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The approval of Biogen’s Alzheimer’s drug aducanumab in spite of limited evidence sent its shares soaring

Here’s  the issue: Biogen started two identical studies in 2015 to test whether the drug slowed early Alzheimer’s. However, the company halted them in March 2019 after an early analysis suggested a low chance of success. It was the presumptive end for the medicine until Biogen popped up a few months later with the shocking announcement that one of the two trials showed a benefit — once it added new data — and that it planned to file for approval.

The early halt was problematic. Biogen collected a fraction of the patient data it wanted, introducing statistical uncertainty. But the biggest issue is that the second study failed, and it wasn’t close. The FDA’s desired standard for approval in Alzheimer’s is evidence from two positive studies. There are good reasons to want a high bar and duplication. It’s much harder to objectively measure mental decline than the size of a tumor, making definitive evidence especially critical.

The FDA ducked this standard by giving the drug a so-called accelerated approval, using a regulatory pathway that lets the agency accept different types of evidence in areas where patients lack options. That doesn’t make the decision more defensible. In this case, the approval centers on aducanumab’s ability to remove amyloid brain plaques believed to play a role in Alzheimer’s. Biogen’s drug (which it will market under the brand name Aduhelm at a hefty price of about $56,000 a year) cuts plaque, but the resulting patient benefit in even the positive trial is so modest that it may not be significant. 

Many other medicines have targeted amyloid. Unfortunately, all failed to help patients, leading scientists to question whether removing the plaque does anything. Biogen’s opposing results only add to the uncertainty about the role of amyloid; they don’t make it acceptable as the basis for a multibillion-dollar approval. What is certain is that removing the plaque causes sometimes serious side effects, including brain swelling. 

Biogen has explanations for the failed trial, blaming insufficient dosing and a few rapidly declining patients. But, unfortunately, this is what’s known as post-hoc analysis, or less politely cherry-picking, and it is fundamentally and irrevocably biased. Good scientists use such methods to generate ideas for future tests, not as tentpoles for generationally significant drug approvals.

You’d expect the FDA to push back. But, in this case, a part of the agency not only shifted its standards but collaborated with Biogen through an approval process in which it was so cozy with Biogen that consumer advocacy group Public Citizen has asked the government to investigate. That’s even as an independent panel of experts convened by the FDA to evaluate the drug universally advised against approval in November. Moreover, the regulator’s own statistical expert was highly critical of the evidence presented in a briefing packet presented as part of the November review. And on June 2, the American Geriatrics Society, a group of health professionals dedicated to older adults, wrote directly to the FDA’s interim commissioner advising against approval. 

The FDA seems to have yielded to the pressure to give hope to patients, even if it may be false, despite the consequences. And there are many. If the agency approves drugs with middling evidence, that’s what it will get. Companies will be more likely to seek approval or advance programs based on weak results, wasting time and research dollars and the health of patients who participate in clinical trials. As for Alzheimer’s, future drugs may be badly delayed. With an approved treatment available, it will likely become harder to recruit people to participate in trials. And now that the FDA has validated amyloid as a target, companies may focus on it at the expense of other potentially more fruitful avenues. 

The price of the drug is just the beginning of the financial damage. Getting it will require doctor’s visits and scans to establish eligibility and monitor side effects, creating significant additional costs for Medicare, patients and their caregivers. Multiply those costs by even a fraction of the millions of Americans with Alzheimer’s, and you have a budget crisis.