Bioequivalence and Bioavailability Forum

Hi ElMaestro,

❝ Some of the Spandinavians are not easy to understand as recent linguistic research has proven.

Interesting! Given these problems did you ever consider to opt for an easier language? Most Irish abandoned “Sweet Gaelic” for the far more simple English. What ’bout Gibberish?

❝ […] as far as I know Potvin's papers and its descendants are the only ones containing anything that just remotely resembles a proof of control over the type I error.

Not even remotely. You cannot plug the decision tree of the frameworks into a formula to estimate power. Hence, a mathematical proof is not possible. The control of the TIE shown over the assessed combos of n₁/CV is purely empirical. That’s why hard-core statisticians without further considerations will tell you that these methods are crap.

❝ But ok, perhaps regulators have a secret method which is acceptable (as long as there is a period in stage term ) and which they forgot to share with the rest of the world. I can't tell if this is the case, but I somehow doubt it.

So do I. The only one which claims to contain a proof is Kieser & Rauch.* IMHO, the two lines in the article are actually no more than a claim… I asked the agency’s statistician whether she means this paper and she replied “No.”

❝ Is the problem simulation rather than math proof?

Yes. As said above this gives statistician hiccups. The ideal situation would be a proof for the type I error. Most statisticians accept simulations only for the type II error. IMHO, a proof for frameworks is not possible.

❝ It isn't my impression that simulations are outright banned or discouraged and some members of the PKWP or BSWP have published enjoyable and useful science based on simulation.

Well, the entire reference-scaling stuff (might it be the FDA’s RSABE for HVDs or NTIDS and the EMA’s ABEL) is entirely based on simulations. These methods are frameworks as well. Proof of the control of the TIE impossible. Do these expert statisticians don’t know that or just ignore it?
Case 1: Bad. Case 2: Double moral standards.

❝ […] research funded under EU's 7th frame programme - it was called "Biosim"…

Ended March 2010. Different cup of tea. Toys for boys. No confirmatory statistics like in BE.

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• Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. Stat Med. 2015;34(6):2403–16. doi 10.1002/sim.6487