The FDA\u2019s recent approval of the Alzheimer\u2019s drug aducanumab is a crucial crossroads in the continuing search for a cure for this devastating disease.<\/p>\n
Federal regulators approved Biogen\u2019s drug, through an accelerated process, earlier this month. The FDA\u2019s approval came over the objections of its own scientific advisers, who had cited a lack of evidence for the drug\u2019s effectiveness. (Several of those advisers have since resigned.) Patient advocates, on the other hand, welcomed the decision because, to date, there is no treatment that clearly slows down the progression of this disease afflicting 6 million Americans. Health policy experts worried, almost immediately, whether an expensive drug of unproven efficacy would send costs for Medicare and private insurance soaring.<\/p>\n
But beyond the immediate effects of aducanumab alone, there is another question lurking after the FDA\u2019s decision: Will this ultimately lead to more drug development for Alzheimer\u2019s disease \u2014 or less?<\/p>\n
\n
\u201cThere could be big-picture harms for incentivizing drug development for truly innovative treatments,\u201d Stacie Dusetzina, who studies drug pricing at Vanderbilt University, says. \u201cIt isn\u2019t a very good signal for investors and innovators. … Why should they push for something more complicated?\u201d<\/p>\n
Because one thing is clear: The evidence on aducanumab is mixed at best. It may, for some patients, slow the disease down. Experts are urging Biogen or Medicare itself to run more clinical trials to be sure. Either way, this should not be the end of the road in searching for a cure for Alzheimer\u2019s disease. <\/p>\n
Alzheimer\u2019s patient advocates are optimistic that it won\u2019t be. They believe one treatment finally getting FDA approval will encourage drug companies to keep investing in this space. <\/p>\n
A representative for the Alzheimer\u2019s Association offered the example of statins as a promising precedent. Since the first drug in that class was approved, six more statins have been introduced, each one more effective than the first. Likewise, the first HIV drug faced serious doubts about its efficacy, but its FDA approval ended up spurring more investment in that research area \u2014 and, with time, better treatment.<\/p>\n
\u201cWhen people are concerned about risk and whether things can get approved, this says, \u2018No, pursue this. There is a major market here, and you need to enter that market as well,\u2019\u201d Robert Egge, chief public policy officer of the Alzheimer\u2019s Association, told me. \u201cTo stand out, to win market share, you have got to make a business case that your treatment is more effective than the incumbent.\u201d<\/p>\n
He is not alone in that view. Three FDA officials, in a Washington Post op-ed explaining their decision to approve aducanumab, cited the approval of cancer drugs through the same accelerated approval pathway and the effect on subsequent research and development: \u201cEven though not every drug worked as expected, these approvals have propelled progress forward.\u201d<\/p>\n
But there is an opposing view, shared by several experts I spoke to, that aducanumab could lead to less drug development. For one, drug makers may not think it\u2019s worthwhile to invest the time and money to find more effective treatments. Biogen cleared a low bar to get the FDA to sign off on its drug, and now it\u2019s setting the list price at nearly $60,000 a year.<\/p>\n
\u201cMaybe now some companies will see that they can get Alzheimer\u2019s drugs approved, so they will start (or keep) investing in that space,\u201d Holly Fernandez Lynch, who studies drug development at the University of Pennsylvania, told me over email. \u201cMaybe some of their drugs will work. But they will have little incentive to prove that definitively if FDA doesn\u2019t make them.\u201d<\/p>\n
On top of that, a lot of Alzheimer\u2019s patients \u2014 millions, maybe \u2014 could now be prescribed aducanumab. Patients understandably take FDA approval to be a sign that a drug works and so, believing now that Biogen\u2019s drug does, they could be reluctant to participate in future trials, whether confirmatory trials for this drug (in which case they risk being randomized to a placebo) or for different, unproven treatments.<\/p>\n
\u201cIf you want to do a trial of different drugs, all your patients are still going to want aducanumab. So you have to start testing different drugs against it or in addition to it,\u201d Lynch Fernandez says. \u201cThat\u2019s going to make it a hell of a lot harder to tell if the new drugs work. There is a lot of negative potential when FDA lowers its standards.\u201d<\/p>\n
This is not a new concern. Three Penn researchers wrote about the same problem in 2019, warning that the FDA\u2019s use of the accelerated approval pathway (the same process used to okay aducanumab) for cancer drugs could dampen future innovation. <\/p>\n
They cited data showing that the FDA often does not force companies to complete the additional trials meant to confirm a drug\u2019s efficacy. And even for those trials that are completed, they frequently find the approved drugs do not have a clinical benefit. On the issue of future innovation, the authors wrote:<\/p>\n
\nApproval of ineffective drugs also crowds out innovation that might produce effective treatment. Once a drug has been approved for a certain indication, other companies and researchers might not invest resources in treatments related to the condition, believing that there is no market.<\/p>\n<\/blockquote>\n
This is partly a result of how US insurers cover prescription drugs, which is generally not <\/em>based on the value that the medication actually provides. Medicare generally covers any FDA-approved drug (though some experts are urging it to restrict or deny access for the Biogen drug, given the clinical record) and has few tools to limit the price it pays. Private insurers, on the other hand, will sometimes enter into arrangements with drug makers that give the insurer a financial incentive not to cover or to limit coverage for future drugs from the same class.<\/p>\n
\u201cThe risk … is that the first drug to market can block downstream innovation,\u201d Robin Feldman, who studies innovation law at the University of California Hastings, told me. \u201cThis can be particularly problematic if the first-to-market drug is sub-optimal.\u201d<\/p>\n
There is one final complicating factor: The science upon which Biogen\u2019s drug is based, known as the amyloid hypothesis, is still very much in dispute. It holds that plaque in the brain found in Alzheimer\u2019s patients is in part responsible for the disease and that therefore removing plaque could help relieve the symptoms.<\/p>\n
As recently as two years ago, when Biogen had halted its clinical trials for aducanumab because of poor evidence, scientists were questioning whether the amyloid hypothesis had been wrong, given how much time had passed without an effective treatment being found. <\/p>\n
The question now following aducanumab\u2019s approval, as Rachel Sachs at Washington University in St. Louis told me, is \u201cwhether the amyloid hypothesis is now being revived and more companies will be investing there, rather than in other hypotheses.\u201d<\/p>\n
It is possible to imagine a future in which companies do invest more in Alzheimer\u2019s research after the FDA\u2019s decision \u2014 but end up going all-in on a hypothesis that turns out to be wrong. Or the aducanumab approval could be the first step through a door that leads to a very effective treatment. <\/p>\n
For now, no one can be sure which path we\u2019re on.<\/p>\n