The first new Alzheimer’s drug to be approved in almost 20 years has sparked a major ethical controversy.1-3 Of the 11-member advisory committee convened by the FDA to review the application for aducanumab, no one voted yes (10 voted no, one voted uncertain).

Nonetheless, the FDA granted accelerated approval of the drug. “As an advisory committee member, I am extraordinarily disappointed that our unbiased advisory committee review was not valued,” says Joel S. Perlmutter, MD, a neurologist at Washington University in St. Louis. “Approval of a drug that is not effective has serious potential to impair future research into new treatments that may be effective for treating Alzheimer’s disease.”

For example, new studies may be required to compare investigational drugs to aducanumab instead of a placebo. “Enthusiasm, from either potential volunteer participants or funders, for new treatments may wane due to thinking that we already have an effective treatment when, in fact, we do not,” Perlmutter says.

“FDA will continue to monitor aducanumab as it reaches the market and ultimately the patient’s bedside,” Patrizia Cavazzoni, MD, director of the FDA Center for Drug Evaluation and Research, said in a statement.4 “Additionally, FDA is requiring Biogen [the drug’s manufacturer] to conduct a post-approval clinical trial to verify the drug’s clinical benefit. If the drug does not work as intended, we can take steps to remove it from the market. But, hopefully, we will see further evidence of benefit in the clinical trial and as greater numbers of people receive Aduhelm.”

On July 9, FDA Acting Commissioner Janet Woodcock, MD, sent a letter to Acting Inspector Christi Grimm to request an Office of Inspector General investigation into the Aduhelm approval process.

“To the extent these concerns could undermine the public’s confidence in FDA’s decision, I believe it is critical that the events at issue be reviewed by an independent body such as the Office of Inspector General in order to determine whether any interactions that occurred between Biogen and FDA review staff were inconsistent with FDA policies and procedures,” Woodcock wrote.5

Meanwhile, some advisory committee members have resigned.6-8 “Many in the field disagree with the decision [to approve the drug], and the efficacy is very much in question,” says Joshua D. Grill, PhD, director of the UC Irvine Institute for Memory Impairments and Neurological Disorders.

It is possible patients who take aducanumab are risking adverse events without potential clinical benefit, according to Grill. The available prescribing information does not recommend confirming the presence of brain amyloid, despite the drug being approved for lowering it, Grill says.

Initially, the available prescribing information suggested the drug was broadly approved for “Alzheimer’s disease,” and did not restrict the drug to patients with disease severity similar to those in the clinical trials (i.e., patients with mild cognitive impairment and mild dementia). “To treat moderately severe patients for whom there are neither safety nor efficacy data would be inappropriate,” Grill says.

On July 8, Biogen, the company that produces Aduhelm, announced the FDA had approved a language update for the drug’s prescribing label. The added language reads: “Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”9

On top of all this is price. Grill notes “the drug price tag of $56,000 is very high, and that is just the price from the sponsor. The patient costs are unknown at this time.” If any portion of this cost is passed to the patient (either in the form of a monthly copay or due to partial coverage), it will be more than many can afford. “This disease itself is already tremendously burdensome and costly,” Grill observes. “The amyloid scans that should be ordered to know if the drug is appropriate are not currently covered and cost several thousands of dollars.”

The cost of the drug “could be unprecedented,” says Tia Powell, MD, director of Montefiore Einstein Center for Bioethics at Albert Einstein College of Medicine in New York City. Depending on whether Medicare and other insurance companies cover the drug, and how widely prescribed it is, Powell believes this could double Medicare’s budget.

“Since it is highly unlikely that Medicare will receive twice as much money from the government, that could mean substantial cuts in other medical care for older people, including for cancer, heart disease, and all else,” Powell says.

The drug’s costs also might preclude other proven beneficial interventions (like support for caregivers and better end-of-life care) for the large number of people with moderate to severe Alzheimer’s who likely will not benefit from aducanumab, Powell adds.

Because the drug is so expensive, it is likely to include high out-of-pocket costs. “This will further exacerbate disparities in access for low-income and minority populations,” Powell laments.

“The most obvious ethical concern is that aducanumab treatment will either be limited to those in upper income brackets, or the medication will serve to drain the savings of individuals whose resources are more limited,” says David S. Knopman, MD, a consultant and professor of neurology at the Mayo Clinic in Rochester, MN.

Dementia care already is unevenly available in the United States because this type of specialty care is geographically limited.10 “Furthermore, because the clinical resources necessary to administer aducanumab safely are considerable, the geographic disparities between well-resourced health systems and safety net healthcare systems will also disproportionately reduce access to aducanumab,” Knopman offers.

Further studies might show evidence for or against benefit. “But it is unclear when those studies will happen,” says Dena S. Davis, JD, PhD, professor of bioethics at Lehigh University in Bethlehem, PA.

Most people for whom aducanumab is considered have limited decisional capacity. That means other people need to make decisions about whether the patient should take the drug. “Risks I might ethically take on myself, as a cognitively competent person, are probably much higher than the risks I would or should take on for a cognitively impaired adult,” Davis observes.

Additionally, pretesting to be eligible for the drug involves at least one PET scan and one MRI. Taking the drug involves regular MRIs and monthly infusions. “Taking this drug presents serious risks of discomfort and disruption to the lives of people whose days are already challenged by confusion and disorientation,” Davis argues.

The drug’s approval spotlights ethical challenges with clinical trials of Alzheimer’s drugs in general. Davis puts these into two categories. The first is clinical trials with participants who already are experiencing disease symptoms. “These raise the same issues of any trials that involve patients who are no longer competent,” Davis says.

For these participants, someone competent usually must give consent. That person often is a family member. “They may be motivated by a need to do something and overestimate the likelihood that the clinical trial will lead to benefit,” Davis says.

The second category is clinical trials that include participants who show markers for elevated risk for the disease but are not currently experiencing symptoms (and, in fact, they may never show symptoms).

“There is a strong belief that if a drug is to work well, it must be started long before the person shows symptoms,” Davis notes.

These trials raise complex ethical questions because they rely on some sort of marker of higher risk (a genetic marker or elevated amyloid). Ethical questions involving biomarkers are “extremely complex,” Davis says.

Biomarkers are crucial to effective research, and can help people make long-term plans. On the other hand, insurers and continuing care communities have an interest in gathering that same information to deny coverage or to raise premiums.

“There are real risks to research subjects if information gets into the wrong hands,” Davis cautions. “But there is also value to subjects who want information for planning purposes.” 

REFERENCES

  1. Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: Scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 2021;325:1717-1718.
  2. Hamilton J. For those facing Alzheimer’s, a controversial drug offers hope. National Public Radio. June 15, 2021.
  3. Hensley S, Hamilton J, Wamsley L. The FDA has approved a new Alzheimer’s drug — Here’s why that’s controversial. National Public Radio. June 7, 2021.
  4. U.S. Food & Drug Administration. FDA’s decision to approve new treatment for Alzheimer’s disease. June 7, 2021.
  5. Twitter. Dr. Janet Woodcock letter to Office of Inspector General. July 9, 2021.
  6. Chappell B. 3 experts have resigned from an FDA committee over Alzheimer’s drug approval. National Public Radio. June 11, 2021.
  7. Burton TM. FDA’s approval of Alzheimer’s drug leads to third adviser’s resignation.
    The Wall Street Journal. June 10, 2021.
  8. Belluck P, Robbins R. Three FDA advisers resign over agency’s approval of Alzheimer’s drug. The New York Times. Updated June 22, 2021.
  9. Biogen. FDA approves updated Aduhelm prescribing information to emphasize population studied in clinical trials. July 8, 2021.
  10. Kawas CH, Corrada MM, Whitmer RA. Diversity and disparities in dementia diagnosis and care: A challenge for all of us. JAMA Neurol 2021;78:650-652.

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