The big factors that make life harder for real quarterbacks that we do not need to deal with are adjustments by individual players and special blitz schemes that defensive coordinators install. Defenses know what offenses are looking for, and both coaches and players are constantly feeding the offense bad information to make reads from.
Individual Player Adjustments
Two clips of analysis from the Denver - San Diego playoff previews make this point well. First, Trent Dilfer on NFL Primetime talks about how Chargers Free Safety Eric Weddle allows the San Diego defense to present quarterbacks like Peyton Manning with difficult pre-snap reads by moving all over the field. Smart players like Weddle change the defense on the fly because they understand the scheme:
Making a freelance decision like that works only when Weddle understands that his choice won’t affect the other parts of the defense. Pagano says that his favorite Weddle moments are in their conversations on the sideline following a given series. Weddle is able to not only describe what he’s seeing, but also to give Pagano the in-game end zone view of the entire defense. If a lineman is out of a gap, or a certain run fit isn’t working, Pagano knows before the photos from the game film are even processed.
Disguised Defenses
The other thing that messes up the offense is when the defense rushes from directions that aren't obvious from the alignment or when they show blitz but don't. Blockers can make mistakes and leave unaccounted for rushers and quarterbacks can be fooled into thinking a covered passing lane is open. There are very few of these types of defenses in Madden and NCAA, the AI rarely calls them, and there are only so many of them to look for.
Here we have a clip by Ron Jaworski on Sunday NFL Countdown going through examples of the disguised coverages used by the Chargers.
Although Madden and NCAA make it feel like it is "easy" to make a read and move the ball, it really is not so simple in real football. Maybe the Detroit Lions do indeed suck... but it's not just them being the "Same old Lions" - the other teams (not just the defenses) are pretty good at what they do.