Bioequivalence and Bioavailability Forum • Deficiency letters

Deficiency letters [Two-Stage / GS Designs]

posted by Helmut – Vienna, Austria, 2013-12-04 15:50 (4154 d 12:07 ago) – Posting: # 12000
Views: 24,649

Hi Kumar,

❝ […] if I want to demonstrate that type error inflation did not impact on my study then can I demonstrate this by simply showing 90% CI as well as 94.12% CI for GMR of PK parameters within the acceptance limits (80% to 125%).

This was actually the response to deficiency #1. However, post hoc switch of statistical methods (from Method C to B) is really bad practice, but the regulator insisted on it. :-(

If you expect problems (only in Europe!) plan the study already for Method B.

❝ also I am not getting how to interpret Response 2

The study’s CV was 30.65% observed in 49 subjects. Potvin’s closest table entry is for CV 30% and n₁ 48 (α_emp 0.0494). I simulated α_emp with the study’s values and got 0.0494 as well (10⁶ simulated studies). It’s easy to calculate the confidence interval based on the binomial test. In R:

sims <- 1e6 # number of simulated studies alpha <- 0.0494 # empiric risk type I binom.test(alpha*sims, sims, alternative="two.sided", conf.level=0.95)

getting:

Exact binomial test data: alpha * sims and sims number of successes = 49400, number of trials = 1e+06, p-value < 2.2e-16 alternative hypothesis: true probability of success is not equal to 0.5 95 percent confidence interval: 0.04897608 0.04982653 sample estimates: probability of success 0.0494

If you run a study with Method B and still get such a weird deficiency letter – and don’t have the means to run simulations – it should be possible to look at the 95% CI. IMHO Bonferroni’s α 0.025 should keep the overall risk type I <0.05 for any two-stage method. Ask a statistician.

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Helmut Schütz

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Complete thread:

Acceptance by FDA/CDER Mahesh 2013-08-06 06:12 [Two-Stage / GS Designs]
- 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 out Helmut 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 lettersHelmut 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