AAN Issues Statement on Ethical Considerations for Aducanumab Use in Alzheimer Disease

The American Academy of Neurology’s statement touched on the roles played by the principles of beneficence, nonmaleficence, justice, and patient autonomy as it relates to the clinical use of the therapy for this patient population.

The American Academy of Neurology (AAN) has published a position statement on the use of aducanumab (Aduhelm; Biogen) for the treatment of patients with Alzheimer disease (AD), assessing the ethical considerations related to its use and offering recommendations for informed consent.1

The AAN acknowledged that the antiamyloid antibody has been the subject of much controversy because of its nontraditional route through the pipeline and the accelerated pathway of approval. The statement covered the role of the principles of beneficence, nonmaleficence, justice, and patient autonomy related to the use of the therapy in this patient population.

“Aducanumab is not a cure for Alzheimer’s disease, yet since it has been approved by the FDA, patients are asking their doctors if this is an option for them,” position statement author Winston Chiong, MD, PhD, associate professor of neurology, and interim director, UCSF Bioethics, University of California San Francisco; and member, AAN Ethics, Law, and Humanities Committee, said in a statement.2 “This is a high-cost drug that was approved by the FDA without convincing evidence of benefits and with known harms, so the purpose of this position statement is to offer ethical guidance on how neurologists can help patients make informed decisions about this treatment.”

AAN President Orly Avitzur, MD, MBA, FAAN, echoed this sentiment in a statement,2 noting that the interest in the agent is understandable even in light of the controversy surrounding the FDA approval, as “it still offers a glimmer of hope to patients and their families.” She noted that the guidance of this position statement by ethical principles of care is aimed “to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care.”

The Principle of Beneficence

As it relates to the principle of beneficence, the AAN statement noted that the evidence of its treatment effect is not enough to warrant its use for patients with moderate or advanced AD dementia, nor for patients without biomarker evidence of brain amyloid-β. Additionally, the organization penned that it was crucial to understand that “there is no prospect of curing Alzheimer’s disease or restoring cognitive function with aducanumab,” and that the cost of the therapy—set at $56,000 annually—may create financial conflicts of interest which can compromise the duty of beneficence in patient care.

Chiong and colleagues wrote that “clinics will initially be reimbursed at 103% of aducanumab’s wholesale acquisition cost” with later reimbursement occurring at 104.3% of the price, allowing these clinics to “realize thousands of dollars in profit per patient for the drug alone, even prior to professional fees and services such as infusion and imaging.” This, they note, may create “misaligned incentives” that could corrupt practice principles if undisclosed. “Markups of thousands of dollars per patient, as a source of revenue entirely dependent on a decision to administer an intervention without proven benefit to patients, are sufficiently large to require disclosure of these interests when neurologists offer recommendations about treatment,” they wrote.

READ MORE: Enrollment Complete for Phase 2 Study of ATH-1017 in Moderate Alzheimer

The Principle of Nonmaleficence

With regard to the principle of nonmaleficence, the AAN statement offered recommendations about the neurologist’s role as a communicator of the data to the patients. The main points focus on the correspondence of the potential adverse effects—such as amyloid-related imaging abnormalities, which pooled data from the clinical trials suggest are mainly asymptomatic, though occurred in roughly 41% of individuals (454 of 1105)3—and the burdens of monitoring for them. “Given the complexities of the data and the unfamiliarity of some of the medical risks, many patients and families will require extended discussions using accessible language to assist them in weighing these burdens,” the group wrote.

Additionally, the group again alluded to the downstream effects of aducanumab’s price, noting that, pending the upcoming coverage decision from the Centers for Medicare & Medicaid Services, patients may be faced with a lack of coverage of the full costs, which “may exceed $100,000 per patient per year” and ensuring patients understand the possible ramifications of this is paramount.

“At a policy level, stakeholders are being convened to propose measures to mitigate these burdens, though it is currently unclear whether these efforts will be successful or what unintended consequences any proposed remedies may have,” Chiong et al wrote.

The Principle of Justice

In addition to the considerations of the therapy’s potential efficacy, the group pointed to the lack of racial and ethnic diversity present in the patient population of the clinical trials of aducanumab as a “significant concern.” This has been a frequent topic of conversation in recent years, and while clinical trials in AD are challenging to conduct for myriad reasons, the lack of racial and ethnic diversity in these trials has been of particular interest, as recent literature has suggested that the percentage of non-White participants included in these clinical trials may be as low as 5%,4 and that differences recruitment, reasons for screen failure, and general eligibility amongst racial and ethnic groups ultimately leads to a smaller portion of non-White individuals meeting eligibility criteria.5

Less than 3% of those enrolled in the aducanumab clinical trials were Hispanic, and less than 1% were Black or Indigenous, the group noted. “This not only deprives potential patients from underserved groups of relevant information about the benefits and harms of a proposed treatment, but also imposes unjust burdens on taxpayers of these backgrounds, who share in the substantial societal costs of paying for an intervention for which no conclusions can be drawn about its relative safety or efficacy in their case,” Chiong et al wrote, adding that “many Hispanic, Black and Indigenous patients would consider materially relevant that all available safety data regarding aducanumab effectively exclude people of their backgrounds.”

Chiong et al pointed additionally to the financial burden placed on taxpayers and Medicare beneficiaries, as estimates of the total annual spending on aducanumab by Medicare exceed $25 billion. They noted that treating even the small portion of patients who may be appropriate to prescribe aducanumab could increase US health expenditures by 1.5% overall.

The Principle of Patient Autonomy

The final ethical consideration of the position statement related to the principle of patient autonomy in the care process, which “is best demonstrated through the process of shared decision-making.” This, the AAN stated, means that the process of decision-making related to aducanumab should cover a number of items, including the patient and family expectations of benefit, the risk-benefit ratio, and more generally, the patients’ values.

“Given the absence of convincing scientific evidence of benefit, known potential harms, burdensome monitoring and financial costs of aducanumab, neurologists should carefully consider whether aducanumab can be recommended to individual patients as the medical course of action that best serves their values,” Chiong et al wrote, noting that several large health systems and insurers have elected not to offer aducanumab to any patients in light of these concerns, such as Mount Sinai and Cleveland Clinic.6

The need for these conversations, the group noted, could hold some negative impacts, as the time and attention needed to conduct them may take counseling about facets of care that often can be even more significant for patient care. These topics, they wrote, “include advance medical and financial planning, driving, accommodations to maintain functional independence, home safety, and caregiver support.”

Some have suggested that the approval of aducanumab may lead to an increased interest from patients in such trials. In October 2021, Jessica Zwerling, MD, MS, director, Montefiore Hudson Valley Center of Excellence for Alzheimer’s Disease, associate professor of neurology, Albert Einstein College of Medicine, told NeurologyLive® that it has begun to drive these conversations among physicians and patients. “The approval opened up the conversation of ‘what is a trial?’ to all of our patients, which may help with the recruitment; however, chronic diseases are prevalent in the Bronx and careful consideration of risk is crucial,” Zwerling said.

In its statement, the AAN recommended that neurologists continue to consider enrolling their patients in clinical trials, noting that these also involve therapies with “unproven efficacy and potential harms of similar magnitude, but which are of social benefit and do not present similar risks of financial harm to patients and their families.”

The AAN statement also acknowledged that respecting patient autonomy “does not require clinicians to offer treatments for which the potential harms, in their judgment, outweigh the anticipated benefits,” but did offer a reminder “the most important interventions for many patients and families are non-medical.”

REFERENCES
1. Chiong W, Tolchin BD, Bonnie RJ, et al. Decisions With Patients and Families Regarding Aducanumab in Alzheimer Disease, With Recommendations for Consent: AAN Position Statement. Neurology. Published online November 17, 2021. doi:10.1212/WNL.0000000000013053
2. AAN Issues Ethical Guidance on Aducanumab. AAN. News release. November 17, 2021. Accessed November 23, 2021. https://www.aan.com/PressRoom/Home/PressRelease/4937
3. Burkett P, Chalkias S, Umans K, et al. Considerations for the Real-World Management of ARIA From the Aducanumab Phase 3 Studies EMERGE and ENGAGE. Presented at: AAIC 2021; Denver, Colorado; July 26-30, 2021. Poster 57498.
4. Raman R, Quiroz YT, Langford O, et al. Disparities by race and ethnicity among adults recruited for a preclinical Alzheimer Disease trial. JAMA Netw Open. 2021;4(7):e2114364. doi:10.1001/jamanetworkopen.2021.14364
5. Franzen S, Smith JE, van den Berg E, et al. Diversity in Alzheimer disease drug trials: the importance of eligibility criteria. Alzheimers Dement. Published online September 30, 2021. doi:10.1002/alz.12433
6. King R. NYT: Cleveland Clinic, Mount Sinai won't prescribe controversial Alzheimer's disease drug Aduhelm. Fierce Healthcare website. July 15, 2021. Accessed November 23, 2021. https://www.fiercehealthcare.com/hospitals/nyt-cleveland-clinic-mount-sinai-won-t-prescribe-controversial-alzheimer-s-disease-drug