This month’s decision by the U.S. Centers for Medicare & Medicaid Services (CMS) to limit coverage of the Alzheimer’s drug Aduhelm to patients enrolled in clinical trials not only dealt a blow to over 3 million Americans who are experiencing mild symptoms of Alzheimer’s but also to patients awaiting other innovative therapies and drugs.
The National Coverage Determination (NCD) by the agency, despite approval of the drug by the U.S. Food and Drug Administration (FDA), will significantly influence future innovation and investments in novel therapies, experts at the Biotechnology Innovation Organization (BIO) explained.
On an institutional level, the main message “is that CMS doesn’t believe the scientific determinations of FDA,” said John A. Murphy, III, BIO’s Chief Policy Officer.
“The market would take that as a signal that future access to certain innovative new products may suffer similar problems,” he said. “It may well be that we see less investment in certain areas.”
The decision is a “significant departure, a significant change” in the way CMS has always operated, said Crystal Kuntz, BIO VP of Healthcare Policy & Research.
“If a Medicare beneficiary has a specific illness and there is FDA-approved treatment for it, they go to their doctor, they get the treatment, a claim is submitted to the Medicare program, and it’s paid. End of story. That’s how the world works today,” said Kuntz. “This isn’t a case where they’ve looked at the coverage differently. They essentially made a national non-coverage decision.”
CMS ‘does not have the expertise’
FDA approved Aduhelm for patients with mild symptoms of Alzheimer’s under the FDA’s accelerated approval process, which permits “earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit,” according to the FDA.
Numerous studies have found that amyloid plaque is a marker of Alzheimer’s and that it contributes to the disease, so the FDA used amyloid plaque as a surrogate endpoint in its trials of Aduhelm.
“FDA determined that by clearing the amyloid plaque, which is what the drug has been shown to do, they could extrapolate that it would have an effect of slowing cognitive decline, which is called a primary endpoint. So in this case, FDA determined, under the Accelerated Approval Path, that the surrogate endpoint of clearing the amyloid plaque was sufficient to allow the drug to be approved,” Murphy said. “CMS has, individually, determined it wants to see more clinical studies to prove the theory that amyloid plaque clearing slows the cognitive decline.”
The CMS decision was not only problematic because it introduces uncertainty regarding FDA decisions, but also because CMS does not have the scientific expertise to make this kind of decision, said Kuntz, who worked at CMS for eight years.
“By nature, what CMS does is different than FDA, and the expertise they have is very different,” she said. “It’s very fair to say that CMS does not have the expertise to make these kinds of decisions.”
Uncertainty for drug development
The reason Congress created the FDA’s Accelerated Approval pathway is that it allows faster development of drugs for incurable conditions such as Alzheimer’s. But the CMS Aduhelm decision “now adds a barrier to the access to those products,” according to Murphy, who said CMS justified the Aduhelm decision by saying “this is a rare circumstance.”
“This is precedent-setting that would make it easy for CMS to just keep pointing out ‘oh this is a unique circumstance’. The next time there’s an accelerated approval drug that they have any questions about, they now have a precedent they can look to,” Kuntz warned.
CMS put no parameters in place for how it used its judgment in this case and how it might determine to use that similar judgment in future cases, the BIO experts said.
“The rest of the market is left without any guidance from CMS as to when it will usurp the FDA’s scientific determinations and will supplant its own. So, it is a demonstrably chilling impact on future innovations,” Murphy said.
He pointed out that CMS made it clear this decision is not only for drugs in the accelerated approval pathway. CMS announced that “it is going to apply to any drug in this class, regardless of its approval pathway, and so, I do think it will color the investment decisions of researchers in new, novel therapeutic areas,” Murphy said.
“It’s going to cause folks to be more aggressive in how they evaluate where to allocate scarce R&D dollars,” he explained. “It is going to be a specific and necessary analysis that any product’s sponsor will have to undergo to determine whether or not the product’s investment is a worthwhile one.”
The way forward
Kuntz said she believes a complete reversal of the CMS Aduhelm decision is highly unlikely. “CMS doesn’t want to rescind something once it has done it,” she said. “Once they’ve drawn that line in the sand they don’t want to say, ‘we were wrong’. There are so many things they could’ve done, but they went to the very extreme.”
Still, Kuntz said, there are many avenues, both politically and patient-driven, that patient’s rights advocates and biotech industry advocates can take in terms of pushing for changes to prevent anything like this from happening again.
Murphy maintained that CMS should be made to clarify its position—including defining the evidence it is going to require before it decides “to remove this NCD and provide a broader access to Alzheimer’s patients” and “the standard that it is going to use to determine when to stop applying this restrictive coverage protocol.”
“CMS has done nothing to tell anyone about that process,” he said, adding that they apparently ignored the many members of Congress who have criticized the CMS decision-making.
With more clarity, the experts said, patients, drugmakers, and investors might be able to return some predictability to the process for approval of new medicines. As it stands now, the situation is very uncertain.