FDA trims Aduhelm's indicated population

Regulatory NewsRegulatory News | 08 July 2021 |  By 

Aaron Kesselheim

Biogen’s newly approved Alzheimer’s disease drug Aduhelm (aducanumab-avwa) received a labeling update Thursday to clarify that the drug is meant for individuals with mild cognitive impairment or dementia due to Alzheimer’s disease.
Just last month, Aduhelm received accelerated approval from the US Food and Drug Administration (FDA), a controversial decision that ran counter to the strong opinions of the agency’s Peripheral and Central Nervous System advisory committee. Three members of the committee have resigned in protest over the FDA decision. (RELATED: Adcomm gives big thumbs down to aducanumab, Regulatory Focus 06 November 2020; FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 07 June 2021)
The original “Indications and Usage” section of the label for Aduhelm noted that the antibody was “indicated for the treatment of Alzheimer’s disease.”
In the revised label released Thursday, FDA has retained the original wording that Aduhelm is indicated for the treatment of Alzheimer’s disease, but added the following language: “Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”
Biogen’s head of research and development, Alfred Sandrock, issued a statement Thursday explaining the labeling change. “Based on our ongoing conversations with prescribing physicians, FDA and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval.”
Business as usual?
The speedy adjustment of a label for a newly approved drug is unusual, confirmed a regulatory expert who sat on the Peripheral and Central Nervous System advisory committee until recently.
“A labeling change like this so quickly after approval is definitely not typical – I’m certainly glad to see the update since it is more reflective of the clinical trial population, but the fact remains that the drug shouldn’t have been approved in the first place,” Aaron Kesselheim, professor of medicine at Harvard Medical School and director of the school’s Program on Regulation, Therapeutics and Law (PORTAL), told Focus. Kesselheim was among the three advisory committee members who resigned after Aduhelm’s approval; he laid out his thinking in a 15 June New York Times guest essay.
“Since the agency approved Aduhelm, prescribers and other stakeholders have expressed confusion regarding the intended population for treatment,” said a CDER official in a statement to Focus.  “A key question has been whether the Aduhelm prescribing information supports the treatment of patients at all stages of Alzheimer’s disease. Hearing these concerns, FDA determined that clarifications could be made to the prescribing information to address this confusion.”
The FDA official’s statement makes the case that the revised labeling is merely a way to highlight information that was already elsewhere in the Aduhelm labeling as it was originally approved, in response to feedback from unspecified stakeholders: “The Clinical Studies section (Section 14) of the original approved labeling provided prescribers with information relevant to the population appropriate for initiation of treatment. Based on stakeholder feedback, the agency determined that the information should be given more prominence and included in the first section of labeling.”
The question of cost
Insurers, other payors, and patient and physician groups are among those who have expressed concern about the implications of including a broad patient population in eligibility for a drug that is projected to cost $56,000 yearly. A Kaiser Family Foundation (KFF) report issued soon after Aduhelm’s approval noted that the approval “has huge implications for Medicare and beneficiaries,” especially since the intravenous route of administration for Aduhelm means reimbursement will fall under Medicare Part B provisions.
A back-of-envelope calculation in the KFF analysis would put potential total spending on Aduhelm at almost $29 billion annually, if just one-fourth of the Medicare beneficiaries who are currently taking any Alzheimer’s treatment were to receive the newly approved drug. “To put this $29 billion amount in context, total Medicare spending for all Part B drugs was $37 billion in 2019,” wrote the report authors.
The trimmed population for whom Aduhelm is now indicated will likely reduce these figures. Medicare and private insurers usually only reimburse therapies used for approved indications, though patients may still receive them for other indications from prescribers who use them off-label.
FDA sought to “clarify intent”
Focus asked the CDER official whether feedback from CMS and other payors played into the agency’s decision to change the Aduhelm label. The official did not reply directly, but focused on FDA’s desire to provide more clarity for prescribers: “The agency believes that it was important to clarify the intent of currently approved labeling for prescribers; specifically, that it is appropriate to initiate treatment in patients with the mild cognitive impairment or mild dementia stages of Alzheimer’s disease. This is the population who were entered into the clinical trials with aducanumab, as described in Section 14 of the prescribing information. However, it is also appropriate for the indication statement to describe the ‘treatment of Alzheimer’s disease,’ because the disease is progressive.
“Some patients may benefit from ongoing treatment even if they progress from mild cognitive impairment or mild dementia to later stages of the disease during treatment with aducanumab. Prescribers should evaluate their individual patient’s response to treatment with aducanumab and determine if there is potential for benefit with continued treatment."
Aduhelm’s accelerated approval was granted on the basis of the drug’s ability to clear amyloid beta plaques from the brain, although whether reduction in these plaques will result in clinical improvement is unknown – and a subject of ongoing debate by Alzheimer’s researchers. The clinical trials upon which the accelerated approval was based involved patients with mild cognitive impairment or dementia from Alzheimer’s disease, rather than the full spectrum of patients included in the original indication labeling.
CDER director Patrizia Cavazzoni took the unusual step of defending the decision in a 7 June statement, issued on the day of the approval.
(Editor’s Note: Michael Mezher contributed to this article.)


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Tags: Aduhelm, biologics, FDA, US

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