Actually, I think the Set Up think is just remnants from last years game. They seemed to change how the defense plays this year (as noticed by the psychic defense that changes its play and formation every time you change your play even if you don't change formation).
Now, on a "Set Up" play, on a play action pass, the safeties and linebackers should bite on the fake hand off and come crashing all the way in to the line, leaving your WRs with only the CB to beat. Meanwhile a "Set Up" run should result in the safeties and linebackers staying back in their zone for at least a little bit (your RB should probably be at least to the line of scrimmage) before their crash forward.
Check an instantly replay ANY TIME you run a "Set Up" play in this year's copy of the game. Does it ever work? I mean EVER?!
In previous years' games, it did work quite well (though I still think it's stupid--the coach should know how often he's running and how often he's passing, and EVERY run successful run play should set up EVERY play action pass, meanwhile, EVERY successful pass play should help clear out the box making all running plays more successful).