Pandemic varies vastly in difficulty depending on the number of players. Does anyone know of any custom rules that make it more even?
Pick up the On the Brink BGG expansion.
The forums at Boardgamegeek state that it definitely eases up the difficulty of the 4 and 5 player versions as well as providing more options.
You could for example always play with the same amount of pawns. If you have 3 players everyone gets a pawn for themself and you have to discuss what happens with the 4th. Considering there's already a lot of discussion on what to do with your own pawns it's not going to be much of a problem...
A big part of the variation in difficulty is the fixed number of event cards. In the base game, you play with 5 event cards in the deck regardless of the number of players. If you pick up "On the Brink" there are more event cards, so you play with 2 event cards in the deck per player. This seems subtle but I've found that it smooths most of the effect of different numbers of players (assuming you are good at coordinating).
Consider making the epidemic cards predictable. Space them out as stated in the rules, but always put them at the bottom of each pile. This keeps the fun of dealing with the challenge, while enhancing the requirement that players work together to handle what they know is coming. It does make it easier though, in general, due to this predictability.
My group feels that Pandemic is easier with fewer players, so as player count goes down we increase the epidemic count to maintain the challenge level.
Other adjustments will depend on how you think the difficulty changes. In player counts that you consider harder, try dealing out multiple roles and letting players choose, or try choosing play order only after seeing roles and starting cards. For player counts that you consider easier, reverse these decisions.
On the Brink adds some variability and complexity. I'm not sure if (after you get past the learning curve of any new variant) it adds difficulty, but it might.
In a 4 player game, you can make sure the researcher is in play for one of the players, and deal the other 3 roles from the deck. I have played with almost every combination of roles (with 2 and 4 players) and the researcher has significant advantage and is very difficult to win with 4 player without her.
If you're playing with 2p, use the next difficulty level in terms of # of Epidemics. For example, if you play 4p on "Easy" (4 Epidemic cards), then with 2p, play on "normal" (5 Epidemics) to get the same effect of difficulty.
If you have On The Brink expansion, rather than adding another Epidemic, consider adding in the Virulent Strain. The rules for that is only 1 page long, so you should be able to learn it in no time. Mutation Challenge is more involving even if it's still only 1 page as well.
I have a number of variations that I like, but I may not use every variation every game. I like the On-the-Brink expansion, but these rules are not specific to it.
Roles: Cures & cards (Researcher & Scientist); Treatments/prevention (Medic & Quarantine Specialist); move/build (Operations Expert & Dispatcher); and misc for everything else. For a 4 player game have at least one of each the first three types.
First research station (instead of Atlanta): When dealing the initial infected cities include 4 (instead of 3) cities with 1 cube; the first research station can go into any the of cities with 1 cube and all the players start there. If there are disagreements, the player going first decides.
Preparing the deck: (1) Put one event card in each the piles with one of the epidemic cards; any remaining cards are shuffled in as normal. (2) If there are extra player cards after put the same number cards in each pile, they go on the top of player deck to delay the earliest epidemic card.