TSDs for RSABE/ABEL [Two-Stage / GS Designs]

posted by Helmut Homepage – Vienna, Austria, 2015-05-06 04:17 (3250 d 06:33 ago) – Posting: # 14753
Views: 13,811

To whom it may concern!

Since Two-Stage Designs were mentioned in various guidelines (EMA, FDA,…) sponsors want to combine them with options for HVDs/HVDPs (EMA: ABEL, FDA: RSABE). I do understand that this a tempting idea. What I have heard at recent conferences gives me the impression that sponsors already performed such studies. I don’t know whether any one of them was accepted. I know of one leading to a deficiency letter.

I will summarize the caveats.

Edit: Easier with the package microbenchmark:

library(microbenchmark)
library(PowerTOST)
microbenchmark(
  power.TOST(CV=0.4,   theta0=0.9, design="2x2x2", n=134, method="nct"),
  power.scABEL(CV=0.4, theta0=0.9, design="2x2x4", n= 30, nsims=1e5),
  power.RSABE(CV=0.4,  theta0=0.9, design="2x2x4", n= 24, nsims=1e5))


On my machine (slow because I have 8 R-sessions running; CPU-load >95%):

Unit: milliseconds
          expr       min         lq      mean     median         uq       max neval
power.TOST()    3.703643   4.336665   5.82738   4.784337   5.475469  67.81569   100
power.scABEL() 84.496413  91.930565 120.51301  97.457502 156.742944 176.92144   100
power.RSABE()  91.391727 103.207520 139.51786 155.408528 167.997411 205.35759   100



    References:
  1. Chow S-C, Liu J-p. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton: Chapman & Hall/CRC; 3rd ed 2009: p. 598.
  2. Endrényi L, Tóthfalusi L. Regulatory conditions for the determination of bioequivalence of highly variable drugs. J Pharm Pharm Sci. 2009;12:138–49. [image] free resource.
  3. Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43. doi:10.1007/s11095-014-1450-z.
  4. Schütz H. Two-stage designs in bioequivalence trials. Eur J Clin Pharmacol. 2015;71(3):271-81. doi:10.1007/s00228-015-1806-2.
  5. Fuglsang A. Controlling type I errors for two-stage bioequivalence study designs. Clin Res Reg Aff. 2011;28(4):100–5. doi:10.3109/10601333.2011.631547.
  6. Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. Stat Med. 2015;34(16):2403–16. doi:10.1002/sim.6487.

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