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).
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
- Aduhelm Administration Remains a Trickle, ARIA a Concern
- Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- Aducanumab Approved to Treat Alzheimer’s Disease
- CMS Plans to Limit Aduhelm Coverage to Clinical Trials
- On Aduhelm, Medicare Agency Gets Pressure From All Sides
- IDEAS Finds Small Drop in Hospitalizations, Missing Goal
- Bio-Hermes: Making Alzheimer’s Diagnosis Fast, Cheap, Accessible
- Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists
- Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
- Aduhelm Lowers Tau; Registry to Track Real-World Performance
- Seeking Real-World Data on Whether Aducanumab Works
- European Regulators Turn Down Aduhelm; Price Drops
Conference Coverage Series Citations
- Liu KY, Schneider LS, Howard R. 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.
- Assunção SS, Sperling RA, Ritchie C, Kerwin DR, Aisen PS, Lansdall C, Atri A, Cummings J. 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.
- Matthews KA, Xu W, Gaglioti AH, Holt JB, Croft JB, Mack D, McGuire LC. 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.
- Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M. Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2021;8(4):398-410. PubMed.
- Aducanumab Still Needs to Prove Itself, Researchers Say
- Advisory Committee Again Urges FDA to Vote No on Aducanumab
- Will Insurance Cover Aducanumab? Jury Is Out
- Aduhelm Approval Reverberates Through Research
- Flurry of Investigations Besets Aducanumab
- Lecanemab Follows Aduhelm’s Path to Accelerated Approval
- European Regulators Turn Down Aduhelm; Price Drops
- Scientists Re-Analyze Aduhelm Data, Try to Parse Who Benefits
- Fallout Continues After Aducanumab Approval