Bioequivalence and Bioavailability Forum • tmax, Canadian approach

tmax, Canadian approach [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2008-11-21 16:41 (6053 d 13:11 ago) – Posting: # 2768
Views: 23,925

Dear D. Labes,

❝ But what can we do if a regulative authority :no: is missing all the discussions and results in the scientific community?

Sometimes I forget the true country of the brave and the free - Canada...
They already had a Notice to Industry on Rapid Onset Drugs back in 2005.

Eric Ormsby (Health Canada, Therapeutic Products Directorate) in his talk at the BioInternational 2008 presented their approach for a partial areas, which will be implemented in their new guideline, namely:
'The relative mean AUC_Reftmax of the test to reference formulation should be within 80 to 125%, where AUC_Reftmax for a test product is defined as the area under the curve to the time of the maximum concentration of the reference product, calculated for each study subject.'
No fiddling around with median t_max, no search for a reference value in the reference's SmPC - just straight out of the study, but:

Example 1:
Original evaluation
Median t_max (ref.) 1.5h
Additive model (nonparametric)
Hodges-Lehman estimate: +0.00h (100%)
Moses CI: -0.25, +0.25 (85.0%, 115%)
Conclusion: BE
New evaluation
Partial AUC individually truncated at t_max of the reference
Multiplicative model (parametric)
GMR: 85.7%
CI: 72.3%, 102.3%
CV_intra 23.8% (AUC_T 13.3%, C_max 17.0%)
Conclusion: not BE

Example 2:
Median t_max (ref.) 1.5h
Additive model (nonparametric)
Hodges-Lehman estimate: +0.26h (116%)
Moses CI: +0.00, +0.50 (100%, 130%)
Conclusion: not BE
Partial AUC individually truncated at t_max of the reference
Multiplicative model (parametric)
GMR: 62.4%
CI: 46.2%, 84.3%
CV_intra 42.4% (AUC_T 6.33%, C_max 9.43%)
Conclusion: not BE

Power to show BE for partial AUC in the 'Canadian way' was also insufficient, even in example 1 (see this post for another method). CV_intra for the partial AUC was five times that of C_max and almost seven times that of AUC_T in example 2. Whatever approach we will choose, IMHO it will be very difficult to show BE for rapid onset drugs if partial areas are a main target parameter due to it's high variability.

--
Edit: Canada doesn't ask for a confidence interval! See this post.

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Complete thread:

Critical review of EU BE guideline (Rev.1) Helmut 2008-08-22 14:30 [Regulatives / Guidelines]
- Critical review of EU BE guideline (Rev.1) d_labes 2008-08-22 15:42
  - Critical review of EU BE guideline (Rev.1) Helmut 2008-08-23 02:02
    - Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 09:14
      - Variations Helmut 2008-08-25 11:06
- Critical review of EU BE guideline (Rev.1) Jaime_R 2008-08-23 16:47
  - Critical review of EU BE guideline (Rev.1) Ravi 2008-08-25 08:19
    - Two Stage Design Helmut 2008-08-25 11:43
      - Two Stage Design JPL 2008-08-28 09:44
        
        Two Stage Design Helmut 2008-08-28 11:50
        
        Two Stage Design d_labes 2008-08-28 12:09
        Sequential Design Helmut 2008-11-05 13:22
  - Critical review of EU BE guideline (Rev.1) banusunman 2008-08-26 16:56
    - Washout Helmut 2008-10-15 16:02
- Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 09:49
  - Critical review of EU BE guideline (Rev.1) Helmut 2008-08-25 12:11
    - Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 13:03
    - Urban legend? Helmut 2008-11-21 16:06
      - Urban legend? d_labes 2008-11-24 15:06
- Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 11:16
- Critical review of EU BE guideline (Rev.1), tmax, MRT, LZ d_labes 2008-08-25 11:32
  - Critical review of EU BE guideline (Rev.1), tmax, MRT, LZ Helmut 2008-08-25 13:10
  - tmax, nonparametrics Helmut 2008-10-13 15:38
    - tmax, nonparametrics d_labes 2008-10-14 08:33
      - tmax, nonparametrics Helmut 2008-10-14 11:29
      - tmax, Canadian approachHelmut 2008-11-21 15:41
        
        tmax, Canadian approach d_labes 2008-11-24 13:53
        
        Early exposure, Canadian approach: GMR only! Helmut 2009-02-08 00:44
        
        Early exposure, Canadian approach: GMR only! d_labes 2009-02-09 08:50
        
        tmax; another example Helmut 2008-12-25 15:59
- Automatic integration janmacek 2008-08-27 12:21
  - Automatic integration Ohlbe 2008-08-27 14:49
    - Manual reintegration! H_Rotter 2008-08-28 11:28
      - Manual reintegration! ElMaestro 2008-08-28 12:44
- Subject accountability, Proc MIXED or equivalent d_labes 2008-09-02 11:13
  - Subject accountability, Proc MIXED or equivalent Ohlbe 2008-09-02 15:20
    - Subject accountability, Proc MIXED or equivalent d_labes 2008-09-02 16:30
- partial AUC, early exposure d_labes 2008-09-03 08:35
- HVDs? Helmut 2008-09-23 12:52
  - HVDs? d_labes 2008-09-23 14:20
  - HVDs? Helmut 2009-01-20 14:33
  - E.g., omeprazole Helmut 2009-03-06 17:21
- BCS-based Biowaiver Helmut 2008-09-25 15:48
  - Dissolution update Helmut 2008-10-13 12:43
- EUFEPS workshop Helmut 2008-12-23 17:03