Why is the FDA’s approval of aducanumab so controversial?
Interview by Carly Kempler and Lindsay Smith Rogers
In a highly anticipated decision, on June 7 the U.S. Food and Drug Administration approved aducanumab (brand name Aduhelm), the first novel therapy for Alzheimer’s in nearly 20 years.
The approval has sparked controversy among experts who say we need to balance the need for new Alzheimer’s treatments with sufficient scientific evidence to back the therapy. In this Q&A, G. Caleb Alexander, MD, MS, an internist and drug safety and effectiveness expert, discusses the science behind the new drug Aduhelm and the far-reaching implications of the FDA’s recent approval. Alexander, a professor in Epidemiology at the Bloomberg School, served on an FDA advisory committee that evaluated aducanumab.
Set the scene for us: What is aducanumab and what does it do?
Aducanumab is a monoclonal antibody that targets a protein in the brain, beta-amyloid, implicated in the pathogenesis of Alzheimer’s disease.It is one of more than two dozen experimental treatments that have been developed based on the “amyloid cascade hypothesis,” namely, that the symptoms of Alzheimer’s disease can be slowed or stopped by decreasing amyloid levels in the brain. However, no prior products have been convincingly demonstrated to work, and in the case of aducanumab, many questions remain.
Are there other similar Alzheimer’s drugs currently on the market?
No, aducanumab, or Aduhelm, is what is considered a “first in class” drug that acts through a new molecular mechanism. But it is hardly the first experimental product that has been tested in an effort to decrease beta-amyloid levels in the brain.
The FDA’s approval drew scrutiny—who is on the critical end of this and why?
There have been lots of surprises along the way with this product, and there are an unusual number of scientific and regulatory concerns.
The evidence has always been murky regarding whether or not the product is safe and effective, and during the course of drug development, the manufacturer conducted two large, similarly designed trials that yielded conflicting results.
Even in the one study that was partly successful, aducanumab’s effect on slowing disease progression was very modest, one of many concerns of an FDA advisory committee that nearly unanimously concluded that the evidence for the product was not persuasive.
Ultimately, rather than approving the product on the basis of this conflicting evidence, the FDA approved it using its “accelerated pathway,” which allows for product approval based on a surrogate outcome, in this case, beta-amyloid reduction.
However, it is far from clear that reducing beta-amyloid will correspond with clinical improvements in the things that people care about: memory, language, cognition. Many other failed products have been demonstrated to reduce beta-amyloid levels in the brain without any improvement in these symptoms of Alzheimer’s disease. And even the data from aducanumab’s failed trial call into question this association. Adding to many people’s surprise, the FDA did not restrict its approval to individuals with mild disease and confirmation of elevated beta-amyloid levels, even though the trials that aducanumab’s developer, Biogen, conducted exclusively enrolled these individuals
Is the drug fully approved, or will more studies need to be conducted before the drug can roll out?
Aducanumab is fully approved, although the FDA has mandated that the manufacturer perform a “confirmatory trial” to demonstrate that the drug doesn’t just lower individuals’ beta-amyloid levels, but also that it improves their clinical symptoms. Yet there is another surprise: Biogen reports this confirmatory trial may not be completed until 2030. This is a long time for caregivers, patients, and providers to wait and see if the product is safe and effective.
What are those in the Alzheimer’s community—patients, caregivers, clinicians—saying?
Millions of Americans and their loved ones are impacted by Alzheimer’s disease. It is a relatively common and often devastating disease, and thus there is an enormous unmet need and demand for new treatments.
Some patients and caregivers, as well as patient advocacy organizations, have embraced this approval. Others are more skeptical.
The key thing to keep in mind is that patients and their caregivers deserve products that work and that we can have confidence in. Our regulatory system is respected worldwide for the work it does, day in and day out, to ensure the safety and effectiveness of our prescription drugs.
Has there been any pushback on the drug’s estimated cost?
The manufacturer has indicated an annual price of $56,000, while the Institute for Clinical and Economic Review, a nonprofit think tank, has done a careful analysis of the evidence to date and estimates a value-based price of the drug between $2,500 and $8,300 per year.
There is simply no way to square these estimates. In addition to the costs of the drug, there will be many other costs as well, ranging from the infusion costs to costs associated with MRI monitoring, as well as providing care for individuals who may experience adverse events from the drug.
Why is this FDA approval significant and what are its implications for future Alzheimer’s research?
This is the most consequential drug approval in modern regulatory history. Regulatory actions such as this signal to drug developers, investors, and other stakeholders the FDA’s expectations for evidence before new experimental treatments are brought to market. Many drug developers have been watching these events closely, and the approval may stimulate reinvestment in treatments based on their ability to lower brain amyloid levels.
Some have questioned whether this marks a fundamental inflection point and lowering of the “evidence bar” FDA requires for market access, whether for Alzheimer’s or other diseases. I think it's too early too tell.
Aducanumab’s approval may have many other ripple effects as well, including making it harder to study potential breakthroughs for Alzheimer’s by decreasing patient interest or eligibility to participate in new clinical studies. After all, patients may have less interest in studies of new experimental treatments if there is an FDA approved treatment that they believe is safe and effective. Also, aducanumab has side effects such as brain swelling that might lead researchers to disallow individuals taking it to participate in studies of new investigational products.
What could happen next?
There are a lot of chapters that have yet to be written. The general public deserves visibility of additional information regarding aducanumab’s development that the manufacturer or FDA may have, including complete information about the two conflicting pivotal trials, as well as the decision-making process that led to approval using an accelerated pathway.
It’s also important that a well-designed, placebo-controlled, double-blinded clinical trial is performed, far sooner than 2030.
Have there been other drugs—not for Alzheimer’s—that got this sort of reception after FDA approval, and what ultimately happened? In other words, is there a similar story out there?
No, this is a once-in-a-century event. FDA decision-makers always have to combine facts with judgments, and this was clearly a case where the FDA was bound to be criticized regardless of what they decided.
With that said, rarely have the stakes been so high, and it is also unusual for the FDA to diverge so markedly from the recommendations of its scientific advisers. Aducanumab’s approval based on its amyloid-lowering abilities is a bet, and unfortunately we will have to wait for some time to learn whether or not this product is truly safe and effective.
G. Caleb Alexander, MD, is a professor in Epidemiology with a joint appointment at the School of Medicine. He is the founding co-director of the Center for Drug Safety and Effectiveness.
Carly Kempler is the media and audience engagement specialist for the Johns Hopkins Bloomberg School of Public Health.
Lindsay Smith Rogers, MA, is the producer of the Public Health On Call podcast and the associate director of content strategy for the Johns Hopkins Bloomberg School of Public Health.
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