FDA approval of new Alzheimer’s drug sets a dangerous precedent

This week, the American Food and Drug Administration (FDA) approved a new treatment for Alzheimer’s disease for the first time in nearly two decades. The new drug aducanumab (brand name Aduhelm) was developed by Cambridge, MA pharmaceutical company Biogen and Japanese pharmaceutical company Eisai Co., Ltd. While certain patient advocacy groups such as the Alzheimer’s Association applauded the FDA’s decision, many other experts — including the FDA’s own advisory panel — were dismayed by the drug’s approval. Not only does was the approval of aducanumab based on a very low level of evidence, but the approval has significant implications for future drug trials, health system costs, patient safety, and conflicts of interest.

The evidence behind the approval

The path to approval for aducanumab was anything but straightforward. In 2015, Biogen started two randomized controlled trials, called EMERGE and ENGAGE, to test the effectiveness and safety of aducanumab. At an interim look at the data in 2019, Biogen shut the trials down, declaring that the drug was not proving to be effective, and that further study would be “futile.” However, data continued to come in from trial participants, and a few months later, Biogen did a reanalysis and found that EMERGE was showing positive results for patients taking a high dose of aducanumab.

“These kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

Dr. Jason Karlawish, in StatNews

Experts were skeptical that this result was enough proof for Biogen to seek FDA approval. For one, the FDA generally requires two controlled trials to approve a new drug, and Biogen had positive results from only one trial. Second, although the trial results were statistically significant, it’s not clear that the results actually show clinical significance– that is, that the drug makes a noticeable difference to patients or their families. The primary endpoint of the trials was change on the Clinical Dementia Rating Scale (CDRS). The range for this scale is from 0-18, with a higher score indicating more severity of illness. Among those taking a high dose of aducanumab in the EMERGE trial, the average decrease on the scale was 0.39 points, according to the Institute for Clinical and Economic Review (ICER) report.

Given the negative results of ENGAGE (as well as the many previous negative trials of drugs that similarly target brain amyloid), the positive results of EMERGE may have been due to random chance as much as anything else. But even if the result is “real,” that doesn’t mean we should rush to approve the drug. In a recent StatNews op-ed, Dr. Jason Karlawish, professor of medicine at the University of Pennsylvania’s Perelman School of Medicine, argued that “these kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

After looking at the evidence, the FDA’s own advisory panel voted overwhelmingly that the trials were not “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.” It’s not uncommon for the FDA to vote against the recommendation of its advisory panels, but this was the first time in many years that the FDA overruled such a decisive vote by a panel. Many of the panel members were shocked by the FDA’s approval of the drug, and as of June 11, three have resigned.

Implications for future drug approvals

So why did the FDA approve aducanumab, given the low level of evidence shown by the trials? It appears that their decision was based mostly on the drug’s performance on a surrogate marker, how well it cleared beta-amyloid plaques from the brain. Surrogate markers are metrics that are not generally meaningful on their own, but correlate with clinical benefits that matter to patients.

In the FDA’s statement, director Dr. Patrizia Cavazzoni wrote, “Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain. The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer’s—is expected to lead to a reduction in the clinical decline of this devastating form of dementia.” 

The FDA’s “Accelerated Approval” pathway allows the agency to approve drugs based on their performance on surrogate markers for serious or life-threatening illnesses, on the contingency that the company does a confirmatory clinical trial to show improvement on meaningful outcomes.

“A general signal being sent to the rest of the drug industry is: If you can get uncertain, maybe suggestive data…we may approve your drug.”

Dr. Peter Bach, in Axios

The use of accelerated approval in recent years has been highly problematic, leading to approval of many cancer drugs based on unproven surrogate markers, that don’t show improvement in survival in post-approval trials. However, the aducanumab approval takes accelerated approval to another level, by bringing a drug to market that applies to a very broad population — about 6 million Americans are living with Alzheimer’s, and 500,000 are diagnosed with the disease each year. Although the trials included only patients with mild dementia, the FDA declined to limit the drug’s indication to patients at a particular stage of the disease. This means that anyone affected by Alzheimer’s could be eligible for treatment with aducanumab.

The FDA’s approval of aducanumab sets a dangerous precedent, because it may become more common for the FDA to approve drugs without proof they are effective and ask for confirmatory trials, rather than waiting for evidence before approving. The FDA rarely holds drugmakers accountable for conducting postmarketing trials to validate drug effectiveness. A 2019 review of 93 cancer drugs approved through accelerated approval found that only 15 of the approvals later had confirmatory trials that showed improvement in overall survival.

“A general signal being sent to the rest of the drug industry is: If you can get uncertain, maybe suggestive data and a post-hoc analysis — get that threshold to us — we may approve your drug,” said Peter Bach, a drug researcher at Memorial Sloan Kettering Cancer Center, in Axios.

Potential for patient harm

Aduhelm’s approval also has implications for patient harm if it becomes widely used. In the combined drug trials, according to the ICER summary report, 1% more patients taking aducanumab experienced a serious adverse event that researchers attributed to the drug, compared to patients taking placebo (0.7% of placebo group vs 1.7% of aducanumab group). If all 6 million Americans diagnosed with Alzheimer’s each year took the drug, that would result in 60,000 more serious adverse drug events each year.

The aducanumab group also reported higher rates of headache (19.6% vs 15.2%), falls (14.1% vs 11.8%), and diarrhea (8.2% vs 6.8%), compared to the placebo group. Applied to 6 million potential aducanumab users, this would result in 252,000 more cases of headache, 84,000 cases of diarrhea, and 138,000 more falls each year.

Implications for health system spending

The reimbursements for Aduhelm infusions and related scans are potentially a gold mine for clinics offering this treatment–not to mention the billions that Biogen is expected to make in profits. But these profits come at a high cost for Medicare and the health system as a whole. The wholesale price for the drug is $56,000 per year, far higher than ICER’s recommended price range of $2,560 to $8,290 based on the drug’s effectiveness. Not only is the cost of the drug itself expensive, but the costs of brain scans to monitor previously mentioned side effects adds an estimated $30,000 per patient.

The introduction of a new expensive drug that could be given to millions of people has serious implications for the cost of health care nationwide. If the Centers for Medicare and Medicaid (CMS) decide that Medicare should cover the cost of aducanumab, this could add hundreds of billions of dollars to Medicare spending.

CMS may decide to limit Medicare coverage of aducanumab through their National Coverage Determination (NCD) process, in which CMS would independently review the evidence around the drug and determine for which beneficiaries the drug should be covered. Without the NCD, other insurers and regional Medicare Part B contractors could still decide to set coverage limits for aducanumab. But even with these limits, aducanumab’s approval will likely strain Medicare’s budget and result in higher insurance premiums.

Conflicts of interest

Finally, the approval of Aduhelm confirms that pharmaceutical companies’ strategy of funding patient advocate groups is working. The Alzheimer’s Association received at least $1.4 million from from Biogen and Eisai since fiscal year 2018. The group has been ardent supporters of Aduhelm, sending letters to the FDA urging approval of the drug (without disclosing their conflicts). The pattern of pharmaceutical funding for patient advocate organizations — which exceeds what pharma companies spend on federal lobbying — is likely to continue, if not increase.

Similarly, the relationship between the FDA itself and pharma should be taken into account. As Shannon Brownlee and Jeanne Lenzer wrote in the Washington Post, the FDA is in many ways a “captive agency” of industry, write Brownlee and Lenzer. The FDA relies on industry fees for 35% of their budget, and many of the scientists that work at the FDA either come from industry or later go on to work in industry (a phenomenon known as the “revolving door”). As a result, the FDA sees drug and device companies as its primary customers, not patients. This cozy relationship may explain why the FDA offered Biogen and Eisai accelerated approval for aducanumab, and did not push them to do additional trials before approval.

A strong response

The pushback from the scientific community against the FDA’s approval of Aduhelm has been strong; so far, three of the FDA advisory panel members have resigned in protest. Even pharma industry insiders say that the FDA should not have approved Aduhelm, and that it’s not worth the high price. Hopefully the FDA will reexamine their decision and take in this lesson for the future.

If nothing else, this episode and its implications will make it clear the issues with lax FDA regulation, and with the accelerated approval pathway especially. As Dr. Vinay Prasad, Associate Professor in the Department of Epidemiology and Biostatistics at the University of California-San Francisco, wrote on Twitter, “We have five or six aducanumabs a year in oncology.” Hopefully, the strong public outcry from the scientific community will make the FDA take notice, and push President Biden to appoint a new FDA commissioner who will priority drug safety and efficacy over speed.