The recent FDA approval of the Alzheimer's drug aducanumab marks a major crossroads in the ongoing quest for a cure for this devastating disease.
Federal agencies approved Biogen's drug earlier this month on an expedited basis. The FDA's approval came because of objections from their own scientific advisors, who cited a lack of evidence that the drug was effective. (Some of these counselors have since resigned.) Patient advocates, however, welcomed the decision as there is no treatment to date that significantly slows the progression of this disease, which affects 6 million Americans. Health policy experts worried almost immediately whether an expensive drug with unproven effectiveness would drive up Medicare and private insurance costs.
But beyond the immediate effects of aducanumab alone, another question lurks after the FDA's decision: Will this ultimately lead to more drug development for Alzheimer's disease – or less?
"If drug development is incentivized for truly innovative treatments, the damage could be far-reaching," says Stacie Dusetzina, who studies drug pricing at Vanderbilt University. “It's not a very good signal for investors and innovators. … Why should you push for something more complicated? "
Because one thing is clear: the evidence on aducanumab is mixed at best. It can slow the disease down in some patients. Experts are pushing Biogen or Medicare themselves to do more clinical trials just to be sure. In any case, it shouldn't end your quest for a cure for Alzheimer's disease.
Alzheimer's patient advocates are optimistic that it won't. They believe that a treatment that finally gets FDA approval will encourage drug companies to keep investing in this area.
A representative of the Alzheimer's Society cited the example of statins as a promising precedent. Since the first drug in its class was approved, six more statins have been introduced, each more effective than the first. Likewise, the first HIV drug faced serious doubts as to its effectiveness, but its FDA approval led to more investment in this area of research – and, over time, better treatment.
“When people are concerned about risks and whether things can be approved, they say, 'No, keep doing this. There is a big market here, and you have to get into that market too, ”said Robert Egge, chief public policy officer of the Alzheimer's Association. "In order to stand out from the crowd and gain market share, you have to make a business case that your treatment is more effective than that of the established provider."
He is not alone in this view. Three FDA officials quoted in a Washington Post comment explaining their decision to approve aducanumab, the approval of cancer drugs through the same expedited route, and the implications for subsequent research and development: “Although not every drug worked as expected , Approvals have driven progress. "
However, there is an opposing opinion shared by several experts I spoke to that aducanumab could lead to less drug development. For one thing, drug manufacturers may not think that it is worth investing time and money into finding more effective treatments. Biogen set a low bar to get the FDA to sign its drug, and now sets the list price at nearly $ 60,000 a year.
"Maybe now some companies will see they can get Alzheimer's drugs approved, so they'll start (or keep investing) in that area," said Holly Fernandez Lynch, who is studying drug development at the University of Pennsylvania, via email. “Maybe some of your drugs will work. But they will have little incentive to definitively prove it if the FDA doesn't make them. "
In addition, many Alzheimer's patients – perhaps millions – could now be prescribed aducanumab. Patients understandably view FDA approval as a sign that a drug is working. Now, if they believe that Biogen's drug will do so, they may be reluctant to participate in future studies, whether confirmatory studies for that drug (in which case they risk being assigned a placebo). ) or for other, unproven treatments.
“If you want to do a study with different drugs, all of your patients will still want aducanumab. So you have to start testing different drugs against it or in addition, ”says Lynch Fernandez. “That'll make it a hell of a lot harder to tell if the new drugs are working. There is a lot of negative potential for the FDA to lower its standards. "
This is not a new concern. Three Penn researchers wrote about the same issue in 2019, warning that using the accelerated pathway (the same process used to approve aducanumab by the FDA) for cancer drugs could dampen future innovation.
They cited data showing that often the FDA does not force companies to complete the additional studies designed to confirm a drug's effectiveness. And even with completed studies, they often find that the approved drugs have no clinical benefit. On the subject of future innovation, the authors wrote:
Approval of ineffective drugs also crowds out innovations that could lead to effective treatment. Once a drug is approved for a specific indication, other companies and researchers may not invest resources in treatments related to the condition because they believe there is no market.
This is in part because of how US insurers cover prescription drugs, which are generally not based on the value that the drug actually offers. Medicare generally covers every FDA-cleared drug (although some experts call for access to the Biogen drug to be restricted or denied based on clinical records) and has few tools to cap its price. Private insurers, on the other hand, sometimes make agreements with drug manufacturers that give the insurer a financial incentive not to insure future drugs of the same class or to limit insurance coverage.
"The risk … is that the first drug to hit the market can block downstream innovation," said Robin Feldman, who studies innovation law at the University of California Hastings. "This can be especially problematic if the first drug on the market is not optimal."
To make matters worse, there is one last factor: the science on which Biogen's drug is based, the so-called amyloid hypothesis, is still very controversial. It states that plaque in the brains of Alzheimer's patients is partly responsible for the disease and therefore removing plaque could help relieve symptoms.
Just two years ago, when Biogen stopped clinical trials of aducanumab because of a lack of evidence, scientists wondered if the amyloid hypothesis was wrong, given how much time had passed without an effective treatment being found.
Now that aducanumab has been approved, I wonder, as Rachel Sachs of Washington University in St. Louis told me, "whether the amyloid hypothesis will be revived and more companies will invest there than in other hypotheses."
One can imagine a future in which companies will invest more in Alzheimer's research after the FDA's decision – but end up going all-in with a hypothesis that turns out to be false. Or aducanumab approval could be the first step through a door leading to very effective treatment.
For now, nobody can be sure which way we are going.