Bioequivalence and Bioavailability Forum

AUCextrap more than 20% [Study Assessment]

posted by Helmut – Vienna, Austria, 2013-08-01 14:32 (4710 d 21:35 ago) – Posting: # 11144
Views: 31,501

Hi Sam,

❝ […] ER formulation for USFDA. The results are very good for the Cmax and AUCinf but the study fails marginally in lower CI in AUCt that is 79.28. The failure in this study is due to the presence of two outlier in the whole study. If we remove these outliers the study qualify the BE criteria for all the three parameters. But as we all know that USFDA don’t encourage the outliers test and its exclusion from the study.

❝ […] The only option is if we remove the AUCt and AUCinf from the from two subjects whose %AUCextrap value is more than 20% and keeping Cmax and Tmax untouched. Our study qualifies the BE criteria of 80-125%.

Some points:

FDA doesn’t have a 20% residual area criterion (see the guidance, p22) – that’s EMA-speak. Even for EMA you must not exclude subjects with higher residual areas (BE GL Section 4.1.8, p14).
You are right about FDA’s thinking about ‘outliers’. BTW, did these two subjects really qualify by a statistical test or was your criterion >20% res. AUC?
You can try to start an argument based on the fact that the formulation was ER. In BE we are interested in comparing the absorption (= formulation + drug specific) not distribution/elimination (= drug specific). With ER the slowest phase might be absorption – not elimination. This is true once you crossed flip-flop PK (k_a = k_el). Even for k_a > k_el the apparent (!) elimination will be contaminated by absorption. Compare half lives of your study with literature data of immediate release formulations. Likely your half lives are longer. Therefore, AUC_∞ is a more relevant metric for extent of absorption than AUC_t.
Your sample size was terribly high given the CVs of 25–27%…

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Complete thread:

AUCextrap more than 20% sam 2013-08-01 06:15 [Study Assessment]
- AUCextrap more than 20% ElMaestro 2013-08-01 10:29
  - AUCextrap more than 20% sam 2013-08-01 11:21
    - AUCextrap more than 20% ElMaestro 2013-08-01 11:39
      - AUCextrap more than 20% sam 2013-08-01 12:01
        
        AUCextrap more than 20% Helmut 2013-08-01 12:52
    - forced BE d_labes 2013-08-01 11:59
      - Gambling ♠ ♣ ♥ ♦ Helmut 2013-08-01 13:31
- AUCextrap more than 20%Helmut 2013-08-01 12:32
  - AUCextrap more than 20% sam 2013-08-01 12:55
    - 46% power in study planning? Helmut 2013-08-01 13:18
      - 46% power in study planning? sam 2013-08-01 13:40
        
        46% power in study planning? jag009 2013-08-01 20:04
        
        Re-dosing Helmut 2013-08-02 03:32
        
        Re-dosing jag009 2013-08-02 05:10
        
        Re-dosing Helmut 2013-08-02 14:44
        
        46% power in study planning? sam 2013-08-02 07:00
        
        Carved in stone? Helmut 2013-08-02 03:22
        
        Carved in stone? sam 2013-08-02 07:02
        
        Carved in stone? luvblooms 2013-08-02 08:37
        
        Carved in stone? sam 2013-08-02 09:01
        
        Ethics (again) Helmut 2013-08-02 14:53
        
        Update jag009 2013-08-02 17:25
        
        Update Helmut 2013-08-02 18:11
        
        Update jag009 2013-08-02 20:11
        
        Outliers (CAN) Helmut 2013-08-02 20:56
        
        Outliers (CAN) jag009 2013-08-02 22:23
        
        OT: Expert Helmut 2013-08-03 10:11
        
        Update jag009 2013-08-02 22:29
        
        Update ElMaestro 2013-08-02 23:08
        
        Update jag009 2013-08-03 23:00
        
        Update luvblooms 2013-08-05 06:02
        
        Update jag009 2013-08-05 20:14

AUCextrap more than 20% [Study As­sess­ment]

Complete thread:

AUCextrap more than 20% [Study Assessment]