Bioequivalence and Bioavailability Forum

Hi Babe_Ruth,

❝ The sponsor specified this fixed-sequence design in their protocol.A little more context regarding this study: Phase I, healthy subjects, with SAD (n=30), food effect (n=12), and MAD (n=24) parts.

Yikes. Do you mean single ascending doses, mutiple ascending doses? That would likely make this a first in man, potentially?? I am not sure I would like to offer opinions on those. Is the API very well known??

❝ I don't know why they designed it to have all subjects take the drug under fasted and then fed conditions. I can't think of any advantage fixed sequence over 2 sequence in this study. Have you ever seen instances where one sequence is advantageous over two sequence?

I don't recall that. I am not so often involved in such studies. But simple is beautiful. Until a regulator thinks otherwise.

❝ Edit: Also, one last question. Somebody proposed the ANOVA model with terms for treatment condition (Fasted and Fed) as fixed effects, and subject nested within treatment condition (fasted and fed) as a random effect. Does this random effect make sense?

That is correct, in principle. Subjects are actually directly treated as random when you do the t-test thing, while when you model it, and you get the exact same result, then the subject is modeled as fixed effect with PROC GLM (or equivalent), even when a random statement is used.
"Subject in sequence" is a very popular term on this forum. Usually we number subjects uniquely, i.e. 1, 2, 3....N and then you don't need to worry about it when evaluating the model. A given subject is the given subject, with no opportunity for confusion (apart from "Hey subject 7 looks like my uncle" and that sorta thing).
However, you might decide that you want to violate GCP § 1.58 (for reasons entirely beyond my comprehension) and decide that you want to call subjects 1,2, 3 and so forth in both sequences. I.e. there is a "subject 1" in the sequence group where they are fasted before being fed, and also a "subject 1" in the sequence group where they are fed before being fasted. Now, to make sure the stats software can distinguish between those (after all they are not identical subjects [or at least I sure hope for everyone's sake they aren't]), you apply syntax to the effect of making sure the stats is done correctly so that there is no confusion about the uniqueness of both "subject 1" 's and so on. That syntax and model fitting is what "subject in sequence" is all about, so it only has relevance if you don't number subjects uniquely.
However, it apparently does sound rather impressive when a guy in a penguin suit in the board room raises a finger and asks if subjects are nested in sequence. It may be the kind of tricks that make you popular with the opposite gender and the CSO. I tend to bang my head into the table when it happens. Am taking anger management classes and large doses of Schützomycin because of those types (it's good for my gonorrhoea as well).

Oh, it seems I digressed a wee bit. Sorry. Let me just go and fetch my medication now.