Bioequivalence and Bioavailability Forum • Inflated type I error with fixed widened limits?

Inflated type I error with fixed widened limits? [RSABE / ABEL]

posted by Helmut – Vienna, Austria, 2020-11-25 11:50 (1245 d 04:39 ago) – Posting: # 22084
Views: 6,954

Dear all,

following this post I had a closer look at the GCC-GL (Version 2.4 of March 2016, page 26):

3.1.10 Highly variable drugs or drug products
Highly variable drug products (HVDP) are those whose intra-subject variability for a parameter is larger than 30%. If an applicant suspects that a drug product can be considered as highly variable in its rate and/or extent of absorption, a replicate cross-over design study can be carried out.
Those HVDP for which a wider difference in C_max is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case, a wider acceptance range (i.e. 75–133%) for C_max can be used. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within- subject variability for C_max of the reference compound in the study is >30%. The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers. The request for widened interval must be prospectively specified in the protocol.
The geometric mean ratio (GMR) should lie within the conventional acceptance range 80.00–125.00%.
The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00 – 125.00% regardless of variability.
It is acceptable to apply either a 3-period or a 4-period crossover scheme in the replicate design study.

What happens if we pre-specify the widened acceptance range and discover in the study that CV_wR ≤30? Assess the study for the conventional AR of 80.00–125.00%? IMHO, that means we have a data-driven decision – which might be false and result in an inflated type I error.

I performed simulations acc. to my understanding of the GL:

[image]

CV_wR = CV_wT = 30%, balanced 4-period 2-sequence full replicate design (TRTR|RTRT), n = 40 (81% power for θ₀ = 0.90), 10⁶ studies with θ₀ = 1.25: ~20.6% passed…

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Helmut Schütz

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Complete thread:

Inflated type I error with fixed widened limits?Helmut 2020-11-25 10:50
- Inflated type I error with fixed widened limits? d_labes 2020-11-25 15:07
  - Inflated type I error with fixed widened limits? Helmut 2020-11-26 00:09
    - Inflated type I error with fixed widened limits d_labes 2020-11-26 15:38
      - Inflated type I error: Not nice Helmut 2020-11-26 17:14
        
        Power of the GCC framework and power of PowerTOST d_labes 2020-11-28 11:20
        
        Sample sizes (ignoring the inflated TIE) Helmut 2020-11-29 11:21
        
        Bug? d_labes 2020-11-29 16:22
        
        “Feature” Helmut 2020-11-30 00:16
- Inflated type I error with fixed widened limits? wienui 2020-11-29 14:03
  - Inflated type I error with fixed widened limits d_labes 2020-11-29 17:51
    - Inflated type I error with fixed widened limits Helmut 2020-11-30 00:14
      - Inflated type I error with fixed widened limits wienui 2020-11-30 03:30
        
        Houston, we have a problem! Helmut 2020-11-30 14:42
        
        Paradox of tolerance Astea 2020-12-01 23:34
        
        Οὐτοπεία ∨ Εὐτοπεία Helmut 2020-12-02 01:37
        
        Uchronia Astea 2020-12-02 09:46
        
        Steampunk Helmut 2020-12-02 11:34
        
        Dieselpunk Astea 2020-12-02 15:28
        
        Dieselpunk Helmut 2020-12-02 16:18
        
        Steampunk? OT d_labes 2020-12-02 19:30
        
        Steampunk? OT Astea 2020-12-02 19:58
        
        PowerTOST 1.5-2.9000 on GitHub Helmut 2020-12-23 12:18