By speeding lifesaving drugs’ way to market and focusing on the underlying causes of disease, the pathway has helped save many lives.
Patients with rare diseases are in dire need of effective treatments. Yet some academics are pushing regulators to deny them access to medicines that could save their lives.
These critics attack the FDA’s accelerated approval pathway, which allows drugs that address unmet health needs onto the market faster if they can show a positive impact on a biomarker that is a reasonable predictor of clinical benefit. The pathway, introduced in 1992, gets drugs onto the market before studies with clinical benefit as a primary outcome have been completed. Companies must complete those confirmatory studies after approval.
For many rare genetic diseases, especially those that afflict the brain, a biomarker can be a much more accurate measure of the underlying cause of disease than downstream clinical symptoms—and these biomarkers are essential to developing treatments for complex neurological and genetic diseases.
I’ve seen as much firsthand: Over my 30-year career in medicine, I have guided several rare disease treatments through the perilous development and approval process. The company I now lead, Ultragenyx, focuses on developing therapies for rare and ultrarare diseases. Our team knows better than anyone how biomarkers can help measure disease progression.
It’s precisely the reliance on biomarkers as predictors of clinical outcome in accelerated approval that has drawn fire. Yet taking a close look at some controversial uses of the pathway reveals what a boon biomarkers can be when it’s vital to deliver therapies quickly to patients who otherwise have no good options.
Aduhelm and Its Critics
One of the pathway’s most prominent critics is Aaron Kesselheim, a Harvard professor who famously resigned from an FDA Advisory Committee following the accelerated approval of Aduhelm, a novel treatment for Alzheimer’s disease, in 2021. In a New York Times article that same year, Kesselheim called the agency’s approval of the drug “the worst [decision] that I can remember” and said there was “no good evidence that the drug works.”
Aduhelm received accelerated approval based on evidence that it reduced levels of the biomarker amyloid in the brains of people with the disease. Critics claimed that the scientific understanding of the amyloid biomarker wasn’t enough to warrant approval. Billy Dunn, the FDA official who oversaw Aduhelm’s approval, came under fire.
But there’s abundant scientific research suggesting that amyloid is a major contributor to Alzheimer’s disease. And data from confirmatory studies for other drugs that target amyloid in the brain—Leqembi, and later Kisunla—show that the biomarker does indeed predict clinical benefit. So Kesselheim was wrong. Billy Dunn made the right decision, even if the drug had limitations.
Aduhelm’s manufacturer, Biogen, pulled Aduhelm from the market voluntarily in January 2024. But the decision had nothing to do with safety or efficacy. Rather, the Centers for Medicare and Medicaid Services essentially refused to cover Aduhelm in early 2022. That gave commercial insurers tacit permission to do the same, also potentially impeding the reimbursement for other drugs approved by accelerated approval, a disastrous and ill-considered decision. Without insurance coverage, there was no market for the drug. In addition, the second-generation amyloid-targeting drugs now on the market have proven more effective than Aduhelm.
Leqembi isn’t perfect, just like Aduhelm wasn’t. But Alzheimer’s research would not be where it is today without Aduhelm’s accelerated approval. That decision invited companies to invest in additional therapies targeting amyloid. Without it, Leqembi or Kisunla might not have received a green light. Or they might have been mothballed altogether. The whole field would have crashed. Instead, there are now over 100 therapies in the drug development pipeline for Alzheimer’s, which was once considered a scientific graveyard.
(Editor’s note: BioSpace reached out to Kesselheim for his response to this opinion article before publication but did not receive a response.)
Accelerated Approval and the AIDS Crisis
Academic opposition to accelerated approval isn’t new. Decades ago, another Harvard academic, Deborah Cotton, warned that accelerated approval of the first retroviral drugs to treat HIV/AIDS using CD4 cell count as a biomarker was a “mistake” and set a “troubling precedent.” She was concerned that using accelerated approval would be counterproductive in the long run and reportedly questioned whether “relying on surrogate markers will hasten a cure or hinder it.”
What happened? Those first HIV antiretrovirals saved thousands of lives, including that of basketball legend Magic Johnson. Their accelerated approval catalyzed the development of more effective therapies that treat the underlying cause of the disease. The HIV/AIDS death rate in the U.S. has plummeted 91% since the FDA granted accelerated approval to a drug using CD4 counts as a biomarker in 1992.
This history indicates that Cotton was not just slightly wrong about the accelerated approval of HIV antiretrovirals. She was completely and totally wrong. Had opinions like hers prevailed, many effective therapies we take for granted would not be here today.
By measuring changes in biomarkers representative of the underlying cause of disease, we can show a drug’s true impact more accurately than would be possible with highly variable and imprecise clinical endpoints.
The Biomarker Advantage
Biomarkers also enable companies and scientists to direct their drug-discovery efforts to attack and defeat what’s causing disease, rather than simply manage late-stage clinical symptoms.
Accelerated approval facilitates medical progress by giving scientists the opportunity to study promising drugs in real-world settings, and to eventually improve upon them through further research.
That additional research tends to validate the FDA’s decisions. Only 12% of drugs that received accelerated approval between December 1992 and December 2021 have been withdrawn. A 2017 Health Affairs study found that drugs greenlit through the pathway tend to be more effective than those approved through the FDA’s traditional process.
Among the rare genetic diseases that I study, no biomarker-based approved drug has ever failed to work or been withdrawn.
Most recently, we at Ultragenyx participated in a public forum with the FDA to establish a well-characterized biomarker to support accelerated approval pathway for a group of ultrarare metabolic disorders called mucopolysaccharidoses (MPS), which may unlock the approval of a host of new therapies for these devastating diseases. This was the culmination of a multiyear effort on the part of the MPS community, showing just how challenging it can be to establish new biomarkers for approval regardless of the body of evidence backing them up.
The reality is that accelerated approval has transformed the treatment landscape for a wide range of life-threatening diseases. Lawmakers and FDA officials must preserve, protect and support the pathway. In so doing, they can ensure that patients suffering from diseases long considered untreatable have access to groundbreaking medicines—and hope.
