The game refreshes every 4 or 5 in-game min and during that time is the moment when the changes that you make take place.If you pay attention to the substitutions in the second half they all take place in a set time 52' 58' 63' 68' . I have never had a sub made on the 66'th minute for example. One other thing I notice is that the last minutes of the game go faster in real time then the first ones.