Bioequivalence and Bioavailability Forum • Model bioequivalence data summary tables-FDA

kumarnaidu
★

Mumbai, India,
2014-08-20 09:04
(3920 d 06:03 ago)

Posting: # 13410
Views: 9,443

Model bioequivalence data summary tables-FDA [RSABE / ABEL]

Hello every one,

I have one question regarding filling of Table 3A and 3B of Model bioequivalence data summary tables-FDA.
Table 3A Statistical Summary of the Comparative Bioavailability Data for
Unscaled Average BE Studies.
Table 3B Statistical Summary of the Comparative Bioavailability Data for
Reference-Scaled Average BE Studies.

As per the form if Reference Scaled Average Bioequivalence Approach Used then complete Tables 3A and 3B

In one of our study we used Reference scaled approach for all three parameters (Swr >0.294 for Cmax, AUCt and AUCinf). Then here should we also need to analyse these parameters using unscaled approach?

—
Kumar Naidu

Helmut
★★★

Vienna, Austria,
2014-08-20 12:44
(3920 d 02:23 ago)

@ kumarnaidu
Posting: # 13411
Views: 7,834

FDA: 90% CI for RSABE

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Hi Kumar,

❝ […] filling of Table 3A and 3B of Model bioequivalence data summary tables-FDA.

❝ As per the form if Reference Scaled Average Bioequivalence Approach Used then complete Tables 3A and 3B

Yes, that’s funny. See this thread and especially what John does.

❝ In one of our study we used Reference scaled approach for all three parameters (Swr >0.294 for Cmax, AUCt and AUCinf). Then here should we also need to analyse these parameters using unscaled approach?

I don’t think so. I would tick ☑ Yes in Table 3A and give in columns Ratio and 90% C.I.: NA. IMHO, it is sufficient to give the required information in Table 3B.

For the 90% CI in Table 3B use the intra-subject contrasts of the RSABE-code (Intermediate analysis – ilat). The statement cl alpha=0.1 gives you the 90% CI in log-scale. Back-transform it to raw scale.

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

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Science Quotes

kumarnaidu
★

Mumbai, India,
2014-08-20 15:30
(3919 d 23:37 ago)

@ Helmut
Posting: # 13414
Views: 7,691

FDA: 90% CI for RSABE

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Thanks Helmut for your valuable comment.
Actually we got pre-screening query from FDA for one of our study that table 3A is not filled. In that study we had Swr >0.294 for all three parameters thats why we filled table 3B and in table 3A we put NA.
After seeing this query some CRO experts suggest that we should also do unscaled approach for filling table 3A. But I think if we are doing by scaled method here because of high variability then what is the purpose of applying unscaled method here.

—
Kumar Naidu

Helmut
★★★

Vienna, Austria,
2014-08-20 16:10
(3919 d 22:57 ago)

@ kumarnaidu
Posting: # 13415
Views: 8,588

FDA: 90% CI for RSABE

Post reply

Hi Kumar,

❝ Actually we got pre-screening query from FDA for one of our study that table 3A is not filled. In that study we had Swr >0.294 for all three parameters thats why we filled table 3B and in table 3A we put NA.

Amazing response. To make the FDA happy, you could give the ratio and 90% CI from Table 3B also in Table 3A. Stupid, IMHO.

❝ After seeing this query some CRO experts suggest that we should also do unscaled approach for filling table 3A.

Experts? The guidance unambiguously states on page 8:

“For PK parameters with a s_WR < 0.294, use the unscaled average bioequivalence approach.”

That’s definitely not the case in your study. Furthermore, the ABE-code given by the FDA sometimes fails to converge if the study was done in a partial replicate design (doesn’t matter which software one uses!). This is due to the over-specified model in coincidence with the specification of the covariance structure as TYPE=FA0(2). If that happens one would have to use TYPE=FA0(1) – which is against the guidance.
A nice detail: The 90% CI from ABE does not equal the one obtained from RSABE (different effects in the models…). ;-)

Example* from Patterson/Jones, 90% CIs:

AUC C_max ──────────────────────────────────── ABE 96.25–116.15% 118.75–158.55% RSABE 96.27–116.13% 118.66–158.67%

Would the CROs’ “experts” suggest to confuse the FDA by giving the first row in Table 3A and the second one in Table 3B? I would expect yet another query from FDA’s review staff approaching:

“The 90% Confidence Intervals reported by the applicant in Tables 3A and 3B are inconsistent. Please justify.”

❝ But I think if we are doing by scaled method here because of high variability then what is the purpose of applying unscaled method here.

Exactly.

Patterson SD, Jones B. Viewpoint: observations on scaled average bioequivalence. Pharm Stat. 2012;11(1):1–7. doi 10.1002/pst.498

PS: IMHO, the “logic” of FDA’s form is bureaucratic crap.

Table 3A Statistical Summary of the Comparative Bioavailability Data for
Unscaled Average BE Studies
Reference Scaled Average Bioequivalence Approach Used ☐ Yes ☐ No
If Yes, then complete Tables 3A and 3B

I see! We tick ☑ Yes for RSABE and have to give in Table 3A the Ratio and 90% CI for Unscaled ABE. Bizarre. I’m fine with the geometric LSMs and Ns, of course.

[image]

Table 3A consists of two parts (fasting/fed studies), but there is only one in Table 3B. I beg your pardon? Pros at work…

—
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

jag009 ★★★ NJ, 2014-08-22 18:40 (3917 d 20:27 ago) @ Helmut Posting: # 13418 Views: 7,549	Not cast in stone Post reply
	Hi guys and gals, But you do realize that you don't have to use the tables exactly as they are right? Example, what if you have to fill in 1) partial AUCs, 2)add in a sprinkled study? You can modify the tables if you want. I have done it for the above examples. I did the same thing when reporting PK parameters for NDA filing as well... John

nobody nothing 2014-08-22 19:17 (3917 d 19:50 ago) @ jag009 Posting: # 13420 Views: 7,439	Not cast in stone Post reply
	...come on! In Europe a form is a form. I mean: A FORM! Can't touch this without severe punishment an/or running completely out of business! No way to alter the numbers or to fill in additional information. NO WAY! — Kindest regards, nobody

jag009
★★★

NJ,
2014-08-23 08:21
(3917 d 06:47 ago)

@ nobody
Posting: # 13423
Views: 7,432

Not cast in stone

Post reply

❝ ...come on! In Europe a form is a form. I mean: A FORM! Can't touch this without severe punishment an/or running completely out of business! No way to alter the numbers or to fill in additional information. NO WAY!

FDA is not as MEAN :-)

We are not altering numbers, just changing the layout of a table(s) so to make the presentation more clearer. By the way, FDA do (as far as I know) run the stats themselves to confirm so you can't really "cheat".

John