## Steampunk [RSABE / ABEL]

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 CVwR 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 CVw. Following the EMA’s model for the estimation of CVwR 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 CVwR ≡ CVwT).
• 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.

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

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