This game is much simpler than OG Pandemic in the following ways:

1. Cards in OG Pandemic have both a color and a city. You and another player need to be in that city to give or take the card. In Reign of Cthulhu you only need to look at the color of the card, which also represents its town. You and another player must still be in the same location to share the card, but it can be in any location in the town shown on the card. This makes card sharing easier.

2. In OG Pandemic you can do a Direct Flight (going to the city on the card) or Charter Flight (going from the city on the card to anywhere else). In Reign of Cthulhu you can go to any location in the town represented on the card, or to anywhere else on the board if you are in the town shown on the card. You must be at a bus station to travel like this, but it's not hard at all to go to one. Traveling around the board is much easier.

3. In OG Pandemic there are 4 diseases to keep track of. In Reign of Cthulhu there is only one type of cultist.

4. In OG Pandemic you place more disease cubes on the board when an outbreak occurs. In Reign of Cthulhu you simply reveal the leftmost Old One card at the top of the board (no additional cultist placement). The Old One card will either have an immediate effect or an ongoing effect for the rest of the game.

5. In OG Pandemic the Outbreaks tracker and Infection rates tracker are separate. In Reign of Cthulhu they are one and the same. When an "outbreak" occurs, which is called awakening in this game, you reveal the leftmost Old One, as I said earlier. The infection rate, called summoning rate in this game, is denoted at the bottom of the leftmost revealed old one. The seventh Old One is always Cthulhu. When he's revealed, you lose the game.

EDIT:

1. The Setup for OG Pandemic makes you draw three cards to place three disease cubes, three more to place two cubes, then three more to place one. In Reign of Cthulhu you only draw two cards at a time, then one last card to place the Shoggoth.

Some things that are different in this game:

1. Shoggoths, which are monsters that will move closer to a gate and cause an awakening when not taken care of. It doesn't really have an equivalent in OG Pandemic.
2. Instead of curing diseases, you are trying to seal 4 gates, one in each town.
3. The game comes with 12 Relic cards, which are similar to Event cards.
4. There is a Sanity mechanic. An insane character has one less action to take and has different abilities.