Bioequivalence and Bioavailability Forum

Two Stage Design [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2008-08-25 13:43 (6141 d 12:21 ago) – Posting: # 2249
Views: 25,515

Dear Ravi,

I would go with ‘Method C’ suggested by Potvin et al. (2007).^* The design was validated in 1,000,000 simulated BE studies in numerous combinations of sample sizes (12–60 subjects in stage 1) and CVs (10–100%).
The α-level (patient’s risk) was maintained at ≤0.052 - which is not the case by methods currently applied in Canada and Japan (evaluation of stage 1 at α=0.05, simple pooling of a second stage; results presented in the reference as ‘Method A’).
Below an outline of the procedure:


For your example you have two possibilities to show BE already in stage 1:

1. Power ≥80%: evaluation at α=0.0500
2. Power <80%: evaluation at α=0.0294

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• Potvin D, Diliberti CE, Hauck WW, Parr AF, Schuirmann DJ, and RA Smith
  Sequential design approaches for bioequivalence studies with crossover designs
  Pharmaceut Statist (pre-print 2007), DOI: 10.1002/pst.294
  Online abstract

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Edit: Our first study with this design was approved by one of Berlin’s IECs and the German BfArM in May 2009.

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Helmut Schütz


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Science Quotes

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 DesignHelmut 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 approach Helmut 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