Decisions With Patients and Families Regarding Aducanumab in Alzheimer Disease, With Recommendations for Consent

Abstract

Alzheimer disease (AD) is a feared and stigmatized condition, with relentlessly progressive impact not only on the independence and health of people with dementia, but also on the health and financial well-being of their families, and the overall health care system and society. Further research towards effective treatment for AD is urgently needed, and patients with AD deserve more support from clinicians and from their communities. One essential condition of this support is trust. Whereas it is important to offer hope to patients and families, these efforts will ring hollow if trust is lost. Neurologists and others who serve patients and the broader public health must continually ask: Are the statements and actions of our profession worthy of the trust placed in us by patients and the public?Neurologists have often depended upon US Food and Drug Administration (FDA) approval as a sign of a medication's safety and effectiveness, but recent decisions indicate a lowering of the standards of scientific evidence used for drug approvals, 1-3 which will require clinicians to scrutinize approved medications more carefully. One recent example is the approval of aducanumab, a monoclonal antibody directed at β-amyloid aggregates implicated in the pathogenesis of AD. Although drug approval has traditionally depended on support from 2 well-conducted clinical trials, aducanumab was approved based upon 2 studies that were both stopped prematurely for futility. In later post hoc analyses of the available data, 1 trial indicated a statistically significant but small benefit with high-dose aducanumab, while the other study continued to indicate no benefit. The clinical importance of the small statistical benefit in 1 trial for daily function is unclear, and aducanumab was also associated with brain swelling and hemorrhage in more than one-third of patients who received the dose approved by the FDA. An advisory committee of outside experts convened by the FDA reviewed the available evidence and decisively concluded (10 votes no, 1 uncertain) that these data did not support a conclusion that aducanumab slows cognitive decline.The FDA approved aducanumab by invoking the accelerated approval pathway rather than the traditional approval process. This contradicted prior assurances by the agency that the determination would depend on clinical endpoints. 4 Instead, as an accelerated approval, the FDA based its decision on the effects of aducanumab on brain β-amyloid levels as a surrogate marker MORE ONLINE

Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease

“…Risk factors for ARIA include: ( 1 ) initial treatment period, ( 7 ) higher dosage, and ( 8 ) ApoE4 genotype—with ApoE4/4 homozygotes having the highest risk ( Table 4 ). Clinicians and patients should strongly consider ApoE genetic testing before treatment initiation as this significantly affects risk of ARIA.…”

“…Second-generation monoclonal antibodies, including aducanumab, target insoluble and fibrillar beta-amyloid (Aβ) peptides and significantly decrease CNS amyloid burden in individuals with MCI and AD—albeit with ongoing controversy regarding their clinical benefits ( 1 ). These monoclonal antibodies are emerging as potential new treatments for individuals with MCI (also known as prodromal AD) and mild dementia due to AD.…”

The Medicolegal and Ethical Dimensions of Physician Prescription Reluctance

“…The AAN position statement addresses a legitimate concern that many neurologists share about the FDA's recent drug decisions (including its aducanumab decision), which show a "lowering of the standards of scientific evidence used for drug approvals, which will require clinicians to scrutinize approved medications more carefully." 1 The key items related to clinical importance were the unclear small statistical benefit in one trial and the potential for brain swelling and hemorrhage in more than one-third of patients. 1 Since the patient in the case is 74 years old, she is most likely a Medicare beneficiary.…”

“…1 The key items related to clinical importance were the unclear small statistical benefit in one trial and the potential for brain swelling and hemorrhage in more than one-third of patients. 1 Since the patient in the case is 74 years old, she is most likely a Medicare beneficiary. The average cost of aducanumab is now $28,000 per year (lowered from an initial cost of $56,000 per year), not including costs related to infusion services, increased physician follow-up, or additional diagnostic studies for monitoring risks associated with the drug.…”

Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus

“…12 Approval of this first-in-class antiamyloid therapy was met with considerable controversy, centered upon the interpretation and application of the evidence supporting the safety and efficacy of aducanumab, [13][14][15][16] and the decision to approve this medication "based on reduction in Aβ plaques observed in patients treated with Aduhelm" rather than compelling evidence of a change in clinical measures. 12 In response, the American Academy of Neurology (AAN) created a number of resources, 18 published a viewpoint regarding the ethics of the approval process, 19 and undertook a systematic review of available evidence. This Evidence in Focus represents the evidence review process.…”