Bioequivalence and Bioavailability Forum

Dear Dan!

❝ Advantage of interim stats: with some luck you'd even need to include fewer subjects than first feared.

Agree with you and EM. Furthermore it's the only possible solution if you don't 'know' the CV beforehand.

❝ Disadvantage: with some bad luck you'd even need include more than first feared due to analyses conducted at adjusted significance levels.

In Boonchai’s example there’s a limit in the clinical capacity. His expected sample size is 80 and he has only the option to start with 40.
Or more generally: Anybody opting for a sequential design should power the first stage as a common 2×2 study - with all the side conditions in mind (point estimate, variability, drop-out rate,…). So if everything works out like you expected, you are in the left branch of Potvin’s method, and the study stops (no adjusted alpha!). The right branch might save the day. What are your options in a conventional (failed) study?
BTW: the penalty for adjusted alpha is not really an issue. For the common ±5%, 80% power, CV 20% we need n=20 (alpha 0.05) and n=24 (alpha 0.0294). Most people would go for 90% power: n=26 (alpha 0.05), n=30 (alpha 0.0294). See it as a price to pay for a study which otherwise will fail anyway. Again: if you plan to be BE in the first stage, and your assumptions are fulfilled - no penalty at all!

❝ Furthermore an interim analysis takes time (you have to perform the bioanalysis of the PK samples before starting the second group). For a generic company this is a strong argument.

Agree with the first part. But if you don't have really good information of the CV (and by good I don't mean literature data or a lousy pilot study) there is always a chance of failure. The only way to deal with a uncertain CV in conventional studies is to add safety margins. According to ICH E9 you have to include a sensitivity analysis in the protocol ('what-if' scenarios).
From my consultancy business: A company tried to be 'on the safe side' and submitted a protocol to the IEC with a power of 95% in the worst case (maximum drop-out rate, deviation from reference 8%, CV 10% higher than ones seen in previous studies). Power without these obstacles would have been 98%. The company didn't care on money and ethics and only wanted to get the product approved 'as fast as possible and for sure'. The IEC rejected the protocol.