It all depends on the situation, but as a general rule for my league (We have 8Min Quarters w/ 15sec accl) is that a 21pt lead in the 4th you should be trying to run the clock out. What is common is a run on 1st and 2nd down and pass on 3rd if needed for the first down but we dislike un-needed deep passes when you have a big lead. If you can kneel the ball out you should but, personally, I continue to run until they cannot get the ball back even if they have 3 timeouts but do not use them.
I recently was complained about 'Running the score up' when my game final was 68-17. Now this is a all-pro league and I have the Browns (Year 2) and playing the Titans. Now I scored 45 points in the 1st two quarters, 3rd and 4th Quarter is was running on 1st and 2nd, passing on 3rd for the 1st. I score 14 in the 3rd and 9 in the 4th. I finished with 4 more rushing attempts them passing and the guy said I did not run enough. I also scored on a run play with 25 seconds left on 3rd down. (He appeared to have called a timeout instead of letting the clock go down to zero, I ran another run play and scored. Apparently there was an injury, atleast thats what he said.)
I did not see much of a problem with what I did. I did nothing cheap, abusive, or gimmiky my opponent just pick very poor defensive plays and gave up after the 1st quarter.
I do not see a problem with trying to score on your run plays, while you may be dominating a game, no team can just give up a game. They continue to put effort even if its with their 2nd and 3rd string players and theres nothing wrong with it.
Now as an assistant for a league, if we see that someone threw passing touchdowns when they could have ran the ball and taken a FG or let the clock run out, thats something I, and my league, are against.
'Safe Leads' varies from difficulty to number of users and quarters. The League I am the browns as only has 16-18 users and is on all-pro with 10M quarters with accl clock (15 sec?) but the League I help run, and have the Chargers (Year 3, Playoffs, btw looking for sim players
www.elitefl.motionforum.net) we are a 32-user league on all-madden and have 8min quarters with acc clock.
For the 1st league the 'Safe Lead' would typically be a much higher margin then and 2nd league. From my experience it would take around a 35+ point lead to consider a safe lead in the 4th (Played the chargers and lost by 3, scored 28 in the 4th alone, final 45-42) but in the 2nd on the margin 21 seems like a good fit. Obviously when that margin is lowered you may try to bring it back.
It seems I have ranted alot, in summary it varies. Average league time 8-7 minutes 21+ lead you should run, run, pass for 1st (Unless in FG range then take the 3). More time = Larger Margin.