Bioequivalence and Bioavailability Forum • Steampunk

Steampunk [RSABE / ABEL]

posted by Helmut – Vienna, Austria, 2020-12-02 12:34 (1233 d 16:28 ago) – Posting: # 22103
Views: 5,280

Hi Nastia,

❝ ❝ The problem starts already here. How reliable is Oodendijk’s result? Is it the only one?

❝

❝ The reliability of someone else's data - that is the question (especially when one of the authors says "waouf" :-)

Willard Oodendijk twittered and Nemo Macron said “waouf”.

❝ ❝ The crucial point is what we consider a “clinically not relevant \(\small{\Delta}\)”

❝

❝ As far as we (and the Agency) proclaim 25% to be clinically not relevant there is no difference in the rate of the harm for the customer's health independently from the a- or b- approach. For the b-approach he'll just receive not worser drug or doesn't receive it at all.

Here you err. In (a) all is good. In (b) everything is in a flux; the applicant and agency agree only that the acceptable risk may be either 20% or 25%.
We are dealing with average BE. Classifying HVD(P)s based on CV_wR is fine in principle. However, once we make this classification post hoc (based on \(\small{\widehat{CV_\textrm{wR}}}\)), troubles start. Hence, I don’t like* the reference-scaling methods and (b) as well.

❝ ❝ Try the function CVCL() in PowerTOST.

❝ I try:

❝

library(PowerTOST)

❝ CVCL(CV = 0.3, df = 3*40-4, side ="2-sided")

❝ lower CL upper CL

❝ 0.2646219 0.3466708

❝ As CI is shifted to the right …

Skewed to the right because the variance follows a \(\small{\chi^2}\)-distribution.

❝ … does it mean that for these initial conditions the probability of the conclusion of HV is higher?

Yes (for any condition).

❝ (By the way shouldn't we lower the degrees of freedom for the CV of the reference drug? 3*40-3 should correspond to the common CV of the Test and Reference, shouldn't it?)

Oops, one more degree of freedom! In the 2-sequence 4-period replicate design we have df = 3n – 4 for the pooled CV_w. Following the EMA’s model for the estimation of CV_wR we have one factor (the treatment) less in the model and therefore, df = 3n – 3:

library(PowerTOST) CVCL(CV = 0.3, df = 3*40-3, side = "2-sided") lower CL upper CL 0.2647549 0.3464397

Not for an initiate like you but others:
- Such a study is not bijective like when assessed for ABE. Whereas in ABE we could reverse the procedure (if T ≈ R also R ≈ T), this is highly unlikely here (only if CV_wR ≡ CV_wT).
- In ABE every application has to follow the same rules and \(\small{\Delta}\) is known. Here every study sets its own rule. The BE-limits and hence, \(\small{\widehat{\Delta}}\) are random variables. Without access to the study report patients and physicians don’t know the risk.

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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
        
        SteampunkHelmut 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