Yesterday the EveryLife Foundation for Rare Diseases held a scientific workshop to discuss therapy development for small populations. Not surprisingly, the first question out of the box was – should there be a regulatory community recognized definition of “ultra-rare.” Based on an EveryLife poll, 70+% said “yes.” No surprise.
Over the course of the workshop, one foundational reason arose to develop and bless an “official” definition: precision counts. Defining “ultra-rare” will assist in designing clinical programs and regulatory review. It will help facilitate investment, if incentives are tied to such a designation. It will move FDA away from “regulatory flexibility” towards a more standardized process. Defining “ultra rare” will provide predictability.
What will comprise such a definition? Obviously, size of patient population, but it’s not going to be “just” a number. After all, if there aren’t other differentiators, why not just consider all ultra-rare diseases the same way we define “orphan” diseases under the Orphan Drug Act (any disease that affects less than 200,000 Americans)? Won’t the same incentives work? Won’t the same regulatory rules apply?
Should such a new definition be strictly numerical? What about severity? Should there be an ultra-rare scorecard and, if so, should the variables be weighted? The question isn’t should there be a definition but rather what are the criteria?
Does defining a new disease category with different rules require legislation for this or can the FDA do so under their current regulatory authority? What are the implications for the broader ultra-rare lexicography? What about vouchers and other incentives? A strategically developed definition of ultra-rare could also help to supercharge (and perhaps better fund) the FDA’s Accelerating Rare Disease Cures (ARC) program.
There was a lot of discussion during the workshop surrounding the FDA’s use of “regulatory flexibility.” Words count. “Flexibility” lacks predictability and doesn’t instill confidence in an increasingly high-risk developmental environment. What the FDA must be is “nimble.”
The development and approval of SKYCLARYS (for Friedrich’s ataxia) via natural history data didn’t happen because the FDA was flexible. It happened because the agency was nimble. It’s a distinction with a difference.
Regulatory Nimbleness understands and respects the need for process. Undefined and anecdotal “flexibility” can easily lead to regulatory pandemonium. Nimbleness must enhance progress through process, not result in entropy. New approaches require well-considered rules because, as Victor Hugo reminds us, “Where the disposal of time is surrendered merely to the chance of incidence, chaos will soon reign.” Flexibility bends rules. Nimbleness reads between the lines. Nimbleness looks to the spirit of the FDA’s mission. Experts are nimble.
The ultra-rare space requires investment nimbleness, developmental nimbleness, regulatory nimbleness, treatment nimbleness. It requires nimbleness in pre-clinical programs and in post-marketing data collection and analysis. Ultra-rare nimbleness delivers a higher degree of certitude across the board. And that starts with a definition.
A more precise focus on definition and process will also help to shine a bright light on the issue of expanding (and paying for) newborn screening panels. So many reasons to do this, starting with the truth that early diagnosis results in more successful therapeutic outcomes. As CBER Director Dr. Peter Marks commented, “We need to be more rare aware.”
The legendary Dr. Tim Franson chaired the EveryLife workshop. He opened the proceedings with a defining acronym, CARE: Clinical, Access, Regulations, and Ethics. Those are four very loaded words that mean a lot of different things to a wide swath of the ultra-rare ecosystem. They could also serve as a go-forward proposition in discussing the criteria for a scorecard-based definition of “ultra-rare.” Not a “flexible” definition – but certainly a nimble one.
When it comes to ultra-rare diseases, let’s amend an existing adage: If you can’t define it, you can’t measure it. And if you can’t measure it, then it doesn’t count. The ultra-rare community counts. Let ‘s give them the respect they deserve and define who they are.
Peter J. Pitts, a former FDA associate commissioner, is president of the Center for Medicine in the Public Interest.
