If the innovation is worthy, believe and persist through regulatory scrutiny
It is scary to develop a regulatory submission that doesn't match conventional wisdom. If the innovation is worthy, do it anyway.
You can be successful with something new that your regulator has never seen before. Persist. Believe. Keep pushing. If it makes sense for patients, it'll work. I've seen a de novo submission that was initially rejected and then overturned on appeal by CDRH's Dr. Shuren because the technology itself held promise. Even though the device had low evidence of benefits (and high uncertainty), it had very low risk (and low uncertainty) and high potential future value. (My educated guess is that the regulator wanted to signal to the industry, "Bring us more technologies like this" by granting the de novo.)
The novelty and potential greatness of the technology is part of the total benefit-risk assessment. It may not be easy and smooth, but it'll work if there's novel value in the innovation. Don't revert to what's easiest to get approved at the expense of your medical innovation. Believe, persist, and get it through.
~Shannon, the Optimistic Optimizer