FDA approves aducanumab for use in Alzheimer’s disease

Regulatory NewsRegulatory News | 07 June 2021 |  By 

Patricia Cavazzoni

The U.S. Food and Drug Administration (FDA) on Monday announced the approval of Biogen’s human monoclonal antibody Aduhelm (aducanumab) for use in patients with Alzheimer’s disease under the agency’s accelerated approval pathway.
FDA’s approval of aducanumab is based on results from two Phase 3 clinical trials of patients with early Alzheimer’s disease (AD), EMERGE and ENGAGE. Both trials were stopped in March 2019 due to apparent futility by a data safety monitoring board. However, in October 2019, Biogen announced they were filing a Biologics License Application (BLA) for aducanumab based on a new analysis of data showing reduction in brain amyloid plaque that became available after the pre-specified futility analysis of EMERGE.
The decision represents the first novel Alzheimer’s drug treatment approved by FDA in 18 years, coming just eight months after a Peripheral and Central Nervous System (PCNS) Drugs advisory committee of independent experts returned a series of strongly negative votes when queried whether the Biogen’s clinical trial program supported efficacy claims for aducanumab.
During the meeting in November 2020, committee members expressed concern about voting questions that asked the committee to consider outcomes from the EMERGE trial separately from ENGAGE’s results. The PCNS advisory committee was also split on whether findings that aducanumab cleared amyloid plaques and reduced tau deposits “correlated with cognitive improvement.”
Tristan Massie, FDA’s statistical analyst, disagreed with the agency’s assessment of aducanumab, noting that “there is no compelling, substantial evidence of treatment effect or disease slowing.” (RELATED: Adcomm gives big thumbs down to aducanumab, Regulatory Focus 06 November 2020)
FDA said the accelerated approval of aducanumab is based on the potential that a surrogate endpoint of “reduction in amyloid plaque will result in a reduction in clinical decline,” Patrizia Cavazzoni, MD, director of FDA’s Center for Drug Evaluation and Research (CDER), said in a press release. “In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.”
Notably, the potential for using the accelerated approval pathway for aducanumab was not discussed at the PCNS advisory committee meeting in November. Billy Dunn, MD, director of CDER’s Office of Neuroscience, also stated at the meeting that FDA was “not using the amyloid as a surrogate for efficacy.”
In a memorandum to the PCNS Drugs Advisory Committee concerning aducanumab approval released soon after FDA announced the approval, Dunn wrote that accelerated approval was considered “earlier in the development program but not directly discussed during the advisory committee meeting given the focus at that meeting on the evidence of clinical benefit.”
FDA’s Cavazzoni took another unusual step on Monday, issuing a statement from CDER’s Division of Drug Information explaining the agency’s decision to grant accelerated approval to Aduhelm. “We are well-aware of the attention surrounding this approval,” wrote Cavazzoni.
She noted that “[T]he data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit. There has been considerable public debate on whether Aduhelm should be approved. As is often the case when it comes to interpreting scientific data, the expert community has offered differing perspectives.”
The statement also acknowledged that the PCNS advisory committee “did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval.”
Next steps after accelerated approval
As part of the accelerated approval process, Biogen is required to conduct a post-approval trial to verify the clinical benefit of aducanumab. “If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market,” Cavazzoni wrote in an statement outlining FDA’s decision.
While market withdrawals of drugs approved through accelerated approval are rare, FDA has shown a willingness to pull products approved under this pathway from the market. In April, FDA’s Oncologic Drugs Advisory Committee (ODAC) met in a 3-day meeting to decide the fate of six cancer immunotherapies that received accelerated approval but failed to show clinical benefit for certain indications in confirmatory studies. Ultimately, the committee recommended pulling a third-line gastric cancer indication for Keytruda (pembrolizumab) and an indication for Opdivo (nivolumab) as a treatment for hepatocellular carcinoma. (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021)
“We expect this study to be conducted in a timely manner,” Cavazzoni said in a media statement following the FDA announcement. “We believe that the data support accelerated approval while holding the company accountable for conducting an additional study to confirm the benefits observed in one of the trials, which we fully intend to do.”
“While our decisions are based on science and the data and the application, we have listened to and carefully considered the needs of the people who are living with this devastating, debilitating and incurable disease,” Cavazzoni said. “The data support patients and caregivers having the choice to use this drug.”
CMS could limit aducanumab use through Medicare NCD process
With more than 6 million patients in the US over 65 years of age living with Alzheimer’s disease, aducanumab is expected to be a treatment used mostly by Medicare beneficiaries. In a blog post published in Health Affairs, Sean Dickson, JD, MPH, director of health policy at the West Health Policy Center in Washington DC, and colleagues noted that aducanumab meets the criteria for undergoing a Medicare National Coverage Determination (NCD) process launched by Centers for Medicare and Medicaid Services (CMS) to determine its eligibility as a covered service.
“FDA approval does not (and should not) translate into automatic CMS coverage; indeed, the fundamental questions for each agency are fairly distinct,” they noted.
Aducanumab meets NCD criteria because the drug may cost up to $70,000 per year under the highest estimates, it is similar to other “expensive and controversial therapies” with the potential for inconsistent local coverage policies, and “the scientific community, as well as FDA’s own advisory board, have voiced serious concerns about coverage,” Dickson and colleagues said.
“It will be up to CMS to assess potential limits on the use of aducanumab, ensuring access only for those patients who are most likely to see some clinical improvement. If it is now impossible to identify those patients, then CMS should deny coverage until those patients can safely be identified,” they wrote.
Based on the findings from the NCD process, CMS could choose to “limit coverage or delay a full coverage determination following collection of more evidence.”
“CMS has a clear path to limit aducanumab usage to only the most appropriate cases, and, should it be approved, it should not hesitate to use this authority,” Dickson and colleagues concluded.


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