FDA Approval of New Alzheimer’s Drug May Harm More Than It Helps

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This post is a part of our Bioethics in the News series

By Jennifer Carter-Johnson, PhD, JD

On June 7, 2021, the United States Food and Drug Administration (FDA) approved a controversial new Alzheimer’s Disease drug—aducanumab—to be sold by Biogen under the name Aduhelm. Alzheimer’s disease is estimated to currently be affecting over 6 million Americans plus their families, who must watch the mental decline of their loved ones and provide increasing levels of care as the disease progresses.

Controversy

Unfortunately, the approval of Aduhelm has generated a large amount of controversy because the FDA approval came despite the rejection of the studies of the drug’s efficacy by the FDA advisory committee. The opposition to the FDA’s approval has been so heated that three of the eleven-person advisory committee have resigned.

Detailed discussions of the science behind Alzheimer’s disease and the Aduhelm clinical studies can be found elsewhere. In summary, as Alzheimer’s disease progresses, protein plaques—amyloid and tau—build up in the patients’ brain. The progression of these plaques correlated with decreased mental acuity in patients. Therefore, drug candidates that target these plaques have been of interest to scientists for many years.

While the clinical data associated with Aduhelm supported a decrease in brain plaques in early-stage Alzheimer’s patients, the data did not show that decreasing plaques by the drug resulted in slowed progression of Alzheimer’s disease. In addition, the data showed that some patients have brain swelling as a result of the drug. Using this data, the FDA approved Aduhelm for broad use for all Alzheimer’s patients.

FDA Approval Process

Generally, to gain approval to sell a new drug, a company will complete a series of clinical trials to determine if a drug candidate is safe and effective for a given disease. Safety and efficacy are balanced against each other and consideration is given to the severity of the disease to determine if approval will be granted. As an example, a highly effective drug that is also highly toxic would not be approved as a simple headache remedy but may be approved as a treatment against a fast-growing, inoperable form of brain tumor. Conversely, an ineffective drug should never be approved no matter how safe it is—such are the wares of snake-oil salesmen of the past.

The FDA also has an Accelerated Approval pathway to allow drugs for diseases that have few treatments to proceed to market more quickly. It is under this accelerated path that the FDA approved Aduhelm. The accelerated pathway allows companies to use biomarker changes rather than disease improvement to show efficacy in the drug approval process. The FDA used the decrease in amyloid plaques as the biomarker for approval of the new Alzheimer’s drug—despite the fact that the clinical trial studies were submitted to show efficacy against disease progression. Moreover, the advisory committee was not informed of potential accelerated approval. Only after the clinical trial data was found unacceptable by the advisory committee did the FDA switch to the accelerated approval pathway. Perhaps most importantly, other drug candidates have been abandoned after amyloid plaque removal did not halt progression of the disease, so biomarkers may not be effective ways to judge the halt of Alzheimer’s progression.

The accelerated approval is, in effect, a contingent approval. Biogen will be allowed to sell Aduhelm, but it must gather data as to whether the drug is actually effective. If clinical data does not eventually support reduced disease progression, then the FDA can rescind the approval, and Biogen will no longer be able to sell the drug. The FDA’s approval of the Aduhelm may be harmful in the long run for several reasons.

Medicine IV infusion
Image description: A close-up photo of an IV drip containing clear liquid. Image source: stux/Pixabay.

Trust in FDA

The move by the FDA to approve Aduhelm could lead to a decrease in trust in the agency. First, the controversial nature of its approval over the recommendations of the scientists who reviewed the data created a controversy that is playing out across the news media as people wonder why an ineffective drug has been approved.

In fairness, the accelerated approval process is contingent, but due to the way the accelerated approval was used scientists did not have the opportunity to weigh-in on the use of biomarkers in that approval. That way in which the accelerated approval process was tapped, only after the regular approval process seemed doomed to fail, may well erode trust that the FDA evenly applies its own rules. Additionally, it is very difficult to rescind these accelerated approvals, and if the drug approval is rescinded public perception will likely be highly negative. Finally, according to Biogen it may take up to nine years to gather the data to complete the required studies.

New Drug Development

Aduhelm is not the only drug candidate in its class in clinical trials for Alzheimer’s disease treatment. Other drug candidates that include patients who receive a placebo rather than the drug candidate are undergoing clinical trials. Since these studies tend to be double-blinded—neither the doctor nor the patient knows if the drug or the placebo has been administered—patients will likely drop out of these other studies in order to be assured of receiving some drug. Thus, Alzheimer’s drug development will be slowed, in favor of a drug that has no demonstrable efficacy. Additionally, these new drug manufacturers may also ask for similar approval, based on biomarkers that may not be indicative of clinical effectiveness.

False Hope

Patients and Alzheimer’s advocates pushed for approval of this drug. But a drug with contingent approval may give these patients and their families false hopes. We have seen in Right to Try legislation–legislation allowing patients to use un-approved drugs in the FDA approval pipeline–both a fundamental lack of understanding of the FDA approval process as well as the desperation of patients for whom there are no clear treatment options. I have argued before that Right to Try laws prey on the emotionally fragile. Here the FDA’s controversial accelerated approval may have the same result—patients clamoring for a drug that does not work.

In addition, the cost of the drug will be borne by insurance companies that may well decide not to cover the drug. While the drug is approved for all stages of Alzheimer’s, clinical studies were only aimed at early-stage disease. In effect, the FDA has shifted its responsibility as gatekeeper for effective drugs to insurance companies for whom profit is a driving force.

Drug Cost

The cost of Aduhelm in light of the lack of efficacy data presents its own problems. Biogen has indicated that the average yearly cost of Aduhelm will be $56,000, not including the cost of doctors, hospital or clinic visits, and supplies to receive the infusions, or the cost of brain scans to monitor for swelling and brain bleeds as side effects. This cost, like most drugs, will be passed on to consumers through direct payments, increased insurance premiums, and higher budget expenditures for Medicare and Medicaid. One study reported that if 500,000 people on Medicare are prescribed the drug, it would cost $29 billion per year with copays of over $11,000 per year.

Biogen defends its pricing of the drug. According to its own press release, Biogen “established the price of Aduhelm based on the overall value this treatment is expected to bring to patients, caregivers, and society.” This expected value seems high for a drug that may not work but admittedly reflects normal drug company calculations in a system where insurance covers most prescriptions and the uninsured either do without or rely on the generosity of the drug company.

Because FDA approval is contingent, the FDA can remove the drug from the market if the required data do not show efficacy. However, the money paid for the failed treatment regime will not be refunded. Patients are paying to take this risk.

In the end, the FDA’s approval of Aduhelm will impact the way the agency is perceived, and the way other companies approach the drug approval process. Neither of these changes will be for the better.

Jennifer Carter-Johnson photo

Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law at the Michigan State University College of Law.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Monday, July 5, 2021. With your participation, we hope to create discussions rich with insights from diverse perspectives.

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Continue reading “FDA Approval of New Alzheimer’s Drug May Harm More Than It Helps”

Dr. Cabrera a co-author of new article in ‘Journal of Alzheimer’s Disease’

Laura Cabrera photoA new article from Center Assistant Professor Dr. Laura Cabrera and co-authors has been published in the Journal of Alzheimer’s Disease. The article, “Alzheimer’s Disease in the Latino Community: Intersection of Genetics and Social Determinants of Health,” was co-authored by Irving E.Vega, Laura Y. Cabrera, Cassandra M. Wygant, Daniel Velez-Ortiz, and Scott E. Counts.
Abstract
Alzheimer’s disease (AD) is the most common type of dementia among individuals 65 or older. There are more than 5 million diagnosed cases in the US alone and this number is expected to triple by 2050. Therefore, AD has reached epidemic proportions with significant socioeconomic implications. While aging in general is the greatest risk factor for AD, several additional demographic factors that have contributed to the rise in AD in the US are under study. One such factor is associated with the relatively fast growth of the Latino population. Several reports indicate that AD is more prevalent among blacks and Latinos. However, the reason for AD disparity among different ethnic groups is still poorly understood and highly controversial. The Latino population is composed of different groups based on nationality, namely South and Central America, Mexico, and Caribbean Hispanics. This diversity among the Latino population represents an additional challenge since there are distinct characteristics associated with AD and comorbidities. In this review, we aim to bring attention to the intersection between social determinants of health and genetic factors associated with AD within the Latino community. We argue that understanding the interplay between identified social determinants of health, co-morbidities, and genetic factors could lead to community empowerment and inclusiveness in research and healthcare services, contributing to improved diagnosis and treatment of AD patients. Lastly, we propose that inserting a neuroethics perspective could help understand key challenges that influence healthcare disparities and contribute to increased risk of AD among Latinos.

The full text is available on the IOS Press website (MSU Library or other institutional access may be required to view this article).

Death the Leading Remedy for Alzheimer’s

Bioethics-in-the-News-logoThis post is a part of our Bioethics in the News series. For more information, click here.

By Tom Tomlinson, Ph.D.

Back in the middle of March, there was a flurry of news about a study by Rush University researchers, reporting that the death rate from Alzheimer’s disease was much higher than previously thought. (James et al.). The New York Times and Washington Post both noted that according to the researchers’ estimate, Alzheimer’s disease kills an estimated 500,000 people a year. This makes it the third leading cause of death in the US, right behind the big killers, heart disease and cancer, and catapults it up from its previous sixth place ranking.

In the Washington Post article, Keith Fargo, director of Scientific Programs and Outreach at the Alzheimer’s Association, complained that the study demonstrates that Alzheimer’s disease research is woefully underfunded compared to heart disease and cancer, receiving only $500 million from NIH in 2012. More recently, a New York Times columnist noted that Alzheimer’s disease causes more deaths in the US in one year than AIDS did in three decades. Alzheimer’s disease needs a social movement to combat society’s ageist neglect, she suggested, just like AIDS needed Act Up to combat homophobic disinterest in combating that disease.

thank-you-flatlineMy first problem with all this hoopla is that death is far from the worst thing about Alzheimer’s. Things wouldn’t be better for Alzheimer’s sufferers if somehow, everything else being equal, they lived longer because of it. Quite the contrary, things would be much worse, if you agree with the overwhelming majority of people who think that a severely demented life is worse than death. (Gjerdingen et al.; Williams et al.)

It’s a blessing, then, that the immediate cause of death for Alzheimer’s patients is not Alzheimer’s itself, but its consequences—becoming increasingly immobile, bedbound, and unable to swallow and protect the airway. These in turn lead to malnutrition, dehydration, and infections, including pneumonia (the most common reported cause of death for persons with Alzheimer’s). These conditions can be fatal, but can also often be successfully treated, at least in the short term. When they occur in the Alzheimer’s patient, therefore, they present an opportunity to withhold treatment so that patients can die rather than survive in a condition they would almost certainly find unacceptable.

So chances are, the proximate cause of death for many Alzheimer’s patients is a merciful decision to withhold treatment. Until we find something better, it may be the best remedy we have. It’s the remedy prescribed in my advance directive, where I ask that my life not be prolonged by any means if I become irreversibly disoriented x 3, and unable to coherently communicate with those around me. I recommend it, and hope that 9 out of 10 doctors do as well.

The other problem here is the idea that death is something to be beaten back, no matter what the age. Not very surprisingly, the Rush University researchers reported that the median survival following diagnosis of Alzheimer’s dropped with age: 4.4 years for those 75-84, compared to 3.2 years for those 85 and over. More strikingly, a British study reported that the median age at death for persons with Alzheimer’s is 90 for women, and 87 for men. (Xie et al.) Life expectancy at birth in the UK was 82 in 2012, according to the World Bank. It’s a cruel irony that the persons most at risk of Alzheimer’s disease are the ones lucky enough to have lived longer than expected.

So now my question is whether there should be some age-related limit to our efforts to conquer death. We might first take that to be a question about fairness. In the context of limited resources—for delivering medical care or doing medical research—is it unfair to focus on those conditions that affect the young more than the old? One very influential argument claims that doing so is not unfair, if opportunity for a normal human lifespan is what we think should be equally distributed. (Daniels) The young person with AIDS has a long life ahead of him if we can prevent his death from that disease. The (very) old person with Alzheimer’s has already enjoyed his chance for a full life. On this conception of fairness, it’s ethically bizarre to draw a parallel between Alzheimer’s disease and AIDS, by suggesting that the resources devoted to them should be the same.

But there is a second way to understand the question about limits, that’s not a matter of fairness, and that goes deeper. Imagine that resources for medical care and research are unlimited, so that money spent on extending the lives of the elderly carries no price for the lives of the young. Should conquering death at any age be our goal, and the measures of our success not just rising life expectancy at birth, but at 65, 85, 105… ?

I confess I’m highly ambivalent. On the one hand, so long as I’m getting a kick out of life, more of the same sounds like just what the doctor ordered. But will I be getting as much kick at 90 as I got at 20? Do people get tired of living only because they’re tired of suffering the effects of illness and disability? Or does life itself become stale at some point, just more of the same old, same old? If there is such a thing as this existential ennui, a terminal illness with good palliative care gives me a way out. But if my ennui strikes at 80, and my terminal illness is still 25 years away, what do I do? Hmm. Suicide, or soma?

And what might be the social consequences, as more and more of the population is older and older, and still healthy?

And still working? Whether yes or no, either answer might have consequences for the younger persons still waiting for employment or promotion, or paying more to support the growing leisure class.

And still capable of new ideas? Humans are creatures of habit, and the longer we practice our habits, the more deeply entrenched they become. If death is one of the great lubricants of human progress, is pursuing immortality really a good idea?

A bunch of questions that leads only to the wimpy conclusion that conquering death may not be an unambiguous good.

When it comes to Alzheimer’s disease, then, I’d rather conquer dementia.

References:

Bahrampour T. New study ranks Alzheimer’s as third-leading cause of death, after heart disease and cancer. The Washington Post. March 5, 2014. http://www.washingtonpost.com/local/new-study-ranks-alzheimers-as-third-leading-cause-of-death-after-heart-disease-and-cancer/2014/03/05/8097a452-a48a-11e3-8466-d34c451760b9_story.html

Bellafante G. Alzheimer’s, a Neglected Epidemic. The New York Times. May 15, 2014. http://nyti.ms/1lvSRz8

Daniels N. 1985. Just Health Care. New York: Cambridge University Press

Editorial Board. High Mortality From Alzheimer’s Disease. The New York Times. March 12, 2014. http://nyti.ms/1grdmKO

Gjerdingen DK, Neff JA, Wang M, Chaloner K. 1999. Older Persons’ Opinions About Life-Sustaining Procedures in the Face of Dementia. Archives of Family Medicine 8: 421-423.

James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K, Bennett DA. 2014. Contribution of Alzheimer’s disease to mortality in the United States. Neurology 82(12):1045-50.

Soma in Aldous Huxley’s Brave New World http://www.huxley.net/soma/somaquote.html. Accessed May 2014.

Williams N, Dunford C, Knowles A, Warner J. 2007. Public attitudes to life-sustaining treatments and euthanasia. International Journal Of Geriatric Psychiatry 22: 1229–1234.

Xie J, Brayne C, Matthews FE. 2008. Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up. BMJ Feb 2;336(7638):258-62.

tomlinsonTom Tomlinson, Ph.D., is the Director of the Center for Ethics and Humanities in the Life Sciences and a Professor in the Department of Philosophy at Michigan State University.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, June 12, 2014. With your participation, we hope to create discussions rich with insights from diverse perspectives. You must provide your name and email address to leave a comment. Your email address will not be made public.