Bioequivalence and Bioavailability Forum • HVDs?

HVDs? [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2009-01-20 15:33 (5993 d 09:40 ago) – Posting: # 3074
Views: 22,850

Dear all!

❝ 4.1.10 Highly variable drugs or drug products, page 16 (lines 631-641)

According to discussions at last week's EUFEPS workshop members of EMEA's PK-group unanimously expressed their point of view as following:
If the reference formulation is suspected to be a HVDP and no clinical reasons speak against widening of the acceptance range for C_max the pivotal BE-study may be started right away in a replicate design (no pilot to demonstrate a HVDP reference followed by a pivotal study to show BE). It is unacceptable to run a two-period study of the reference alone, because regulators suspect that the performance of such a study will be intentionally sloppy in order to obtain a high CV.
The study should be powered to demonstrate BE for the conventional BE-range if CV<30%. If in the study CV>30% the acceptance range may be widened to 75%-133%.
Example (expected PE 0.95, 80% power):

CV%    2-way       3-way replicate       4-way replicate

      80%-125%   80%-125%   75%-133%   80%-125%   75%-133%

 30   40 ( 80)   30 ( 90)   18 ( 54)   20 ( 80)   12 ( 48)

 40   66 (132)   50 (150)   28 ( 84)   34 (136)   20 ( 80)

 50   98 (196)   74 (222)   42 (126)   50 (200)   28 (112)

 60  134 (268)  102 (306)   56 (168)   68 (272)   38 (152)

 70  174 (348)  130 (390)   72 (216)   88 (352)   48 (192)

 80  214 (428)  162 (486)   90 (270)  108 (432)   60 (240)

 90  258 (516)  194 (582)  108 (324)  130 (520)   72 (288)

100  300 (600)  226 (678)  124 (372)  150 (600)   84 (336)

The table gives samples sizes and number of treatments (which are a rough estimate of study costs). Though more treatments are needed in 3-way design, one must expect higher drop-out rates in 4-way design.
The draft defines (line 639) the limit of a HVDP with CV>30%, whereas generally a cut-off of CV≥30% is used. Hopefully this definition will change in the final version.

Going deeper in the example: You suspect that the CV will be 40%. Since you are not sure, you should power your study for 80%-125% (CV<30%). The sample sizes will be 50 (150 treatments) in a 3-way replicate and 34 (136 treatments) in a 4-way replicate. If it turns out that CV=30% you are powered with 95% to demonstrate BE within the conventional range - since you (mis-)used 50 subjects instead of the needed 30. If CV=40% as expected you may widen the acceptance range and are powered with 99.8% (or for 80% power your PE may lie with 85.4%-117.1%). You may also have performed the study as a conventional 2x2 in 66 subjects (with fewer treatments). IMHO the only gain is the larger allowed deviation from the reference. I'm not sure whether this was the primary intention of the 'inventors' or maybe I'm misunderstanding something terribly...

P.S.: In the US with RSABE you probably would perform the study as a 3-way replicate design in 34 subjects independent from the CV...

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Helmut Schütz

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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 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