FDA defends Aduhelm's accelerated approval, while others call for reform

Regulatory NewsRegulatory News | 14 July 2021 |  By 

Three papers published as Viewpoints in JAMA Internal Medicine this week highlight the rationale provided by the US Food and Drug Administration (FDA) on the agency’s approval of aducanumab (Aduhelm; Biogen Inc), implications the approval could have for the Medicare program, and a contemplation on the future of FDA’s accelerated approval pathway.
Writing on behalf of FDA, Billy Dunn, MD, director of the Office of Neuroscience with FDA, and colleagues said the agency’s decision to approve Aduhelm was based on results from the Phase 1 PRIME trial (study 103), the Phase 3 ENGAGE trial (study 301), and the Phase 3 EMERGE trial (study 302). In the small PRIME trial, there was a “clear dose-dependent and time-dependent reduction in [amyloid-β] Aβ plaque and dose-related improvements in standard Alzheimer disease end points,” Dunn and colleagues wrote, while “conflicting results” were seen in the ENGAGE and EMERGE trials. Both Phase 3 trials were stopped for futility, with a subsequent analysis revealing EMERGE was “a strongly positive study” whose results were not replicated in the similarly designed ENGAGE trial, they said.
“After reaching this conclusion, we faced a challenge: available evidence was strongly suggestive of a benefit from aducanumab but was complicated and in some respects contradictory; yet patients with Alzheimer disease are in urgent need of treatments that delay disease progression and loss of function,” Dunn and colleagues wrote. “Such a situation is recognized and addressed in the statute that provides the FDA with the authority to approve a drug using the accelerated approval pathway.”
In their Viewpoint, Dunn and colleagues argued on behalf of FDA that Aduhelm “fits into this regulatory paradigm” of the accelerated approval pathway because the drug meets the criteria for treating a disease with an unmet need, is “expected to provide meaningful clinical advantage over available therapy,” and shows an effect through a surrogate endpoint; finally, it is “reasonably likely that the effect on the surrogate end point predicts clinical benefit of the drug.”
“Based on the FDA’s assessment that the clinical trial data provided a strong suggestion of clinical benefit in the presence of a surrogate end point shown to be improved by the drug, and with solid data supporting the conclusion that the surrogate end point is reasonably likely to predict clinical benefit, we concluded that accelerated approval for aducanumab was appropriate and warranted,” explained Dunn and his coauthors, who included CDER director Patricia Cavazzoni and Peter Stein, the director of CDER’s Office of New Drugs (OND).
The drug was approved for use in patients with Alzheimer’s disease on 7 June, and Aduhelm’s labeling was updated by FDA on 8 July to clarify the drug is intended for patients with mild cognitive impairment and dementia associated with Alzheimer’s disease. (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 07 June 2021; FDA trims Aduhelm's indicated population, Regulatory Focus 08 July 2021)
Notably, FDA’s Peripheral and Central Nervous System Advisory Committee disagreed with this assertion and overwhelmingly voted against approving Aduhelm in November 2020, with 10 members voting against and 1 member voting “uncertain.” After the agency approved Aduhelm, three committee members stepped down from their positions on the FDA advisory committee. (RELATED: Adcomm gives big thumbs down to aducanumab, Regulatory Focus 06 November 2020)
FDA has acknowledged the “significant attention and controversy” resulting from the Aduhelm decision. On 9 July, Janet Woodcock, acting director of the FDA, asked the Office of Inspector General to conduct an investigation into Aduhelm’s approval. (RELATED: Woodcock calls for investigation into Aduhelm approval, Regulatory Focus 09 July 2021)
Implications of Aduhelm on Medicare 
Francis J. Crosson, MD, of Kaiser Permanente Bernard J. Tyson School of Medicine in Pasadena, Calif., and colleagues believe that Aduhelm’s approval will significantly impact Medicare. With a yearly cost of at least $56,000 for the 10 mg/kg maintenance dose and the likelihood that Aduhelm would be covered under Medicare Part B, “the cost of this drug alone might threaten the financial viability of the program,” Crosson and colleagues said.
Describing the annual cost as “astronomical,” the authors said Aduhelm’s price may increase premiums and create a financial hardship for beneficiaries, especially those without supplemental coverage or who don’t have Advantage plans to cover coinsurance for Medicare Part B. Crosson and colleagues estimated that “if half of Medicare beneficiaries with Alzheimer disease were to be placed on aducanumab treatment, the annual cost could be in excess of $160 billion.”
“Congress and the Biden administration should act, and act swiftly, to control drug costs and safeguard the financial health of Medicare and its beneficiaries. Rigorous evidence of an appropriate ratio of potential benefit to potential harm is required for any treatment covered by Medicare, regardless of FDA approval,” they said.
Making a coverage decision on Aduhelm should a top priority for Centers for Medicare & Medicaid Services (CMS), according to the authors. Options for CMS include not covering Aduhelm based on the “reasonable and necessary” criteria, undergoing a Medicare National Coverage Determination (NCD) process to determine Aduhelm’s eligibility as a covered service, or deciding Aduhelm will only be covered in a clinical trial under a coverage with evidence development (CED) designation, Crosson and colleagues explained. On 12 July, CMS announced it was opting for the second option and performing a NCD analysis.
Revisions to accelerated approval pathway?
Bishal Gyawali, MD, PhD, of the Departments of Oncology and Public Health Sciences, Queen’s University, Kingston, Ontario, Canada, and colleagues discussed FDA’s accelerated approval process in light of Aduhelm’s approval as well as the failure of several cancer drugs to demonstrate benefit in confirmatory studies.
These two approval areas highlight several concerns, such as the consistency of how FDA determines surrogate endpoints meet the “reasonably likely” standard for clinical benefit under the accelerated approval pathway, Gyawali and colleagues said. Amyloid plaques have been targeted by other Alzheimer’s drugs without evidence of clinical benefit; it is an open question whether amyloid plaque reduction is a reliable surrogate endpoint, they said. FDA also “explicitly discounted changes in the number of amyloid plaques as a basis for approving the drug,” the authors—who included Aaron S. Kesselheim, MD, JD, MPH, one of the FDA advisory committee members who resigned his position following the Aduhelm decision—explained.
Gyawali and colleagues also criticized the 9 years FDA gave Biogen to complete confirmatory trials for Adulhelm, comparing that timeline with the median 3.4 years for oncology drugs have received under the accelerated approval pathway. In the case of cancer drugs undergoing confirmatory trials, “there are examples of the FDA ‘verifying’ and converting an accelerated approval to a regular approval despite the drug failing to achieve the primary end point in the postapproval trial, waiving the postapproval trial requirement, or holding off on making a formal regulatory decision for years without any action, creating so-called dangling approvals,” they said.
Another problem comes from using surrogate endpoints to satisfy the “verified benefit” criteria. “Using the same surrogate markers or any nonvalidated surrogates in the confirmatory trials is a major concern because multiple studies have shown that surrogate markers commonly used for oncology drug trials have limited or unclear correlation with key clinical outcomes, such as overall survival and quality of life,” Gyawali and colleagues explained.
There are examples of FDA’s Oncologic Drugs Advisory Committee (ODAC) both upholding accelerated approvals and recommending certain cancer drugs be pulled from the market. In a 3-day meeting in April, ODAC considered whether to recommend revoking accelerated approval for six cancer drugs that failed confirmatory trials. In the end, ODAC recommended Merck Sharp & Dohme’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab) be pulled from the market. (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021)
“Although the FDA is not bound to follow an advisory committee’s recommendations, it is concerning that the ODAC recommended that some approvals be maintained even without evidence of the clinical benefit of the drugs for the given indications,” the authors said.
A revision to the accelerated approval process is needed, Gyawali and colleagues argued, particularly in how biomarkers are selected, confirmatory trial protocols are finalized, and drugs under the pathway are pulled from the market.
“The demonstration of clinical benefit should be based on clinical end points, and the approved indication should be promptly and automatically withdrawn if the confirmatory trial is negative,” the authors concluded.
JAMA Intern Med Dunn et al.
JAMA Intern Med Crosson et al.
JAMA Intern Med Gyawali et al.


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