The Regulatory Paradox
The FDA announced in January it would accept single clinical trials as sufficient evidence for drug approvals, ending a 60-year requirement for duplicate studies. That same month, the agency rejected at least 23 therapies for rare diseases, conditions affecting fewer than 200,000 Americans each. At a Senate hearing this week examining that disconnect, one witness testified that engaging with FDA regulators felt "like talking to a brick wall."
The contradiction exposes a structural problem in how the U.S. evaluates medical treatments. As approval standards ease for common conditions that can generate large-scale trial data, rare disease therapies face what another witness called "death by technicality", rejected not because they don't work, but because they can't produce the volume of evidence the FDA's framework demands.
The Impossible Math
More than 7,000 rare diseases exist, affecting 30 million Americans total. Roughly 90% have no FDA-approved treatment, per the Senate Special Committee on Aging.
The evidentiary trap works like this: FDA standards were designed for common conditions where pharmaceutical companies can recruit thousands of patients, run randomized controlled trials, and generate statistical significance across multiple studies. But many rare diseases affect only hundreds or thousands of patients globally. You can't run a 1,000-person trial for a condition affecting 500 people. You can't establish a control group when every patient is desperate for any intervention. You can't wait 15 years for long-term data when patients are dying now.
Congress recognized this problem and tried to fix it. The 21st Century Cures Act and the Accelerating Access to Critical Therapies Act gave the FDA new tools to evaluate treatments that don't fit conventional trial designs. The agency built infrastructure in response: a Rare Disease Innovation Hub, Evidence Principles from the Center for Biologics Evaluation and Research, pathways theoretically designed to accommodate smaller datasets and alternative evidence.
Yet since January 2025 alone, the FDA has refused to approve investigational rare disease therapies at least 23 times.
The Vanishing Advisory Committees
The FDA hasn't convened an advisory committee meeting since July of last year, according to the Senate committee.
These committees exist precisely to evaluate marginal cases, therapies that don't fit cleanly into approval categories, conditions where conventional evidence is impossible to generate, situations requiring expert judgment rather than algorithmic review. They're the mechanism meant to bridge the gap between rigid standards and messy reality.
Their absence suggests the infrastructure Congress mandated and the FDA built isn't actually functioning. The Innovation Hub exists. The Evidence Principles are published. The statutory authority is clear. But the 23 rejections indicate that when rare disease therapies reach decision points, the default answer remains no.
What the Hearing Revealed
Chairman Rick Scott and Ranking Member Kirsten Gillibrand called the hearing to examine why the gap between policy and practice persists. The session brought FDA Commissioner Dr. Martin Makary before the Senate Special Committee on Aging to answer a straightforward question: Congress gave you tools, you built programs, why isn't this working?
The "brick wall" testimony captures the experience from the other side. Families and researchers describing years spent developing therapies, navigating FDA guidance documents, submitting applications that meet stated criteria, only to hit rejection based on standards that weren't disclosed upfront or that prove impossible for rare conditions to satisfy.
"Death by technicality" isn't an exaggeration when the technicality is "insufficient sample size" for a disease affecting 300 people worldwide.
The System's Structural Bias
The FDA's single-trial decision for common drugs makes sense: if you can demonstrate safety and efficacy in one well-designed study with thousands of participants, requiring a duplicate study adds years and costs without meaningfully improving certainty. The math works when large populations are available.
But that same logic inverts for rare diseases. The fewer patients available, the harder it becomes to meet evidentiary bars designed for common conditions. The system punishes conditions for being uncommon, precisely the population Congress intended the Orphan Drug Act and subsequent legislation to protect.
This creates a perverse regulatory outcome where the sickest, most neglected patient populations face the highest barriers to treatment. Not because their therapies are more dangerous or less effective, but because their diseases don't generate the data infrastructure FDA reviewers are trained to evaluate.
What Happens Next
The hearing puts Makary in the position of explaining why existing statutory authority and agency infrastructure haven't translated into approvals. The 23 rejections since January suggest either the tools Congress provided are inadequate, or the FDA isn't using them.
If advisory committees aren't meeting, that's a choice. If Evidence Principles exist but reviewers default to conventional trial requirements, that's a training or enforcement problem. If the Innovation Hub operates but doesn't change approval rates, it's theater.
The 30 million Americans with rare diseases don't need more infrastructure announcements. They need the infrastructure that exists to function, or an honest assessment that the regulatory framework can't accommodate diseases that don't generate conventional evidence at scale.
The Senate hearing suggests Congress is done accepting the gap between promise and practice. Twenty-three rejections in two months isn't a statistical anomaly. It's a pattern that demands explanation.