Bioequivalence and Bioavailability Forum

Hi ElMaestro,

❝ So let me ask the forbidden question: "Can you reformulate?"

❝

❝ ❝ Higher sample size ⇒ more degrees of freedom ⇒ narrower CI ⇒ higher probability to pass BE.

❝ ❝ In other words, the TIE will also increase and one would have to use a lower adjusted α.

❝

❝ This is one thing I did not get.

I’ll give two examples. Both at the location (n₁ 12, CV 20%) of the maximum TIE.
Simulating for power (at 0.95):

1. No lower limit of n₂
   library(Power2Stage)
power.2stage(method="B", alpha=rep(0.0294, 2), CV=0.2,
             n1=12, GMR=0.95, targetpower=0.8, min.n2=0)

TSD with 2x2 crossover
Method B: alpha (s1/s2) = 0.0294 0.0294
Target power in power monitoring and sample size est. = 0.8
Power calculation via non-central t approx.
CV1 and GMR = 0.95 in sample size est. used
No futility criterion
BE acceptance range = 0.8 ... 1.25

CV = 0.2; n(stage 1) = 12; GMR= 0.95

1e+05 sims at theta0 = 0.95 (p(BE)='power').
p(BE)    = 0.84174
p(BE) s1 = 0.41333
Studies in stage 2 = 56.34%

Distribution of n(total)
- mean (range) = 20.6 (12 ... 82)
- percentiles
 5% 50% 95%
 12  18  40
   
   
2. Lower limit of n₂ = 1.5 × n₁
   power.2stage(method="B", alpha=rep(0.0294, 2), CV=0.2,
             n1=12, GMR=0.95, targetpower=0.8, min.n2=18)

TSD with 2x2 crossover
Method B: alpha (s1/s2) = 0.0294 0.0294
Target power in power monitoring and sample size est. = 0.8
Power calculation via non-central t approx.
CV1 and GMR = 0.95 in sample size est. used
No futility criterion
Minimum sample size in stage 2 = 18
BE acceptance range = 0.8 ... 1.25

CV = 0.2; n(stage 1) = 12; GMR= 0.95

1e+05 sims at theta0 = 0.95 (p(BE)='power').
p(BE)    = 0.91564
p(BE) s1 = 0.41333
Studies in stage 2 = 56.34%

Distribution of n(total)
- mean (range) = 23.5 (12 ... 82)
- percentiles
 5% 50% 95%
 12  30  40

If we require that the minimum sample size in the second stage = 1.5 × n₁, naturally the same percent of studies will proceed to the second stage. However, the expected total sample sizes will be larger (E[N] 23.5 vs. 20.6, median 30 vs. 18). The sponsor gains power (91.6% vs. 84.2%).

❝ Does that logic also work when we simulate true GMR 0.8 or 1.25 for type I error? I find it hard to convince myself.

Yes, it does – and this was my point. This time simulating for the TIE (at 1.25):

1. No lower limit of n₂
   library(Power2Stage)
power.2stage(method="B", alpha=rep(0.0294, 2), CV=0.2,
             n1=12, GMR=0.95, targetpower=0.8, min.n2=0, theta0=1.25)

TSD with 2x2 crossover
Method B: alpha (s1/s2) = 0.0294 0.0294
Target power in power monitoring and sample size est. = 0.8
Power calculation via non-central t approx.
CV1 and GMR = 0.95 in sample size est. used
No futility criterion
BE acceptance range = 0.8 ... 1.25

CV = 0.2; n(stage 1) = 12; GMR= 0.95

1e+06 sims at theta0 = 1.25 (p(BE)='alpha').
p(BE)    = 0.046262
p(BE) s1 = 0.028849
Studies in stage 2 = 87.86%

Distribution of n(total)
- mean (range) = 23.1 (12 ... 98)
- percentiles
 5% 50% 95%
 12  22  40
   
   
2. Lower limit of n₂ = 1.5 × n₁
   power.2stage(method="B", alpha=rep(0.0294, 2), CV=0.2,
             n1=12, GMR=0.95, targetpower=0.8, min.n2=18, theta0=1.25)

TSD with 2x2 crossover
Method B: alpha (s1/s2) = 0.0294 0.0294
Target power in power monitoring and sample size est. = 0.8
Power calculation via non-central t approx.
CV1 and GMR = 0.95 in sample size est. used
No futility criterion
Minimum sample size in stage 2 = 18
BE acceptance range = 0.8 ... 1.25

CV = 0.2; n(stage 1) = 12; GMR= 0.95

1e+06 sims at theta0 = 1.25 (p(BE)='alpha').
p(BE)    = 0.048816
p(BE) s1 = 0.028849
Studies in stage 2 = 87.86%

Distribution of n(total)
- mean (range) = 29.2 (12 ... 98)
- percentiles
 5% 50% 95%
 12  30  40

The Type I Error increases from 0.046262 (no minimum n₂) to 0.048816 (minimum n₂ = 1.5 × n₁). No problem with ‘Method B’ but gets nasty with ‘Method C’ (see the plot in my OP).

❝ Somehow I guess regulators just wanted to say that inclusion of a single subject in stage 2 would not be ok. They are right and that is not rocket science.

I think not to perform the second stage with one subject is a no-brainer. I guess that two was a compromise. AFAIK, Alfredo suggested 12 subjects to the BSWP.*

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• García-Arieta A, Gordon J. Bioequivalence Requirements in the European Union: Critical Discussion. AAPS J. 2012;14(4):738–48. doi:10.1208/s12248-012-9382-1