There are a couple of things that affect when they come in. And some of this may or may not be exactly correct...just the best I can tell after playing 8 seasons...every game.
The first are your "Auto Subs" settings. Those are found under the "MY NCAA" tab in the Dynasty screen under "Strategy". Set those as to when your players will come out after they are tired. There seems to be a wear-and-tear factor involved in playing games. A player will never be 100% fresh in the 4th quarter if he's played the other three. So it seems as if once they get so tired, they never do get back to even 90%. If your Auto Sub is set to only sub them in after they hit 90%, they'll never come back in the game. This seems to happen a lot with RBs as, presumably, they take a beating. You will be wanting to milk the clock or pile up stats, and he'll never come back into the game. This can hurt you though as you will see WRs and LBs playing DB late in games unless you have good players to sub in behind the starters. The game just picks the next best available player to sub in...regardless of where he might actually play. This is why you'll see FBs and DTs playing OL on long drives if you aren't careful. Or QBs playing CB...it happens. So, be careful using this until your team is deep enough to withstand a long drive...yours or your opponent's.
The other way is under the "TEAM MANAGEMENT" tab under "Coach Philosophy". There you set your Offensive and Defensive Substitution rates. This is where the cpu will take over and take your guys out of the game after you have an insurmountable lead. This also has a negative affect if the team you are beating makes a comeback. Once the game determines to take them out, they are out for the rest of the game. The more quality depth you have, the higher these values can be. For Offense, 75 works well for me and 85 for Defense. I try to play as many as possible to avoid injuries (I don't Redshirt many players due to the auto-subs glitch of playing guys out of position).
Then, of course, there is "MASS SUBS" in the Strategy section of the Pause menu during the game where you can sub in your entire 2nd string.
I think that answers your question. Some may know better...that is just how it has seemed to me in the time I have been playing.