Bioequivalence and Bioavailability Forum

Dear Joy,

sorry for the late reply

❝ 1. Are these acceptable in bioequivalence studies if specified a priori in the protocol? Would you know if US FDA, EMEA, Canada, ASEAN accept such design?

❝ 2. When an add-on study is conducted (and combined with the original study), what would be the statistical method of analysis?

❝ 3. Can we still apply the 90% Confidence Interval criteria for bioequivalence or would it have to be more restrictive i.e. 95% CI?

First a little review of international guidelines (maybe answering you questions #1-#3)

Canada
If BE is not shown, additional subjects are included. If an F-test (equality of variances) shows no significance, you may go for a pooled analysis. No alpha-adjustment needed.
Japan
If BE is not shown, a second part with sample size of at least half of the 1st part is initiated. Pooled analysis without alpha-adjustment.
South Africa
Maximum sample size must be stated a-priori; for details see Ahmed's post and the followings.
New Zealand
Group Sequential Design with alpha-adjustment (Gould's* method?).
USA
No way

Second some notes on the European practice.

Add-On and Group Sequential Designs are not covered in the NfG on BA/BE.
Group sequential designs are standard in clinical research.
Although discussed at BioInternationals '89 to '96, no consensus about their application in BE was reached.

Personal Experience:
A proposed method* was not accepted in the planning phase (three cases by the German BfArM).
Gould's method is an adaption of 'classical' procedures in clinical research (e.g., P. Armitage, 1975; J. Whitehead, 1992).
With such a method you are penalized for 'looking' at the data, i.e., the combined sample size is always larger than the one of an optimal fixed-sized study.
Unfortunatelly both the deviation from the reference and the variability are not known with certainty; therefore such an optimal study may be an illusion (i.e., in the long run less subjects are needed with Group Sequential Designs).

The following Add-On design was accepted in the EU (two cases Germany, one case France):
Evaluation of first part by an independent statistician (calculation of CV only!), performance of a second part, evaluation of pooled data without alpha-adjustment (by another statistician). The maximum additional sample size (stop criterion) was stated in the protocol. Drawback: since no point estimate must be calculated for the first part, such a study may fail even after pooling (if your assumptions are not met).

❝ 4. Could the first study be discarded if the second study passed the 90% CI BE criteria on its own?

At the first glance I saw no practical application. But it may be possible (as always if stated a-priori) if the F-test (Canada!) rejects pooling, and the second part is large enough...

❝ 5. More importantly, what are its pros and cons with regards to consumer protection or risk.

With the exception of US-FDA, all other regulators are answering with a 'Positive Maybe'
I think it's hypocritical accepting Group Sequential Designs (or even Adaptive Designs) in phase III, but rejecting them in BE...

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• Gould LA. Group Sequential Extension of a Standard Bioequivalence Testing Procedure. J Pharmacokinet Biopharm. 1995;23(1):57-86.