BRB
☆    

Canada,
2018-06-19 00:53
(2109 d 22:37 ago)

Posting: # 18915
Views: 4,184
 

 Updated TPD BE guidances [BE/BA News]

Helmut
★★★
avatar
Homepage
Vienna, Austria,
2018-06-19 03:32
(2109 d 19:59 ago)

@ BRB
Posting: # 18916
Views: 3,560
 

 Updated TPD BE guidances

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 [image] !


  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.

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

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

India,
2018-06-27 14:36
(2101 d 08:55 ago)

@ BRB
Posting: # 18976
Views: 3,359
 

 Canada-Comparative bioavaiability standards

Dear all,

Guidance Document of "Comparative Bioavailability Standards: Formulations Used for Systemic Effects" is updated and shall be effective from 01/07/2018 and applicable for submission after september 1 2018.

This guidance is now more descriptive in bioequivalce standards specially in critical and HVD proudcts.


Edit: Please don’t shout! Post moved to a related thread. [Helmut]
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,636 registered users;
68 visitors (0 registered, 68 guests [including 3 identified bots]).
Forum time: 22:31 CET (Europe/Vienna)

Nothing shows a lack of mathematical education more
than an overly precise calculation.    Carl Friedrich Gauß

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5