After months of uncertainty, the hammer fell for Biogen: In a draft decision released January 11, the Centers for Medicare and Medicaid Services proposed to cover the anti-amyloid antibody Aduhelm only in the context of clinical trials approved by the CMS itself or by the National Institutes of Health. Many observers had predicted the CMS might choose this route, called coverage with evidence development (CED), but the draft requirements are more stringent than expected. They include only randomized controlled trials conducted in hospital-based outpatient settings, and require patient diversity reflecting that of the U.S. population diagnosed with Alzheimer’s. Another surprise was that this decision applies to the whole class of anti-amyloid monoclonal antibodies, giving it far-reaching implications.
- In a draft decision, the CMS proposed covering Aduhelm only in clinical trials.
- Most Alzheimer’s researchers support the proposal.
- Some challenged its practicality.
The announcement triggered pushback from Biogen, its partner Eisai, and from advocacy groups. The Alzheimer’s Association and UsAgainstAlzheimer’s issued statements criticizing the decision, as did the Global Alzheimer’s Platform. These groups announced campaigns to flood the CMS during the 30-day comment period with demands to change its proposal (Politico article).
The manufacturers of the other anti-amyloid antibodies in advanced clinical trials, Eli Lilly and Roche, have yet to weigh in publicly. The Centers’ final decision is expected by April 11.
Alzheimer’s researchers largely agreed with the current proposal. Comments from more than 40 scientists, most expressed publicly and some off-record, ran 2:1 in favor. Most who supported it said the CMS struck a reasonable compromise between access to a new drug and patient safety, especially in light of the scant efficacy data for aducanumab. “The CMS decision could be seen as a corrective on the FDA’s original approval,” said Ian Grant at Northwestern University, Chicago, expressing a common view. “It sends a message to companies that trials need to show clear benefit before drugs will be covered.”
Other scientists questioned whether the CMS proposal is workable. “No one besides Biogen is going to have the incentive or money to run another sufficiently large, randomized, placebo-controlled Phase 3 study of aducanumab, and Biogen is already doing this,” said Erik Musiek at Washington University in St. Louis (full comment below).
Some noted the diversity requirement sets a high bar that no other AD drug development program has met, and predicted the decision would be counterproductive. “The proposed National Coverage Determination (NCD) … is essentially a non-coverage decision that restricts access and stifles innovation,” said Stephen Salloway at Butler Hospital in Providence, Rhode Island (full comment below).
The U.S. Congress has weighed in. The chairs of two House committees—Energy and Commerce, and Oversight and Reform—on January 13 sent a nine-page letter to the CMS administrator, Chiquita Brooks-LaSure, commending the draft decision.
Reasonable and Necessary? The Center Has Its Doubts
Before it pays for a new drug, the CMS must determine that it is “reasonable and necessary” for treatment of the given illness. For aducanumab, the CMS found insufficient evidence for this determination, but acknowledged the high unmet need for Alzheimer’s treatments and urgency for patients. “Because of the early but promising evidence and the immense burden of this devastating disease on the Medicare population, we are proposing CED to support rigorous trials to answer whether anti-amyloid monoclonal antibodies improve health outcomes for patients,” the agency wrote.
Many Alzheimer’s researchers think this was the best solution in a difficult situation. Jason Karlawish at the University of Pennsylvania, Philadelphia, noted that the FDA’s use of accelerated approvals creates a flaw in the regulatory process, potentially compelling Medicare to pay for ineffective treatments. “The magnitude of Aduhelm’s costs and harms and uncertainties turned this flaw into a chasm … CED is a best effort to repair it,” he wrote to Alzforum. Eric Ross at Massachusetts General Hospital, Boston, concurred. “I think they’ve made the right decision from a cost-effectiveness standpoint,” he wrote (full comments below).
In addition, aducanumab treatment frequently causes the brain bleeds and edema known as ARIA (Oct 2021 news; Dec 2021 news). Many clinicians fear this would be less well managed in clinical practice than in trials. “I applaud the CMS in restricting the use of the drug. This class of drugs needs to be rolled out in a controlled environment, first and foremost for patient safety,” Ron Petersen at the Mayo Clinic in Rochester, Minnesota, told Alzforum.
Daniel Gibbs, a retired neurologist at Oregon Health and Science University, Portland, participated in the ENGAGE Phase 3 trial of aducanumab and survived severe ARIA that required hospitalization. “Those potentially life-threatening side effects should not be taken lightly. The CMS decision offers a reasonable path forward,” he wrote (comment below).
But How Will This Work?
Nonetheless, many AD researchers wondered how feasible these CED trials would be, given the logistical challenges of assembling a large nationwide cohort that would use a standardized protocol. “It is very difficult to understand which groups of clinicians are experienced, available, and ready to organize and write these multi-institution protocols,” Dennis Selkoe at Brigham and Women’s Hospital, Boston, wrote to Alzforum (comment below).
Others questioned the ethics of asking some patients to take a placebo control when there is an FDA-approved drug. The CMS does not explicitly call for a placebo control in its draft decision, instead asking for “an appropriate control representing the standard of care.” This could mean comparing patients on aducanumab to those who choose not to take the drug, for example.
“It is not possible to include a placebo control in CED since patients are liable for co-pays,” noted Gil Rabinovici at the University of California, San Francisco, who runs the IDEAS CED study for amyloid PET imaging (Aug 2020 news). Rabinovici believes the aducanumab CED trial could follow a similar large national model. Others, including Salloway and Selkoe, suggested that a prospective registry design would work better than randomized trials.
Another hurdle is that the draft decision specifies the CED trial should demonstrate a clinically meaningful benefit in cognition and function, defining this as a 1-2 point benefit on the CDR-SB, or 3-5 points on the Functional Activities Questionnaire (Andrews et al., 2019). Pierre Tariot at the Banner Alzheimer Institute in Phoenix noted that a benefit of this size may be unattainable when treating people with minimal cognitive deficits. “Is the CMS indicating that a prevention trial … would not be eligible for approval?” he asked (full comment below).
Researchers agreed that these and other issues, including how much evidence will be required for full approval, need to be clarified in the CMS’ final decision. Mark McClellan at the Duke-Margolis Center for Health Policy in Durham, North Carolina, helped develop the CED process when he ran the CMS from 2004-2006. He told Alzforum that the agency has previously revised draft coverage decisions based on feedback. “We’re not done with this NCD process,” he said.
Others see potential for innovative CED trial designs. Statistician Kert Viele at Berry Consultants in Austin, Texas, suggested enrolling 10,000 or more patients in a huge platform trial, with streamlined assessments and minimal requirements that would allow patients in remote areas to participate. Because of the size, only a small fraction would need to receive placebo (InvesBrain news story). Maria Glymour at the University of California, San Francisco, also thinks pragmatic trial designs may hold the answer. “I hope we as an Alzheimer's research community can band together to ensure rapid fielding of large, inclusive randomized trials,” she wrote (comment below).
What Are the Implications for Patients?
If finalized, the decision will further restrict access to aducanumab, already scarce due to its high price and clinicians’ doubt about its efficacy. While some regional Medicare offices have been covering the treatment, the NCD would halt reimbursements outside of clinical trials. Some private insurers have been covering as well, but most typically follow the CMS’ lead. For their part, state Medicaid programs would still be on the hook, as they are obligated to cover any FDA-approved drug. However, Medicaid administrators can, and often do, impose usage restrictions to try to limit costs, McClellan noted.
Some patients who have been trying to get the drug will have to wait longer. Marwan Sabbagh at the Barrow Neurological Institute in Phoenix told Alzforum that he has several patients who have been on hold, waiting for a green light from the institute’s Pharmacy & Therapeutics committee to start the drug. Now, because of the CMS ruling, the committee has delayed its own decision. “This has real practice implications,” Sabbagh said.
High Bar for Diversity
Regarding the CMS requirement that CED trial participants reflect the diversity of the U.S. population of AD patients, researchers agreed on its importance, but said that, in practice, meeting it will likely be impossible in the near future. “The CMS’s diversity requirement is as strict as it can be, in that they ask for full sociodemographic representation. This is flatly unattainable, because our national health systems aren’t structured to give equitable care to begin with,” Lon Schneider at the University of Southern California, Los Angeles, wrote to Alzforum (comment below).
Jeffrey Cummings at the University of Nevada, Las Vegas, agreed. “We need to do better, but we cannot achieve this suddenly; it is a long-term trust-building enterprise,” he wrote (comment below). McClellan said that the CMS itself could help foster diversity by providing incentives such as bonus payments for Medicare providers to enroll patients in trials, as the agency currently does for COVID research.
Alzheimer's patients in the U.S. are diverse in many ways. William Hu at Rutgers Biomedical and Health Sciences in Newark, New Jersey, noted that older people with poor vision and hearing, and those who do not speak English, also tend to be excluded from clinical trials. People who live in rural areas far from medical centers are at a disadvantage as well. In addition, because AD trials are burdensome for participants, requiring many procedures and regular travel, they are biased toward more educated and well-off patients, noted Todd Golde at the University of Florida, Gainesville (comments below).
Sudha Seshadri, University of Texas Health Science Center, San Antonio, stressed the importance of including people with health issues besides AD in the CED trial population. “We need to expand to study persons with mixed etiology dementias, particularly co-existing vascular cognitive impairment and dementia; studying a small, healthy, easy-to-study subset and then pushing the drug at marketing to a larger group is neither scientifically sound nor wise, ethical policy,” she wrote (comment below).
Because of the diversity requirement, all ongoing trials of anti-amyloid antibodies, including Biogen’s planned confirmatory trial for aducanumab that is due to start this spring, likely will not qualify for the CMS coverage, McClellan noted. Notably, that trial has already been approved by the FDA as meeting its post-marketing RCT requirements. “If this decision stands, Biogen may have to go back to the drawing board,” he told Alzforum. “In the future, it will be helpful for the CMS and FDA to share information and work together to nail down these issues beforehand, so we can design trials efficiently and make sure we’re getting the most out of patients’ willingness to participate in research.”
The Biden administration’s nominee to lead FDA, Robert Califf, also thinks coordination between the agencies could be improved. In remarks at a recent regulatory science summit, he likened the agencies’ relationship to a relay race in which FDA needs to more smoothly pass off the baton to the CMS (Endpoints story).
Caution Extends Worldwide
The picture looks broadly similar overseas, where European and Japanese regulatory authorities have both pushed the pause button on the aducanumab licensing applications before them. Bruno Imbimbo at Chiesi Pharmaceuticals in Parma, Italy, called the CMS decision “scientifically logical and clinically prudent” for requiring clear evidence of efficacy and acceptable safety. “I believe EMA will follow this same approach with other apparently more promising monoclonal antibodies,” Imbimbo wrote (comment below).
In Japan, the regulatory agency PMDA chose to suspend the decision on aducanumab until more efficacy and safety data are available, noted Takeshi Iwatsubo at the University of Tokyo. “I believe the approval review process by PMDA, which should strictly be based on scientific evaluation, will not be affected by the CMS decision in the U.S.,” he added (comment below).
Judged As A Class
Perhaps the most controversial aspect of the draft decision was how broad a brush it applied. Many AD researchers argued that each anti-amyloid antibody should be assessed on its own merits after completing Phase 3 trials. Both gantenerumab and lecanemab are expected to have Phase 3 data this year, with donanemab not far behind.
“Making a blanket coverage decision for this class of anti-amyloid antibodies prior to them having undergone and completed FDA review does not make sense,” wrote David Holtzman at Washington University School of Medicine in St. Louis. Eric Siemers of Siemers Integration LLC agreed. “The notion that all monoclonal antibodies used for the treatment of AD should be considered as a class is uninformed,” Siemers wrote (comments below).
Those familiar with the regulatory process expect the CMS to tweak its decision in the near future, depending on the data from upcoming trials. “Time, new science, and new trial results will change the therapeutic landscape,” Schneider said. Philip Scheltens at VU University, Amsterdam, wondered if a CED trial will even get off the ground. “Given the prospect of seeing three other drugs in the same class reading out in one to two years’ time, it is not very likely that such a trial with Aduhelm will be initiated,” he wrote (comment below).
Steven Pearson, who leads the Institute for Clinical and Economic Review (ICER) in Boston, believes the CMS’ stance may discourage drug companies from applying for accelerated approval in the future. “The big question is whether some of the developers will now view it as preferable to accelerate their clinical studies and seek FDA approval using the regular pathway, when we can all actually know whether the drug works,” he wrote (comment below).
Rachelle Doody of Roche said that is her company’s priority. “We are highly focused on completing our ongoing Phase 3 trials this year to really test the question of whether lowering fibrillar amyloid leads to clinical benefit. We hope to have clear answers soon,” she told Alzforum (comment below).
Bart De Strooper at the Dementia Research Institute, London, worried that the CMS decision could have a chilling effect on other companies. “I hope that, as a field, we do not lose momentum again,” he wrote (comment below). John Hardy at University College London struck a similar note. “Uncertainty is part of science, but having so much bureaucratic uncertainty in addition cannot be helpful,” he told Alzforum.—Madolyn Bowman Rogers
- Aduhelm Administration Remains a Trickle, ARIA a Concern
- Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious
- IDEAS Finds Small Drop in Hospitalizations, Missing Goal
- Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. 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.
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