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

posted by Helmut Homepage – Vienna, Austria, 2020-11-25 10:50 (169 d 19:11 ago) – Posting: # 22084
Views: 2,451

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 Cmax 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 Cmax 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 Cmax 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 CVwR ≤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:


CVwR = CVwT = 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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