The Approval of Aducanumab Scares Me. It Should Scare You Too.

The practice of medicine is based upon the Hippocratic Oath. This oath, attributed to the Greek physician Hippocrates, set the ethical framework for our profession over two thousand years ago. Scholars revised this oath to fit the changing ethics of modern-day society, yet many of its core tenets remain the same. Today, four main principles guide medical doctors- patient autonomy, beneficence, nonmaleficence, and justice. Hospital ethics committees often use these four principles to determine what separates an ethical decision from an unethical one. These four principles are briefly summarized below [1]:

• Patient autonomy- The belief that patients are allowed to make medical decisions regarding their own health without undue outside influence
• Beneficence- All actions physicians take should be for the good of the patient
• Nonmaleficence- All actions physicians take should not cause more harm than good; “First, do no harm”
• Justice- All patients should have equal access to healthcare

Unfortunately, we practice medicine in an environment where it is impossible to adhere to all four principles. A disjointed multi-payer healthcare system prevents physicians from providing the same quality of care to all patients. Often, physicians are unable to treat patients due to exorbitant drug prices. Furthermore, hospital systems may pressure physicians to over-treat patients and order tests and procedures that have little therapeutic value due to financial incentives and a litigious healthcare system. One could argue that healing is a business, not a virtue.

Despite these shortcomings, medicine has benefited from the FDA’s rigorous approval process for prescription drugs. The FDA (Food and Drug Administration) has required two large-scale human clinical trials that show the drug’s effectiveness versus placebo or control, with a few minor exceptions [2]. These rigorous clinical trials take years but are required to maintain the public’s trust in currently marketed medications. Take, for example, the Pfizer and Moderna vaccine Emergency Use Authorization (EUA) granted by the FDA. These two vaccines were tested in thousands of patients before the EUA and continue to show efficacy and safety within  millions of vaccinated people [3]. Yet, vaccine hesitancy remains a challenge, as less than 60% of the US population is fully vaccinated.

Aducanumab is a drug developed by Biogen for use in Alzheimer’s patients. It removes a pathological hallmark feature of Alzheimer’s disease, beta-amyloid plaques. These beta-amyloid plaques have spurred the Amyloid Hypothesis, a hypothesis that proposes plaques are the main pathological reason behind the memory and cognitive decline these patients experience. Aducanumab is highly effective in removing these plaques, and patients receiving the drug show markedly reduced levels of beta-amyloid plaque. As a result, the FDA forwent the traditional approval process and approved the drug based solely on the drug’s ability to remove this surrogate marker [4]. This ‘accelerated approval process’, based on removing a surrogate marker, has been used before for HIV and cancer medications [5]. This approval process is logical for these conditions, as HIV and cancer patients may be too ill to wait years for a new drug to go through rigorous clinical trials.

The problem is that there is serious doubt regarding the legitimacy of the Amyloid Hypothesis. More than 30 different clinical trials failed after drugs successfully targeting beta-amyloid plaques didn’t result in cognitive benefits [4]. Moreover, Aducanumab itself essentially failed clinical trials, as an FDA advisory committee almost unanimously voted that there was not enough evidence for its approval. More damning, Biogen stopped Aducanumab’s clinical trials midway through after a futility analysis determined the drug was likely ineffective [6]. Interestingly, after a post hoc data analysis and a closed-door meeting with an FDA official, Biogen decided to apply for FDA approval anyway. At the time of writing this, three advisory committee members have resigned, and the FDA chief has called for an independent investigation into the approval of Aducanumab [6 7]. Pressure from physicians has also led the FDA to change the drug label to indicate it should only be used for early-stage Alzheimer’s patients [8]. Yet, the damage is done. As you read this, elderly and cognitively impaired patients are being shuttled to treatment centers to receive IV infusions of a drug that lacks evidence of clinical efficacy.

Perhaps the saddest and striking aspect is that patients taking Aducanumab are required to undergo MRIs to monitor the potentially lethal side effect of cerebral edema [9]. This horrifies me. This drug could kill someone. Yet, the FDA still approved it. The FDA approved a drug that failed to show clinical efficacy for a desperate patient population. A patient population that consists of individuals being slowly robbed of their cognitive ability. A patient population that lacks the autonomy to appreciate the risks and potential benefits (if any) of Aducanumab. Furthermore, even if the drug was hypothetically effective, it costs $56,000 a year [5]. This price tag puts Aducanumab out of reach for hundreds of thousands of Alzheimer’s patients. Unfortunately, physicians may feel a moral obligation to recommend the drug as Alzheimer’s patients have few options.

By bringing this medication to market, the FDA allows the medical community to violate all four tenets of medical ethics. First, without evidence of its effectiveness, we violate beneficence. Second, with evidence of its dangerous side effects, we violate nonmaleficence. Third, with the drug’s price tag, we violate justice. Finally, with the drug’s patient population, we violate autonomy. 

Aducanumab symbolizes what is wrong with medicine today. Yet, working with USF physicians has given me hope that we can make a difference. We can all make a difference by entering medicine for altruistic reasons. We must advocate for the four tenets of medical ethics when we graduate. We must fight back against the approval of medications and of legislation that goes against these tenets, just as we have done with Aducanumab. Only then can we heal the institution of medicine.

1. Addai EA. Medical Ethics: A Physician’s Guide to Clinical Medicine: Fulton Books, Inc., 2021.

2. Darrow JJ, Avorn J, Kesselheim AS. FDA Approval and Regulation of Pharmaceuticals, 1983-2018. Jama 2020;323(2):164-76 doi: 10.1001/jama.2019.20288[published Online First: Epub Date]|.

3. Mishra SK, Tripathi T. One year update on the COVID-19 pandemic: Where are we now? Acta Trop 2021;214:105778-78 doi: 10.1016/j.actatropica.2020.105778[published Online First: Epub Date]|.

4. Hooker JM. FDA Approval of Aducanumab Divided the Community but Also Connected and United It. ACS Chem Neurosci 2021 doi: 10.1021/acschemneuro.1c00393[published Online First: Epub Date]|.

5. Rosenthal E. Why we may never know whether the $56,000 Alzheimer’s drug actually works. Washington Post 2021 July 7th, 2021.

6. de la Torre JC, Gonzalez-Lima F. The FDA Approves Aducanumab for Alzheimer’s Disease, Raising Important Scientific Questions. Journal of Alzheimer’s Disease 2021;Preprint:1-2 doi: 10.3233/JAD-210736[published Online First: Epub Date]|.

7. Lovelace Jr B. Biogen stock falls after FDA calls for federal investigation into Alzheimer’s drug approval. Secondary Biogen stock falls after FDA calls for federal investigation into Alzheimer’s drug approval  2021.

8. Brooks M. FDA Updates Label for Controversial Alzheimer’s Drug Aducanumab (Aduhelm)   Secondary FDA Updates Label for Controversial Alzheimer’s Drug Aducanumab (Aduhelm)   2021.

9. Hershey LA, Tarawneh R. Clinical Efficacy, Drug Safety and Surrogate Endpoints: Has Aducanumab Met All of Its Expectations? Neurology 2021:10.1212/WNL.0000000000012453 doi: 10.1212/wnl.0000000000012453[published Online First: Epub Date]|.