A lot of it is being able to get an effective run game in. It's tougher to run and you can't run power from a spread set. In the pro's other than Indy, you have to be able to take a snap from center, drop 3-5-7 steps all while reading the play and progressions and then set and make throw. In a spread set the QB takes a shotgun snap and just has to watch the play progress. Qb's can learn to go back under center but that drop back and read along with handling a proper running game is a huge change at the pro levels. Handing off isn't as simple as just handing the ball to the running back, there are ways to do it, ways to hide it, and a lot of timing in order to ensure the back has the ball at the right time and location. Adding in fakes, play action, etc... makes it roughly 50-60% of the offense the QB must learn.