Why The FDA's Approval Of A New Alzheimer's Drug Should Worry You

You might expect Mariah Robertson to applaud last week’s approval of a new drug for Alzheimer’s disease. The 38-year-old Johns Hopkins University physician has seen the toll it takes on her patients, as well as on her own mother, Nancy Dreisinger, who was diagnosed with it at age 57.

Dreisinger, who was a senior officer at the local bank, started forgetting the details of projects and showing up late to meetings, straining relationships with co-workers and friends. Later, she lost motor skills and the ability to perform daily tasks ― which was especially painful to watch, Robertson told HuffPost, because her mom took such pride in her self-reliance. “She was so dynamic and so brilliant and so hardworking.”

Once Dreisinger required round-the-clock care, Robertson, then in her 20s, helped provide it while juggling graduate studies in public health. By the time Dreisinger died in 2012, Robertson had enrolled in medical school in order to become a doctor.

“I wanted to understand the medical side of it,” she said, and “change the way we care for people who are experiencing dementia, and also their caregivers and their families.”

Aduhelm, the new Biogen drug that got clearance from the U.S. Food and Drug Administration (FDA) last week, is supposed to offer that kind of change. It’s the first federally approved drug that seeks to slow the underlying biological process of Alzheimer’s rather than simply mitigate symptoms.

Nobody thinks it’s a cure, but advocates say it can stall disease progression and maybe be the first in a series of new treatments that will turn Alzheimer’s into a manageable chronic condition.

Robertson takes a very different view. She says the scientific evidence comes nowhere close to justifying the claims on the drug’s behalf, let alone the $56,000 Biogen plans to charge for a year’s worth of treatment.

She is thinking about her patients, she said, but also about herself, because the kind of early-onset Alzheimer’s that Dreisinger suffered is thought to have a genetic component.

“I would be lying if I said I didn’t always think about the potential that I will acquire dementia someday,” said Robertson. “I want this to be the treatment. I want this to work. I want the medicine that might help slow down my progression of dementia in the future. I want it for my patients who are suffering so much. ... But this isn’t it.”

Robertson’s sentiments are not unusual. Scientists across the country have expressed dismay over the FDA’s decision and the process that led to it, including the agency’s willingness to ignore the advice of an outside advisory committee that voted almost unanimously against approval. Three members of that committee have since resigned in protest, with one, Harvard Medical School Professor Aaron Kesselheim, calling the FDA decision “probably the worst drug approval … in recent U.S. history.”

Aduhelm is not the first drug to generate such controversy. But it may prove to be the most financially consequential, given the price and number of Americans who could end up taking it. That, in turn, could reshape ongoing political debates over whether to reform the FDA itself and whether to enact legislation that would force down the price of prescription drugs.

The common thread linking those debates is a long-running argument over whether giving the government more sway over the pharmaceutical industry will dampen innovation. The answer, according to a variety of political conservatives and industry advocates, is yes ― that holding drug approvals to higher standards or restricting manufacturers’ ability to set prices will lead to fewer medical breakthroughs.

If Aduhelm’s critics are correct, its story may end up demonstrating why that argument is flawed. The FDA’s decision could actually steer future research in less productive directions, prolonging the wait for a successful treatment, while simultaneously making it harder to fund programs that Alzheimer’s patients and their families need.

In short, it could mean more suffering rather than less.

A Sticky Problem

Aduhelm seeks to slow the progress of Alzheimer’s by attacking so-called amyloid proteins that accumulate in patients’ brains. These “sticky” proteins have been an object of scientific inquiry ever since the early 1900s, when the German psychiatrist Alois Alzheimer first saw them in the autopsy of a woman he had been treating after she developed dementia while still in her 50s.

More than a hundred years later, exactly what role amyloid proteins play in Alzheimer’s remains unclear. One theory is that, as they form clumps or “plaques,” they somehow prevent the transmission of chemical signals among cells, interfering with the thinking and memory processes. It’s also possible amyloid plaques damage the brain by causing inflammation or by hindering blood flow that supplies oxygen.

The hope has been that reducing or preventing the plaques can stall the disease. And “hope” is the right word. Pharmaceutical companies have now tried this with more than a dozen drugs, refining the approach with each successive attempt. Each one failed to produce clear, significant improvement.

Interim results from a pair of large Aduhelm trials suggested it was no different. Although the drug was clearing out amyloid plaques, it wasn’t producing significant clinical benefits, and Biogen ended the studies. But when company researchers went back over the data, including three months of late results that weren’t part of earlier analyses, they found better outcomes in a group within one of the two trials.

“Better” is a relative term. Patients in that group, all of whom had gotten the highest doses of medication, were still losing cognitive and intellectual abilities. They just weren’t losing them as quickly as those who had gotten the placebo. And the difference was less than what researchers or the FDA would typically consider clinically meaningful.

On top of that, the difference hadn’t shown up in the parallel study. Biogen researchers argued that with more analysis and culling of data, it was possible to see signs of the positive effects in that other trial, too. But that kind of after-the-fact reasoning made many outside experts even more skeptical.

Among them were members of that FDA outside advisory panel, including University of Washington biostatistician Scott Emerson. At a public hearing about the drug, he likened the company’s argument to “someone first firing a shotgun at a barn and then painting a target around the bullet holes.”

In the end, 10 of 11 members sitting on the FDA’s outside advisory committee recommended against approval, with the eleventh abstaining.

The FDA’s Great Departure

The FDA’s decision to ignore that outside recommendation was unusual. It does that only about one-fifth of the time, and almost never in the face of such an overwhelming vote against approval.

It also happened in an unusual way. To justify its decision, the FDA recognized the weak evidence of clinical benefits and cited, instead, Aduhelm’s ability to reduce amyloid plaques. In making that judgment, the agency was relying on its authority to offer “accelerated approval” for treatments when a drug’s proven biological effect “is reasonably likely to predict clinical benefit.”

The original impetus for giving the agency that power was the experience with early HIV treatments, which were understood to reduce viral load before they were shown to deter the opportunistic infections associated with AIDS. Since then, the FDA has used the authority frequently to approve cancer drugs based primarily on their ability to reduce tumor size.

But many of those drugs have since proven ineffective at changing outcomes. Scientists working on Alzheimer’s think the same thing could happen with Aduhelm ― in part because scientists aren’t sure that getting rid of the plaques will really alter the disease’s course.

Among the reasons for doubt, according to Donovan Maust, a University of Michigan geriatric psychiatrist who treats Alzheimer’s patients, is that scientists still aren’t sure reducing plaques will actually affect the deterioration of mental skills.

“In studies where people get regular cognitive testing and then you look at the brains at autopsy, the amount of sticky protein does not closely correlate with their cognitive performance,” Maust said.

The FDA’s willingness to endorse Aduhelm anyway has some critics wondering about the agency’s reliability, especially because FDA scientists worked closely with Biogen throughout the process. The watchdog group Public Citizen has called for an investigation, blasting what it called an “inappropriate close collaboration with Biogen.”

At the public hearing over the drug’s application, the FDA official in charge of the neuroscience division “was overwhelmingly positive in a way that we’ve never simply never seen before,” according to one biotech analyst who watched the proceedings and was quoted in the trade publication Endpoints.

Cooperation between industry and the agencies regulating them is common nowadays. It’s supposed to make the approval process less cumbersome and inscrutable. But many experts have long called for measures to put more distance between the FDA and drug manufacturers, precisely because they worry it makes the agency too eager to approve questionable drugs.

In the meantime, the Aduhelm decision could set a precedent for how the FDA approaches other treatments ― an “enormously risky move,” as STAT writer Matthew Herper put it, “that could accelerate the public’s access to medicines but upend the future of drug regulation, forcing the 114-year-old agency to do the equivalent of redesigning a fighter plane in mid-flight.”

The Patients And Their Advocates

Aduhelm has some strong advocates, too. None may be as visible or influential as the Alzheimer’s Association, a massive organization that provides direct assistance to families and lobbies Congress to spend more on research and support.

Maria Carrillo, the association’s chief science officer, laid out the case for the drug in an interview with HuffPost. She suggested it could draw yet more money into drug development. She also talked about the significance of a seemingly small improvement in symptoms or a short delay in their onset.

“I remember when my mother-in-law had early dementia, before she transferred into moderate, and what that meant for our family,” Carrillo said, relating her own firsthand experience just as Robertson had. “Once you get into moderate, you’re talking 24-hour care and a much heavier burden on the family. … Can you push that back three, six months, a year? That’s precious time.”

A big focus for the association has been showcasing patients’ perspectives, which it says critical scientists like those on the FDA’s advisory committee don’t always appreciate.

Among its more visible efforts was a public relations campaign this year touting the value of “more time” that included tweets from celebrities like the actor Samuel L. Jackson. And in response to independent assessment questioning Aduhelm’s value, the association wrote in a public letter that it could “add weeks, months, or even years of active life for those affected every day by the crushing realities of Alzheimer’s.”

But those kinds of statements alarm critical experts like Jason Karlawish, a University of Pennsylvania professor of psychiatry and author of a new book, “The Problem of Alzheimer’s.”

“The results of studies of aducanumab don’t allow reasonable conclusions about the count of days of active life a person living with Alzheimer’s disease will receive from taking the drug,” he said.

Maust, the University of Michigan professor, had a similar reaction when he heard the association’s claim: “It ... unrealistically inflates expectations of people who are desperate ― potentially increasing demand for the treatment, but then also setting people up to be incredibly disappointed when these unrealistic expectations are inevitably not met.”

Other experts are more supportive ― among them, health economists Dana Goldman and Darius Lakdawalla from the Schaeffer Center for Health Policy and Economics at the University of Southern California, who wrote in an op-ed for STAT that “every week symptoms are delayed is a psychic and financial blessing.”

But, as they noted, they have both served as consultants to Biogen, potentially giving them a financial incentive to tout the drug.

Possible financial interest in the drug’s success has also become an issue for the Alzheimer’s Association. Like many disease advocacy groups, it receives support from the drug industry, including from Biogen.

Harry Johns, the association’s president and CEO, said in response to questions about these donations, “No contribution from any company, entity or individual impacts Alzheimer’s Association decision-making, nor our positions on issues related to people living with Alzheimer’s, other dementia and their families. We act solely based on the science and the needs of our constituents.”

The Mind-Boggling Costs

Even a small chance of mild improvement might seem like reason enough to approve a drug for a disease as awful as Alzheimer’s. But like all medications, Aduhelm has potentially dangerous side effects, including brain swelling. Doctors administering the drug during the trials watched for that aggressively using brain scans. One concern is that clinicians outside of academic settings will be less attentive.

And then there is the drug’s financial cost. Rather than approving the drug strictly for people in earlier phases of the disease, which is what Biogen studied and when scientific theory would predict it has the best chance of impact, the FDA approved it for all Alzheimer’s patients. That’s nearly 6 million people, most of them elderly and on Medicare.

It makes the financial impact of Aduhelm approval mind-boggling, even if you’re the type of person who has followed these debates for years and long ago became jaded about high drug prices. Annual Medicare spending on the treatment could top $100 billion, dwarfing the $39 billion it now spends on all similarly infused drugs.

Aduhelm will also strain state governments because the Medicaid programs they run will pick up part of the costs through coverage of low-income Alzheimer’s patients, including seniors on Medicare who use Medicaid as a supplement. Unlike the federal government, states cannot deficit spend, so even a modest responsibility for such an expensive drug could cause financial problems.

And the part of the Aduhelm bill that doesn’t put a claim on federal or state treasuries will impose costs on private insurers and consumers in the form of higher premiums or out-of-pocket costs.

The dollars that governments and individuals spend on Aduhelm are dollars they won’t be able to spend elsewhere. And that’s another reason so many experts and clinicians are angry about the approval.

As it is, patients and families struggle to pay for the support that people with Alzheimer’s need ― starting with the cost of direct caregivers, whether in homes or in group settings. The inability to pay for these things cascades through the system, resulting in underpaid caregivers and understaffed facilities, all of which lead to more patient suffering.

Biogen, whose stock soared on the announcement of FDA approval, said in a statement to HuffPost that “we believe the price of Aduhelm is substantiated by the value it is expected to bring to patients, caregivers, and society.” It also reiterated its pledge to work collaboratively with government agencies to alleviate the drug’s financial strain on both individuals and society as a whole.

The likely result will be a combination of discounts and special charity programs, similar to the programs that drug companies run for high-priced drugs to treat cancer and other ailments. But typically, those efforts do more to shift spending than to reduce it. And they don’t cover associated costs like brain scans to check for swelling.

As Rachel Sachs, a law professor at Washington University in St. Louis and top expert on drug pricing, wrote this week in the journal Health Affairs, “the potential financial implications for our health care system are staggering.”

The Debate In Washington

In other developed countries, governments decide whether a drug is safe and effective ― and, then, how much the drug should cost. In some places, like France, Taiwan and the U.K., independent agencies make recommendations about price based on a variety of factors, like how new therapies compare to existing ones and just how much benefit they actually provide.

The closest thing to that in the U.S. is an independent nonprofit organization called the Institute for Clinical Effectiveness Research, which conducts such analyses on its own. When ICER looked at Aduhlem, it concluded that a year’s worth of therapy should cost no more than $8,300 per patient ― in other words, one-seventh of what Biogen plans to charge.

The federal government can’t do anything about that, because, unlike its foreign counterparts, it has no mechanism for direct negotiation of prices. Changing that has been a cause of reformers going back to the 1990s. But it has mostly been a campaign of futility, thanks in part to advocacy and lobbying from the pharmaceutical industry, which is among Washington’s most powerful groups.

President Joe Biden and Democratic leaders in both houses have said they want to enact some kind of legislation giving the government more power, perhaps based on a 2019 bill that House Democrats passed. But it’s not clear whether House Democrats can pass a new version of the same bill now, because their majority is much smaller. Getting votes in the Senate promises to be even harder, given that Democrats have just 50 votes, the bare minimum it would take to pass legislation.

The news about Aduhelm could push the cause forward. Among those attacking Biogen’s proposed price as “unconscionable” was Sen. Ron Wyden (D-Ore.), chairman of the Senate Finance Committee. Similar dynamics have played out before, most memorably, when a surprise premium hike from a California health insurer helped Democratic leaders really support that they needed to pass the Affordable Care Act in 2010.

But Aduhelm is set to hit the market within a month ― long before legislation can pass, let alone take effect. For now, the federal government’s most effective tool to control what Medicare spends may be to issue what’s known as a “national coverage determination,” limiting the circumstances in which it paid for the treatment. That could mean, for example, covering the drug only for patients in the early stages of the disease.

The agency that runs Medicare has made such decisions before, though rarely for pharmaceutical products. It would surely disappoint many patients and families who are now hoping for the drug and just as surely create a political backlash, with Republicans accusing the Biden administration of rationing life-altering treatment in a preview of how they imagine a government takeover destroying American health care.

The Real Effect On Research

Behind the cartoonish “death panel” version of that argument is a more serious claim that more FDA scrutiny or more government leverage over prices will discourage drug companies from making the inherently risky research investments that breakthroughs require.

The precise relationship between drug company profits and innovation is a subject advocates and experts have been arguing over for decades, and about which reasonable people can disagree. But critics of the Aduhelm decision worry that drug companies now have less reason to sweat out whether experimental Alzheimer’s products show meaningful clinical progress.

“You’re going to have all sorts of companies asking to be treated the same way as Biogen, under the same rules and using the same surrogate, bringing ever more expensive therapies to market,” said Joseph Ross, a Yale professor of medicine and public health who specializes in the drug regulatory process. “You’re going to get a whole bunch of ineffective, ‘me too’ drugs that aren’t going to improve the lives of our patients.”

Karlawish agrees. “The FDA has now lowered the bar for what it takes to put a drug into practice. That’s not a good thing for my patients, their families, and added up across the millions who have the disease, that’s not a good thing for society.”

As an example, Karlawish pointed to another Alzheimer’s drug in development, this one from Eli Lilly, that had some promising early results but whose ultimate clinical effects remain unknown. “It’s very interesting data … I cannot wait to see what more trials show. But given what the FDA just did, an awful rhetorical question looms: Why not just approve it tomorrow?”

Going forward, the best-case scenario is probably that reducing amyloid plaques has the effect that Aduhelm proponents hope ― and that, with improvements, such treatments can stop disease progression by acting on their own or (more likely) in combination with other therapies, much as the HIV “cocktail” of multiple drugs now works.

But many scientists worry that the intense focus on amyloid protein has distracted researchers from other theories of the disease that need more study. With the FDA’s decision, drug companies now have less financial incentive to pursue those approaches.

One way to help settle those ongoing arguments on the drug’s effectiveness would be to get a fuller understanding of it ― which, in theory, Biogen is now going to do. A condition of the FDA’s approval was that the company conduct another randomized and controlled trial to establish more clearly whether the improvement from the one subgroup was real. This is a standard requirement for accelerated approvals.

But shortly after FDA announced approval, Biogen’s CEO said he thought the follow-up trials could take nine years to complete. And even that might be wishful thinking. Drugmakers frequently fail to meet requirements for confirmatory experiments ― in part because recruiting people for studies gets a lot harder when a drug is available.

“The sad thing is that one more study of aducanumab could have told us answers to the question [over the precise role of amyloid] because clinical studies are one of the best ways to validate causal mechanisms,” Karlawish said. “Together, FDA and Biogen blew it.”

Robertson agrees and said she isn’t looking forward to the conversations that await. Biogen has said Aduhelm will soon be available in 900 facilities around the country. This week, she starts a new position as an assistant professor at Johns Hopkins and knows that patients will be asking for the drug.

She plans to tell them what she thinks about it, even though she doesn’t relish deflating their hopes ― and even though she believes science really will find a way to fight Alzheimer’s. She just doesn’t think it’s happened yet.

CORRECTION: An earlier version of this story misidentified Dana Goldman and Darius Lakdawalla as clinicians.