Bioequivalence and Bioavailability Forum

VSL ☆ India, 2015-04-20 23:46 (3624 d 16:09 ago) Posting: # 14721 Views: 14,251	Study Results [Study Assessment] Post reply
	Dear All, Please explain what to do if following results obtained in BE-Study: Study is passed in CI but mean T/R ratio is not within the 0.80-1.25. Study is passed in CI but there is significant p-value for treatment/period/sequence Shall we submit the study to regulatory agencies? Regards... VSL Edit: Category changed. [Helmut]

ElMaestro
★★★

Denmark,
2015-04-21 01:47
(3624 d 14:08 ago)

@ VSL
Posting: # 14722
Views: 12,617

Study Results

Post reply

Hi VSL,

❝ Please explain what to do if following results obtained in BE-Study:

❝ 1. Study is passed in CI but mean T/R ratio is not within the 0.80-1.25.

This does not correspond to the world I know. Can you show the example?
If I am not mistaken HRotter or some other guru once mentioned on this forum that a PE outside the CI is theoretically possible; from the equation for the 90% BE CI -which I hope is generally accepted- I think it is evident that the PE is not outside the CI.

❝ 2. Study is passed in CI but there is significant p-value for treatment/period/sequence

The term is nuisance effect. This forum has discusssed it many times, try and search for it. Basically, it should not be too much of a worry. Those p-values correspond to a null hypothesis you are not really interested in when testing for BE.
Pre-dose levels of the analyte is, however, more tangible ground for concern.

—
Pass or fail!
ElMaestro

Helmut
★★★

Vienna, Austria,
2015-04-21 02:39
(3624 d 13:16 ago)

@ ElMaestro
Posting: # 14724
Views: 12,622

upper CL < PE

Post reply

Hi ElMaestro,

❝ If I am not mistaken HRotter or some other guru once mentioned on this forum that a PE outside the CI is theoretically possible;

Thomas Jaki. When he tried to explain that to me I got mental hickups. But was other stuff: The one-sided CI of a CV with an α >0.5 – which is nuts.

library(PowerTOST) CV <- 0.2 df <- 22 alpha <- 0.55 CL <- CVCL(CV=CV, df=df, side="upper", alpha=alpha) cat("CV :", CV, "\nCL of CV:", CL[1], "to", CL[2], "\n") # CV : 0.2 # CL of CV: 0 to 0.1992335

Implemented according to Chow/Liu… Beyond me.

❝ from the equation for the 90% BE CI -which I hope is generally accepted- I think it is evident that the PE is not outside the CI.

Rightyright. Not possible.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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Helmut
★★★

Vienna, Austria,
2015-04-21 02:24
(3624 d 13:31 ago)

@ VSL
Posting: # 14723
Views: 12,349

PE restriction for HVDs/HVDPs; testing effects

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Hi VSL,

❝ 1. Study is passed in CI but mean T/R ratio is not within the 0.80-1.25.

ElMaestro’s answer is correct – if the acceptance range (AR) is 0.8–1.25 (unscaled ABE). If you applied reference-scaling (in FDA’s or EMA’s flavor) such a result is possible indeed, especially if:

CV_WR ≫ CV_WT.
Large “true” deviation of T from R.
… or both.

The modified acceptance range depends only on the variability of the reference. If the test’s variability is comparatively small, the CI might be relatively narrow. That would mean a formulation could pass with a GMR far away from 1 (even <0.8 or >1.25). Statistically that would still make sense, but for political reasons the restriction of the PE of 0.8–1.25 was introduced. Actually for CV_WR ≥50% the scaled AR (and the CI inclusion rule) is of little importance at all. It is mostly the PE which counts. Tons of papers.

In the future please give complete information (acceptance range, CI, CVs, regulatory agency).

❝ 2. Study is passed in CI but there is significant p-value for treatment/period/sequence

❝ Shall we submit the study to regulatory agencies?

Ahem – did your read the guidelines?

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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jag009 ★★★ NJ, 2015-04-21 18:49 (3623 d 21:06 ago) @ Helmut Posting: # 14728 Views: 12,250	PE restriction for HVDs/HVDPs; testing effects Post reply
	? You guys are messing with me... If the T/R Ratio is <0.8 or >1.25, how can you generate a 90 CI that is within 80.00 – 125.00 since the 90% CI consists of (PE ± values)? John

Helmut
★★★

Vienna, Austria,
2015-04-21 19:12
(3623 d 20:43 ago)

@ jag009
Posting: # 14729
Views: 12,451

PE restriction for HVDs/HVDPs; testing effects

Post reply

Hi John,

❝ You guys are messing with me... If the T/R Ratio is <0.8 or >1.25, how can you generate a 90 CI that is within 80.00 – 125.00 since the 90% CI consists of (PE ± values)?

If we are dealing with unscaled ABE, ElMaestro’s answer (and your doubt) is correct: No way.

VSL’s post is ambiguous:

❝ Study is passed in CI but mean T/R ratio is not within the 0.80-1.25.

If the study was reference-scaled, the (implied) BE limits may be much wider (my answer).
Example in FDA’s flavor: CV_WR 60%, implied limits 60.96–164.04%, CI 97.00–162.00%; would pass (CI within limits), but fail due to the PE of 125.36 >125.00%.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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jag009 ★★★ NJ, 2015-04-22 17:47 (3622 d 22:08 ago) @ Helmut Posting: # 14732 Views: 12,078	PE restriction for HVDs/HVDPs; testing effects Post reply
	Hi Helmut, ❝ VSL’s post is ambiguous: And guess what, he still hasn't replied But if he was talking about ref scaled, then why would he bring up 90 CI? Strange, actually scary... John

Helmut
★★★

Vienna, Austria,
2015-04-22 18:41
(3622 d 21:14 ago)

@ jag009
Posting: # 14733
Views: 12,173

PE restriction for HVDs/HVDPs

Post reply

Hi John,

❝ ❝ VSL’s post is ambiguous:

❝

❝ And guess what, he still hasn't replied :-|

❝

❝ But if he was talking about ref scaled, then why would he bring up 90 CI? Strange, actually scary...

Duno. That’s why I asked for more information. He/she didn’t mention a 90% CI, only told us

❝ Study is passed in CI

Maybe he/she meant the upper 95% CL of FDA’s approach (≤0)? BTW, since for the EMA scaling is capped at CV_WR 50% passing with a 90% CI and failing on the PE is very, very unlikely.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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Averroes
☆

Spain,
2017-05-19 13:53
(2865 d 02:02 ago)

@ Helmut
Posting: # 17372
Views: 7,419

GMR outside the limits when using ABEL

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Dear Helmut,

Recently we performed a full replicate (4-period) study using ABEL for EMA and actually the results shows AUC within 80-125, Cmax within expanded CI but unfortunately GMR fall outside 80-125.

I found in the forum that the GMR constrant is there for political reasons more than for scienfic or statistical reasons. Do you think we could still have an opportunity with European regulatory agencies?

Thanks,

Helmut
★★★

Vienna, Austria,
2017-05-19 16:07
(2864 d 23:48 ago)

@ Averroes
Posting: # 17373
Views: 7,473

Regulations ≠ Science

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Hi Averroes,

❝ […] the GMR constrant is there for political reasons more than for scienfic or statistical reasons.

Exactly. Suggested by Les Benet.

❝ Do you think we could still have an opportunity with European regulatory agencies?

I’m always happy to challenge regulatory practices. But in this case the chances to succeed are close to nil. IMHO, even trying is a complete waste of time. Alfredo will never, ever buy it.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Averroes ☆ Spain, 2017-05-22 22:51 (2861 d 17:04 ago) @ Helmut Posting: # 17389 Views: 7,240	Regulations ≠ Science Post reply
	❝ I’m always happy to challenge regulatory practices. But in this case the chances to succeed are close to nil. IMHO, even trying is a complete waste of time. Alfredo will never, ever buy it. Thanks Helmut!!

Study Results [Study As­sess­ment]

Study Results

upper CL < PE

PE restriction for HVDs/HVDPs; testing effects

PE restriction for HVDs/HVDPs; testing effects

PE restriction for HVDs/HVDPs; testing effects

PE restriction for HVDs/HVDPs; testing effects

PE restriction for HVDs/HVDPs

GMR outside the limits when using ABEL

Regulations ≠ Science

Regulations ≠ Science

Study Results [Study Assessment]