Clinicians frequently face thorny ethical dilemmas when caring for patients. Take time to reflect on all components of these issues before discussions with patients.
On June 4, 2021, the Food and Drug Administration (FDA) approved a new treatment for Alzheimer’s Disease (AD), aducanumab (Aduhelm™). The indication is treatment of AD without specifications as to severity of symptoms. This decision has been widely reported in the media since it’s the first new FDA-approved AD treatment in 20 years. Reaction has ranged from highly negative to concerned about unwarranted patients to a major breakthrough.
As a physician with expertise in AD who’s now called upon to make recommendations to patients about using this therapy, I wanted to try to help other clinicians make sense of the issues involved. I’ve led the Johns Hopkins Memory and Alzheimer’s Treatment Center since it was founded 2007. I work closely with an interdisciplinary, interprofessional team, and have had the privilege over the years to take care of thousands of people with AD and their families. I have firsthand experience of how AD affects patients and families, in some instances for decades. I’m a strong advocate of the need for big treatment advances.
AD is a neurodegenerative disease that leads to progressive cognitive, behavioral, and functional symptoms several decades after onset of the process in the brain. The disease leads to dementia with devastating effects, eventually leading to death for patients don’t pass away from a comorbid condition.
Our field has focused the last several decades on the accumulation of brain proteins associated with AD that I refer to here as amyloid. Multiple therapies have been developed to block, reduce, or remove these proteins in the forms of pills, subcutaneous injections, or IV infusions. The accumulated evidence is that while many are effective in reducing amyloid in the brain they have essentially no benefits to patients’ symptoms.
This is where the controversy begins for aducanumab, a monthly IV infusion. While effective at doing what is intended biologically, which is to remove brain amyloid, it hasn’t been proven beneficial for symptoms. Most other drugs like it are no longer in development. In early 2019, the developing drug company decided to discontinue the aducanumab program based on futility analysis of two Phase 3 trials. The company later reversed its course citing the accrual of additional data after the trials were stopped. These data seemed to indicate that at higher doses, and for patients who took more of the monthly doses, the drug was effective in improving symptoms. There have been reports from two identical studies examining this question. In both studies, on the drug everyone’s symptoms and functioning worsened on average. The open question is whether some patients worsen slower on the drug than on placebo. One of the two studies did not show a difference from the placebo while the other suggested a small, clinically uncertain, benefit after months of infusions. Because of these contradictions, an advisory panel last November unanimously recommended that the FDA not approve the drug until a third study resolves the discrepancies. Proposed treatments for AD are on an accelerated pathway, with a lower bar for proof of benefit because it’s a devastating disease with few options. Essentially, the FDA has chosen to approve while expecting the company to do a post-marketing confirmatory study. It is not clear, should the study not show benefit, if the FDA will take aducanumab off the market.
Where does this leave patients, families, and the doctors who are going to be called upon to advise them? I think the best approach in this complex ethical dilemma is to be transparent, conservative, and careful. Transparent, detailed patient and family education will be critical.
In terms of whom is eligible to receive the drug, the conservative focus should be on individuals with very mild symptoms who are diagnosed by experts with mild cognitive impairment or mild dementia and are proven through a biologic study, either analysis of CSF or a brain PET scan, to have substantial amyloid in their brain. Eligible patients will have to undergo expert clinical and cognitive testing as well as a biologic study to demonstrate the presence of amyloid. Thus, patients with moderate to severe dementia are not candidates, even if they have amyloid in the brain because it’s unlikely the drug will be helpful to them. Being conservative, my recommendation is that experts in psychiatry, neurology, or geriatrics be involved in every case when making decisions about use and monitoring of aducanumab.
Eligible patients would be referred for a monthly infusion and be carefully watched. Aducanumab and drugs like it are associated with Amyloid Related Imaging Abnormalities (ARIAs). As these can only be detected on brain MRI, frequent imaging is needed. ARIAs likely reflect accumulation of fluids around brain blood vessels related to removal of amyloid from vessel walls. ARAIs were observed in about 40 percent of patients on aducanumab in the trials. In most instances they were asymptomatic. In about five percent of patients, infusions were discontinued because of symptoms. Patients will have to be closely watched with MRIs every six months or possibly more often. Patients, families, and doctors must pay careful attention to catch new symptoms ASAP that could reflect these ARIAs. There’s a lot of uncertainty about ARIAs because we don’t know enough about them and what risks they pose, such as strokes and/or brain damage. This safety issue is compounded as patients in the trials were healthy, with few comorbidities. They were only treated for up to 18 months whereas in the era of approval we may be talking about treating patients for much longer.
The last point raises the question of duration of therapy. The double-blind trials went out to 18 months and participants on the drug worsened for the most part. Hence, those started on the drug are very likely in the ensuing months to no longer meet criteria for initiation of therapy and we expect symptoms to advance. Does that mean that we should stop infusions? This needs to be clarified with data. Unless compelling evidence suggests benefit beyond 18 months, infusions should be discontinued when patients progress to where they would no longer have been eligible to start treatment.
The final question is about cost. I won’t to get into this in great depth other than to point out that costs are likely to be extremely high. There are estimates of $55,000 a year per patient for the drug plus the cost of the PET scans, clinical monitoring, and MRIs. At least one estimate concludes that costs above $10,000 per year can’t be justified based on the observed benefit. It’s also unclear whether insurance companies will pay.
Clinicians frequently face thorny ethical dilemmas in the course of caring for patients. Often, the best approach to tackling these is to be transparent, conservative, and careful. This reflection is a starting point for ongoing discussion illustrating the dilemmas that clinicians and patients are going to face around aducanumab. Many questions are already being posed to our Memory Center clinicians and arising in primary care environments as well. I’m hoping to update this post over time to provide guidance to colleagues not specialized in this area and who undoubtedly will receive queries about using this drug.
This piece expresses the views solely of the author. It does not represent the views of any organization, including Johns Hopkins Medicine.