Flawed evaluation accepted [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2020-01-31 11:19 2a02:8388:6bc2:ce80:59da:2536:a4ac:85cd – Posting: # 21116
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Hi Mikalai,

» The identical decision tree was used in the BS of rasagiline (registration required) and was accepted by EMA. https://clinicaldata.ema.europa.eu/web/cdp/home

I succeeded at the end and you are correct. Why am I not surprised that the study was performed in India? OK, the sponsor was European. One of my clients – should have asked me before… :-(
Clinical phase ended Jun 2009, study report v1 Oct 2009, v2 Mar 2011, v3 (final) Jul 2011. What happened in those 21 (!) months – waiting for the BE GL (published Jan 2010, effective Jul 2010)?

The procedure for Cmax was almost like Elena described.Interesting:In the corresponding EPAR we read:

Statistical methods
Analysis of variance (ANOVA) was performed on the ln-transformed Cmax, AUC0–t and AUC0–∞. The fixed effects sequence, subject nested within sequence, period and treatment were used in the ANOVA model to calculate the pharmacokinetic parameters. The test to reference ratio of geometric LSmeans and the corresponding 90% confidence interval based on the ln-transformed Cmax and AUC0–t data were calculated. The parameter Tmax was analyzed using a non-parametric approach.

Criteria for conclusion of bioequivalence:
Bioequivalence was concluded if the test to reference ratio of geometric LSmeans and the corresponding 90% confidence interval for the Cmax and AUC0–t fell within the acceptance limits of 80.00 to 125.00%. Widening of the acceptance criteria for Cmax was proposed for conclusion of bioequivalence. However, since the results of the bioequivalence study for the pharmacokinetic parameter Cmax were within the normal acceptance criteria of 80–125% (as shown below) widening of the criteria for Cmax was not necessary.

The 90% confidence interval of the test/reference ratio (difference in least square means) derived from the ANOVA of the log-transformed pharmacokinetic parameters AUC0–t and Cmax for rasagiline in plasma was within the 80.00% – 125.00% acceptance range. Therefore the test formulation (███████) is judged to be bioequivalent to the reference product (███████) in healthy adult volunteers under fasting conditions.


“The fixed effects sequence, subject nested within sequence, period and treatment were used in the ANOVA model…”
Cough: Not an ANOVA with all effects fixed but a mixed-effects model with restricted maximum likelihood estimation, no nested structure.

Cheers,
Helmut Schütz
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