US prospects for contentious AD drug

Table of Contents National determination could be a positive signCED route last resort over denialPrecedent…

Need to know:

  • The Center for Medicare & Medicaid Services is making a national determination on whether to cover Biogen’s Aduhelm for Alzheimer’s disease.
  • Medicare drug coverage decisions typically take place at the local level, but a national determination grants more flexibility to provide some limited form of coverage
  • A much more restrictive label and the Coverage with Evidence Determination process are both viable outcomes with significant uptake implications.

 

By opening a National Coverage Determination (NCD) on Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease, the US’s Medicare has signaled a willingness to provide some level of coverage without outright denying its use.

Typically, the Center for Medicare & Medicaid Services (CMS) makes coverage decisions through Local Coverage Determinations (LCDs), which can largely go under the radar. Meanwhile, NCDs are normally employed for controversial medical technologies.

But in the case of Aduhelm, a former CMS official said an NCD is a promising sign for Biogen. Because the drug has faced uniquely intense public scrutiny, most LCDs would have denied coverage to avoid controversy. However, an NCD signals CMS’s openness to significantly restricting the drug without completely denying coverage.

Given the thorough, transparent process of an NCD, CMS could more confidently stand behind a decision to provide limited coverage in the face of political pressures, a healthcare regulatory consultant explained. And arguably CMS’s best tool for narrowing coverage—the rarely used Coverage with Evidence Determination (CED) process—is only available via an NCD, a bioethicist added. A CED would only provide Aduhelm coverage to patients in open-label studies or enrolled in future, planned clinical trials, subject to the population coverage restrictions CMS applies.

Nevertheless, a trend toward more stringent NCDs and pressure to avoid the kind of controversy that befell the FDA following its Aduhelm approval add uncertainty to the process.

On 29 July, the expected nine-month NCD process began with an open public comment period. Biogen did not respond to a request for comment.

National determination could be a positive sign

Under an NCD, all Medicare Administrator Contractors (MACs) – which normally make Medicare coverage decisions on the regional level – are bound to follow the NCD outcome. Historically, NCDs are extremely rare for drugs, with almost all NCDs taking place for medical devices, said Tufts Medical Center researcher Professor James Chambers. Chambers, who has researched trends in NCDs, noted that NCDs have almost always provided coverage for FDA-approved therapies but occasionally deny coverage for devices.

Given the unprecedented backlash against Aduhelm, the safest – and most likely – decision from MACs would be to deny Aduhelm coverage because its evidence does not meet Medicare coverage requirements, the former CMS official, now a regulatory consultant, said. As a result, the decision to pursue an NCD is likely a positive sign for Biogen, he explained. By pursuing this route, CMS has signaled a recognition that the tools available in an NCD are more helpful to granting some Aduhelm coverage than if left to regional MACs, he said.

Nevertheless, LCDs give the manufacturer multiple opportunities to gain regional coverage without the risk of national noncoverage as a result of one NCD, Chambers noted. But CMS normally strongly considers the impact of any debilitating condition on patients and their families in its coverage decisions, the former official noted. And as a result, it is very unlikely an NCD would deny Aduhelm coverage without first pursuing every possible route to providing some form of limited coverage, he said. In addition, though Biogen has requested MACs to make coverage decisions while awaiting the NCD, it is unlikely any MAC would make a coverage decision given all the attention Aduhelm garners, the former CMS official said.

CED route last resort over denial

In the likely scenario that evidence gathered in the NCD process mounts against Aduhelm, CMS would likely cover the drug under CED over an outright coverage denial, the former CMS official said.

Though the CED process is exceedingly rare and normally unexpected for an FDA-approved drug, the unprecedented scrutiny of the Aduhelm decision and competing political pressures make it a much more likely outcome, said a Medicare healthcare consultant. Still, this decision would be largely unprecedented, as a CED designation is typically reserved for “close call situations” when the CMS decides more evidence is needed for a Medicare-specific population, the former CMS official explained.

But even with a CED, it is debatable whether additional data collected outside of a randomised control trial would be valuable, Chambers noted. Because Aduhelm is intended to slow disease progression—rather than stop or reverse progression—it is unclear if patients who experience cognitive decline on Aduhelm are gaining no benefit or if they would have been worse off without it, said bioethicist Professor Leonard Fleck of Michigan State University’s Center for Bioethics and Social Justice.

In a November 2020 FDA Advisory Committee meeting, Aduhelm’s efficacy was overwhelmingly rebuked by a panel of experts and biostatisticians. But in June, the FDA granted Aduhelm accelerated approval after determining demonstrated reduction in amyloid plaque is “reasonably likely” to translate to clinically meaningful improvement on cognitive decline.

As part of the accelerated approval process, Biogen has nine years to complete a confirmatory trial establishing whether reduction in amyloid plaque does in fact translate to clinically meaningful disease outcomes. If the trial fails to do so, the FDA could remove marketing authorization for Aduhelm.

Precedent for narrower label

On 7 June, the FDA granted Aduhelm accelerated approval for all Alzheimer’s disease patients, despite clinical testing only covering mild patients. But on an 8 July press release, Biogen said Aduhelm should be used in patients with “mild cognitive impairment or mild dementia stage of disease”.

Beyond this initial narrowing, if CMS does not pursue the CED route in favour of greater coverage, it is likely the coverage would come with even further restrictions, the former CMS official said. CMS has several options available for limiting aducanumab’s use, including restrictions on age group, disease severity, disease biomarkers, and who can prescribe the treatment, the healthcare consultant explained.

And beyond the NCD label decision, it is likely the growing scrutiny of Aduhelm will, in effect, further limit the label, said Professor George Perry, Semmes Foundation Distinguished University chair in Neurobiology at the University of Texas at San Antonio. That is, clinicians will be reluctant to prescribe the drug given its safety and efficacy concerns, and it is likely many would try and sway patients against its use, Perry explained.

Medicare hampered by bargaining, cost analysis restrictions

In an ideal scenario, Medicare would cover Aduhelm at the price of manufacturing of approximately $2,500 to $5,000 plus a modest profit for Biogen, Fleck said. However, given the enormous restrictions on Medicare, this outcome is far from likely, he noted. Medicare cannot negotiate prescription drug prices, nor does it explicitly consider cost in its coverage decisions, Chambers explained.

The FDA is tasked with determining if a drug is “safe and effective”, while CMS determines if a drug is “reasonable and necessary” with no specific mandate related to cost-effectiveness. Biogen announced Aduhelm will have a list price of $56,000 per patient per year. However, to be cost-effective, the Institute for Clinical and Economic Review (ICER) independently determined Aduhelm should be priced at $2,950 to $8,360 per person per year.

But overall, the NCD process can only determine if and to what extent a drug should be covered, and it does not deal with the amount Medicare will reimburse for a specific drug or device, the former CMS official explained. As a result, considering Medicare’s many restrictions and the unprecedented scrutiny surrounding Aduhelm, the NCD process’s flexibility to provide some level of coverage in the face of mounting criticism could be the best sign for Biogen, he said.