Drug development is hard. The difficulty stems primarily from the complexity of biology and our relatively limited understanding of it.
Add to that a strict regulatory process -- which is a good thing.
The U.S. Food and Drug Administration is tasked with ensuring that experimental drugs and medical devices are safe, effective, and useful. The agency provides an essential safeguard for the well-being of patients. Failing to uphold that mandate could jeopardize its credibility and erode public trust.
Right now, regulators are on the cusp of doing exactly that. Again.
Regulatory Flexibility
The FDA, under a rarely used precedent, can green-light experimental treatments that raise questions about safety or efficacy but address a severe unmet need.
For example, in June 2021 regulators approved Aduhelm from Biogen (BIIB). This drug, the first direct treatment for Alzheimer's disease, offered hope for patients and their families and boosted prospects for other experimental treatments.
At the same time the evidence showing that Aduhelm worked was mixed. In recent months, the scientific community learned that the beta amyloid hypothesis -- which assumes that plaque buildup drives the progression of Alzheimer's disease -- was based on manipulated data. Biogen didn't develop the hypothesis or manipulate data, but Aduhelm and many other experimental treatments are based on it.
The FDA's approval of Aduhelm was defended by leaning on the regulatory-flexibility argument.
An earlier example: Regulators in 2016 approved Exondys 51 from Sarepta Therapeutics (SRPT).
The evidence as to whether the muscular-dystrophy drug provided meaningful clinical benefit to patients was limited. Rather, the company proved it could raise levels of a key protein by a statistically significant amount, although levels were just over 1% of normal.
Multiple officials retired from the FDA in the wake of the decision.
The drugmaker used similar controversial data to earn approval for two similar drugs, Vyondys 53 and Amondys 45. All three muscular dystrophy drugs utilized the regulatory flexibility argument. All three remain on the market.
Another Controversial Decision Ahead
Now, the FDA is nearing an approval decision for a treatment for amyotrophic lateral sclerosis, or ALS, commonly referred to as Lou Gehrig's disease, from Amylyx Pharmaceuticals (AMLX)
If a recent vote from an independent review board is any guide, then approval could be imminent.
Regulators thus seem close to approving another controversial drug candidate based on the regulatory-flexibility argument.
Amylyx Pharmaceuticals is developing AMX0035 to treat ALS, a devastating neurodegenerative disease that's always fatal.
The data submitted for approval are from a Phase 2 clinical trial that wasn't designed to answer important questions doctors have about the drug's safety and efficacy. A larger Phase 3 study is under way but won't be completed until 2024.
The FDA knew the regulatory filing was controversial. In March 2022 it convened an advisory committee meeting to allow independent stakeholders, including patient advocates, to weigh in on the decision. The panel voted 6 to 4 against approval.
Regulators aren't bound by an advisory-committee vote. And at first the FDA decided to do nothing. It delayed an approval decision date from June 29 to Sept. 29. It also made the unusual decision to convene a second advisory committee vote to consider new, albeit still controversial, data. The second panel vote, on Sept. 7, tallied 7-to-2 in favor of approval.
Supporters argue that the experimental drug could potentially extend the lives of ALS patients. Considering that no treatments that affect the disease's progression have been approved, they argue that this is exactly the time for regulatory flexibility.
Critics argue that the life-extension data in the Phase 2 trial were cherry-picked and not compared with a control arm.
They're right, but the dilemma remains. Should the FDA approve a controversial drug ahead of more robust data in 2024? What if the drug proves ineffective?
The FDA Should Resist External Pressures
Amylyx's co-founder and co-chief executive, Justin Klee, has promised to yank the drug from the market if AMX0035 fails the ongoing study. That would be appropriate -- and something regulators could force anyway -- but it does nothing to protect the FDA's credibility or maintain public trust in an important institution.
Giving patients false hope is bad, especially considering the FDA has no power to regulate drug prices. Exondys 51 debuted on the market for $300,000 a year. Aduhelm launched at a price of $56,000 a year.
Ironically, there's tremendous pressure from patient-advocacy groups to approve ineffective drugs. Giving into that pressure again would set a dangerous precedent.
Patient advocates play an important role in drug development by providing important insights to real-world treatment challenges, settings, and concerns.
But these groups increasingly measure their success in drug approvals rather than patient outcomes. That has led to instances where safety and efficacy data are disregarded. Worse, many have conflicts of interest due to close financial ties with the industry.
Patient advocacy groups played a significant role in the approvals of Exondys 51, Vyondys 53, Amondys 45, and Aduhelm. Whether patients are benefitting is unclear, although drug developers certainly are.
Sarepta Therapeutics expects its trio of muscular dystrophy products to generate at least $825 million in full-year 2022 revenue.
Biogen eyed even greater revenue from Aduhelm but ran into fierce pushback from physicians and insurance companies. The initial $56,000 annual price tag was halved after the drug's traction in the market was weak. The drug developer has since nixed one ongoing study altogether and played down the product's significance.
What will happen with Amylyx Pharmaceuticals' experimental ALS treatment? The FDA appears likely to approve the drug candidate, but let's hope the agency learned from the Aduhelm debacle and returns its focus to patient outcomes.
If regulators do allow conditional approval under the guise of regulatory flexibility, then it must issue strict usage and labeling guidelines that properly set expectations for patients and their families.
When more robust data are released in 2024, regulators must act swiftly to communicate the results (including potential successful results) to patients and the ALS community.
