ICH M13A: Changes to Step 2 [BE/BA News]

posted by Helmut Homepage – Vienna, Austria, 2024-08-05 14:53 (128 d 15:36 ago) – Posting: # 24132
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Dear all,

the story continues.
Reordered and expanded for multiple dose studies.
Why the weird phrase »AUC(0–72h) may be used as AUC(0–t)« and not keep what was stated in the draft or simply “AUC(0–72h) may be used instead of AUC(0–t)”?
Contrary to the guidances of the FDA and Health Canada, nothing is stated about rounding of the confidence interval. Based on a clinically relevant difference \(\small{\Delta=20\%}\) we get the BE-limits in the multiplicative model by $$\small{\left\{\theta_1,\theta_2\right\}=\left\{100\left(1-\Delta\right),100\left(1-\Delta\right)^{-1}\right\}=\left\{80\%,125\%\right\}}$$ These limits are exact, i.e., a study with a CI of 79.995 –125.005% would fail. Since the limits are stated as 80.00 – 125.00%, does that imply that we have to round to two decimal places? Then the same study would pass* and – slightly – inflate the Type I Error.
Why on earth was the important last sentence removed‽ Without, I expect that applicants will use of the crappy ‘All at Once’ approach (i.e., analysis of pooled data).1,2 I got many studies with the wrong method on my desk, although the EMA stated already in its 2010 guideline:

In studies with more than two treatment arms (e.g. a three period study including two references, one from EU and another from USA […]), the analysis for each comparison should be conducted excluding the data from the treatments that are not relevant for the comparison in question.

Very similar recently the FDA:3,4

In BE studies with more than two reference treatment arms (e.g., a three-period study including two references, one from the European Union (EU) and another from the United States […]), the BE determination should be based on the comparison between the relevant test and reference products, using only the data from those products. The BE analysis for this comparison should be conducted excluding the data from the non-relevant treatment(s) — for example, in a BE study with a T product, an EU reference product, and a U.S. reference product, the comparison of the T product to the U.S. reference product should be based on an analysis excluding the data from the EU reference.

For details see this article, a presentation by David Brown (MHRA),5 and the Q&A.6Only slight rewording in all but the last paragraph.
To be continued.



  1. Schuirmann DJ. Two at a Time? Or All at Once? International Biometric Society, Eastern North American Region, Spring Meeting. Pittsburgh, PA. March 28–31, 2004. Abstract.
  2. D’Angelo P. Testing for Bioequivalence in Higher‐Order Crossover Designs: Two‐at‐a‐Time Principle Versus Pooled ANOVA. 2nd Con­fe­rence of the Global Bioequivalence Harmonisation Initiative. Rockville, MD. 15–16 September, 2016.
  3. FDA (CDER). Draft Guidance for Industry. Statistical Approaches to Establishing Bioequivalence. Silver Spring. December 2022. Re­vi­si­on 1. Download.
  4. FDA (CDER, OGD). Navigating the First ICH Generic Drug Draft Guideline “M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms”. SBIA Webinar. May 2, 2023. Online.
  5. Brown D. Presentation at the 3rd EGA Symposium on Bioequivalence. London. June 2010. Slides.
  6. European Generic Medicines Association. Revised EMA Bioequivalence Guideline. Questions & Answers. Brussels. 2010. Online.

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