Bioequivalence and Bioavailability Forum

Dear colleagues,

since I saw a couple of deficiency letters concerning C_min in the recent past, I want to start a little survey and discussion. The BE-Draft (2008) states (lines 558-559):

For studies to determine bioequivalence at steady state AUC_tau, C_max,ss, and C_min,ss should be analysed using the same acceptance interval as stated above.

and in lines 551-552:

For these parameters the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80-125%.

Lines 561-562 state:

[…] for highly variable drugs the acceptance interval for C_max may in certain cases be widened (see section 4.1.10).

I would say the same rationale for widening the acceptance range (clinical justification, high variability) for C_max is justifiable for C_min.

1. How do you define C_min in steady state?
   1. Minimum concentration within the profile
      
   2. Pre-dose concentration
      
   3. Last concentration within the dosing interval
      
   4. Minimum concentration within time of administration and t_max
      
   5. Additional question: your rationale for either of the above
2. Do you only report values for the formulations (geometric mean, sd) or do you calculate and report a confidence interval?
   
3. If the latter, do you use the metric in a confirmatory analysis (e.g., state an acceptance range)?
   1. Yes, always
      
   2. Yes, but only if clinical concerns, e.g. for long-term use analgetics, antibiotics, …
      
   3. Yes, but one-sided (i.e., not inferior to reference)
      
   4. No
      If yes, which acceptance range?
      
   5. 0.80-1.25
      
   6. 0.75-1.33
      
   7. 0.70-1.43
      
   8. other
   How do you deal with the inherent variability (low power)?
   
4. Did you have any problems with your approach?
   
5. Do you see a change in point of views by European regulators within the last years – especially after publication of the BE-Draft?
   
6. Do you consider widening of the acceptance range in a replicate design in steady state (i.e., TTRR-RRTT), which would need measuring four profiles?

P.S.: C_min is a quite nasty metric. In a recent study (n=40) with ≈100% PTF (C_min ≈25% of C_max) I saw a CV_intra of 15.6% for C_max, but 62% (!) for C_min…

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Edit 1: In the final BE Guideline C_min is not given any more as a steady state metric (for IR formulations). So the question stays valid for MR formulations – would you dare to go with scaling?

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Edit 2: The comment-document (see this post) states at page 89:

By C_min,ss we mean the concentration at the end of the dosage interval, i.e. C_trough. However, in bioequivalence studies for immediate release formulations there is no need to report C_trough and fluctuation. The guideline has been revised.