In response to the controversy concerning aducanumab, the approval of which ended a decades-long drought in the Alzheimer’s disease therapeutic pipeline, the American Academy of Neurology issued a starkly worded guidance for its members considering prescribing the drug. The article, republished here, was initially published Nov. 18. Click here to see the originally published article and obtain CME/CE credit for the activity.
In an unusual and often harshly worded statement, the American Academy of Neurology (AAN) set forth the ethical implications for neurologists who may prescribe the recently approved Alzheimer’s drug aducanumab.
“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, of the University of California San Francisco and a member of the AAN’s Ethics, Law, and Humanities Committee, said in an AAN press release. “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.”
Aducanumab-maker Biogen did not respond to numerous BreakingMED emails and calls requesting comment on the AAN’s statement.
The statement, published in Neurology, considered whether a neurologist should prescribe aducanumab or not with respect to the ethical principles of beneficence, nonmaleficence, justice, and autonomy. Following each detailed discussion of those principles, the AAN called out key points that are essentially guardrails to keep members on a narrow prescribing pathway.
Moreover, Chiong and colleagues also provide a number of talking points for discussions with patients. Among the suggested discussion topics are these:
- “Absence of convincing scientific evidence of efficacy.
- Potential benefits are modest with no prospect of cure or restoring cognition even if clinical trial data are interpreted optimistically.
- Risks of cerebral edema, hemorrhage, and hospitalization. This includes efforts to quantify the risk of cerebral edema and hemorrhage (e.g., >1/3) and the risk of symptomatic ARIA (e.g., 1 in 10).
- Financial costs to the patient and family, including Medicare copayments.
- Financial interests of the physician, practice group, or institution in aducanumab may create a conflict of interest regarding recommendations its use.”
“While neurologists have often depended upon the U.S. Food and Drug Administration’s approval as a sign of a medication’s safety and effectiveness, recent decisions indicate a lowering of the standards of scientific evidence used for drug approvals, which will require clinicians to scrutinize approved medications more carefully,” wrote Chiong and co-authors.
“While drug approval has traditionally depended on support from two well-conducted clinical trials, aducanumab was approved based upon two studies that were both stopped prematurely for futility. In later post hoc analyses of the available data, one trial indicated a statistically significant but small benefit with high dose aducanumab, while the other study continued to indicate no benefit,” the position statement authors added.
“The clinical importance of the small statistical benefit in one trial for daily function is unclear, and aducanumab was also associated with brain swelling and hemorrhage in over one-third of patients who received the dose approved by the FDA,” they observed.
Brain inflammation with swelling or hemorrhage is known as amyloid-related imaging abnormalities (ARIA) in this setting. One in 14 patients in clinical trials randomized to full-dose treatment were permanently removed due to persistent ARIA. Those with the APOE4 allele showed an increased risk for ARIA.
The FDA used the accelerated approval pathway to approve aducanumab and based its decision on the effects on brain β-amyloid levels as a surrogate marker of reasonably likely clinical benefit. Chiong and co-authors suggested that insufficient reason was given by the agency for using a surrogate marker in this decision, an important point “because the link between brain β-amyloid reduction and clinically meaningful outcomes in patients with symptomatic Alzheimer’s disease remains unclear,” they noted.
Beneficence requires physicians to provide care in the best medical interests of patients based upon scientific evidence, Chiong and colleagues pointed out.
The aducanumab clinical trials were conducted only in patients with mild cognitive impairment or very early Alzheimer’s dementia and with biomarker evidence of brain β-amyloid deposition. “Outside these inclusion criteria, safety and efficacy data are lacking, and there is no physiologic rationale for the use of this medication in patients without brain β-amyloid deposition,” the AAN authors wrote. “Under the principle of beneficence, therefore, there are insufficient grounds to warrant offering aducanumab to patients with moderate or advanced dementia due to Alzheimer’s disease, or to patients without biomarker evidence of brain β-amyloid.”
Another possible threat to beneficence affects the obligation of physicians to direct care towards the medical benefit of patients, not to their own personal benefit. Neurologists and their clinics will be reimbursed for the medication, professional fees, infusion, and imaging.
“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,” Chiong and co-authors wrote.
- There are insufficient grounds to warrant offering aducanumab to patients with moderate or advanced dementia due to Alzheimer’s disease, or by patients without biomarker evidence of brain β-amyloid.
- Aducanumab will not cure Alzheimer’s disease or restore cognitive function.
- Potential financial conflicts of interest compromise the duty of beneficence in patient care.”
Nonmaleficence requires meaningful awareness and weighing of several types of harm that may be associated with a treatment. The principal medical risk of treatment with aducanumab is ARIA. In trials, most ARIA symptoms and imaging findings resolved or stabilized with temporary cessation of the drug, though rare cases with severe symptoms required hospitalization.
“Neurologists must communicate information about potential adverse effects and the burdens of monitoring, and should assist patients and families in quantifying complex information in familiar terms.,” the AAN authors wrote.
The cost of aducanumab may also represent financial harm to patients and families. “Neurologists have a responsibility to inform patients and families that the full costs of treatment may not be covered and about the financial ramifications of decisions to pursue treatment,” Chiong and colleagues stated.
- Neurologists must communicate potential adverse effects and the burdens of monitoring. 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.
- Neurologists have a responsibility to inform patients and families that the full costs of treatment may not be covered and about the financial ramifications of decisions to pursue treatment.”
Justice requires physicians to consider whether the benefits, risks, and burdens of interventions are fairly distributed. “Even conservative estimates of aducanumab utilization have staggering implications for health system costs,” the authors said.
In addition, the reasonable patient standard of informed consent obligates clinicians to disclose information that a reasonable patient would consider material to a treatment decision, they noted.
“Many Hispanic, Black, and Indigenous patients would consider materially relevant that all available safety data regarding aducanumab effectively exclude people of their backgrounds,” Chiong and co-authors observed. “Given the magnitude of potential harms and uncertain benefits of aducanumab, informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups.”
- The absence of racial and ethnic diversity in the clinical trials of aducanumab is a significant concern for justice.
- Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups.”
“Respect for autonomy is not simply a matter of acceding to initial requests for treatment, but instead calls for a shared process of understanding and interpreting the values that motivate patients’ wishes,” the statement authors wrote.
Since aducanumab should be considered only in people with mild cognitive impairment or very early dementia due to Alzheimer’s disease, shared decision-making should generally include patients rather than rely solely on a surrogate decision-maker, they added.
“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 and co-authors pointed out.
“If in a neurologist’s professional judgment, the potential harms of treatment with aducanumab for an individual patient outweigh the anticipated benefits, the neurologist is ethically obligated to decline to offer such a treatment,” they stated.
- Respect for patient autonomy in complex medical decisions is best demonstrated through the process of shared decision-making, in which clinicians play an active role in interpreting patients’ values and recommending care that promotes those values.
- Respect for patient autonomy does not require clinicians to offer treatments for which the potential harms, in their judgment, outweigh the anticipated benefits.”
Chung and co-authors concluded by acknowledging the desperate need for Alzheimer’s treatments, but added a blunt assessment:
“Aducanumab is very far from a cure for Alzheimer’s disease. While many hope that its approval will lead to better treatments in the future, there are also grounds to worry that its availability will hinder enrollment in clinical trials of more effective interventions.”
Paul Smyth, MD, Contributing Writer, BreakingMED™
The authors report no targeted funding.
Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from NIH.
Cat ID: 33
Topic ID: 82,33,730,33,192,725,925
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