Bioequivalence and Bioavailability Forum

Hi nobody,

❝ Any info on what has changed from 2012 draft to 2015 version?

Jun 2012

• Design: Single-dose, two-way crossover in vivo
  
  
• Additional Comments: Applicants may consider using a reference-scaled average bioequivalence approach for dabigatran etexilate. Please refer to Progesterone Capsules Guidance for information regarding statistical analysis method using the reference scaled average bioequivalence approach.
  
  
• Bioequivalence based on (90% CI): free (non-conjugated) dabigatran

Sep 2015

• Design: Single-dose, 2-treatment, 2-sequence, 4-period, fully replicated crossover in vivo
  
  
• Additional comments: Dabigatran demonstrated a steep exposure-response relationship for both efficacy and safety. Therefore applicants should not use the reference-scaled average bioequivalence (BE) approach to widen the BE limits for dabigatran BE evaluation. Applicants should use the average BE approach, with BE limits of 80–125%. The within-subject variability of test and reference products should be compared and the upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5. For details about the Method for Statistical Analysis comparing within-subject variability of test and reference products, refer to Guidance on Warfarin Sodium.
  
  All subjects should have prothrombin time (PT), activated partial thromboplastin time (aPTT), and creatinine clearance (CrCl) measured. The PT and aPTT should be within the normal range and the CrCl value should be more than 50 mL/min for each subject before dosing in order to prevent or avoid the possibility of bleeding.
  
  
• Bioequivalence based on (90% CI): free (non-conjugated) dabigatran and total dabigatran (non-con­ju­gated plus conjugated dabigatran)

Apart from the additional safety parameters for inclusion and the BE requirement of total dabigatran the statistics are interesting – going from RSABE (widening of implied limits) to sumfink similar to Warfarin. No narrowing of BE limits but still the comparison of variances.*

This gives yet a fourth BE approach stated by the FDA:

1. Generally average BE; acceptance range 80.00–125.00%. Designs: Two-period crossover, higher-order crossovers, parallel, full (4-period) or partial replicate (3-period).
   
2. RSABE for HVDs/HVDPs if \(\small{s_\text{wR}\geq 0.294}\). GMR-restriction 0.8000–1.2500. Designs full (4-period) or partial replicate (3-period).
   
3. RSABE for NTIDs. Narrowing BE-limits based on \(\small{s_\text{wR}}\). Must pass conventional ABE as well. Upper CL of \(\small{s_\text{wT}/s_\text{wR}\leq 2.5}\). Design full (4-period) replicate.
   
4. As above but conventional BE limits (no downscaling).

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• How could one estimate the sample size? Yet another method for the wish-list of PowerTOST?
  You could work by trial-and-error; assessing p(BE-ABE) and p(BE-sratio):
  library(PowerTOST)
theta0 <- 0.95 # GMR
n      <- 16   # minimum mandated by the FDA
CV     <- 0.2  # average (pooled) CV
ratio  <- 1    # ratio of SEs
CVs    <- CVp2CV(CV = CV, ratio = ratio^2)
print(CVs)
power.NTIDFDA(theta0 = theta0, CV = CVs, n = n, design = "2x2x4", details = TRUE)
  For a ratio of 1 I get p(BE-ABE)=0.95041 and p(BE-sratio)=0.95128. Fine.
  The maximum ratio for 80% power seems to be 1.25 (CV_T 0.221, CV_R 0.176): p(BE-ABE)=0.95041 and p(BE-sratio)=0.80843.