Bioequivalence and Bioavailability Forum • Widening of acceptance range for Cmin

Helmut
★★★

Vienna, Austria,
2012-08-30 19:47
(5051 d 12:56 ago)

Posting: # 9129
Views: 3,247

Widening of acceptance range for Cmin [Regulatives / Guidelines]

Dear all,

see EMA’s 60-day referral procedures to CMDh finalised in 2012. Look at row 22 dealing with nasty ropinirole:

Grounds for referral to CMDh
Bioequivalence study was only submitted for the lowest strength (2 mg) but was requested by several member states also for the highest strength.
Furthermore, it was not accepted that the C_min found in the 2 mg studies was outside the CI limits of 80–125%.
Outcome
The requested bioequivalence study (steady state) on the highest strength 8 mg was submitted by the applicant. The study methodology was accepted and the study demonstrated bioequivalence to the reference product. High intra-subject variability was shown in the 8 mg study with replicate design which justified extended CI limits for C_min. Since bioequivalence was shown for the lowest and the highest strength and strength waiving criteria were fulfilled, the RMS came to a positive conclusion. All concerned member states^* agreed to positively finalise the procedure.

The 1999 MR NfG states in Section 5.1:

Assessment of bioequivalence will be based on AUC_τ, C_max and C_min applying similar statistical procedures as for the immediate release formulations.
Any widening of the acceptance criteria should be established prospectively in the clinical study protocols. They should be justified from a clinical point of view by the applicant.

It is not clear whether widening of the acceptance range (to 75–133%) was performed according to the (obsolete) 2006 Q&A-document or ABEL in accordance with the IR GL and the accompanied Q&A. This example leaves hope for the MR draft (scheduled for QIII/2012) – though a replicate design steady state study is no fun.

Austria, Germany, Greece, Finland, Iceland, Ireland, Italy, The Netherlands, Norway, Portugal, Spain, United Kingdom of Great Britain and Northern Ireland.

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

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The Outlaw Torn
★

Europe,
2012-08-31 10:47
(5050 d 21:57 ago)

@ Helmut
Posting: # 9130
Views: 2,699

Widening of acceptance range for Cmin

Post reply

Good morning, Helmut,

If you look four slots up in the referal document you'll see another referral for ropinirole for the same reason. The 8 mg study provided for the committee was not replicate in design and did not need widening of the confidence intervals for Cmin (although the "intra-subject" variability, as calculated for crossover designs, approached 50%).

If you look at the history of galantamine in front of the same committee, their are some fairness concerns that creep up in my mind. It would be nice to get some kind of consistency from the committee (but I've been told that another precedence is not considered meaningful with some on the committee, that each application is judged on "its own merits" (cough, cough). Seems like an excuse to play fast and loose with the guideline as they see fit. Since Cmin is such a variable metric, it would be prudent for every protocol written to prospectively propose widening of the limits—just in case. That's the message I'm getting from this kind of decision.

Ciao,
Outlaw