Funny... I immediately had an answer in my head when I saw the thread title, which was
The Biggest Issue In 5E. Then when I opened the thread up and saw the poll's actual request was
The Biggest Issue In 5E Design, I realized that my answer wouldn't actually apply.
Cause my original answer was that the biggest issue of 5E was going to be the incessant caterwauling of some players who discover that 5E won't actually play in exactly the same tight, restrictive, inflexible, 'this is what D&D is to me and I have to play in this specific fashion and I refuse to compromise' way that they want. And they are going to spend years bemoaning this fact, especially claiming that WotC lied to them said from the beginning that they were "going to make a game that was all-inclusive, but which they failed miserably at and most certainly did not!"
And the rest of us will have to listen to it for years.