Bioequivalence and Bioavailability Forum • Widened acceptance limits without a replicate study

CLR
☆

Singapore,
2013-04-02 06:29
(4835 d 03:29 ago)

Posting: # 10322
Views: 6,061

Widened acceptance limits without a replicate study [Design Issues]

Hi all,

We have been looking at some past BE studies which have been submitted to various agencies as well as the publicly-available assessment reports. We have seen many BE studies (pre-2010) where the acceptance limits for Cmax were widened for a highly-variable drug such as atorvastatin. However, in many of such studies, a conventional 2-period, 2-sequence study design was used, and not a replicate study design. If I have understood the current EMA guidelines correctly, the acceptance limits can only be widened if the intra-subject CV > 30% in the BE study and if prospectively specified in the protocol. Nevertheless, there are UKPARs showing that widened acceptance limits have been allowed without a replicate study design. Can someone please help me understand this?

Thanks!

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Best regards,
Clare

drgunasakaran1
★★

2013-04-02 10:43
(4834 d 23:15 ago)

@ CLR
Posting: # 10323
Views: 5,270

Widened acceptance limits without a replicate study

Post reply

Dear Clare,

❝ If I have understood the current EMA guidelines correctly, the acceptance limits can only be widened if the intra-subject CV > 30% in the BE study

As per EMA's Guideline on the Investigation of Bioequivalence, "For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%. EMA will accepts Expandable BE limits only for replicate design if the intrasubject variability for Cmax of the reference is more than 30%.

❝ Nevertheless, there are UKPARs showing that widened acceptance limits have been allowed without a replicate study design.

May be EMA would have accepted expandable limits without replicate design before, but as per the recent guidance, expansion of BE limits are allowed only in the replicate design.

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Dr Gunasakaran Sambandan MD
Disclaimer: The replies/posts are my personal opinions, and they do not represent my company's views on the same. LinkedIn

Helmut
★★★

Vienna, Austria,
2013-04-04 04:20
(4833 d 05:38 ago)

@ CLR
Posting: # 10339
Views: 5,058

European history lesson

Post reply

Hi Clare,

❝ If I have understood the current EMA guidelines correctly, the acceptance limits can only be widened if the intra-subject CV > 30% in the BE study and if prospectively specified in the protocol.

Almost correct (as Dr. Gunasakaran already pointed out). Currently you have to state in the protocol:

Intention to widen the acceptance range based on [L, U] = ℯ^{∓0.760·s_WR} if CV_WR >30% (and limited with 50%) – GMR within 80.00–125.00%;
unscaled AR (80.00–125.00%) otherwise.
Sound justification that the widening is clinically irrelevant.

Don’t forget the second point.

❝ Nevertheless, there are UKPARs showing that widened acceptance limits have been allowed without a replicate study design.

Since the Q&A-document (July 2006) CV_WR >30% in a replicate design was required in order to widen the limits (for C_max only) to 75.00–133.33%.
Before it was possible to widen the limits to e.g. 75.00–133.33% without a replicate design. Note the “e.g.”! There were many products approved with an AR of 70.00–142.86%. In exceptional cases widening was also accepted for AUC…

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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

CLR ☆ Singapore, 2013-04-04 12:16 (4832 d 21:42 ago) @ Helmut Posting: # 10341 Views: 4,917	European history lesson Post reply
	I see! OK so now I just need to get my head around the mathematics involved. Thank you both for the insight.