Biopharmaceutical Report II
By opening a National Coverage Determination (NCD) on Biogen’s (NASDAQ:BIIB)
Aduhelm (aducanumab) for Alzheimer’s disease, Medicare has signaled a willingness to
provide some level of coverage in the US without outright denying its use.
Typically, the Center for Medicare & Medicaid Services (CMS) makes coverage decisions through Local Coverage Determinations (LCDs), which largely remain unnoticed. NCDs are normally employed for controversial medical technologies.
However, in the case of Aduhelm, a former CMS official said an NCD is a promising
sign for Biogen. Since the drug has faced uniquely intense public scrutiny, most LCDs
would have denied coverage to avoid controversy. However, an NCD signals the CMS’
openness to significantly restricting the drug without completely denying coverage.
Given the thorough, transparent process of an NCD, the CMS could confidently stand
behind a decision to provide limited coverage in the face of political pressures, a
healthcare regulatory consultant explained. The CMS’ 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 studies and planned
clinical trials, subject to the population coverage restrictions applied by the CMS.
Nevertheless, there has been a trend toward more stringent NCDs and increased pressure
to avoid the same kind of controversy as the FDA faced following its Aduhelm approval,
adding 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 James Chambers, PhD, researcher, Center for the Evaluation of Value and Risk in Health, Tufts Medical Center, Medford, Massachusetts.
Chambers, who has researched trends in NCDs, noted NCDs, have almost always
provided coverage for FDA-approved therapies but occasionally deny coverage for
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, the CMS has signaled the tools available in an NCD
are more useful for granting some Aduhelm coverage than if the issue were 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. However, the 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, an NCD is very unlikely to deny Aduhelm coverage without first
pursuing every possible route to providing some form of limited coverage, he said.
Additionally, although Biogen has requested for 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
If the evidence gathered in the NCD process opposes Aduhelm, the CMS would likely
cover the drug under CED over an outright coverage denial, the former CMS official
Although 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.
Even with a CED, it is debatable whether additional data collected outside of a
randomized 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 without it, said bioethicist Leonard Fleck, PhD, professor,
Center for Bioethics and Social Justice, Michigan State University, East Lansing.
In a November 2020 FDA Advisory Committee meeting, Aduhelm’s efficacy was
overwhelmingly rebuked by a panel of experts and biostatisticians. However, in June, the FDA granted Aduhelm accelerated approval after determining the 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 a 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.
"If the evidence gathered in the NCD process opposes Aduhelm, the CMS would likely cover the drug under CED over an outright coverage denial"
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. Still, in 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 the CMS does not pursue the CED route in favor of
greater coverage, the coverage would likely come with even further restrictions, the
former CMS official said. The CMS has several options available for limiting
aducanumab’s use, including restrictions on age groups, disease severity, disease
biomarkers, and who can prescribe the treatment, the health care consultant explained.
Beyond the NCD label decision, the growing scrutiny of Aduhelm will likely further limit
the label, said George Perry, PhD, Semmes Foundation Distinguished University chair in
Neurobiology, University of Texas, San Antonio. 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, at
approximately USD 2,500–5,000, 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 the 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 USD 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 USD 2,950–8,360 per person per year.
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’ flexibility to provide some level of coverage in the face of mounting criticism could be
the best sign for Biogen, he said.
Prophylactic antibiotics may be a valuable tool to extend survival
Another possible way to help increase Pepaxto’s OS data is to use prophylactic
antibiotics, Martin said. Triple-class refractory multiple myeloma patients are already
fragile, having gone through many prior lines of therapy on top of having low bone
marrow reserves, he explained. And Pepaxto can further negatively impact these reserves,
increasing risk of infection, he added. And so, preventive antibiotics might be able to
Apart from prophylactic antibiotics, another way is to increase these patients’ leukocyte
count, especially neutrophils, to be able to combat infections, Mellqvist added. Pepaxto’s
FDA label warns of thrombocytopenia, neutropenia, anemia and infections, among
others. Patients who end up with neutropenia become highly sensitive to infections, and
severe cases can be fatal, Martin explained.
But the spokesperson noted OCEAN did allow for antibiotics as prophylaxis and was
recommended in both arms. While prophylactic antibiotics might be helpful, Schjesvold
said that the number of infections in OCEAN between arms is not dramatically different.
Pomalyst had slightly more infection events than Pepaxto in OCEAN, according to a 26
May company presentation.
OCEAN efficacy data still worth digging into
While it was judicious for the FDA to pause ongoing Pepaxto trials on the back of new
OS data, there is still potential for the treatment to be used in its present setting where
there are currently limited options, experts said. In OCEAN’s primary endpoint,
progression-free survival (PFS), final analysis shows Pepaxto was superior to Pomalyst
In OCEAN, while the OS data might favor Pomalyst, the confidence interval of the
hazard ratio shows it may not be a definitive finding, Schjesvold added. The hazard ratio
for OS of Pepaxto versus Pomalyst was 1.104, with a 95% confidence interval range of
0.846 and 1.441.
"While it was judicious for the FDA to pause ongoing Pepaxto trials on the back of newm OS data, there is still potential for the treatment to be used in its present setting where there are currently limited options"
However, based on available data so far, it might be challenging for Pepaxto to
demonstrate dramatic superiority over Pomalyst in the OS endpoint, Schjesvold said.
Pomalyst is a high bar, in contrast to Pomalyst’s registrational trial which only compared
it to steroids, Mellqvist noted. Pomalyst was FDA approved in multiple myeloma in
Oncopeptides has a SEK 3.08bn (USD 358.1m) market cap.
Reporter, New York
William Newton is a healthcare reporter for GlobalData focusing on central nervous system diseases and ophthalmology. Previously, he worked at the healthcare information firm Close Concerns, where he covered breaking news in diabetes therapeutics and technology for the company’s industry-facing publication, and at the digital health startup Fitscript, where he assisted in researching digital health and lifestyle intervention approaches to treating diabetes. He graduated Williams College with a BA in Economics and Spanish and worked as a News Editor, Executive Editor, and Managing Editor of the Williams Record.