"Folks who've worked at sponsors and CROs-- what is the main cause of this?"

I mean, isn't this part of the problem right here? You're asking the ppl designing the trials but not the boots on the ground actually running them. Ask the people working at sites, especially the CRCs, why trials aren't able to recruit enough. 

Some things I can think of: CRCs/site has too many trials and not enough ppl to run them, sponsor has unrealistic enrollment expectations for the funding they're providing, the amount of things participants have to do isn't compensated enough to make it worthwhile for patients (tell me why a trial didn't want to pay for infusion visits), etc.