMA oracle ElMaestro 2010-02-01 14:54
- Final EMA oracle d_labes 2010-02-01 15:20
- Teaching Helmut 2010-02-01 16:07
- Final EMA oracle d_labes 2010-02-01 15:20
- Final EMA oracle ElMaestro 2010-02-01 14:54
- More then two EMA oracles d_labes 2010-02-01 13:30
- Cmin really gone? tmax reappeared? d_labes 2010-02-01 14:02
- Cmin really gone. tmax reappeared - but how? Helmut 2010-02-01 23:30
- Interpol or not d_labes 2010-02-01 14:52
- Interpol! Helmut 2010-02-02 00:02
- Interpol! ray_be 2010-02-03 18:31
- WinNonlin/Phoenix extrapolation to t=tau Helmut 2010-02-03 20:26
- Interpol! ray_be 2010-02-03 18:31
- Interpol! Helmut 2010-02-02 00:02
- Meta-analysis Helmut 2010-02-07 17:41
- Final version published Panks.79 2010-03-08 07:22
- Cmin for MR-formulations? Helmut 2010-03-08 18:16
- Cmin for MR-formulations? Marcel 2010-04-23 10:09
- MR-Guideline? Helmut 2010-04-23 12:34
- Cmin for MR-formulations? Marcel 2010-04-23 10:09
- Cmin for MR-formulations? Helmut 2010-03-08 18:16
- Final version publishedElMaestro 2010-01-29 17:02
- Overview of comments published Helmut 2010-02-10 18:33
- Comments commented d_labes 2010-02-11 08:19
- Definition of Cmin by EMEA Ravi 2010-03-13 12:05
- The EMA’s Cmin & WinNonlin Helmut 2010-03-13 12:52
- Final version published Helmut 2010-01-29 14:29
Ing. Helmut Schütz