If you were in Boston last month for the World Orphan Drug Congress, you felt the shift. For years, rare disease drug development operated within a regulatory relationship defined by flexibility, good faith, and the recognition that small patient populations warrant a different kind of regulatory imagination. That relationship is now being renegotiated – openly, urgently, and with real consequences for programs already in flight. The question driving nearly every hallway conversation was the same: how do you build a regulatory strategy that holds when the ground keeps shifting beneath it?
Lumanity convened a panel of experts who pulled no punches on what the current environment demands of sponsors. The discussion, Rare Disease Regulatory Pathways in Flux: Navigating FDA and EMA Changes in 2026, brought together Katie McCarthy, SVP of Clinical & Regulatory at Lumanity; Sam Zappia, VP of Regulatory Affairs at Spolia Tx; Brigid DeCoursey Bondoc, leader of Morrison Foerster’s FDA and Healthcare Regulatory group; and Jennifer Burke, Sr. Principal Consultant at Lumanity. Together, they covered ground that most conference panels spend hours dancing around.
What follows is not just a conference recap. It is diagnostic.
5 Things Rare Disease Sponsors Need to Reassess Right Now
1. This is Not a Normal Tightening Cycle, and Treating it Like One is a Risk
The most important thing to understand about the current FDA environment is that it isn’t a temporary correction. It is structural.
Significant leadership instability at the FDA, compounded by workforce attrition, has created a sense of regulatory uncertainty among drug sponsors. The past 18 months have been marked by unprecedented leadership turnover at FDA’s two primary review centers, CDER and CBER. Both are currently led by acting directors after a succession of leadership changes since January 2025, with CDER alone cycling through six leaders during that period.
The downstream effect for sponsors is direct and serious. Less experienced staff are now making calls on difficult packages. The institutional knowledge that once allowed for nuanced, relationship-informed engagement is thinner than it has been in a generation. The removal of staff with regulatory expertise to think innovatively and implement flexible, fit-for-purpose pathways raises real concern about whether review divisions will be well-resourced enough to move at the pace the industry expects.
For sponsors, that changes how you write, frame, and defend your submissions. It also raises the ceiling on what good regulatory strategy needs to accomplish before you ever file.
2. Don’t Abandon FDA, but Don’t Engage the Way You Used to
Some sponsors are pausing applications. Others are quietly exploring whether to lead with EMA or another jurisdiction. The panel’s advice: do not run from FDA but engage smarter.
The strategic imperative right now is obtaining Agency feedback early and often. Every interaction with FDA should be structured to generate documented, referenceable positions because if things shift, the documented feedback can be a key resource. If your package has weaknesses, be explicit about why you meet requirements rather than hoping reviewers will infer it. If you do go to another jurisdiction first, make sure the data architecture supports a US filing. You cannot avoid the US market indefinitely.
There is, however, reason for cautious optimism. The regulatory doors are reopening for rare disease companies that faced more stringent regulatory actions under recent FDA leadership. In a notable example, FDA reversed course on uniQure’s Huntington’s disease gene therapy, agreeing that three-year data from its ongoing Phase 1/2 program could support an accelerated approval application. The agency also indicated that a confirmatory study using a concurrent standard-of-care control, rather than the previously requested sham surgery-controlled Phase 3 trial, may be acceptable. This example shows that the window is open, but only for sponsors whose regulatory strategy is tight enough to walk through it cleanly.
3. Accelerated Approval is Now a Deal-Level Risk Factor
Accelerated approval is no longer just a regulatory strategy question. It is a transaction-level risk factor that your deal team, your board, and your investors need to understand explicitly.
FDA guidance makes clear that accelerated approval carries defined criteria, and that expedited withdrawal procedures apply when confirmatory commitments are not met. Conditional approvals are now explicitly surfacing in transaction negotiations. Asset valuations are being discounted at the point of accelerated approval, not just at confirmatory failure, because market sustainability is uncertain. Payers are reading conditional approval status as a signal of risk, and the Agency has demonstrated a willingness to withdraw approvals that, historically, would have been sustained.
For anyone building or acquiring a rare disease asset in 2026: accelerated approval cannot be treated as a path to certainty. It must be priced for risk accordingly, with C-suite and board visibility, not just regulatory affairs management.
4. Confirmatory Trials are the New Bottleneck
In ultra-rare settings, the evidentiary bar for “confirmatory” is genuinely unresolved, and the gap between regulatory theory and practice is wider than most sponsors realize.
Real-world evidence and external controls are, in principle, accepted. In practice, the standards for pre-specified matching, endpoint alignment, and data quality are raising the bar, not lowering it. Delays in confirmatory trials attenuate learning, and delayed confirmatory evidence is correlated with low levels of clinical benefit. FDA is becoming more willing to initiate withdrawal proceedings when timelines slip.
What does that process look like? It is adversarial, it is public, and for many companies it is existential. The instinct to fight is understandable, but the legal and reputational costs are significant.
The lesson: design your confirmatory strategy with the full range of outcomes already mapped. Anticipating every outcome is not pessimism, it is what rigorous regulatory planning looks like in 2026.
5. The 2026 Strategic Playbook: What We’d Do Differently
Asked what they would do differently if starting a rare disease program today, the panel converged on three principles. These apply whether you are pre-IND or approaching your NDA- but the earlier they are implemented, the more value they create.
Consider your regulatory strategy earlier. Companies that move efficiently have strategic regulatory expertise at the table from day one, not brought in to clean up later. If regulatory affairs is still a downstream function in your organization, that is a structural vulnerability. Sponsors who engage proactively, with a well-prepared strategic team, will be positioned to take advantage of that alignment. Those who don’t, won’t.
Make confirmatory design a pre-IND conversation. The question of “what will we need to confirm, and how?” should be answered before Phase 1 endpoints are locked. Committing to the framework early, and building the data architecture to support it, is the difference between a confirmatory trial that converts and one that becomes a liability.
Get executives closer to regulatory risk. The downstream consequences of regulatory missteps, including legal exposure, market withdrawal, deal devaluation, are now operating at a level that requires C-suite and board-level engagement. This is not a regulatory affairs management issue anymore. It is a governance issue.
What This Means for Your Program
The rare disease space has long operated on a premise of earned flexibility, that small patient populations, high unmet need, and biological complexity warrant regulatory accommodation. That premise hasn’t disappeared. But the conditions under which it applies are being actively renegotiated, in real time, by an agency navigating an unusual period of leadership instability and organizational change.
“The companies that emerge from this period in the strongest position won’t be the ones that waited for clarity. They’ll be the ones that treated regulatory strategy as a design input from the start and built the internal infrastructure to execute on it before they needed to.”
How Lumanity Can Help
Lumanity’s Clinical & Regulatory team works with rare disease sponsors at every stage of development, from regulatory strategy and submission planning to confirmatory trial design and FDA engagement. We help companies build the regulatory infrastructure needed before problems arise, not after.
We’ll be reaching out in the coming weeks to discuss how these priorities apply to your program specifically. If your challenge is more urgent, we welcome that conversation sooner.
