Study costs: Replicate vs. 2×2×2 [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2017-03-20 13:12  – Posting: # 17169
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Hi ElMaestro & John,

» » My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294)

» That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intra-CVR of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers.

I lean towards John’s idea. Say you estimated the 31% from a previous 2×2×2 study in 40 subjects and assume that CVwR=CVwT=CVw. The 95% CI of the CV is 25.1–40.6%. Hence, in the best case (high CVwR) the FDA’s implied BE-limits would be 70.58–141.69%. That’s rather substantial.

» Would be interesting to discuss an objective function here :-)

Some ideas: The number of treatments in a 2×2×4 study is roughly the same as in a 2×2×2 study – if we don’t plan for reference-scaling (which I likely would do in a borderline case).I would not be worried about the higher chance of dropouts in the replicate study. The impact on power is low (unless the drug is nasty and dropouts are caused by AEs).
Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. ;-) If you hope for RSABE (for CVwR 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%.

Helmut Schütz

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