FDA stokes controversy with Alzheimer’s drug approval – what will it mean?

By Max Rex, Consultant

Email: [email protected]

On Monday 7th June, the FDA approved aducanumab, the first new treatment for Alzheimer’s in 18 years. Aducanumab, manufactured by Biogen, was granted accelerated approval by the FDA based on results from Phase III trials showing reduction of amyloid beta plaque in patients’ brains.

Aducanumab approved in spite of negative recommendation from FDA advisory committee

This approval has been shrouded in some controversy for a number of reasons. In November 2020, an FDA advisory committee voted strongly in opposition of approving the drug, based on its current data – 0 out of 11 advisors considered the drug ready for approval. The expert panel did not believe that the evidence supported that aducanumab could slow cognitive decline. In the few days since the approval was announced, three members of the independent committee have resigned in protest, and the fallout from this decision may not be over.

It is not unheard of for the FDA to go against the recommendation of one of its advisory committees and occurs around 20% of the time. Sarepta’s Exondys 51 is the most famous example – it was granted accelerated approval by the FDA in 2016 for the treatment of Duchenne Muscular Dystrophy (DMD), despite the advisory panel voting against it. The approval was based on a very small trial (12 patients) that measured a surrogate endpoint. However, the committee in that instance voted 7-6 against accelerated approval, a far closer result than that of aducanumab. The additional studies requested by the FDA for Exondys 51 have still not been completed, but the drug has brought in significant revenue for Sarepta since launch. There were concerns at the time of its approval about the impact of the Exondys 51 decision on the future of FDA accelerated approvals and looking back now it seems that since that point, the agency has been more willing to accept drugs with data on surrogate endpoints that are not proven beyond doubt to have an impact on the disease.

Pressure mounting on FDA leadership

Given the near unanimity of the advisory committee’s recommendation not to approve aducanumab, the decision by the FDA puts it in an unprecedented situation. The wider implications of this move for the FDA and the backlash that will result from it are difficult to predict. In the last few days, one of the leading non-profit consumer rights advocacy groups, Public Citizen, has called for the resignations of acting commissioner Janet Woodcock and other senior leaders in the FDA, specifically due to this decision. Public Citizen’s letter to Secretary of Health and Human Services (HHS), Xavier Becerra, called the decision “one of the most irresponsible and egregious decisions in the history of the agency”.

In the most recent P4A podcast, the delay in nominating a new permanent FDA commissioner was discussed. Although Janet Woodcock remains the favorite to take on the role permanently, this decision and the public backlash could put further pressure on her candidacy. Questions were raised by Woodcock not releasing a statement or joining the FDA panel announcing the aducanumab decision, but it appears that President Biden is still happy with her leadership and the approval of the drug (via Politico).

How will Medicare respond to this monumental approval?

This approval also puts Medicare in a difficult situation. With a list price of $56,000 annually and a large target population covered by Medicare, this will have a significant budget impact for the public insurance program. Aducanumab was approved for a very wide label (“the treatment of Alzheimer’s disease”), of which there are an estimated 6 million patients covered by Medicare. Even assuming a fraction of those patients are treated, the costs to Medicare from this drug alone could be in the $10s or $100s of billions per year. Given this potentially enormous impact on the Medicare budget, it is possible that the Centers for Medicare and Medicaid Services (CMS) will produce a National Coverage Determination (NCD) for all Medicare beneficiaries. This NCD could be used to limit the population of patients who are eligible for aducanumab, such as limiting to the trial population or potentially even more restrictive. Medicare aims to limit reimbursement to patients who are likely to experience a benefit from a particular treatment, and given the clinical benefit from this product is far from certain, the possibility of restriction seems like a viable option.

Further fuel for the drug pricing reform debate

Biogen have come under fire from many stakeholders over their pricing strategy for the drug. The Institute of Clinical and Economic Research (ICER), a non-profit organization that assesses the value of new drugs, concluded that there is little evidence of any benefit to patients from aducanumab treatment, and suggested that to be considered cost-effective, the price would have to be in the range of $2,500 and $8,300 annually per patient.

Democratic members of both the Senate and House of Representatives, including Senator Ron Wyden, have come out strongly against the high price and believe this is further evidence to support the need for Medicare to be able to negotiate drug prices directly with manufacturers, something that is currently not possible. Many of these Democrats have been calling for such price controls to be introduced for some time, so this new development is hardly groundbreaking. The question is whether any Republicans can be brought on side – as of yet, there is no sign of any change following this development. In fact, many Republicans have voiced their support for the approval, and see it as a development that will lead to further investment in developing innovative new drugs.

Will this result in meaningful change?

Although there has been significantly more backlash to this decision than previous controversial decisions, it is still unclear that this will result in any fundamental changes. On the side of the FDA, there is increased pressure on the President’s upcoming decision on who to nominate to lead the FDA, and it could lead to increased scrutiny of the accelerated approval system. There has already been discussion around the suitability of the process, with ICER publishing a report into its shortcomings. However, it is perhaps more likely that the opposite occurs, and this is a sign that we will see more accelerated approvals based on more limited and controversial data.

The argument over drug pricing reform in the US will continue unabated, with fundamental differences limiting any significant changes in the short-to-medium term. Perhaps the most interesting aspect of the ongoing aducanumab story to witness unfold will be how CMS handles its reimbursement. A decision by CMS to limit reimbursement could be an important precedent for weakening the link between FDA approval and CMS reimbursement.



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