Bioequivalence and Bioavailability Forum

Hi HS,

thanks for the post.
I just read through the document rather quickly, and I am not sure what to think of it. The document imho makes a mistake in that it does not address the equivalence issue (or non-inferiority) in a direct fashion.
The scope is confirmatory clinical trials. The definitions in Europe are a mess; the only document that I am aware of which helps on this matter is the trial application form. Using that document as basis, the scope of the guideline must be phase III, and this includes therapeutic equivalence.

Highlights could be:

6.2: Complete case analysis is not recommended
...therefore I guess an applicant must deal actively with missing data...

6.3: "Factors that affect the acceptability of individual methods include differences between the treatment groups in the proportion and timing of withdrawals, the direction of any spontaneous changes over time, and the reason for the withdrawals. All of these factors must be comprehensively displayed and their influence discussed when the method used to impute missing data is justified. This highlights the importance of proper planning"
...So how do you impute in the phase III equivalence setting? I don't think the available literature will help much.

2: "The method chosen should aim to provide a conservative estimate of the treatment effect."
...This statement is spot-on for superiority trials, as the intention is not to approve products that don't work, of course. Now, in equivalence trials things are always upside down, and it is utterly unclear to me what this means; conservativism here might perhaps decrease the cance of finding a treatment difference. I am sure no regulator is interested in that.

That said, I am just an amateur with limited knowledge of the literature and of imputation. Does anyone have any thoughts?

Sincerely,
EM.