Bioequivalence and Bioavailability Forum

Hi Angus!

❝ I am interested in what folks think of this …

Well, I have no idea what Pharsight calculated here – I get other values. See also a comparison with Table I of Tóthfalusi et al. (2009).

CV%  Pharsight slide 15    FDA’s limits       EMA’s limits
30       80% - 125%      [77.0% - 129.9%]    80.0% - 125.0%
35       77% - 130%       73.9% - 135.3%     77.2% - 129.5%
40       74% - 135%       71.0% - 140.9%     74.6% - 134.0%
45       71% - 141%       68.2% - 146.5%     72.2% - 138.6%
50       68% - 147%       65.7% - 152.3%     69.8% - 143.2%
55                        63.3% - 158.0%    [67.7% - 147.8%]
60                        61.0% - 163.8%    [65.6% - 152.4%]
Values in red: The calculated limits at CV=30% are not applicable with FDA's method; 80%-125% are used instead. Expanded limits for CV>50% are not allowed by the EMA; the limits for CV=50% are used instead.

❝ … expansion of the confidence intervals.

<nitpicking>

The confidence interval is the same – the acceptance range (bioequivalence limits) is expanded.

</nitpicking>

It’s important to note that FDA’s and EMA’s approaches are different; FDA’s leads to a discontinuity of the acceptance range at CV=30%, because the scaling CV is 25% – but only applied at CV >30%: See the following two plots (lin and log scale):




The dotted red lines demonstrate FDA’s procedure: from their formula scaling would start at CV 25%, but is only allowed for >30% – with the scaling factor of 25%. Therefore this nice step. So far about global harmonization.
Orange dots are Pharsight’s values. A vendor-specific ‘compromise’ across the Atlantic?

For some background see

• Haidar SH, Davit B, Chen M-L, Conner D, Lee LM, Li QH, Lionberger R, Makhlouf F, Patel D, Schuirmann DJ, and LX Yu
  Bioequivalence Approaches for Highly Variable Drugs and Drug Products
  Pharm Res 25(1), 237–41 (2008)
  DOI 10.1007/s11095-007-9434-x
  free online resource
  
• Endrényi L and L Tóthfalusi
  Regulatory Conditions for the Determination of Bioequivalence of Highly Variable Drugs
  J Pharm Pharm Sci 12(1), 138–49 (2009)
  online abstract, free online resource
  
• Tóthfalusi L, Endrényi L and A García-Arieta
  Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence
  Clin Pharmacokinet 48(11), 725–43 (2009)
  online Abstract

Personally I would prefer EMA’s approach, because no ‘sudden jump’ is introduced at CV=30%. Unfortunatelly EMA restricted scaling to CV ≤50% (higher CVs are to be treated as if CV=50%) for political reasons. No scaling for AUC is scientifically nonsense, IMHO.
If you have to deal with the FDA, simply follow the progesterone guidance from April 2010.

The restriction on the point estimate (GMR) of 80–125% in both regulations is statistically not justified, but entirely political.

P.S.: Search the forum for RSABE, reference scaled bioequivalence, or HVD – a lot of stuff is waiting for you.