The verdict is in—but what now? The Centers for Medicare and Medicaid Services will only cover aducanumab in the context of a clinical trial. Impassioned lobbying on both sides of the issue moved the agency to make a few changes from its draft decision laid out in January, but as per the final ruling, all anti-amyloid immunotherapies approved by the Food and Drug Administration will be subject to “coverage with evidence development.” CED is a restrictive process CMS uses when it wants more data about the effects of a new treatment.

  • CMS spelled out three questions it wants answered before providing full coverage for anti-amyloid antibodies.
  • The questions address whether the benefits of treatment outweigh harms in the general Medicare population.
  • CMS promised to swiftly reconsider its decisions once sponsors generate new data on clinical benefit.

The April 7 announcement sparked headlines and strong reactions, and yet it left many researchers confused about what this National Coverage Determination (NCD) actually means for the development of these therapies. The 67-page decision memo was written by CMS analysts led by Tamara Syrek Jensen. It contains a wealth of detail that explain key issues and is worth a deeper examination. Here's an Alzforum primer to help you understand the nuances of this important decision.

For starters, the final decision did answer some questions researchers had asked about how the proposed CED process would work. For example, CMS will cover Aduhelm and tests ascertaining the presence of brain amyloid in FDA-required confirmatory trials, and it loosened proposed restrictions such as requiring the drug to be administered in a hospital.

Essentially, the final decision creates two pathways for obtaining full coverage. One is for antibodies that have accelerated approval based on amyloid removal, the other is for antibodies with traditional approval based on clinical efficacy data. The former need to complete at least one additional randomized controlled trial (RCT), but the latter can use registry-based comparative studies or pragmatic trials, which compare treatment options in routine clinical practice.

Why ask for additional information on anti-amyloid antibodies with demonstrated efficacy? Because CMS wants answers to three questions: whether the treatment's clinical benefit replicates in the general Medicare population, whether certain subgroups experience different benefits and harms, and how those benefits and harms change over time.

CMS acknowledged that these requirements would limit Medicare participants’ access to anti-amyloid immunotherapies in the near future. The agency said this is necessary due to the high risk of the brain edema and microhemorrhages known as ARIA, which in the aducanumab Phase 3 trials occurred in 41 percent of people on drug (Oct 2021 news; Dec 2021 news).

“It is appropriate access that matters, and we have real concern about potential harms to Medicare patients … CMS needs evidence that an anti-amyloid monoclonal antibody for the treatment of AD demonstrates improved health outcomes, with reasonable risk of harm, in broader community practice and in the broader Medicare population,” the agency wrote. This evidence would enable anti-amyloid immunotherapy to meet the “reasonable and necessary” criteria CMS uses for coverage of new treatments, it added.

A Field Divided
Among Alzheimer’s researchers, reactions to the final decision fell along established lines, mirroring their response to the earlier draft decision. For that, supporters had outnumbered detractors by 2:1, though fewer supporters weighed in with detailed comments this time. Russell Swerdlow at Kansas University Medical Center, Kansas City, reflected this group's overall view. “The CMS approach is reasonable. To me it looks like a compromise between stakeholders with different perspectives,” he wrote (full comment below).

The critics were more vocal. “This is essentially a non-coverage decision,” said Paul Aisen at the University of Southern California, San Diego. Stephen Salloway at Butler Hospital in Providence, Rhode Island, said the 20 patients taking aducanumab at his center would likely have to stop treatment. “With this decision, CMS has effectively taken away the ability of patients with a terminal illness and limited treatment options to weigh the risks and benefits of this new FDA-approved medication with their doctor and determine if it’s right for them,” Salloway wrote (full comments below).

Some critics complained that CMS was setting the bar higher for Alzheimer’s than it has for other diseases such as cancer. “Requiring agents to show effects in the general population before coverage is unprecedented,” said Dennis Selkoe at Brigham and Women’s Hospital, Boston. He co-wrote an editorial with Jeffrey Cummings at the University of Nevada, Las Vegas, objecting to the ruling (STAT news). John Dwyer, who leads the Global Alzheimer’s Platform (GAP) foundation, told Alzforum, “This NCD has no parallel in terms of its restrictiveness.”

CMS acknowledged this is the first time it has required an RCT for a drug/biologic, though it has required RCTs for other types of treatment, such as vagus nerve stimulation for depression. The agency said its request for additional data is justified because no drug has yet meaningfully slowed the progression of AD, and plaque reduction has not been established as a reliable surrogate of clinical benefit. CMS pledged to swiftly reconsider this NCD once its three CED questions are answered.

Unsurprisingly, companies developing anti-amyloid antibodies are disappointed. “We are ultimately discouraged by the final CMS NCD,” Genentech said in a statement. Genentech/Roche’s anti-amyloid antibody gantenerumab will complete Phase 3 trials at the end of the year. Roche will apply for regular FDA approval, i.e., can now anticipate registry-based requirements. “If approved, we are committed to partnering with CMS and other relevant payers to optimize access to gantenerumab for as many patients as possible,” the company wrote (full comments below).

Lobbying Blitz
How did the field wind up here? Approval of this first anti-amyloid antibody was controversial from the get-go, with the FDA’s advisory committee voting no and the agency then pivoting to accelerated approval without outside feedback (Nov 2020 news; Jun 2021 news). While this put aducanumab on the market, its cost, currently $28,200 per year, means it will be widely used only if insurance covers it. Amid fears the expense could bankrupt Medicare, CMS initially proposed limiting coverage of all anti-amyloid antibodies to clinical trials that it approves (Jan 2022 news). Private insurers typically follow CMS’ lead.

The proposal unleashed a torrent of heated commentary pro and con. CMS received a record 10,025 comments during the 30-day comment period (Feb 2022 news). In its final ruling, CMS noted that 65 percent of these comments supported its proposal, 7 percent opposed it, and 27 percent had an unclear stance. In the latter category, making up 18 percent of the total, were about 1,800 comments from a letter-writing campaign advocating for people with Down’s syndrome to be able to access aducanumab and other anti-amyloid antibodies. Aducanumab has not been trialed in people with Down’s.

In addition to this deluge, advocacy groups lobbied for CMS to change its proposal. The controversy caused schisms. In one notable example, after the Alliance for Aging Research held a rally in front of CMS headquarters, more than half its scientific advisory board resigned in protest. The resignations occurred partially at the urging of another group, PharmedOut, which lobbies against the influence of the pharmaceutical industry (STAT news). For its part, Biogen hired a former transportation lobbyist who is related to U.S. Congressman James E Clyburn, D-SC, to help it prevail in D.C. (FiercePharma news).

Accelerated Approvals Need Additional Clinical Trials
So what exactly does the CMS memorandum say? CMS maintained the RCT requirement for aducanumab and any future anti-amyloid antibodies approved under the accelerated pathway. That said, CMS specified that any RCT approved by the FDA or NIH qualifies; trials do not have to get approval from CMS to be covered. For aducanumab, this means the drug will be covered in its FDA-required confirmatory trial, Envision. CMS noted this modification was in response to concerns about CMS-required trials duplicating the efforts of the FDA. CMS was vague about how many RCTs would be required. Conceivably, solid data showing a clinical benefit from a completed Envision might suffice. As of this writing, screening for this trial is set to start in May.

Medicare will also reimburse for “routine items and services” that are part of the trial. This includes an amyloid PET scan, which would be covered under the IDEAS CED study for those agents (Aug 2020 conference news). The IDEAS CED allows only one amyloid PET scan in a person’s lifetime. Alzheimer’s researchers have asked CMS to remove this restriction so an antibody trial can measure change in amyloid load in response to treatment, and the agency said it is considering it.

CMS left unclear if “routine services” also include infusion costs and MRI scans needed for safety monitoring. Even if they do, critics noted that trials incur administrative services, infrastructure, personnel, and data analysis costs as well, which are unlikely to be covered. Because of this expense, and the other anti-amyloid antibodies coming along in the near future, Alzheimer’s researchers expect no one but Biogen to invest in an aducanumab RCT. “Clinical use of aducanumab is essentially restricted to those wealthy enough to pay for treatment,” Aisen said. CMS said this is appropriate for the time being, given the uncertainty about the drug's benefits and harms.

Traditional Approvals Need Registry-Based Studies
Even for future anti-amyloid antibodies that show clear clinical efficacy and receive FDA approval by the traditional pathway, CMS wants more data on benefits and harms before it offers full coverage. In a change from the draft decision, CMS said these studies can be “prospective comparative studies” approved by CMS. However, the agency does not specify what the comparator should be. Possibly, patients on drug could be compared to patients who choose not to take the drug, or to historical data on disease progression, or even to a different anti-amyloid antibody. All such CED studies must be listed in clinicaltrials.gov and report their findings in a timely manner.

“The CMS document is seemingly intentionally vague on how comparative effectiveness studies would be designed. How much leeway would be allowed in such a registry/study?” asked David Knopman at the Mayo Clinic in Rochester, Minnesota (full comment below).

These CED studies are for amyloid-positive people with mild cognitive impairment or mild AD. Amyloid positivity can be determined by any method supported by the peer-reviewed literature, presumably including CSF and blood tests. In another change from the draft proposal, CMS specified no exclusion criteria. This was in response to concerns about excluding people with Down’s syndrome from trials. The final ruling gives researchers discretion to run a variety of studies in different populations, including people with co-morbidities who were barred from the clinical trials used for FDA approval, the agency said. These might include vascular or metabolic conditions common in old age.

CMS also relaxed restrictions on what type of providers can administer anti-amyloid antibodies and be covered, indicating that outpatient departments or infusion centers could now qualify. Critics had charged that the original restriction to hospital settings would have de facto shut out people in rural areas. Despite the broader range of settings allowed, CMS stressed the importance of these facilities having a multidisciplinary team and the ability to monitor safety by MRI.

The outcome measure for these CED studies must evaluate both cognition and function. CMS listed the CDR-SB, MMSE, or ADAS-Cog as possibilities, but did not mention newer, more sensitive composites such as the ADCOMS or iADRS. Any outcome measure must have been independently validated and used in prior trials.

On the question of what constitutes a “meaningful clinical benefit,” CMS spelled out that it considers this to be a statistically significant difference on a prespecified composite measure that combines cognition and daily function, in accordance with the 2018 FDA guidance. It is no coincidence that leading researchers in the field are debating this question with renewed urgency (Liu et al., 2021; Assunção et al., 2022).

CED Questions: Bricks on The Road to Full Coverage
The purpose of such prospective comparative studies is to answer three CED questions. The first is whether anti-amyloid antibodies are as effective in the general Medicare population—where many people have co-morbidities—as they were in the highly selected trial population.

As part of its effort to gather findings representative of the general population, CMS will require CED studies to reflect the racial/ethnic diversity of the U.S. population with MCI or mild AD. The agency does not specify how diverse that population is, but a 2018 study found that among the 5.8 million Americans over 65 who have AD or a related dementia, 72 percent are white, 12.5 percent black, 10.2 percent Hispanic, 3.6 percent Asian, 0.7 percent Native American, and 1 percent multiracial (Matthews et al., 2019). 

Few AD studies have come close to achieving 28 percent diversity. The Bio-Hermes biomarker study run by GAP reached 22 percent, making it one of the most diverse AD studies to date, Dwyer noted (Apr 2021 news). Eisai reported reaching 33 percent in its worldwide Phase 3 Clarity trial of lecanemab, and Biogen has committed to 18 percent in Envision (Nov 2021 news).

The second CED question asks whether the antibody at hand has a different risk/benefit profile in specific subpopulations, such as people with cardio- or cerebrovascular disease or diabetes, or people in different ethnic groups. This could also include differences seen with age or APOE genotype. With this question, CMS is likely responding to concerns about a greater risk of ARIA in certain groups, such as APOE4 carriers, and wants to learn whether this risk would be managed as closely in general practice as it is in specialty clinics.

To this point, leading Alzheimer’s clinicians recently updated their Appropriate Use Recommendations for anti-amyloid antibodies. They now call for APOE genotyping, an assessment of cardiovascular disease, inflammation, and seizure risk, and additional MRIs to catch edema early. The updated AUR also articulate guidelines for stopping treatment due to ARIA (Aug 2021 conference news; Cummings et al., 2021). 

Finally, CMS wants to know how the benefits and harms of treatment change over time. The agency specified it is not asking for studies that assess when to stop treatment, or how long the treatment effect lasts. “Due to the extended follow-up that may possibly be needed, we are not requiring these questions, but would highly encourage the development of such evidence for patient treatment decision-making,” the agency wrote. It left unsaid how much follow-up it wants to see.

Will these CED studies work as intended? Alzheimerologists had their doubts. Eric Siemers at Siemers Integration LLC said registry-based studies typically assess safety, not efficacy. Knopman agreed. “Detecting a genuine improvement in health outcomes will be impossible in an observation registry, but adverse event rates and treatment adherence could be determined reasonably well,” he wrote. Ranjan Duara at Mount Sinai Medical Center in Miami Beach, Florida, thinks the many different medical conditions and variable Alzheimer's disease progression rates in the general population would make data analysis a “nightmare.” Researchers also worried that some patients would decline joining a registry, or drop out early (full comments below).

Step Up, Anyone? On the question of what groups would run such registries, AD researchers are more optimistic. Both the Alzheimer’s Association and UsAgainstAlzheimer’s are developing such registries already, dubbed ALZ-NET and ADEA, respectively (Nov 2021 conference news; Feb 2022 news). Biogen might nest its iCARE post-market study within ALZ-NET, Dwyer told Alzforum (Aug 2021 conference news).

GAP coordinates a network of trial centers in the U.S. and Canada and has aided AD trials with recruitment (Mar 2019 conference news). It wants to assist with CED studies as well. “We would advocate for it to be extraordinarily efficient, minimizing the burden on patients and practicing physicians,” Dwyer said. He hopes CMS will flesh out the framework in its decision memo to guide researchers with more detail on what kind of comparators would be acceptable. CMS has no neurologists on its staff, nor specific expertise in developing AD trials, Dwyer noted.

Quibbles aside, the requirement for registry-based studies is far easier to meet than the RCTs that had been proposed in the draft decision. “I am pleased that CMS backed away from binding the class,” Marwan Sabbagh at the Barrow Neurological Institute in Phoenix wrote to Alzforum (full comment below).

Still, many chafed at any CED requirements for drugs that show clinical efficacy in Phase 3. “We believe that anything short of full coverage to label for anti-amyloid treatments where the Phase 3 program delivers direct evidence of clinical benefit, as we expect from TRAILBLAZER-ALZ 2, deprives patients of the access they deserve,” Eli Lilly said in a statement. Lilly’s Phase 3 study of donanemab is expected to read out next year. Unlike many anti-amyloid antibody trials, this study did not exclude people with co-morbidities.

CMS promised to quickly reconsider its NCD once the three CED questions have been answered. Importantly, the agency said that the more rigorous the Phase 3 findings are for a given antibody, the less rigorous CED studies need to be. Moreover, CMS held out hope that CED could be skipped altogether if Phase 3 provides a “high level of evidence” of efficacy. This was defined as a body of data with few deficiencies, and stable findings that can be generalized to the Medicare population in broad community practice settings.

Eisai researchers were encouraged by this. “Eisai believes Clarity AD has a robust design, which could meet the “high level of evidence” criteria set forth by CMS in the NCD decision memo if the result is positive; therefore, creating the potential for CMS to reconsider full coverage of lecanemab should it be approved by the Food and Drug Administration,” the company said in a statement. Eisai, Lilly, and Genentech/Roche each sent a brief statement (see below), but did not respond to specific questions.

What About the Long Game? The CMS decision seems to lay to rest fears of bankrupting Medicare, and Health and Human Services Secretary Xavier Becerra promised to consider lowering Medicare premiums based on it (STAT news). Some critics decried the focus on cost, with the Wall Street Journal editorial board accusing CMS of rationing care (WSJ story). In its decision memo, CMS stated that, as a matter of department policy, cost was not a consideration in determining this NCD. Some researchers were skeptical. “I think CMS is understandably concerned about the cost to Medicare and society,” Selkoe noted.

Given that Medicare reimbursement will stay limited for now, will state Medicaid programs have to pick up the tab? CMS did address this, noting that for people with dual Medicare and Medicaid coverage, the NCD applies to both programs, hence Medicaid would not cover Aduhelm. For people insured only by Medicaid, it would be covered, and state programs can control cost via prior authorization and medical necessity criteria.

Some researchers expressed dismay about mixed messages from the FDA and CMS. “Better collaboration between FDA and CMS is required to accelerate drug development, innovation, and investment in AD research,” Salloway wrote. The new FDA director, Robert Califf, has pledged to improve the hand-off between the agencies (STAT news).

Others see a lesson for the field in these stumbles. The lack of consensus that plaque reduction meaningfully improves a person’s disease led to this restrictive coverage decision, they say. “If we don’t have confidence in a surrogate endpoint that’s reasonably likely to predict clinical benefit, the field is at a huge scientific and regulatory disadvantage,” Dwyer told Alzforum. “Cancer is further along in this regard. The neurology field hasn’t done the hard work to get there.” Until the field comes to an agreement on validated surrogate endpoints, accelerated approvals are likely to remain an unworkable option for bringing antibodies to patients, he predicted.

For the time being, perhaps this quote best captures the essence of the CMS deliberations: “Medical innovation must include clinical trials that demonstrate benefit to patients,” the agency wrote. “Covering a drug that has not been shown to be effective may incentivize production, marketing, and sales of similarly ineffective drugs.”

For its part, Biogen on April 20 withdrew its application for aducanumab approval in Europe (Endpoints news). The European Medicines Agency had rejected the application last year, and Biogen initially planned to appeal the decision (Dec 2021 news).—Madolyn Bowman Rogers

Comments

  1. The CMS approach is reasonable. To me it looks like a compromise between stakeholders with different perspectives. In this debate were stakeholders who are willing to take their chances with an intervention of unproven efficacy and known side effects, provided that intervention is affordable to them. In this case the intervention in question is not affordable to most, and they were hoping a third party would pick up the cost. However, doing so could have negative consequences in that it could slow the development of innovative research that could ultimately provide the degree of benefit people really want to see, and which aducanumab is very unlikely to deliver.

    In doing it this way, CMS avoids a hard no on reimbursement, while stressing that before it goes all in we simply need more information. They pass this challenge back to those who really believe in aducanumab.

    Now it’s up to those who really believe Aduhelm is the best we can do to treat AD to figure out a way to confirm or refute that supposition. To that end, CMS is incredibly generous in its offer to subsidize those studies. In the meantime, they seem to be asking the right questions, specifically: Does it meaningfully improve health outcomes, do the benefits outweigh the harms, and do the benefits and harms change over time? Usually we get answers to these questions before a drug is approved. This, though, is a different situation. To that point I agree with CMS, we need to push toward getting answers to these questions.

    I also agree that, for any monoclonal that is approved through the accelerated pathway because it cleared plaques but did not pass the established hurdles for demonstrating efficacy, these questions need to be answered before going all in.

    Regardless, I hold onto the hope that when it comes to treating AD, ultimately we will reach a level of knowledge that will suggest interventions that do a way better job than we are currently able to.

  2. This is essentially a non-coverage decision. The FDA granted accelerated approval to aducanumab based on evidence from multiple trials of aducanumab (PRIME and EMERGE), lecanemab, and donanemab that substantial amyloid reduction in brain is associated with clinical benefit. CMS has decided that this FDA decision does not warrant coverage.

    Remarkably, despite an enormous body of evidence (including highly compelling genetic evidence), CMS does not accept a causative role for amyloid accumulation in AD. The text of the decision summarizes the CMS view of the etiology and diagnosis of AD as follows: “The etiology of AD is unknown and may be multifactorial; clinical diagnosis is poor (Beach et al., 2012; Knopman 2001) and can be improved by biomarkers, but to a degree that is debated; the role of Aβ as cause vs marker of disease remains controversial.” 

    With this CMS decision, clinical use of aducanumab (and any other anti-amyloid antibodies given accelerated approval) is essentially restricted to those wealthy enough to pay for treatment on their own.

    It is unclear that the CMS coverage of the cost of treatment within approved trials has any significance. CMS is not funding such trials, just the cost of treatment and amyloid PET. It is likely that the only trial that would meet CMS criteria for this coverage is the Biogen post-marketing study required by the FDA.

    References:

    . Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol. 2012 Apr;71(4):266-73. PubMed.

    . Cerebrospinal fluid beta-amyloid and tau proteins for the diagnosis of Alzheimer disease. Arch Neurol. 2001 Mar;58(3):349-50. PubMed.

  3. We are disappointed with the final CMS NCD, which essentially denies access to treatment with aducanumab and future amyloid-lowering treatments receiving accelerated approval. Aducanumab will only be available to patients who can afford to self-pay and the 20 patients currently receiving aducanumab at our center will likely be discontinued as a result of the decision.

    Alzheimer’s disease is a progressive illness, ultimately leading to disability and death. Prolonging time in a milder stage of disease is associated with greater independence and quality of life. Patients’ voices and preferences need to be heard and respected. With this decision, CMS has effectively taken away the ability of patients with a terminal illness and limited treatment options to weigh the risks and benefits of this new FDA-approved medication with their doctor and determine if it’s right for them.

    CMS stated their NCD is based on their view that patients with early AD are doing well and should not be exposed to treatments with significant risk, but I suspect the main reason behind the decision is due to the potential cost to the Medicare program. CMS took a similar approach in denying coverage for FDA-approved amyloid and tau PET tracers, which are not used in clinical practice even though they are very helpful in making an early and accurate diagnosis of AD. Medicare beneficiaries helped make these advances possible and they deserve to have access to them.

    A more reasonable coverage decision would be coverage with evidence development that utilizes an open-access, prospective, longitudinal design to monitor safety and efficacy aligned with a national treatment registry. The Alzheimer’s National Registry for Treatment and Diagnostics, currently under development by the Alzheimer’s Association, in partnership with the American College of Radiology, the American College of Neuroradiology, and the Brown Center for Biostatistics, will provide critical real-world data on safety and efficacy with the oversight needed to ensure the appropriate patients are being treated.

    Our Memory and Aging Program has treated more than 90 patients with aducanumab, many of those patients for more than five years. This number includes 26 patients since FDA approval 10 months ago. Providing amyloid-lowering drugs safely is essential, and the Alzheimer’s Disease and Related Disorders Therapeutic Working Group has published and recently updated recommendations to help guide the use of aducanumab in clinical practice (Cummings and Salloway, 2021). 

    What is the precedent for making a coverage determination for future drugs that may be approved when the safety and efficacy data is not available? Will CMS be applying these same restrictions to drugs approved for cancer through accelerated approval or require a registry-based CED for cancer drugs receiving full approval?

    The coverage decision for future FDA-approved amyloid-lowering antibodies should not be arbitrarily tied to the initial NCD for aducanumab, but be made independently based on each drug’s efficacy, side effects and level of FDA approval. CMS has suggested they want to be nimble in the future and revise coverage restrictions as data on new drugs become available. I hope this is true, but so far that has not been the case.

    Better collaboration between FDA and CMS is required to accelerate drug development, innovation, and investment in AD research. We look forward to important Phase 3 trials reading out over the next 12-18 months. Though treatment options are very limited in the short term, we are at a turning point in the treatment of AD, and I am hopeful that these treatments and other strategies will be successful over time.

    Disclosures:
    Dr. Salloway was co-chair of the Investigator Steering Committee for the aducanumab Phase 3 studies and site PI for the PRIME and ENGAGE studies. He was a site PI for the donanemab Phase 2 and lecanemab Phase 3 studies. He was the Project Arm leader for the DIAN-TU gantenerumab study. He is a member of the planning committee for the Alzheimer’s National Registry for Treatment and Diagnostics. Dr. Salloway is the lead author of the report of ARIA in the aducanumab Phase 3 program. He is also an author of Aducanumab: Appropriate Use Recommendations. He provides consultation to Biogen, Eisai, Lilly and Roche. He owns no stock or royalty interest in any pharmaceutical or biotech company.

    References:

    . Aducanumab: Appropriate use recommendations. Alzheimers Dement. 2021 Jul 27; PubMed.

    . Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2021;8(4):398-410. PubMed.

  4. The CMS Decision Memo issued on April 11 is a complex document. There are two separate coverage with evidence development (CED) determinations. For the first, the requirement for participation in a randomized controlled trial to cover an anti-amyloid monoclonal antibody that received FDA approval based on a change in a surrogate biomarker such as amyloid lowering made sense to me. Despite the absolute certainty in some quarters that amyloid lowering is necessarily good for patients, the fact is that, in the case of aducanumab, there was a striking dissociation between amyloid lowering and the lack of convincing clinical benefit in the two Phase 3 trials. It was rather brave of CMS to stand up and say in effect: “Amyloid lowering is not sufficiently established as a predictor of clinical benefit.” The CMS CED covering agents approved by FDA under an accelerated approval mechanism has definitely made accelerated approval less attractive.

    The second CED concerns anti-amyloid monoclonal antibodies approved by the FDA based on demonstration of clinical benefits. Rather than agreeing to cover such agents without restriction, CMS will require participation in a registry supporting comparative effectiveness studies (not necessarily randomized nor controlled) in order to establish whether the agents “improve health outcomes in Medicare beneficiaries.”

    The CMS document is seemingly intentionally vague on how comparative effectiveness studies would be designed. How much leeway in such a registry/study would be allowed is unclear. I would be thrilled if qualifying patients were tracked in some sort of user-friendly national registry (such as used in the IDEAS study) that collected a minimum amount of data and left the longitudinal outcomes to later extraction from Medicare databases. Detecting a genuine improvement in health outcomes will be impossible in an observation registry, but adverse event rates and treatment adherence could be determined reasonably well. The randomized, placebo-controlled trials that are about to report for donanemab, gantenerumab, and lecanemab are the best shot we have to learn about clinical benefits.

  5. The CMS decision on aducanumab made on April 7 was an unprecedented action for CMS, i.e., refusing to reimburse a medication that has received accelerated approval from FDA. This disagreement could be decided ultimately by Xavier Becerra, Secretary of HHS. While many may feel that CMS has overextended its bounds relative to FDA, their decision for aducanumab will stand.

    Perhaps more important is that the decision memo indicates that other monoclonal antibodies for Alzheimer’s disease may be required to have a CED even if they have a full rather than accelerated approval. This issue has received substantial discussion already, and advocacy groups will have additional inputs regarding this position. Other monoclonal antibodies in clinical trials, e.g., gantenerumab, lecanemab, donanemab, and ACU193 by Acumen have differing selectivity for different forms of Aβ or amyloid, and therefore may have distinctly different benefit/risk profiles compared to aducanumab. These differences have important implications for patients and their families, and CMS should judge each by its own clinical data rather than imposing a CED before their data are available.

    An important clarification in the CMS decision is that a CED for a mAb that receives FDA accelerated approval could utilize a study performed by the pharmaceutical company as part of an FDA requirement or could be funded by NIH. Apparently a specific “CMS study,” as described in the draft CMS decision, is not necessary. Remaining questions include who would provide a grant application to NIH for such a trial, and how CMS might be involved in an NIH-funded study. Such questions are likely to be difficult to resolve and require substantial time to reach agreement. 

    For mAbs that receive FDA full approval based on clinical data, CMS will continue to require a CED, but CMS changed the categorical term used to describe CED studies from "prospective longitudinal studies" (in the proposed decision) to “prospective comparative studies” (in this final decision). The phrase “prospective comparative studies” (emphasis added) is ambiguous since what is being compared is not specified. If a drug is compared to placebo, the study is in fact an RCT. Using a currently available symptomatic drug such as a cholinesterase inhibitor as a comparator is not possible since over half of patients are already taking one of these medications.

    CMS indicates that a “registry” may be able to satisfy the CED requirement. Registries are typically used when the FDA requires a Risk Evaluation and Mitigation Strategy (REMS) and generally they are used to address a specific safety issue, not an efficacy issue. If the comparator is a placebo, a “registry” would simply be the dataset of a RCT. This ambiguity creates confusion and will slow the availability of new medications to patients with AD.

    Other apparent requirements by CMS in their decision are not likely to be possible. CMS notes that the CED could be lifted when the question is answered “Does the antibody meaningfully improve health outcomes in the general clinical population (as opposed to the trial population, which tends to be healthier)?” Phase 3 trials try to simulate “real world” populations, but addressing this question precisely is unrealistic. The CMS decision notes that to lift the CED, an understanding of “Do the benefits and harms of the treatment depend on specific patient characteristics, or on the doctor or setting where care is provided?” is needed. These are reasonable questions for clinical care, but regardless of the amount of data available, a full understanding of these issues is generally not possible. These questions indicate that CMS has an unrealistic view of AD drug development that is worrisome, and unfortunate for patients and their families.

    One important consideration that came from the open comment period and the CMS decision is how aducanumab should be studied for patients with Down’s syndrome. Given the increasing longevity for people with Down’s, many of them will develop Alzheimer’s pathology in their fifth decade and cognitive impairment in their sixth decade.  However, given that the benefit/risk ratio of aducanumab and other monoclonal antibodies is not known for patients with Down’s, clinical trials in this population are urgently needed. 

    In summary, CMS has taken the unprecedented position not to reimburse as “reasonable and necessary” a medication that was given accelerated FDA approval based on a biomarker that FDA has determined is “reasonably likely” to predict clinical benefit. While the CMS criteria of “reasonable and necessary” should not be influenced by cost or impact to the CMS budget, one cannot help but speculate that conscious or unconscious bias on the part of CMS may have influenced their decision.

    The data for aducanumab are complex and difficult to understand completely. Within in the next 18 months, data from Phase 3 studies for three different antibodies will become available. CMS should evaluate these unique antibodies on their own merits, without regard to the evaluation of aducanumab.

  6. I believe the three specific questions posed by CMS are essentially non-starters, for the following reasons:

    1. The cost of Aduhelm is only a small fraction of the cost for organizing a study that could conceivably answer any one of those CED questions. It would require an investment of funds and recruitment of personnel which only a large pharmaceutical company could afford. Which pharmaceutical company, other than Biogen, would even begin to consider funding such a study?
    1. The RCT would need to be on a general clinical population, in which retention of participants is likely to be poor, for the duration in time required to answer any of those questions. The number of participants who would need to be recruited would likely be so large that the study would be unaffordable.
    2. The heterogeneity in the symptomatology, the rate of progression of the disease, the response to the treatment, and the frequency and type of adverse effects is likely to be much greater in the general clinical population than in a typical, carefully selected RCT population. This would make the analysis of the data a nightmare, and almost guarantee that the drug will be deemed ineffective.
  7. This final decision was almost inevitable. I am pleased that CMS backed away from binding the class, but the huge initial enthusiasm for Aduhelm that has diminished precipitously will be dampened further. There have been real and substantive challenges to deploying Aduhelm, so access to date has been limited. Most clinicians, except those who have clinical trial infrastructures at their disposal, may not add Aduhelm to their menu of options for treatment.

    Other companies in the class (Roche, Lilly, Eisai) will likely prepare for the possibility for post-approval RCTs or registries. Registry studies should be run by large consortia who can be more exacting in determining outcomes. Outcomes might include, in addition to the continuous variables, time-to-event analyses, quality-of-life analyses, and pharmacoeconomic analyses. 

    The mAbs have the potential to alter the trajectory of decline and might affect change beyond removal of amyloid. They will only address the needs of a minority of MCI/AD patients who meet criteria, which leaves a majority of patients with unmet needs.

    One huge concern with the CMS decision is the adjudication of science by controlling reimbursement. This is the second time it has been done in the AD field, and makes clinicians wonder why AD patients are not as deserving as other groups of patients for innovations that have the potential to positively impact lives.

  8. It was notable that CMS broadly “stuck to their guns” and adjusted the proposed NCD in only relatively minor ways. Essentially, CMS basically have taken a position that they won’t accept accelerated approval for mAb drugs (at least until the surrogate has been better validated).

    The decision is unprecedented for various reasons. CMS rarely, if ever, has restricted access to newly FDA-approved Part B drugs, and certainly has not limited Medicare beneficiaries’ access in this way, i.e., through being enrolled in clinical studies. However, important context is that FDA approved the drug through accelerated approval, and that there is notable uncertainty about the validity of the surrogate endpoint, reduction in Aβ plaques. The potential budget impact for this drug was also huge.

    A risk is that CMS’s decision may discourage innovation in Alzheimer’s disease, but I am hopeful that this is not the case. One impact it will likely have is that drug manufacturers will be less inclined to pursue accelerated approval from the FDA, and rather will aim to achieve approval through standard means. Another potential consequence of this decision is that CMS and FDA collaborate more in the future, which would be a good thing!

    It is unclear what will happen next. It could be that CMS faces a lawsuit. It will be interesting to see how private plans and Medicaid plans cover aducanumab, a research question we are currently examining in my center.

    For two Health Affairs Forefront articles on this issue see, Tunis et al., 2022, and Chambers et al., 2021.

  9. I don’t think this coverage decision changes much. Practically, it’s a denial of coverage. I don’t know of any trials that would qualify for CMS support under these criteria that are not being run by Biogen (and thus already have free drug). Perhaps some academic centers will enter into this arena, but it will take time and will be very expensive. We will see how interested NIH is in funding such studies, or what incentive academic centers might have to run them. 

  10. I think the CMS final decision was the right call. I also agree with the adjustment altering the blanket statement that said other drugs in the class would not be covered. It wouldn’t make sense to not cover a similar drug if that drug actually completed a Phase 3 study that showed clear clinical benefit. 

    I think some of the other aspects of the decision are aimed at generally improving the conclusions that we can draw from clinical trials by ensuring that results are clearly generalizable. This seems particularly important in studying diseases with complex mechanisms that are extremely common but may affect different groups within the population in different ways.

    I don’t foresee that entities other than Biogen are likely to develop new clinical trials involving aducanumab specifically unless in the setting of a head-to-head comparative effectiveness study. There are other antibodies that are advancing and getting to the later stages of development/study that I think have a higher likelihood of showing benefit. I doubt that there would be much incentive, other than a financial one, given the coverage decision, to develop new trials with the drug.

  11. I fully agree with the CMS decision regarding Aduhelm, given the equivocal clinical trial results and the fact that not one of the 11-member FDA advisory committee recommended approval. Three of these advisory board members resigned in protest over the decision to grant approval. In my view, it’s completely appropriate for Medicare to pay for the drug only for clinical trials, so that the results can be tracked in Phase 4.

  12. Although we recognize the Centers for Medicare & Medicaid Services did take certain industry and community feedback into account, we are ultimately discouraged by the final CMS National Coverage Decision.

    We are concerned that the CMS decision to cover anti-amyloid monoclonal antibodies with standard regulatory approval only as part of a CMS-approved registry study or qualifying clinical trial will severely compromise patient access and exacerbate existing inequities. It also disregards and discounts the rigor of the standard FDA review process for future treatments for which data are yet to be generated or reviewed.  

    We remain focused on progressing our Phase 3 GRADUATE program for gantenerumab, an investigational Aβ antibody developed for subcutaneous administration with the potential for at-home administration. If positive, we look forward to providing regulators with a dataset as comprehensive as possible—including both biomarkers and clinical measures—as part of a standard regulatory filing submission for gantenerumab to further understanding of its efficacy, safety, and potential to impact people living with Alzheimer’s. If approved, we are committed to partnering with CMS and other relevant payers to optimize access to gantenerumab for as many patients as possible. 

    Regardless of the outcome, we expect results from the GRADUATE program to be one of the most important datasets to emerge from the Alzheimer’s disease field in part because it will deliver two completed trials from a large number of patients studied for more than two years, measuring impact on cognitive and functional decline.

  13. Lilly continues to believe that coverage with evidence development (CED) in any form is unnecessary, restrictive and inappropriate for donanemab upon FDA approval. We believe that anything short of full coverage to label for anti-amyloid treatments where the Phase 3 program delivers direct evidence of clinical benefit, as we expect from TRAILBLAZER-ALZ 2, deprives patients of the access they deserve.

    We note that CMS acknowledged that each therapy should be assessed on its own clinical benefit. Lilly’s TRAILBLAZER-ALZ study of donanemab is the first Alzheimer’s study to have ever successfully met its prespecified primary endpoint and demonstrate statistically significant slowing of cognitive and functional decline. Lilly is proud of our published data in the New England Journal of Medicine, and we are excited for the Phase 3 data for donanemab that are expected in mid-2023. We will continue to advocate for broad patient access to donanemab based on the clinical evidence.

  14. At Eisai, we respect that the Centers for Medicare and Medicaid Services has committed to quickly reconsider the National Coverage Determination once an anti-amyloid drug for the treatment of AD has met the Coverage with Evidence Development requirements with quality evidence.

    Eisai anticipates completing our anti-Aβ protofibril antibody lecanemab’s rolling submission of a Biologics License Application to the FDA under the accelerated approval pathway in the first quarter of our fiscal year 2022, which began April 1, 2022.

    Additionally, the readout of the Phase 3 confirmatory Clarity AD clinical trial will occur in the fall of 2022. Eisai believes Clarity AD has a robust design, which could meet the “high level of evidence” criteria set forth by CMS in the NCD decision memo if the result is positive; therefore creating the potential for CMS to reconsider full coverage of lecanemab should it be approved by the Food and Drug Administration. We look forward to engaging constructively with CMS to ensure appropriate Medicare beneficiaries have access to this potential new therapy.

    Eisai serves as the lead of lecanemab development and regulatory submissions globally, with both Eisai and Biogen co-commercializing and co-promoting the product, and Eisai having final decision-making authority.

  15. As a European, I do not comment on a specific U.S. health agency decision and its implications. From a global point of view, these two recent CMS and EMA decisions seriously hamper the use of aducanumab after the FDA's controversial approval. These contradictory decisions somehow reflect the large controversy in the field. They demonstrate the ability of the global health system to cope with scientific and medical controversies, as well as the existence of efficient safeguards in drug market access. This reassures fears that emerged following aducanumab's approval, that the FDA decision was tantamount to opening Pandora's box.

    From a European prescriber's point of view, the EMA decision is a relief, since the estimated benefit/risk ratio of aducanumab and high-clearance anti-amyloid immunotherapies, with the currently available data, remains low after an 18-month regimen. On the one hand, efficacy, whose statistical significance is disputed, is in any case below the minimal clinically relevant values determined by precedent works (Andrews et al., 2019; Schrag and Schott, 2012). On the other hand, serious and symptomatic ARIA does exist at the highest doses, as illustrated by the case report by VandeVrede and colleagues (VandeVrede et al., 2020), and seems to occur in 1 per 200 treated patients (3/1,029 of the high-dose group from the pooled aducanumab Phase 3 trials (Salloway et al., 2021), 2/131 in the donanemab Phase 2 trial (Mintun et al., 2021), and 2/161 in the highest dose group of the lecanemab Phase 2 trial (Swanson et al., 2021), i.e., 7/1321 ~0.5 percent).

    I do not think it is heartless or cynical to ask for more data before prescription. In my opinion, with currently available evidence, refusing aducanumab approval or coverage still corresponds to giving the best possible chance to the patient.

    References:

    . Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019;5:354-363. Epub 2019 Aug 2 PubMed.

    . What is the clinically relevant change on the ADAS-Cog?. J Neurol Neurosurg Psychiatry. 2012 Feb;83(2):171-3. PubMed.

    . Symptomatic amyloid-related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement (Amst). 2020;12(1):e12101. Epub 2020 Oct 9 PubMed. Correction.

    . Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022 Jan 1;79(1):13-21. PubMed.

    . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.

    . A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021 Apr 17;13(1):80. PubMed. Correction.

  16. This article provides helpful clarification and analysis of various forces at play in the CMS decision not to pay for Aduhelm, although it had been approved by the FDA. Following it, a bevy of experts commented.

    Interestingly, the word "efficacy" appeared only twice in all those remarks. To my mind, this lack of clear effectiveness seems to underlie most of the resistance of many physicians, scientists and major hospitals. Expensive, yes. But if Aduhelm clearly worked, you'd have to fight for a place in the line of professionals wishing to use it for their patients.

    Most of the opponents to the CMS decision cite the earlier FDA approval, which in their view should have guaranteed CMS payment. However, this "approval" turns out to be hanging by a thread, else why would it be under investigation by the HHS Inspector General, two Congressional committees, and be the subject of a class action lawsuit?

    Recall that the entire FDA advisory committee turned down the drug, and several members resigned in protest of the FDA's decision to approve despite this. Allegations of excessive FDA staff's coziness with the drug's manufacturer remain to be resolved.

    The drug's manufacturer also splashed money around to various advocacy groups as if to curry their favor. In many instances they succeeded, as few if any such organizations did their own analysis of clinical trials before parroting "the party line." Outfits which usually operate in the shadows, e.g. High Lantern, also bear illumination in such activities. 

    All researchers and clinicians fervently hope for an efficacious anti-Alzheimer's drug. But most are against puffery and pressure tactics to get approval and payment for a questionable new agent. Therefore, they support the CMS decision, viewing it as the final backstop to protect patients against a flawed decision by the FDA.

  17. The final NCD discriminates against patients with AD compared to other diseases. CMS extended their decision beyond amyloid antibodies approved by accelerated approval, planning to restrict coverage of a traditionally approved antibody that unambiguously meets its clinical endpoints to Medicare beneficiaries able and willing to participate in “prospective comparative” research. This is an unprecedented denial of coverage outside the controversy regarding amyloid PET as a surrogate biomarker.

    CMS has never before required patients to participate in registry studies to cover an FDA-approved drug, let alone one approved traditionally. It is unjust to require AD patients, but not patients with other diseases, to participate in research to receive a traditionally FDA-approved efficacious drug. Their rationale uses an argument that is not unique to AD: that ongoing RCTs (which are not even completed yet) do not contain enough patients with common comorbidities like heart disease, hypertension, diabetes, and concurrent medications. Patient homogeneity for initially testing new disease-modifying agents in RCTs and their application to the “real world” is an issue in all medical fields, and it is best addressed by post-market studies. But these are done alongside allowing access to a useful drug outside of research—otherwise they are not truly post-market, and many qualified patients could turn out not to receive a useful treatment. 

    What exactly is CMS trying to protect Medicare beneficiaries against through such extreme caution applied uniquely to amyloid antibodies in AD? Their argument is presented as complex and scientific but reduces to a type of ageism. The idea that age-related Aβ-amyloid accumulation is somehow normal (it isn’t) reflects the old concept of dementia as a normal extension of aging. Even their statement that age is the biggest risk factor for AD breaks down: One could say age is the biggest risk factor for practically any disease of late adulthood. The concept that AD-MCI patients should tolerate less risk from a clinically proven medication than victims of other diseases implies that their lives are less worth extending. 

    CMS is ignoring the FDA and has trod into medical decision-making. This is moral ground best left for patients and their physicians to navigate.

    COI: DJS is a director and consultant to Prothena Biosciences and has consulted to Eisai. AS has nothing to declare. 

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References

Therapeutics Citations

  1. Aduhelm
  2. Gantenerumab
  3. Lecanemab
  4. Donanemab

News Citations

  1. Aduhelm Administration Remains a Trickle, ARIA a Concern
  2. Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious
  3. FDA Advisory Committee Throws Cold Water on Aducanumab Filing
  4. Aducanumab Approved to Treat Alzheimer’s Disease
  5. CMS Plans to Limit Aduhelm Coverage to Clinical Trials
  6. On Aduhelm, Medicare Agency Gets Pressure From All Sides
  7. IDEAS Finds Small Drop in Hospitalizations, Missing Goal
  8. Bio-Hermes: Making Alzheimer’s Diagnosis Fast, Cheap, Accessible
  9. Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists
  10. Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
  11. Aduhelm Lowers Tau; Registry to Track Real-World Performance
  12. Seeking Real-World Data on Whether Aducanumab Works
  13. European Regulators Turn Down Aduhelm; Price Drops

Conference Coverage Series Citations

  1. GAP-Net Site Optimization Conference 2019

Paper Citations

  1. . The need to show minimum clinically important differences in Alzheimer's disease trials. Lancet Psychiatry. 2021 Nov;8(11):1013-1016. Epub 2021 Jun 1 PubMed.
  2. . Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer's disease. Alzheimers Res Ther. 2022 Apr 19;14(1):54. PubMed.
  3. . Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015-2060) in adults aged ≥65 years. Alzheimers Dement. 2019 Jan;15(1):17-24. Epub 2018 Sep 19 PubMed.
  4. . Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2021;8(4):398-410. PubMed.

External Citations

  1. STAT news
  2. STAT news
  3. FiercePharma news
  4. FDA guidance
  5. STAT news
  6. WSJ story
  7. STAT news
  8. Endpoints news

Further Reading