## So many questions, so few answers [BE/BA News]

❝ should we submit a dataset to EMA and suggest them to publish it along with a description (numerical example) of how exactly they wish to derive the decision?

Maybe better not only a data set but also a proposed method for evaluation.

❝ When FDA indicated that they were going in the direction of in vitro popBE for inhalanda and nasal sprays they published a dataset and showed exactly how to process the data to figure out the pass / fail criterion that satisfies the regulator.

I have a counter-example. This goody was recommended in Apr 2014 and revised in Jan 2020. Nobody knew

*how*the FDA arrived at the BE-limits and

*why*. Last month I reviewed a manuscript explaining the background. Made sense (based on lots of data of the originator) but for years it was a complete mystery.

❝ If EMA would do the same here we'd have all doubt eliminated.

Utopia. Notoriously the EMA comes up with unsubstantiated ‘inventions’ made up out of thin air and leaves it to

*to figure out if and how they work. Examples?*

**us***Rounded*regulatory constant*k*= 0.760 and upper cap at*CV*_{wR}= 50% in reference-scaling,

*sequence*(*stage*) term in TSDs,

- ‘substantial’ accumulation if
*AUC*_{0–τ}> 90% of*AUC*_{0–∞},

- for partial
*AUC*s default cut-off time*τ*/2,

- comparison of
*C*_{ss,min}for originators but of*C*_{ss,τ}for generics,

- …

❝ I think we need to know exactly:

❝ 1. Do we use nonparametrics or not?

Guess.

❝ 2. Do we use logs or not?

Logs? Possibly

*t*

_{max}follows a Poisson distribution.

❝ 3. Is the decision of 20% comparability based on a confidence interval or on something else?

Likely the former; made up out of thin air.

❝ 3a. If there is a CI involved, is it a 90% or 95% CI or something else?

90%.

❝ 4. Are we primarily working on ratio or on a difference?

IMHO, calculating ratios of discrete values with potentially unequal intervals is plain nonsense. Data are on an ordinal scale. Only (‼) allowed operations: addition, subtraction, ranking. Nothing else.

❝ 5. Is the bootstrap involved?

A possible approach but why?

❝ 6. How should we treat datasets from parallel trials, and how should we treat data from XO (i.e. how to handle considerations of paired and non-paired options)?

I would suggest the Mann–Whitney

*U*test (parallel) and the Wilcoxon signed-rank test (paired / crossover). Requires some tricks in case of tied observations (practically always) for the exact tests,

*e.g.*, function

`wilcox_test()`

of package `coin`

instead of `wilcox.test()`

.❝ My gut feeling is that they want nonparametrics for the Tmax comparability part (yes I am aware of *the sentence*).

I doubt it. Really.

❝

Actually, perhaps they just want the decision taken on basis of the estimates of medians and ranges from min to max?

I think so (see also Ohlbe’s post). However, that’s statistically questionable (politely speaking). See the updated article and hit to clear the browser’s cached version.

❝ If we submit a dataset, let us make sure we submit one with ties (the one I pasted above had none).

It’s extremely unlikely that you will find one without…

I explored one of my studies. Ibuprofen 600 mg tablets, single dose, fasting, 2×2×2 crossover, 16 subjects (90% target power for

*C*

_{max}), sampling every 15 minutes till 2.5 hours. Re-sampled the reference’s

*t*

_{max}in 10

^{5}simulations and applied the ‘≤±20% criterion’:

` median re-sampled med. diff (%) pass.pct `

Min. :1.000 Min. :1.000 Min. :-50.000 Mode :logical

1st Qu.:1.375 1st Qu.:1.375 1st Qu.:-15.385 FALSE:34887

Median :1.500 Median :1.500 Median : 0.000 TRUE :65113

3rd Qu.:1.750 3rd Qu.:1.750 3rd Qu.: 18.182

Max. :2.500 Max. :2.500 Max. :100.000

Dashed lines 2.5 and 97.5 percentiles

Bonus question: Which distribution? Skewness +0.627.

The generic tested in this study was approved 25 years ago and is still on the market. Any problems?

If you want to give it a try:

`R <- c(1.25, 2.00, 1.00, 1.25, 2.50, 1.25, 1.50, 2.25,`

1.00, 1.25, 1.50, 1.25, 2.25, 1.75, 2.50, 2.25)

P.S.: Amazing that this zombie rises from the grave. See this post and this thread of June 2013…

*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:

- EMA: New product-specific guidances Helmut 2022-04-08 15:17 [BE/BA News]
- How would you implement it? ElMaestro 2022-04-09 11:45
- Confuse a Cat Inc. Helmut 2022-04-09 18:40
- Confuse a Cat Inc. ElMaestro 2022-04-09 21:47
- Confuse a Cat Inc. Ohlbe 2022-04-11 11:29
- Confuse a Cat Inc. Helmut 2022-04-11 13:59

- So many questions, so few answersHelmut 2022-04-11 13:03
- Preliminary simulations Helmut 2022-04-30 14:59
- Preliminary simulations ElMaestro 2022-04-30 19:10
- Preliminary simulations Helmut 2022-05-01 15:56
- Revisions of the PSGLs final Helmut 2023-06-23 13:29
- Revisions of the PSGLs final dshah 2023-06-28 14:43
- EMA: No problems with many sampling time points… Helmut 2023-06-28 15:59
- New simulations & some desultory thoughts Helmut 2023-06-29 11:34
- SCNR. A heretic alternative. Helmut 2023-06-30 11:50

- Revisions of the PSGLs final dshah 2023-06-28 14:43

- Preliminary simulations ElMaestro 2022-04-30 19:10
- Simulated distributions Helmut 2022-05-02 13:43

- Confuse a Cat Inc. Ohlbe 2022-04-11 11:29

- Confuse a Cat Inc. ElMaestro 2022-04-09 21:47

- Confuse a Cat Inc. Helmut 2022-04-09 18:40

- How would you implement it? ElMaestro 2022-04-09 11:45