Aduhelm (Biogen): LOWN Institute vs FDA

 

BY Judith Garber | June 14, 2021

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.

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FDA aprueba Aduhelm / Biogen, nuevo tratamiento para Alzheimer

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. Más