Is that a problem? I mean, really, besides Nick Fury, Dum Dum Dougan, and maybe Sharon Carter, most of Marvel's SHIELD agent characters have pretty flat personalities, so he'd be building them basically from the ground up anyway. With wholly original characters, they're doing the same amount of work with more creative freedom.
Plus, odds are that the villains are going to be established Marvel characters, and they're going to be the real draw as far as hardcore Marvel fans are concerned. In a show like this, what you hear most from the fans is them asking when villain X is going to be on the show.
I'm hoping for an Arcade episode myself. I'm not a huge fan of Arcade, but I feel like the Whedons could do him really well.