Put Pandemic on Xbox!
1) The deck runs out of cards. I can see the flavor here being that the diseases have had enough time to go around killing people that society as we know it ceases to function, at which point all you can do is quarantine people and rebuild Earth.
2) You had too many outbreaks occur. Outbreaks happen when one city just gets so infected that all it can do now is spread to other nearby cities.
3) You have to infect, and there are no more cubes to represent that infection. I can see the flavor behind both of these being that the diseases have simply gotten beyond your control.
This would work great as a video game, and the biggest impact it would have would be the set-up time. It typically takes me about 15 minutes to set up a game, and there's lots of decisions to be made before then. Let me give you a picture of how setup goes down.
1) Place all cure, outbreak, and infection markers on the board. Add Mutation square and cure marker if using that expansion.
2) Shuffle role cards and deal one to each player.
3) Shuffle all event cards, put 2 random events into the deck per player involved.
4) Shuffle main deck, deal out cards to players (varies for number of players).
5*) If playing with Mutation expansion, place the 2 Mutation infection cards in discard pile and add the 3 Mutation event cards.
6) Shuffle the main deck.
7*) If playing with Virulent Strain, shuffle those Epidemic cards and make 1-card piles with them. Number varies based on decided difficulty level. Otherwise, simply make 1-card piles with the standard Epidemics.
8) "Pile shuffle"the main deck onto each stack so that all are roughly even.
9) Shuffle each individual pile, then place them on top of each other for the main deck.
10) Place a research station and all players' pawns in Atlanta.
11) Shuffle Infection deck and put the top 3 cards in the discard pile. Those cities get 3 infection cubes of their color each. Deal out the next 3 cards and put 2 cubes on each city. Finally, do the next 3 and place 1 cube in each of those cities.
* The game sets up somewhat differently when using Bio-Terrorist, but you get the point.
Now, if you had this in a video game, the starting process is much simpler. Simply choose the difficulty, number of players, any expansions, and bam! The game is able to orchestrate all the setup itself. That's about the same level of choice involved in Carcassone, and that does just fine on Xbox 360. Personally speaking, I absolutely would purchase Pandemic if it were made for Xbox. Heck, I might even get it for PC. I'd be less enthusiastic about getting the Bio-Terrorist expansion though, since there's no way that could be played locally.