Bioequivalence and Bioavailability Forum

Cmin really gone? tmax reappeared? [Regulatives / Guidelines]

posted by d_labes  – Berlin, Germany, 2010-02-01 15:02 (5974 d 03:19 ago) – Posting: # 4680
Views: 27,830

Dear Helmut,

❝ t_max is back (instead of partial AUC truncated at t_max,ref) - but no statistical analysis ("no apparent difference in median t_max and its variability").

What ever this means ! t_max reappeared as toothless tiger. Report the values, give some descriptive statistics and forget.

I find it very strange that the abhorrence for non-parametric methods leads to such a featureless evaluation guidance, even in the case t_max is clinically relevant.
Implicitly this accepts that t_max can only be analyzed non-parametrically, but "... Non-parametric analysis is not acceptable. ...". Thus we have no statistical method left.

❝ C_ss,min has vanished.

I liked this, because as we know this is a nasty parameter with sometimes high variability. Likewise it seemed fluctuation (PTF) had also gone.

But I noticed yet this is only true for immediate release products.

The CPMP/EWP/280/96 Corr "Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: SECTION II (Pharmacokinetic and Clinical Evaluation)" mentions explicitly Fluctuation and Cmin in section 4.1.1. Rate and extent of absorption, fluctuation as parameters of interest in multiple dose studies.

Thus we have the situation that we need distinct sets of PK parameters for multiple dose studies depending on the product characteristics immediate or modified release. The question is: Why?

What is now really gone I think is MRT. Ok, this was only an parameter nice to have. Only reported and handled descriptively in BE studies.

Complete thread:

• EMA BE guideline - final version Ohlbe 2010-01-28 18:31 [Regulatives / Guidelines] 
  • Final version published Helmut 2010-01-29 14:29
    • Final version published ElMaestro 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
      • ANOVA only - no doubts Helmut 2010-02-10 23:41
        • ANOVA only - no doubts ElMaestro 2010-02-12 21:09
    • 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
          • Effective with 1 Aug 2010 Helmut 2010-02-02 00:55
          • Bias? ElMaestro 2010-02-04 11:27
            • Bias? Helmut 2010-02-05 02:03
              • Bias? ElMaestro 2010-02-05 09:33
                • Bias? Helmut 2010-02-05 10:21
              • Bias? d_labes 2010-02-05 13:59
              • Bias? ElMaestro 2010-02-05 16:00
                • Bias? Helmut 2010-02-05 19:14
        • 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
    • 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
    • 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
  • 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