All seven members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee (AdComm), which reviewed and rejected aducanumab, published a Perspective in NEJM that questioned the criteria used to justify approval of aducanumab. The AdComm pointed out that approval was based on a reduction of beta-amyloid that was measured through positron-emission tomographic brain imaging. The committee found available clinical evidence from trials to not support lowered beta-amyloid as a prediction of clinical benefit. The AdComm did not find a single positive study as justification for clinical benefit. They also reiterate the FDA’s statistical review of EMERGE and ENGAGE failed to find evidence that amyloid changes correlated with cognitive or functional changes. Aducanumab labeling does not require verification of elevated beta-amyloid despite the FDA basing approval on beta-amyloid reduction. This becomes an important issue since almost half of patients with mild cognitive impairment that are being assessed for Alzheimer’s disease do not have elevated levels of beta-amyloid.
Four FDA officials involved in the approval of aducanumab supplied a rebuttal to the Peripheral and Central Nervous System Drugs Advisory Committee Perspective in NEJM in the same issue of the journal. The FDA officials argue that use of beta-amyloid as a surrogate marker was justified due to more recent studies demonstrating that larger decrease in amyloid plaque correlates with the effect on clinical end points. They point out that while earlier studies of amyloid reducing drugs did not demonstrate a clinical benefit, the products used had little or no effects on amyloid plaque. The decision to approve aducanumab under an Accelerated Approval was justified because they judged the drug to be “reasonably likely” to predict clinical benefit”. There was no explanation for approval without requiring establishment of amyloid plaque nor the reason for disagreeing with the FDA Biostatistical Review. Data that supports a beneficial response in relation to plaque reduction is not currently published.
We have updated our review of aducanumab and the revised report can be downloaded on our sample drug review web page. In addition to the information above, we have added live links for all references in our review.
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