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Why Should You Be Concerned About The FDA's Approval Of A New Alzheimer's Drug
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Why Should You Be Concerned About The FDA's Approval Of A New Alzheimer's Drug


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

Dreisinger, a senior officer at a local bank, began forgetting project details and arriving late to meetings, straining relationships with coworkers and friends. Later, she lost motor skills and the ability to perform daily tasks, which was especially painful to watch, Robertson told Stardia, because her mother took pride in her independence.

When Dreisinger needed 24-hour care, Robertson, then in her twenties, assisted in providing it while also juggling graduate studies in public health. By the time Dreisinger died in 2012, Robertson had enrolled in medical school to become a doctor.

“I wanted to understand the medical side of it,” she explained, and “change the way we care for people suffering from dementia, as well as their caregivers and families.”

Aduhelm, a new Biogen drug approved by the U.S. Food and Drug Administration (FDA) last week, is intended to provide that kind of change; it is the first FDA-approved drug that seeks to slow the underlying biological process of Alzheimer's rather than simply alleviate symptoms.

Nobody believes it is a cure, but supporters believe it can slow disease progression and may be the first in a series of new treatments that will make Alzheimer's a manageable chronic condition.

Robertson, on the other hand, believes that the scientific evidence is insufficient to support the drug's claims, let alone the $56,000 Biogen plans to charge for a year's worth of treatment.

She is concerned for her patients, but also for herself, because Dreisinger's type of early-onset Alzheimer's is thought to have a genetic component.

“I would be lying if I said I didn’t constantly consider the possibility of acquiring dementia someday,” Robertson said. “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.”

Scientists across the country have been outraged by the FDA's decision and the process that led to it, including the agency's willingness to disregard 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 Kessler, resigning in protest.

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

The common thread connecting those debates is a long-running debate about 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 result in fewer medical breakthroughs.

If Aduhelm's critics are correct, his story may end up demonstrating why that argument is flawed. The FDA's decision may actually steer future research in less productive directions, lengthening the wait for a successful treatment while making it more difficult to fund programs that Alzheimer's patients and their families require.

In short, it may result in more rather than less suffering.

A Perplexing Issue

Aduhelm aims to slow the progression of Alzheimer's disease by attacking amyloid proteins that build up in patients' brains. These "sticky" proteins have been the subject of scientific investigation since the early 1900s, when German psychiatrist Alois Alzheimer discovered them in the autopsy of a woman he was treating after she developed dementia while still in her 50s.

More than a century later, it is still unclear what role amyloid proteins play in Alzheimer's disease. One theory is that as they form clumps or "plaques," they somehow prevent the transmission of chemical signals among cells, interfering with thinking and memory processes. It is also possible that amyloid plaques harm the brain by causing inflammation or by obstructing blood flow that supplies oedema.

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The hope has been that reducing or preventing plaques can halt 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, but none have produced clear, significant improvement.

I want this to be the treatment. I want it to work. I want the medicine that will help slow my dementia progression in the future.... But this isn't it.

Mariah Robertson is a Johns Hopkins University assistant professor of medicine.

Although the drug was clearing out amyloid plaques, it wasn't producing significant clinical benefits, and Biogen terminated the studies. However, when company researchers went back over the data, including three months of late results that weren't included in earlier analyses, they discovered better outcomes in a group within one of the studies.

Patients in that group, all of whom received the highest doses of medication, were still losing cognitive and intellectual abilities; they just weren't losing them as quickly as those who received the placebo, and the difference was less than what researchers or the FDA would typically consider clinically meaningful.

Furthermore, the difference had not been seen in the parallel study. Biogen researchers argued that with more data analysis and culling, it was possible to see signs of the positive effects in that other trial as well, but that kind of post-hoc reasoning made many outside experts even more skeptical.

Members of the FDA's outside advisory panel were among them, including University of Washington biostatistician Scott Emerson, who likened the company's argument to "firing a shotgun at a barn and then painting a target around the bullet holes" during a public hearing on the drug.

In the end, ten of the eleven members of the FDA's outside advisory committee recommended against approval, with the eleventh voting against it.

The Big Departure of the FDA

The FDA's decision to disregard that outside recommendation was unusual; it does so only about one-fifth of the time, and almost never in the face of such a large number of people voting against approval.

It also happened in an unusual way: to justify its decision, the FDA acknowledged the lack of clinical benefit evidence and instead cited Aduhelm's ability to reduce amyloid plaques. In making that determination, the FDA relied on its authority to grant "accelerated approval" for treatments when a drug's proven biological effect "is reasonably likely to predict clinical benefit."

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, was the original impetus for granting the agency that power. Since then, the FDA has frequently used the authority to approve cancer drugs based primarily on their ability to reduce tumor size.

Many of those drugs, however, have since been shown to be ineffective at changing outcomes, and scientists working on Alzheimer's believe the same could happen with Aduhelm, in part because scientists aren't sure that removing the plaques will actually change the course of the disease.

According to Donovan Maust, a geriatric psychiatrist at the University of Michigan who treats Alzheimer's patients, one of the reasons for skepticism is that scientists are still unsure whether reducing plaques will actually slow the deterioration of mental skills.

“In studies where people receive regular cognitive testing and then have their brains autopsied, the amount of sticky protein does not closely correlate with their cognitive performance,” Maust explained.

You're talking about 24-hour care and a much heavier burden on the family... Can you push that back three, six, or a year? That's valuable time.

The Alzheimer's Association's chief science officer, Maria Carrillo

The FDA's willingness to endorse Aduhelm despite this has some critics questioning the agency's dependability, especially given that FDA scientists collaborated closely with Biogen throughout the process. The watchdog group Public Citizen has called for an investigation, blasting what it calls an "inappropriate close collaboration with Biogen."

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

Cooperation between industry and the regulatory agencies is common nowadays, and it is intended to make the approval process less cumbersome and opaque. However, many experts have long advocated for measures to put more distance between the FDA and drug manufacturers, precisely because they are concerned that it will make the FDA too eager to approve questionable drugs.

Meanwhile, 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 while upending the future of drug regulation, forcing the 114-year-old agency to do the equivalent of redesigning a fighter plane in mid-flight.”

Patients and Advocators

Aduhelm has some powerful supporters as well, though none are as visible or influential as the Alzheimer's Association, a massive organization that provides direct assistance to families and lobbyes Congress to increase funding for research and care.

In an interview with Stardia, Maria Carrillo, the association's chief science officer, laid out the case for the drug, claiming that it could attract even more money into drug development and emphasizing the importance of a seemingly minor 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 dementia, and what that meant for our family,” Carrillo said, echoing Robertson’s experience. “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.”

The association has made a priority of highlighting patients' perspectives, which it claims critical scientists, such as those on the FDA's advisory committee, do not always value.

Among its more visible efforts this year was a public relations campaign touting the value of "more time," which included tweets from celebrities such as actor Samuel L. Jackson. In response to an independent assessment questioning Aduhelm's worth, 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 repercussions."

Critical experts, such as Jason Karlawish, a psychiatry professor at the University of Pennsylvania and author of the new book "The Problem of Alzheimer's," are concerned by such statements.

“The findings of aducanumab studies do not allow reasonable conclusions about the number of days of active life gained by a person with Alzheimer’s disease from taking the drug,” he said.

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

The FDA has now lowered the bar for what it takes to get a drug approved for use, which is bad news for my patients.

Jason Karlawish is the author of “The Alzheimer's Problem.”

Others are more optimistic, including Dana Goldman and Darius Lakdawalla of the University of Southern California's Schaeffer Center for Health Policy and Economics, who wrote in an op-ed for STAT that "every week symptoms are delayed is a psychic and financial blessing."

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However, as they both pointed out, they have both worked as consultants for Biogen, which may have provided them with a financial incentive to promote the drug.

The Alzheimer's Association, like many disease advocacy organizations, receives funding from the pharmaceutical industry, including Biogen.

In response to questions about the donations, the association's president and CEO, Harry Johns, stated, "No contribution from any company, entity, or individual influences Alzheimer's Association decision-making, nor our positions on issues affecting people living with Alzheimer's, other dementia, and their families; we act solely on the science and the needs of our constituents."

The Unbelievably High Prices

Even a small chance of mild improvement may appear to be reason enough to approve a drug for a disease as terrible as Alzheimer's, but Aduhelm, like all medications, has potentially dangerous side effects, such as brain swelling, which doctors administering the drug during the trials aggressively monitored using brain scans.

Then there's the financial cost of the drug: rather than approving it only for people in the early stages of the disease, as Biogen had studied and when scientific theory predicted it would have the greatest impact, the FDA approved it for all Alzheimer's patients, which amounts to nearly 6 million people, the majority of whom are elderly and on Medicare.

Even if you've been following these debates for years and have grown jaded about high drug prices, the financial impact of Aduhelm approval is mind-boggling: annual Medicare spending on the treatment could top $100 billion, dwarfing the $39 billion it currently spends on all similarly infused drugs.

Aduhelm will also put a strain on state governments because the Medicaid programs they run will cover a portion of the costs through coverage of low-income Alzheimer's patients, including seniors on Medicare who use Medicaid as a supplement. States, unlike the federal government, cannot deficit spend, so even a minor responsibility for such an expensive drug could cause financial difficulties.

And the portion of the Aduhelm bill that does not levy 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 expenses.

The money spent on Aduhelm by governments and individuals is money that cannot be spent elsewhere, which is why so many experts and clinicians are upset about the approval.

As it stands, patients and families are struggling to pay for the care that people with Alzheimer's require, beginning with the cost of direct caregivers, whether in their homes or in group settings; this inability to pay cascades through the system, resulting in underpaid caregivers and understaffed facilities, all of which lead to increased patient suffering.

Biogen said in a statement to Stardia 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 outcome will be a combination of discounts and special charity programs, similar to those offered by drug companies for high-priced drugs used to treat cancer and other ailments. However, those programs typically do more to shift spending than to reduce it, and they do not cover associated costs such as brain scans to check for swelling.

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

Washington's Debate

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

In the United States, the Institute for Clinical Effectiveness Research (ICER) is an independent nonprofit organization that 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, or one-seventh of what Biogen intends to charge.

The federal government can't do anything about it because, unlike its foreign counterparts, it lacks a mechanism for direct price negotiation. Changing that has been a cause of reformers since the 1990s, but it's mostly been a futile campaign, thanks in part to advocacy and lobbying from the pharmaceutical industry, one of Washington's most powerful groups.

It is unconscionable to ask seniors and taxpayers to pay $56,000 per year for a drug that has yet to be proven effective, and Medicare must be able to negotiate a fair price for prescription drugs. https://t.co/MTjGHcXEs8 — Ron Wyden (@RonWendy) June 8, 2021

President Joe Biden and Democratic leaders in both houses have stated that they want to pass legislation giving the government more power, possibly based on a bill passed by House Democrats in 2019. However, it is unclear whether House Democrats can pass a new version of the same bill now, because their majority is much smaller, and getting votes in the Senate promises to be even more difficult, given that D.C.

The news about Aduhelm could help the cause. Among those calling Biogen’s proposed price “unconscionable” was Sen. Ron Wyden (D-Ore.), chairman of the Senate Finance Committee. Similar dynamics have played out before, most notably when a surprise premium hike from a California health insurer provided Democratic leaders with the support they needed to pass the Affordable Care Act.

However, Aduhelm is set to hit the market within a month, long before legislation can be passed, let alone implemented. For the time being, the federal government's most effective tool for controlling what Medicare spends may be to issue what's known as a "national coverage determination," limiting the circumstances under which it paid for the treatment. This could mean, for example, covering the drug only for patients in the United States.

The agency that runs Medicare has made such decisions before, though rarely for pharmaceutical products; it would undoubtedly disappoint many patients and families who are now hoping for the drug, and it would almost certainly spark a political backlash, with Republicans accusing the Biden administration of rationing life-altering treatment in a preview of how they envision a government takeover destroying America.

The Actual Influence On Science

Behind the cartoonish “death panel” version of that argument is a more serious claim that increased FDA scrutiny or government price-control leverage will discourage drug companies from making the inherently risky research investments required for breakthroughs.

The precise relationship between drug company profits and innovation has been debated for decades, and reasonable people can disagree on it. However, critics of the Aduhelm decision worry that drug companies now have less reason to sweat whether experimental Alzheimer's products show meaningful clinical progress.

“You’re going to have all kinds 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 drug regulation.

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“The FDA has now lowered the bar for what it takes to put a drug into practice, which is not good for my patients, their families, and, when multiplied by the millions of people who have the disease, it is not good for society,” Karlawish agrees.

You'll get a slew of ineffective, "me too" drugs that won't help our patients' lives.

Professor of Medicine and Public Health at Yale, Joseph Ross

As an example, Karlawish cited another Alzheimer's drug in development, this one from Eli Lilly, that had some promising early results but whose long-term clinical effects are unknown. "It's very interesting data... I cannot wait to see what more trials show," Karlawish said, "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 that reducing amyloid plaques has the effect that Aduhelm supporters hope for, and that, with improvements, such treatments can stop disease progression by acting on their own or (more likely) in combination with other therapies, similar to how the HIV “cocktail” of multiple drugs now works.

Many scientists, however, are concerned that the intense focus on amyloid protein has diverted researchers' attention away from other theories of the disease that require further investigation, and that the FDA's decision has reduced drug companies' financial incentives to pursue those approaches.

One way to help settle those ongoing debates about the drug's efficacy would be to gain a better understanding of it, which, in theory, Biogen will now do. A condition of the FDA's approval was that the company conduct another randomized and controlled trial to determine whether the improvement from one subgroup was real, which is a standard requirement for accelerated approval.

However, shortly after the FDA granted approval, Biogen's CEO stated that the follow-up trials could take up to nine years to complete, which may be wishful thinking. Drugmakers frequently fail to meet requirements for confirmatory experiments, in part because recruiting people for studies becomes much more difficult once a drug is available.

“The unfortunate thing is that one more aducanumab study could have given us answers to the question [about the precise role of amyloid] because clinical studies are one of the best ways to validate causal mechanisms,” Karlawish said.

Robertson agrees and says she isn't looking forward to the upcoming conversations. Biogen has stated that Aduhelm will soon be available in 900 facilities across the country. This week, she starts a new position as an assistant professor at Johns Hopkins and knows that patients will request the drug.

She intends to tell them what she thinks, despite her aversion to dash their hopes, and despite her belief that science will eventually find a way to combat Alzheimer's; she just doesn't believe it has yet.

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