## [Opinion] Should the 90% CI for GMR be required to encompass 1 [RSABE / ABEL]

❝ I am a new poster, long time lurker.

Welcome to the club. Do you know what Groucho Marx said about clubs?

❝ I am […] crazy (but not formally trained) about statistics.

Welcome to the Amateur League.

I try to respond not only to this post but to others of yours.

❝ My question involves the case where an entire GMR 90% confidence interval is outside of 100.00 […]. For HVD with wide therapeutic index, I believe this is reasonable. But what about for a NTID with doses that differ by less than 15%?

❝

❝ I understand this is part of the reason that RSABE and ABEL are implemented. However, let us assume that the Swr is 22% and essentially expands reference scaling to ABE limits. Let us also assume that a 7% difference in BE is clinically significant.

You’ve chosen a nice s

_{wR}! With the FDA’s RSABE for NTIDs the “implied BE limits”

*would be*wider than the conventional ABE’s 80.00–125.00% for any CV

_{wR}>21.42% (s

_{wR}0.2118). Hence, according to the book you have to pass the conventional limits as well.

❝ […] I am saying that a large enough sample size can force a test product with e.g. 89% relative BA (e.g. 100mg/112mg) relative to RLD to pass. The difference between 100 and 112mg is clinically significant for this product. I am wondering if adding the condition I talked about from the beginning would help.

OK, let’s ignore ElMaestro’s and John’s concerns about potency for a minute and assume that both drugs have a true potency of 100% (of their labeled contents of 100 and 112 mg).

I know that you are R-geek. Do we really need a

*large*sample size?

`library(PowerTOST)`

sampleN.NTIDFDA(CV=0.22, theta0=100/112, design="2x2x4", details=FALSE)

+++++++++++ FDA method for NTIDs ++++++++++++

Sample size estimation

---------------------------------------------

Study design: 2x2x4

log-transformed data (multiplicative model)

1e+05 studies for each step simulated.

alpha = 0.05, target power = 0.8

CVw(T) = 0.22, CVw(R) = 0.22

True ratio = 0.8928571

ABE limits = 0.8 ... 1.25

Regulatory settings: FDA

Sample size

n power

36 0.810220

If everything comes out exactly as assumed, what will we get?

`round(100*CI.BE(pe=100/112, CV=0.22, n=36, design="2x2x4", robust=TRUE), 2)`

lower upper

83.98 94.93

```
sigma0 <- 0.1 # CV 10.02505. Why? Ask the FDA.
```

Impl.Limits <- exp(c(-1, +1)*log(1.11111)*CV2se(0.22)/sigma0)

names(Impl.Limits) <- c("L", "U")

round(100*Impl.Limits, 2)

L U

79.53 125.74

_{wR}the condition “must pass ABE” is important. If you want to explore the overall-power (plus the ones of the three tests) try:

`power.NTIDFDA(theta0=100/112, CV=0.22, n=36, design="2x2x4", details=TRUE)`

p(BE) p(BE-sABEc) p(BE-ABE) p(BE-sratio)

0.81022 0.83051 0.90737 0.99986

OK, the study passes despite that the GMR is with 82.64% below your clinically significant difference (–7%).

No qualified opinion about your

❝ […] is it reasonable to require the 90% CI for GMR to fall within 1?

But:

*θ*is within the 90% CI of the GMR. The upper CL (94.93%) overlaps with your “relevant” lower limit of 93%.

BTW, for the EMA (fixed BE-limits of 90.00–111.11%) try this:

`sampleN.TOST(CV=0.22, theta0=100/112, theta1=0.90, design="2x2x4", details=FALSE)`

*Dif-tor heh smusma*🖖🏼 Довге життя Україна!

_{}

Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮

Science Quotes

### Complete thread:

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 18:43 [RSABE / ABEL]
- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 19:07
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 19:23
- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 19:44
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 20:05
- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-28 21:25
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 21:59
- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 23:03
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 23:57
- Black Swan again mittyri 2018-04-05 17:57

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 23:57

- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 23:03

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 21:59

- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-28 21:25

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 20:05

- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 19:44

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-28 19:23
- [Opinion] Should the 90% CI for GMR be required to encompass 1Helmut 2018-03-28 23:57
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-29 13:46
- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-29 16:52
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-29 16:57
- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-29 19:55
- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-29 20:30
- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-29 21:22
- Paper & Presentations Helmut 2018-03-30 01:33

- Donald Schuirmann’s opinion Helmut 2018-04-10 14:41

- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-29 21:22

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-29 20:30

- [Opinion] Should the 90% CI for GMR be required to encompass 1 jag009 2018-03-29 19:55

- [Opinion] Should the 90% CI for GMR be required to encompass 1 bebac_fan 2018-03-29 16:57

- [Opinion] Should the 90% CI for GMR be required to encompass 1 ElMaestro 2018-03-28 19:07