Bioequivalence and Bioavailability Forum

Hi BRB,

❝ Health Canada recently posted their updated BE guidances:

THX for the notification! These are the first ones which are not only esthetic appealing but contain sumfink coming close to a change control.

❝ https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/conduct-analysis-comparative.pdf

No more BE based on urine data, pAUC for multiphasic release products (cut-off time(s) based on PD, not on PK like for the EMA).
This one in Section 2.3.1 is tricky:

In cases where more than two formulations are under study, or are studied under different conditions, a higher order design (that is (i.e.), more periods and sequences) should be considered. Since the intra‐subject error term of these designs has more degrees of freedom, smaller sample sizes are often adequate. The choice of a variance balanced design (Williams’ Design) or separate incomplete block design should be justified.

It doesn’t matter whether a Williams’ design or Latin Squares are used. Crucial is the evaluation. I would always opt for separate incomplete blocks (see this post).

Unchanged but still questionable:

• 2.3.2.1 Group sequential designs
  Problematic. Requires two guesstimates of the CV (a “most likely” one to estimate n₁ and a “worst‐case scenario” for n=n₁+n₂). The stated α 0.0294 given by Pocock is valid only for superiority testing (one-sided) and one interim analysis at exactly n/2. For equivalence (two-sided) the correct α is 0.0304.¹ Cases exist where even the more conservative (but wrong) α 0.0294 will lead to an inflated type I error (Schütz 2015, supplementary material).²
  Disappointing.
  
• 2.7.4.3 Testing of fixed effects
  A summary of the testing of sequence, period and formulation effects should be presented. Explanations for significant effects should be given.
  Oh dear! Never heard how futile testing for sequence (better: unequal carry-over) effects is?³ Period effects are irrelevant. Treatment effects? Gimme a break! Significant ≠ relevant. See this post for a summary.

❝ https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/bio/comparative-bioavailability-standards-formulations-used-systemic-effects.pdf

No big deal. Strange in

2.1.1.8 Highly variable drug products
As an alternative to the use of expanded bioequivalence limits for HVDPs, the variability in the drug’s pharmacokinetics may be addressed through the study design. For example, it may be possible to justify, a priori, conducting the study in a pre‐screened sub‐population such as slow metabolizers, in which the variability may be lower for the particular drug being studied. This type of flexibility in study design does not require the application of special bioequivalence standards.

Depending on the phenotype and ethnicity we have 5–10% of poor metabolizers. Yes, concentrations will be higher but variability lower‽
   In God we trust;
all others must bring data.   W. Edwards Deming

❝ The effective date is July 1 (Canada day!)

Happy partying  !

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1. Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. Stat Med. 2015;34(6):2403–16. doi 10.1002/sim.6487.
   
2. Schütz H. Two-stage designs in bioequivalence trials. Eur J Clin Pharmacol. 2015;71(3):271-81. doi:10.1007/s00228-015-1806-2. Supplementary material.
   
3. Freeman P. The performance of the two-stage analysis of two-treatment, two-period cross-over trials. Stat Med. 1989;8(12):1421–32. doi:10.1002/sim.4780081202.