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The scientific community has identified more than 10,000 rare diseases, but the path to accurately diagnosing and treating these illnesses has been fraught with regulatory and logistical hurdles that U.S. policymakers must address.

Very little is known about the biology of rare diseases, which is what makes them especially challenging. Most of them are genetic, and many are chronically debilitating, progressive, and life-threatening, according to Rare Diseases International.1 Collectively, they are not all that “rare” given that 30 million people in the United States alone—about 1 in 10—suffer from one of these illnesses. Half of the sufferers are children and 30 percent of them will die before they are 5 years old due to the lack of marketed treatments.2

These grim statistics underscore the urgent need for a regulatory framework that encourages safe therapeutic innovations and helps ensure their quick delivery to patients, according to medical experts, lawmakers, and patient advocates who recently gathered in Washington, D.C. for a symposium hosted by STAT and sponsored by Alexion, AstraZeneca Rare Disease. The panelists offered insights into how to improve the diagnostic process and access to treatments.

Bringing therapies to patients faster 

“One of the hardest things for patients with rare diseases is getting the right diagnosis,” said Sharon Barr, a senior vice president and head of research and product development at Alexion, AstraZeneca Rare Disease. On average, it takes about 4.8 years to accurately diagnose a patient, Barr said. During that time, the patient sees at least seven different specialists, often undergoes difficult tests, and then gets the wrong diagnosis and the wrong therapeutic.

“As a parent, I can tell you that this exactly reflects the journey we faced with one of our children,” said Barr, whose two children were each diagnosed with a different rare disease. “And so at Alexion, my team realized that if what we want to do is create better therapies for patients, the first thing that we have to do is create better diagnostics to get them to those therapies faster.”

Barr said the rare-disease community would benefit from the creation of a “knowledge base” that researchers can share, similar to the huge databases of genetic variants in tumors available to oncologists. Barr also suggested “conditional approval” of drugs that show a reasonable expectation of effectiveness while data is gathered for full approval.

Patients are desperate; only 5 percent of all the known rare diseases have FDA-approved treatments.3

Clinical trials: Big needs, small numbers

Although there are financial incentives such as tax credits and market exclusivity to spur research and development in rare disease treatments, their path to approval is onerous. The patient population for any single disease is so small that it’s time-consuming, costly, and often impossible to recruit people for the clinical trials needed to bring a drug to market.

Stealth BioTherapeutics can attest to that. For years, the Massachusetts-based firm has tried to gain FDA approval for a drug that would treat Barth Syndrome, a rare genetic disorder characterized by weakness of the heart and muscles as well as repeat infections. The disorder affects less than 300 people worldwide.

The company designed a three-month clinical trial that proved to be too short in duration, said Stealth BioTherapeutics Chief Executive Reenie McCarthy. For four years, the company kept tracking a few patients who agreed to continue post-trial treatment and found “statistically significant” improvements in muscle strength and cardiac function, McCarthy said.4

But the FDA refused to consider the company’s new drug application last year, citing insufficient data, the company said.5 The agency suggested another clinical trial.

“We’ve already used most of those patients, so it’s just not really feasible,” McCarthy added. “We’ve had really good dialogue with FDA. But there’s kind of a ‘you can’t get there from here’’ in terms of the relative rigor and robustness of what you would want to do in a clinical trial.”

The company is working with the FDA to find another regulatory pathway.

Frank Sasinowski, director at Hyman, Phelps & McNamara, suggested that when it comes to authorizing drugs for exceptionally rare diseases, regulators should consider adopting the Emergency Use Authorization standard that was applied to Covid-19 vaccines.

“That standard for getting authorization is whether or not the known and potential benefits outweigh the known and potential risks,” Sasinowski said.

Whats happening on Capitol Hill?

Recent legislative initiatives suggest that rare disease patients and their advocates are gaining some traction on Capitol Hill.

Last year, President Biden signed the “ACT for ALS” legislation, which led to the recent launch of a public-private partnership designed to speed the development and approval of therapies for amyotrophic lateral sclerosis, a fatal neurological disorder known as ALS. The new law also created an FDA grant program for research on ALS and other neurodegenerative diseases.6

Holly Fernandez Lynch, assistant professor of medical ethics and law at the University of Pennsylvania, said that the new law is especially innovative in its handling of expanded access programs, which would make it easier for ALS patients to receive experimental treatments outside of clinical trials.

These programs are typically expensive for clinical trial sponsors to administer, sometimes requiring them to pull their staff of larger trials to treat one patient, Lynch said. The programs also raise fairness questions when a larger clinical trial is underway, such as whether it’s fair to give the drug to people outside the trial when some people participating in the trial are getting the placebo.

The new law addresses these issues by covering the cost of expanded access programs at small companies through federally-funded grants, Lynch said. It also requires collecting data from patient who participate.

“The only criticism I have,” she said, “is why stop at ALS?”