Bioequivalence and Bioavailability Forum

Hi ElMaestro!

❝ […] a PSRtPH at CMDh or CHMP […]

Excuse my ignorance but I’m not familiar with EMA’s terminology: What’s a “PSRtPH”?

❝ […] the extra little power that is the true advantage.

The gain in power is massive. Look at my example: A fixed sample design in 24 subjects would have a power of 83.6% (α 0.0294), Potvin B 88.0% (α_emp 0.0317), but the “Pseudo Pocock” 99.0% (α_emp 0.0489). That’s not ethical. Since when are regulators interested in keeping the producer’s risk low?

Potvin et al. stated:

This study did not seek to find the best possible two-stage design, but rather to find good ones that could be used by sponsors without further validation.

As a side effect for many combinations of CV and n₁ the framework is very conservative (α_emp ⇒ α_adj).


I always thought that regulators’ main interest is to protect public health; they should be happy with a method which demonstrated to be conservative.

Now for something completely different: How do you interpret this part?

• A extreme case it is acceptable to design no alpha
  expenditure in the interim analysis when designed to
  obtain information of formulation differences and intra-
  subject variability and 90% CI are not estimated at the
  interim stage.

What does that mean? Sample size re-estimation based on PE and CV? Since we don’t assess BE in the first stage (that would be similar to Potvin’s “internal pilot” Method A – which they dropped due to α-inflation) we have to introduce a futility rule. Sample size estimation if the PE is not within the acceptance range simply doesn’t work. Is the following a scheme we could test?

BTW, I have performed studies of a similar design 10–15 years ago (for BfArM, AFFSAPS), but never simulated anything… Dunno how to set up sim’s properly. By chance one might get a PE far away from unity and a high CV requiring thousands of subjects. R kicked my ass with a nice “Error: cannot allocate vector of size 1983.8 Mb”.