Biomarkers, Surrogates, and Endpoints: The Unseen Language That Decides Rare Disease Progress
In rare disease, treatments don’t fail because science is behind. They fail because the system refuses to measure success in ways that reflect the reality of ultra-rare conditions. That failure often comes down to one word: biomarkers.
They determine whether a clinical trial gets funded, whether the FDA will approve a drug, and whether a disease community is left with hope—or heartbreak. But for families, advocates, and even small biotech firms, understanding what biomarkers are—and how they relate to endpoints—can feel like navigating a maze built for someone else.
This post aims to change that.
What Is a Biomarker?
A biomarker is a measurable indicator of some biological state or condition. That could mean a toxin building up in the body, a molecule indicating disease progression, or a genetic expression that signals damage.
FDA definition: "A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention."
Examples:
Blood sugar (for diabetes)
LDL cholesterol (for cardiovascular risk)
Galactitol or GAL1P(for galactosemia—though not yet accepted by FDA)
In classic galactosemia, galactitol builds up in the brain, lens, and ovaries, causing irreversible damage. It’s easy to measure and correlates with known outcomes like tremors, cataracts, and infertility. Gal-1-P, meanwhile, disrupts energy systems inside cells, leading to cellular starvation and death. It’s a direct biochemical culprit, not just a signal.
And yet—neither galactitol nor Gal-1-P is officially recognized as a qualified biomarker by the FDA.
That gap between science and regulatory acceptance is where rare disease progress dies.
Surrogate Endpoints: When Biomarkers Stand In
A surrogate endpoint is a type of biomarker used as a stand-in for a clinical outcome. Instead of waiting to see if a patient gets better in the long term, you measure something that is likely to predict that improvement.
FDA definition: "A laboratory measurement or physical sign used as a substitute for a clinically meaningful endpoint that is expected to predict the effect of the therapy."
Examples:
HIV viral load reduction (instead of waiting to see fewer infections)
Tumor shrinkage (instead of waiting for longer survival)
Galactitol reduction of GAL-1-p (proposed in galactosemia)
Surrogate endpoints are common in FDA approvals:
Over 50% of oncology drugs use surrogate endpoints.
They are core to the Accelerated Approval Pathway.
Yet in rare diseases, the same logic is often dismissed. That inconsistency is especially devastating when a known toxic molecule (like galactitol) is reduced by a drug, but FDA says, *"That doesn't count."
Composite Endpoints: Measuring Complex Reality
A composite endpoint combines multiple measures into one. This is especially useful in rare diseases, where:
Sample sizes are small
Disease affects multiple body systems
Outcomes are variable
Definition: A combination of individual outcomes (e.g., symptom improvement, lab values, quality of life) into a single measure of treatment effect.
Example in galactosemia:
Speech improvement
Reduced tremor
Lowered galactitol
Patients improving in at least two areas may be considered responders. These endpoints help capture real-world benefit where no single metric tells the whole story.
Why It’s So Hard in Rare Disease
Despite guidance documents, FDA often won’t weigh in on a proposed biomarker or endpoint until you submit a New Drug Application (NDA).
You can:
Ask in a Type C meeting (free)
Submit under the Biomarker Qualification Program (slow, costly)
But the most common answer is: **"We can’t comment until you apply."
This leaves rare disease advocates and early-stage companies in a bind:
They need FDA to say what to measure
FDA won’t say without millions spent on trials
It’s a Catch-22 that stalls innovation.
Validating the Complexity
Even when families know what’s harmful—even when a toxin is measurable and preventable—FDA may still reject it as an endpoint. Rare diseases often:
Lack a "gold standard" diagnostic benchmark
Present with varied symptoms and progression
Require small trials that can't meet traditional statistical thresholds
"Gal-1-P isn’t just a marker—it’s a cellular toxin. Yet no drug targets it."
If a drug reduces that toxin and improves symptoms—but doesn’t hit a narrow endpoint pre-approved by FDA—it may be rejected.
Call to Action: End the Catch-22
Rare families shouldn’t have million-dollar trials without knowing what counts. Or the burden of drug trail participating before a biomarker is accepted. The FDA advocates for early trial design engagement with patients, groups, and industry, but won’t comment on the clarity need to protect patients.
We need:
FDA to accept galactitol and Gal-1-P as biomarkers in galactosemia
NIH to invest in validating biomarkers
Congress to mandate biomarker transparency in rare disease reviews
Industry and advocates to co-design endpoints that reflect real-world function but have the 3rd party FDA confirm these design inputs.
As one parent said:
“Galactitiol is a sugar alcohol, its in my child’s brain, she’s waking around with this. You can measure blood alcohol levels and know someone is drunk. I can see the tremors in galactosemia, but they(FDA) dons’t see this marker as a disease aspect.”
