Flawed approach even if accepted ? [RSABE / ABEL]

posted by Helmut  – Vienna, Austria, 2020-01-31 21:28 (1099 d 15:09 ago) – Posting: # 21124
Views: 18,311

Hi Mikalai,

❝ It appears quite interesting. I again disagree with you.


Why am I not surprised?

Seems that your line of argument is a financial one (though veiled behind words like taxpayer’s money). I’m interested in the patient’s risk – possibly more than some regulators.

I asked myself whether all is lost when ABE fails. I wouldn’t bet on a lucky punch.
We know that TOST is not a uniformly most powerful test (“… the TOST procedure can be quite conservative, i.e., the achieved Type I error rate may be lower than the nominal 0.05 significance level.”)1 That means for nasty combinations of PE and CV with a given sample size the actual TIE might be <0.05. This opens a back door to recalculate the CI but with α = 1 – TIEact) and assess the study for ABEL whilst keeping the overall TIE controlled.
10,000 simulated studies, PE 0.85–0.95, CV 0.25–0.60, 2×2×4 design, powered (≥80%) for ABEL:



Studies which passed ABE (90% CI, CVwR not calculated).
Studies which failed ABE, CVWR >30%, and the wider CI passed ABEL.
Studies which failed (stopped in ABE because CVwR ≤30% or in ABEL).

Nasty are the close misses in ABE. There is practically no α left and the study will likely fail ABEL as well because the new CI would be extremely wide.
Example: CV 52.92%, PE 0.9118, n 26. With a 90% CI of 77.52–107.25% fails ABE and the actual TIE is 0.04809 (α for ABEL 0.00191). We continue to ABEL with the maximum expansion of 69.84–143.19%. The 99.618% CI is 68.15–121.98%, which fails ABEL as well.
With the common approach we have a 81.2% chance of passing and with 0.0382 the TIE is easily controlled.

Now for the money-wise argument: 45.9% passed ABE and only 7.7% ABEL (i.e., overall power 53.6%); that’s hardly better than tossing a coin.

I checked a couple of other studies in the meantime. In all of them calculation of CVwR was the first step. In some the CVwR was <30% and the study assessed by ABE. I found two cases where CVwR was >30% and studies passed ABEL and the 90% was within 80.00–125.00%. The report correctly stated that ABEL (with expanded limits) was demonstrated and noted that conventional ABE would have passed as well. The latter was just a remark and not part of the procedure.

Given all that, I consider the approach we discussed here as crap and IMHO, it should not be used for the following reasons:It amazes me that nobody (on both the CRO/industry and regulatory side) seemingly bothers to read the relevant papers. In all it is clear that for ABEL one has to first assess whether the drug / drug product is highly variable.2–5 BTW, a coauthor of the last one is a member of the EMA’s PK Working Party.

EOD from my side unless we concentrate on science rather than profits.


  1. Jones B, Kenward MG. Design and Analysis of Cross-Over Trials. Boca Raton: Chapman & Hall/CRC; 3rd ed. 2014. p. 371.
  2. Boddy AW, Snikeris FC, Kringle RO, Wei GCG, Oppermann JA, Midha KK. An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs. Pharm Res. 1995; 12(12): 1865–8. doi:10.1023/A:1016219317744.
  3. Tóthfalusi L, Endrényi L, Midha KK. Scaling or wider bioequivalence limits for highly variable drugs and for the special case of Cmax. Int J Clin Pharmacol Ther. 2003; 41(5): 217–25. doi:10.5414/cpp41217.
  4. Endrényi L, Tóthfalusi L. Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs. J Pharm Pharmaceut Sci. 2009; 12(1):138–49. doi:10.18433/j3zw2c.
  5. Tothfálusi L, Endrényi L, García Arieta A. Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence. Clin Pharmaco­kinet. 2009; 48(11): 725–43. doi:10.2165/11318040-000000000-00000.

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


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