The Food and Drug Administration’s approval of aducanumab on June 7 for Alzheimer’s disease sparked a storm of controversy over the drug’s effectiveness – and its price. The FDA’s independent advisory committee recommended against approval of the drug due to concerns about its effectiveness, but the FDA took the unusual step of overriding the committee’s decision. A month after approving the drug, the FDA restricted its use – another rare decision – and limited it to people with early or mild cases of the disease.
Substantial disagreement persists over payment for the drug – which Biogen, its developer, plans to sell under the brand name Aduhelm for $ 56,000 for a one-year plan – and whether Medicare should foot the bill, given that many scientists believe that it is largely ineffective and has significant safety. concerns.
In an article published on July 19 in JAMA, Kevin Schulman, MD, professor of medicine and director of the Clinical Excellence Research Center, or CERC, at Stanford; Michael Greicius, MD, professor of neurology and neurological sciences; and CERC Visiting Fellow Barak Richman, JD, examine the issues for regulators, payers and patients. Schulman spoke to CERC editor Laurie Flynn about the controversy surrounding the drug’s efficacy, safety and cost.
1. What are the clinical results of the aducanumab trials?
Schulman: Michael, Barak, and I took an in-depth look at the clinical trial results and statistical issues that were brought to the advisory committee. Few of the underlying assay design and analysis issues were covered by the lay press, and we felt we had the opportunity to provide some transparency on this data.
There have been two clinical trials. When a predefined combined analysis of the trials was performed, it was found that there was no benefit to the drug, and the study was terminated for uselessness. Biogen then looked at the two trials individually and found a benefit at the higher dose in one of the trials: a very modest slowing in the rate of cognitive decline compared to the placebo arm. The other identical trial showed no benefit with the same dose. Interestingly, the placebo groups in the two studies had different rates of decline, so it is not clear whether the benefit comes from aducanumab or from a more rapid deterioration in patients on placebo. In addition, aducanumab is not without risk: swelling of the brain or microhemorrhages occurred in up to 40% of the trial participants.
Ultimately, the FDA approved the drug not on the basis of clinical results, which it said left “residual uncertainties about clinical benefit”, but on the basis of a measured reduction in a biomarker – amyloid plaques in the brain. While amyloid is associated with Alzheimer’s disease, it is not clear whether amyloid is the root cause of this devastating disease or a marker for another destructive process occurring with nerve cells. No trial of amyloid-lowering drugs has resulted in cognitive improvement for patients.
2. You write that sometimes the responsibilities of the Centers for Medicare and Medicaid Services require limiting or denying what the FDA approves. What’s the right approach to make such difficult decisions, especially with such a widespread and debilitating disease like Alzheimer’s?
Schulman: There is no doubt that Alzheimer’s disease is a horrible disease. Michael and I have treated a lot of patients with this disease, and it would be very exciting to provide patients with effective treatment options. But with all the controversy surrounding science today, it’s important that the medical community be transparent about the facts, risks and benefits of therapies, and whether there is an opportunity for improvement. We know patients really want hope, but we also warn in the document that false hope could have even more serious consequences for patients and their families.
We didn’t dwell on the FDA approval; instead, we wondered if CMS should pay for this drug. Alzheimer’s disease is a disease of aging, so reimbursement comes primarily through Medicare and, for most of those hardest hit, Medicaid. The responsibility of CMS is different from that of the FDA: CMS must determine whether this therapy should be considered a covered benefit, and under what conditions and for which population. The legal criteria for what can be considered a Medicare benefit are set by law: reasonable and necessary. FDA approval is a minimum threshold for determining if something is reasonable and necessary treatment, but it’s not the only criteria for CMS.
CMS needs to be a patient advocate, addressing what is right for patients, which is difficult in this case, given the risks of this therapy and the FDA’s determination that there are “residual uncertainties” as to its advantages. CMS must also be an advocate for other Medicare beneficiaries and the general public to ensure that the drugs they cover are proven to work.
3. With most Alzheimer’s disease patients on Medicare, this means that part of the cost of the drug would be paid by taxpayers. What impact would that have?
Schulman: My mother always said that she paid her Medicare benefits because she paid Medicare payroll taxes. Unfortunately, this is not entirely true. Medicare payroll taxes support Medicare hospital benefits, or Medicare Part A. I had to explain to her that her taxes were mainly used to support people in the system when she paid the taxes, and after she retired. I paid for his Medicare hospital insurance through my Medicare payroll taxes.
Aducanumab is an outpatient infusion drug. It would be considered as part of the medical service, or part B. This part of the service is financed mainly (74%) by general tax revenues, and not by social charges. If CMS adds aducanumab as a benefit, we will all pay for the drug through our federal income taxes.
In our analysis, we calculated the per capita spending that could arise if Medicare decided to pay for it. If all Alzheimer’s disease patients with mild cognitive impairment received this drug, it would cost every American $ 211 per year. In my family with four children, we would pay $ 1,266 per year for therapy that has no proven benefit.
4. In your opinion, what are the possible intermediate solutions?
Schulman: In health policy circles we often talk about moving from fee-for-service to pay-for-value, and in writing this article we have tried to think of pay-to-value as an approach to paying back. this medicine. But we’ve also written about the challenges of evaluating benefit based on clinical trial results. Another idea is to give patients the opportunity to try this drug to see if they benefit from it, but again it is not clear if we can measure the benefit for an individual patient. Data from clinical trials do not support more traditional measures of value, such as demonstrating clinical improvement in cognition or a significant change in the ability to participate in activities.
By law, Medicare is not allowed to negotiate prices with manufacturers. This could be a circumstance where Congress decides it is time to lift this restriction – either by giving CMS the ability to negotiate the price directly with the manufacturer, or based on some of the criteria we outline in the document, as a value-based model with a conditional payment program. In this scenario, patients undergo treatment for a fixed period of time, but treatment would then be discontinued if there were no objective signs of improvement or if the disease progressed. If there is reluctance to allow CMS to directly negotiate the price of an approved product, we suggest that CMS can only cover this therapy in clinical trials, and that Congress may perhaps let CMS negotiating the price of products used in clinical trials, which would make this a very limited exception.
5. The Scientific Director of the Alzheimer’s Association, along with other strong supporters of drug approval, argue that it is better to offer something that patients can try now rather than keep them waiting for years. . What are the downsides to taking this approach?
Schulman: We don’t have inside information, but one wonders how Biogen came to justify a price tag of $ 56,000 for a product that, at best, modestly slows down the decline in cognitive status in patients. Biogen knows, along with the Alzheimer’s Association, how devastating this disease is and, frankly, how insensitive Alzheimer’s patients and their families would be to the price for an approved product even if its benefits are minimal.
The idea that patients with life-threatening illnesses may look for risks in treatment choices, overestimate the benefits, and underestimate the risks, comes from Stanford’s work in behavioral economics. As a result, patients ignore cost in treatment decisions, and this leaves them vulnerable to the exploitation, marketing and pricing strategies of pharmaceutical manufacturers.
But it’s not just a matter of the price. If this new product were to hit the market at $ 1 per day, concerns would remain about the safety and effectiveness of this therapy for patients with Alzheimer’s disease.