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July 30, 2021

Faculty voice: Alzheimer’s, the FDA, and Aducanumab

Leonard Fleck is a professor at the Center for Bioethics and Social Justice in the College of Human Medicine. The following faculty voice is repurposed from an op-ed for the Hastings Center Report regarding aducanumab and Alzheimer’s.

At this writing three members of the FDA Advisory Committee have chosen to resign in protest over the FDA’s decision to approve aducanumab for the treatment of mild cognitive impairment.  This decision is commendable.  However, it is very unlikely that their decision will alter the unwise and unjust consequences of the FDA’s approval decision. I would recommend a much stronger response which the Centers for Medicare and Medicaid Services could implement, perhaps with Congressional and judicial support.

The FDA is requiring Biogen to conduct a Phase 4 trial of aducanumab as a way of determining whether aducanumab yields any substantial benefit. That trial could take as long as nine years to complete. In the meantime, Biogen would reap billions in profits for a drug that current evidence suggests is of both uncertain value and uncertain efficacy. What is at stake?

There are 6.2 million Americans diagnosed with some degree of Alzheimer’s who are over age 65. Roughly half of them currently have mild cognitive impairment.  These are the individuals who would potentially benefit from aducanumab.

Biogen has indicated that aducanumab will have an average price of $56,000 per year. Given that 3.1 million individuals with mild Alzheimer’s over age 65 would all be eligible for Medicare coverage, the potential cost to Medicare per year would be $173 billion. Aducanumab is given by monthly infusion. Roughly 40% of patients on higher doses of aducanumab experienced brain swelling or small vessel brain bleeds. This requires either MRI or PET brain scans to monitor these potential side effects on a regular basis for at least the first year of treatment. Consequently, the first-year additional costs for the infusions and brain scans are estimated to be $30,000 per patient, or an additional $93 billion in potential costs to Medicare. That figure would be reduced by 50% for each subsequent year of treatment. This is what is at stake as a result of that FDA decision.

Aducanumab does reduce β-amyloid plaque in the brain. Advocates for the drug contend that this is a reasonable basis for concluding that the drug is clinically effective. Critics point out that several prior drugs have reduced amyloid in the brain with no more than marginal and temporary cognitive improvement.  Dr. David Knopman, who resigned from the advisory committee and who is a clinical neurologist at the Mayo clinic, is quoted as saying, “Biomarker justification [reduced amyloid] for approval in the absence of consistent clinical benefit after 18 months of treatment is indefensible.” What can be done?

I would propose limiting reimbursement for the drug to the actual cost of drug production: No marketing costs, no research costs, no executive salary costs, no inflated overhead. I would add 5% as a profit margin. That number would likely be in the $2,500-$5,000 range. Biogen would have the opportunity to determine whether the drug is significantly clinically effective without putting Medicare finances and taxpayer resources at risk for a drug that has not been able to prove itself thus far to provide meaningful clinical benefit. Critics will still see this as a waste of resources. In fairness, critics do not know with certainty that this is the case.

We can readily imagine the message that Biogen and the Alzheimer’s Association will craft to propel demands for aducanumab among patients and families who see themselves as being at risk for advancing Alzheimer’s dementia. Such desperation should be acknowledged, but false hopes should not be encouraged. Generating false hopes is both unethical and unaffordable. Providing very limited reimbursement for the drug yields access to the drug for desperate patients and families without unjustly squandering Medicare resources. I recognize this proposal will create a significant burden for clinicians caring for these patients.  They will need to be especially careful in conveying to patients the risks of brain swelling and small vessel brain bleeds for the very small and uncertain benefits that research with aducanumab has demonstrated so far. This is another ethical issue that must be considered.

Finally, I imagine Biogen will not welcome this proposal. However, it would certainly motivate speedier effort to complete a Phase 4 trial. Also, if the trial were successful enough, any years lost on the patent clock could be restored. If the trial were not successful, the drug would be removed from the market. There are other drugs similar to aducanumab in the pipeline, such as donanemab. My proposal would establish an important precedent for those pharmaceutical companies. They could expect the same crimped profits (and potential revenue losses from accrued research expenses) if they could not prove decisively that their drug yielded substantial clinical benefit at a reasonable cost. This would be a memorable lesson.

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