Jay
☆

India,
2018-03-26 13:31
(edited by Jay on 2018-03-26 13:50)

Posting: # 18595
Views: 3,680

## FDA: RSABE for NTID [RSABE / ABEL]

Dear all,

In one of the full replicate study of NTID the results are as per below,

 Parameters   Swr    95%CI LnCmax       0.04   0.0001 LnAUC0-t     0.07   -0.003 LnAUC0-inf   0.07   -0.004 

The ABE results are as below,

 Parameters   T/R    90%CI-L    90%CI-U LnCmax       97     95         99 LnAUC0-t     99     97         101 LnAUC0-inf   99     97         101 

The point estimate is near to 100 and ABE is also within 80% to 125%.

But in SABE, the Cmax criteria is more than 0 i.e. 0.0001 which leads to bioinequivalence.

So can it be scientifically justified the 95%CI of Cmax value as its very borderline to 0 and T/R shows less difference between test and reference.

Thanks

-Jay

Edit: Category and subject line changed; see also this post #1 and #2. [Helmut]
jag009
★★★

NJ,
2018-03-26 17:57

@ Jay
Posting: # 18596
Views: 3,265

## FDA: RSABE for NTID

Did you check individual data? Any strange ones?
If FDA, "no" As in good luck in trying to convince them.

John
Jay
☆

India,
2018-04-02 06:28

@ jag009
Posting: # 18628
Views: 2,831

## FDA: RSABE for NTID

I would like to understand that how come the study passing in ABE within 80% to 125%, low T/R and low ISCV would not meet the BE criteria of scaled average bioequivalence.

As we generally proceed with scaled approach when the ISCV is high (more than 30%) and would not meet BE criteria with ABE approach.

Regards,
Jay
pjs
★

India,
2018-04-02 15:07
(edited by pjs on 2018-04-02 15:17)

@ Jay
Posting: # 18633
Views: 2,789

## FDA: RSABE for NTID

Dear Jay,

» I would like to understand that how come the study passing in ABE within 80% to 125%, low T/R and low ISCV would not meet the BE criteria of scaled average bioequivalence.

As per the Swr data shared scaled BE limits would be 95.87-104.30%. Now as per the ABE data you shared lower limit is mentioned to be 95%.

Now please note that variability in ABE and SABE would be different as there will be different models for the estimation. Also for SABE only subjects who had completed all four Periods would be included and in ABE any subject with atleast one reference and one test product would be included.

You may refer the lower limit for the ilat output in SABE approach which would be outside 95.87%. This could be reason behind the upper bound value marginally more than 0. Just one quick question in the outputs for upper bound, value to be rounded off till which decimal? If you consider three decimals study is passing and with four decimals same is failing.

Also with variability as low as 4%, you also need to check test product variability to comply with variability comparison criteria.

Just to check with forum members is there any method for outlier detection in such full replicate studies? In one of the earlier posts there was discussion for use of method proposed by Lazlo for the same. Any further update for the acceptability of this approach.

Can you pls confirm how many subjects were included in the study and how sample size was defined.

Regards
Pjs
Jay
☆

India,
2018-04-04 14:24

@ pjs
Posting: # 18639
Views: 2,504

## FDA: RSABE for NTID

Dear pjs,

In any two way ABE study, if the 90%CI is not within the range of 80-125%, most of time the same is reflected in the T/R and also the dissolution graphs.

For highly variable product, if the 95% CI is not ≤0, the T/R ratio would be very high and beyond the range of 80 to 125%.

For NTID as per USFDAs GL below three criteria should be followed,
- Upper 95% CI ≤0 (SABE)
- 90% CI should be within 80-125%
- UL of 90% CI for σWT/σWR should be ≤ 2.5 (ABE)

As per the case mentioned in above post, the ISCV of test and ref is very low (around 6-7), T/R is near to 100 and also meeting BE criteria in ABE. So if only 95% CI in SABE does not meet criteria (0.0001) so how the reason for the difference between test and reference can be interpreted.

-Jay
Helmut
★★★

Vienna, Austria,
2018-04-04 15:03

@ Jay
Posting: # 18640
Views: 2,555

## β = 1 – π

Hi Jay,

» In any two way ABE study, if the 90%CI is not within the range of 80-125%, most of time the same is reflected in the T/R …

Well, the CI is constructed around the GMR.

» … and also the dissolution graphs.

Nope. Only if dissolution would be the rate-limiting step. Otherwise in vitro cannot (!) be predictive of in vivo. There a tons of studies with completely dissimilar dissolution profiles which passed BE easily.

» For NTID as per USFDAs GL below three criteria should be followed,
» - Upper 95% CI ≤0 (SABE)
» - 90% CI should be within 80-125%
» - UL of 90% CI for σWT/σWR should be ≤ 2.5 (ABE)

You are mixing something up. Actually:
- Upper 95% CI ≤0 (SABE)
- 90% CI should be within 80-125% (ABE)
- UL of 90% CI for σwT/σwR should be ≤ 2.5 (comparison of variabilities)

» As per the case mentioned in above post, the ISCV of test and ref is very low (around 6-7), T/R is near to 100 and also meeting BE criteria in ABE. So if only 95% CI in SABE does not meet criteria (0.0001) so how the reason for the difference between test and reference can be interpreted.

The FDA’s “implied BE limits” can be calculated by $e^{\mp \log{(1.11111)}\cdot \sqrt{\log{(0.30^2+1)}}/0.1}$ which are in your case:

CV (%)  BE-limits (%)   6     93.88  106.52   7     92.90  107.64

Does the conventional ABE (90% CI) pass these narrower limits?

These three tests are not directly related. Fine if you pass the latter two. Bad luck if you fail the first by a small margin. How was the study powered? If you targeted a power of 80–90%, the chance of failing for a product which is BE would be 10–20%. Daily life. See John’s reply above.
Counterquestion: Did you ever succeed in convincing the FDA to accept a conventional BE study which showed a 90% CI of 79.99–125.01%?

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Nirali
★

India,
2019-01-30 15:38

@ Helmut
Posting: # 19830
Views: 1,348

## Warfarin Sodium 95% Upper bound criteria

Dear Helmut,

I need the same guidance for Warfarin Sodium case.
If the 95% upper bound for Cmax parameter is 0.002, should we conclude this study as a bioequivalent for Cmax?

There is no specific criteria given for 95% upper bound in the OGD of Warfarin Sodium.

Regards
Nirali
Helmut
★★★

Vienna, Austria,
2019-02-02 14:15

@ Nirali
Posting: # 19844
Views: 1,198

## Upper bound in RSABE ≤0

Hi Nirali,

» If the 95% upper bound for Cmax parameter is 0.002, should we conclude this study as a bioequivalent for Cmax?

No, since the upper bound has to be less or equal to zero. No rounding here …

» There is no specific criteria given for 95% upper bound in the OGD of Warfarin Sodium.

≤0 is the general rule for the FDA’s RSABE.

• Endrényi L, Tóthfalusi L. Determination of Bioequivalence for Drugs with Narrow Therapeutic Index: Reduction of the Regulatory Burden. J Pharm Pharm. 2013;16(5):676–82. PMID 24393551.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Nirali
★

India,
2019-02-12 07:10

@ Helmut
Posting: # 19902
Views: 1,108

## Upper bound in RSABE ≤0

Thank you Helmut.

Nirali Mehta
(PHARMA-STATS)
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