Bioequivalence and Bioavailability Forum

Flawed approach even if accepted ? [RSABE / ABEL]

posted by Helmut  – Vienna, Austria, 2020-01-31 21:28 (1913 d 22:28 ago) – Posting: # 21124
Views: 26,312

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 – TIE_act) 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, CV_wR not calculated).
• Studies which failed ABE, CV_WR >30%, and the wider CI passed ABEL.
• Studies which failed (stopped in ABE because CV_wR ≤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 CV_wR was the first step. In some the CV_wR was <30% and the study assessed by ABE. I found two cases where CV_wR 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:

• One has to hope [sic] that the study passes ABE. If the study is powered for ABEL, chance to demonstrate ABE <50%.
  
• If the possibility of a second evaluation is foreseen, Bon­ferroni’s 95% CI requires an increases of the sample size by at least 30%.
  
• If ABE fails with the 90% CI, CV_wR >30%, and ABEL is assessed (a second time by the 90% CI), massive inflation of the TIE.
  
• If a wider CI is possible for ABEL, extremely low power.

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; 3^rd 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


The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

• Statistical evaluation and BE hypo­theses in full replicate design Elena777 2020-01-28 07:02 [RSABE / ABEL] 
  • Inflation of the TIE as well Helmut 2020-01-29 15:38
    • Inflation of the TIE as well Elena777 2020-01-29 20:01
      • Tricky… Helmut 2020-01-30 12:07
        • Tricky… Mikalai 2020-01-30 13:08
          • Terrible… Helmut 2020-01-30 15:09
            • Tricky… Mikalai 2020-01-30 16:02
              • Deep shit Helmut 2020-01-30 16:59
                • Deep shit Mikalai 2020-01-30 18:39
                  • Deep shit Mikalai 2020-01-30 19:31
                  • Deep shit Helmut 2020-01-30 20:07
                    • Deep shit Mikalai 2020-01-31 11:14
                      • Deep shit Helmut 2020-01-31 14:00
                        • Deep shit Mikalai 2020-01-31 16:07
          • Flawed evaluation accepted Helmut 2020-01-31 12:19
            • Flawed evaluation accepted Mikalai 2020-01-31 12:40
              • Flawed evaluation accepted Helmut 2020-01-31 14:17
                • Flawed evaluation accepted Mikalai 2020-01-31 16:41
                  • Flawed approach even if accepted ?Helmut 2020-01-31 20:28
                    • Flawed approach even if accepted ? Mikalai 2020-02-01 16:18
                      • misunderstanding mittyri 2020-02-01 21:34
                        • misunderstanding Mikalai 2020-02-06 13:41
                          • misunderstanding mittyri 2020-02-06 16:23
                      • The globe is flat! d_labes 2020-02-05 19:16
        • Tricky… wienui 2020-01-30 18:53
          • Tricky… Helmut 2020-01-30 19:18
            • Tricky… wienui 2020-02-03 07:10
              • ABE vs. ABEL Helmut 2020-02-03 12:25
                • zigzag d_labes 2020-02-05 18:53
                  • zigzag Helmut 2020-02-05 19:46
                    • zigzag Mikalai 2020-02-06 11:38
                      • helter-skelter Helmut 2020-02-06 20:12
                        • helter-skelter Mikalai 2020-02-10 16:10
    • Inflation of the TIE as well zizou 2020-02-01 17:00
      • Inflation of the TIE as well nobody 2020-02-01 23:30
    • Inflation of the TIE as well Elena777 2020-03-10 19:28
      • Fishing in the dark Helmut 2020-03-10 21:06
  • Statistical evaluation and BE hypo­theses in full replicate design nobody 2020-02-03 15:07
    • TIE, repeat once more please... Astea 2020-04-02 12:41