FDA:Type II Errors for Ultra-Rare Diseases

Understanding the Two Types of FDA Errors:

In drug development, there are two main kinds of mistakes regulators can make:

• Type I Error (false positive): Approving a drug that turns out not to work—or worse, proves unsafe.

• Type II Error (false negative): Rejecting or delaying a drug that actually works and is safe.

The FDA’s default stance is to guard against Type I errors at all costs. That instinct may make sense in large, common diseases with thousands of patients and multiple treatment options. But in ultra-rare diseases, where patients have nothing else, the bigger danger is almost always Type II errors.

Denied First, Approved Later: Type II Errors in Action

The FDA’s history is filled with examples of drugs first denied or delayed—only to be approved years later:

• Migalastat (Galafold) – Fabry disease
  FDA denied in 2016, approved in 2018 after advocacy and resubmission.

• Amifampridine (Firdapse) – Lambert-Eaton Myasthenic Syndrome (LEMS)
  Rejected in 2016, approved in 2018, later expanded.

• Tafamidis (Vyndaqel/Vyndamax) – Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
  Denied in 2012, approved in 2019 with confirmatory data.

Each of these “false negatives” cost patients years of access to treatment. They are Type II errors that only persistence and advocacy could overturn.

Still Waiting: Ultra-Rare Communities Trapped by Type II Errors

The cost of FDA’s fear of making a mistake falls hardest on the smallest, most fragile communities. Each of these groups has lived through denials, Complete Response Letters (CRLs), or endless delays:

• Classic Galactosemia
  Govorestat (AT-007) showed clear biomarker reduction and clinical benefit, yet the FDA issued a CRL in 2023 over missing survey data in a 42-patient trial. Today, 3,500 Americans still live without a single FDA-approved therapy.

• Prader–Willi Syndrome (PWS)
  DCCR (Carbetocin) has repeatedly been delayed, despite strong signals of benefit in reducing hyperphagia, a life-threatening hallmark of PWS. Families continue to fight for recognition.

• Barth Syndrome
  A small trial showed functional improvements, but strict statistical thresholds were not met. No FDA-approved therapy exists, leaving children vulnerable to severe cardiac complications.

• Sanfilippo Syndrome (MPS III)
  Gene therapy trials have shown evidence of slowing decline, but inconsistent endpoints and tiny patient numbers have stalled FDA approval. Families describe watching their children lose speech and mobility as regulatory disputes drag on.

• Other Ultra-Rare Conditions
  From mitochondrial diseases to lysosomal storage disorders, dozens of ultra-rare programs face the same trap: promising results dismissed as “insufficient evidence” simply because the trials can’t meet conventional statistical size and power.

This isn’t anecdotal. As Yingling, Sena-Esteves, and Gray-Edwards (2024) documented in Human Gene Therapy:

“In what has been coined the ‘Great Abandonment,’ since 2021, drugmakers have shelved, abandoned, or rolled back development in more than 50 rare disease programs.”

These aren’t unsafe drugs. They are casualties of a system that clings to statistical purity while families watch irreversible damage unfold.

My Story: Living the Type II Error

Last year, I got the call that literally made me fall to my knees. I was at a children’s park, watching my daughter play happily. I walked to the curb, lay flat on the sidewalk, and cried. My own daughter on placebo for 3 years, now on drug improving. Seizures controlled, out of diapers, tremors gone, white matter improvement.. the list goes on for govorestats benefit.

That morning, I learned that Govorestat was given a CRL not because of safety, not because of efficacy, but because of an electronic health record error. A third-party glitch had crushed years of hope.

The calls poured in from other galactosemia families, my rare mom friends, and the community I support. Almost a year later, I just read the same story from Sanfilippo families: another CRL, more children left behind. I know the next months for them will be brutal, because that’s how it was for me.

We are told our numbers are too small, our risks too high. I can understand FDA’s caution, but not enough as a person living the ultra-rare life to accept that “this is just the way it is.” There are solutions. There are opportunities. “That’s just the way it is” is not acceptable. For years now I have heard “until we find a way…thats just the way it is.”

What About Type I Errors in Ultra-Rare?

Here’s the truth: as of right now, there are no clear examples of Type I errors in ultra-rare disease approvals.

That’s important. Despite fears of approving “bad drugs,” the FDA has not flooded ultra-rare patients with unsafe or ineffective therapies. If anything, approvals are rare, tightly restricted, and monitored to a degree that exceeds most common disease programs.

So why is the FDA still unwilling to bend when the risk of harm from inaction is so much higher? Why do they hold ultra-rare conditions to the same statistical standards as cancer, diabetes, or Alzheimer’s, when trial sizes are 50 children, not 5,000 adults?

This is why ultra-rare disease needs its own regulatory definition and flexibility. The current framework does not fit. For ultra-rare, the greater threat is not approving the wrong drug—it’s never approving anything at all.

Solutions for Regulators

If the FDA and policymakers truly want to protect ultra-rare families, they must rebalance risk and embrace the tools already at their disposal:

• Create an Ultra-Rare Definition: Distinguish ultra-rare (affecting <20,000 in the U.S.) from rare. This enables regulatory flexibility tailored to micro-populations.

• Accept Smaller Datasets: Apply statistical standards proportionate to trial size. One trial plus confirmatory evidence should be enough, as FDA guidance already allows. Exmaples: rare disease statistical bayesian model

• Use Biomarkers and Natural History: Validate surrogate endpoints (e.g., galactitol in galactosemia, hyperphagia scores in PWS) to prevent Type II errors.

• Conditional Approvals: Approve safe therapies with strong post-market surveillance, instead of shelving them until “perfect” evidence arrives.

• Transparency and Dialogue: Engage with patient groups early, explain CRLs in plain language, and collaborate on solutions instead of leaving communities in limbo.

• Incentivize Industry: Expand voucher programs, tax credits, and grants so companies don’t abandon ultra-rare programs under financial strain. Read more about the Rare Disease Pediatric Priority Review Voucher

• Legislative Fix: Redefine “Substantial Evidence”: Former FDA Commissioner Janet Woodcock has called for Congress to establish a rare disease–specific standard for drug approval. This would allow smaller trials, stronger use of biomarkers, natural history data, and conditional approvals with post-market verification — hardwiring flexibility into law without lowering safety standards. See pink sheet link.

Solutions for Patients and Families

Families can’t solve regulatory science alone, but they can drive change:

• Tell Your Story, On Record: Calls, emails, and written submissions to Congress and FDA create legal documentation. Without it, your struggle “doesn’t exist.”

• Join Registries: Every datapoint helps build the evidence FDA says is “missing.” If you haven’t joined your disease registry—do it today.

• Prepare for Delays: Know the system is slow. Tissue banking, data sharing, and advocacy packets can keep momentum alive even if a drug stalls.

• Find Allies: Partner with other ultra-rare groups (Galactosemia, PWS, Barth, Sanfilippo). Alone, we’re too small; together, we’re undeniable.

• Push State and Federal Policy: Medicaid coverage, nutrition acts, and bills like the PROTECT Rare Act matter. Don’t assume national policy will trickle down to your family.

• Protect Your Mental Health: Advocacy is exhausting. Drink water, take naps, and find support. No fight is won alone.

Final Word

The FDA is right to guard against mistakes. But ultra-rare families are living with the consequences of the wrong emphasis.

• Type I errors—unsafe approvals—have not materialized in ultra-rare disease.

• Type II errors—safe, effective drugs denied or delayed—happen every day.

Ultra-rare deserves its own definition, its own pathway, and its own flexibility. Because for these families, the greatest risk is not getting it wrong it’s getting nothing at all.