Bioequivalence and Bioavailability Forum • Open your mouth and forcefully spit the water out

Open your mouth and forcefully spit the water out [Two-Stage / GS Designs]

posted by Helmut – Vienna, Austria, 2013-10-18 15:29 (4266 d 05:55 ago) – Posting: # 11695
Views: 26,277

Hi Shuanghe,

❝ Q: "..., we'd like to ask about the current status of 2-stage design BE study, ... if the BE protocol with Potvin's Method C is acceptable now ..."

❝

❝ A: "Potvin's methods are not acceptable in EMA."

Simply mad. And I don’t mean the MAD.
Have you asked them which methods would be acceptable according to their impeccable wisdom instead? They should enlighten us simpletons.

❝ so, first question, how could it be? Have some of you guy's dossiers with Potvin's method(s) been approved/accepted (no deficient letter, rejection letter etc)?

Yes. For some recent (this year’s) experiences see slide 45 of this presentation. Method C [sic] accepted by Germany (RMS) and CMSs Austria, Denmark, Sweden, and The Netherlands. Spain asked for an all-fixed effects analysis (subjects within sequence were random in the original analysis).
Note that in a previous case (slide 44) MEB didn’t like intermediate power.

❝ I always had the impression that method B is practically mentioned in the guide. Not quite. :no: There's no mention of interim power analysis in the BE guide while method B... you know. So I guess the power analysis is probably the "evil" here causing all the fuss...

Maybe. I suspect the guys writing the GL failed to comprehend the published methods, which – with no exception! – depend on an intermediate power estimation step. I hope someone has the balls and goes for a referral. If a GL (not a law anyway) states 2×2=5 I would wholeheartedly ignore it for sure.

BTW, the additional term introduced in the Q&A Ref.7 is futile as well. I have heard that this section was excreted by EMA’s Biostatistical Working Party and the PK Working Party is just “hosting” it. What the heck? A paper “On the Statistical Model of the Two-Stage Design in Bioequivalence Assessment” by Karalis/Macheras is currently under review (J Pharm Pharmacol). From their key findings:

The overall performance in terms of % BE acceptance is identical. The additional term, ‘Sequence × Stage’, suggested in the EMA method is in most cases non-significant. The same results were obtained regardless of the type (fixed or random) of the effect applied to the ‘Subjects’ term.

And the conclusions:

Any BE study either finished or in progress which relies on the existing literature methodology leads to the same % BE acceptance as if it was analyzed with the recently proposed EMA method.

So what?

❝ There's rumour that some working party is currently discussing this topic. Anyone has any insight?

Not me.

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Complete thread:

Acceptance by FDA/CDER Mahesh 2013-08-06 06:12
- Two stage BE design ElMaestro 2013-08-06 10:05
- Two stage BE design Helmut 2013-08-06 15:31
  - Two stage BE design Mahesh 2013-08-07 06:51
    - Two stage BE design kumarnaidu 2013-10-17 15:08
      - Two stage BE design ElMaestro 2013-10-17 17:28
        
        Two stage BE design kumarnaidu 2013-10-18 05:59
        
        EMA vs. rest of the world Helmut 2013-10-18 14:42
        
        Two stage BE design — cold water thrown on our head Shuanghe 2013-10-18 10:05
        
        Open your mouth and forcefully spit the water outHelmut 2013-10-18 13:29
        
        Change in statistical design kumarnaidu 2013-10-19 07:52
        
        Bad idea Helmut 2013-10-19 15:04
        
        Bad idea kumarnaidu 2013-10-21 06:01
        
        Change to Method B? Helmut 2013-10-21 14:51
        
        Change to Method B? kumarnaidu 2013-10-22 06:15
        
        Simulations Helmut 2013-10-22 13:20
        
        Open your mouth and forcefully spit the water out Shuanghe 2013-10-22 09:03
        
        Reach for the stars Helmut 2013-10-22 13:05
        
        Alpha inflation in two stage design kumarnaidu 2013-12-04 13:43
        
        Deficiency letters Helmut 2013-12-04 14:50
        
        Deficiency letters kumarnaidu 2013-12-05 06:18
        
        Simulations Helmut 2013-12-05 15:51
        
        Simulations kumarnaidu 2013-12-05 16:07
        
        Simulations Helmut 2013-12-05 16:55
        
        Simulations kumarnaidu 2013-12-06 06:07
        
        Ejaculatio praecox Helmut 2013-12-06 14:30
        
        Ejaculatio praecox kumarnaidu 2013-12-06 15:13
        
        All effects fixed Helmut 2013-12-06 15:31
        
        All effects fixed kumarnaidu 2013-12-09 07:33
        
        EMA… Helmut 2013-12-09 12:45