Two things:
Firstly: Casey Hudson is technically still in charge, but he's still hanging out in Vancouver(?) and the new game is being developed by Bioware Montreal. There's a pretty good chance that him not standing over the shoulders of the devs in the Montreal studio means that they'll turn out an interesting title.
Secondly: While the only logical thing for the series is to make it a either a prequel or an interquel, as trying to make it take place after the existing trilogy sets up a whole lot of problems, there are issues with that. The first is that if it's an interquel, the fact that there is already a conflict of galactic importance occurring, (or on the horizon), means that, in order to make the story at all interesting, it's going to have to be extremely personal. Otherwise, the stakes won't seem large enough. You could technically set it in the two years where Shepard is being rebuilt by Cerberus, hunting down the remnants of Saren's Geth, turning up evidence of the impending Reaper threat that the Council just won't listen to, but the problem is, we all know how that story is going to end: with Shepard fighting the Reapers. However, if that same story also revolved around some kind of intensely personal journey, I could see it working. But I don't know if Bioware has the chops to do a story like that.
If they make it a prequel, there is only one problem: no humans. I don't mean this from a personal standpoint: I never play as a human when I have the option of another race. But I can't think of a single Bioware game where you had the choice to pick a race, and human wasn't an option. It's like they're too scared to design a game like that. I don't think that anything in humanity's history leading up to entering galactic civilization is interesting enough to base the game around. I mean, what have they got, the First Contact War? Ehh. But, if you go back further than that, you don't have humanity at all, and, again, I don't know if Bioware have the guts to do that. I really hope they do. I guess we'll have to see.
Ignoring the story aspect, this series is set in SPACE! I want SPACE! battles. Running around on the ground shooting at things always felt like a missed opportunity. I want to see them explore the whole futuristic aspect of the setting in gameplay more than they have so far.
That's just what I think, anyway. Feel free to disagree.