Aducanumab’s Groundbreaking Approval Brings Mixed Perspectives
The Regulatory Landscape Perspective – A New Model?
The team at Halloran Consulting Group, Inc (Halloran) is still feeling the aftershock from the accelerated approval of aducanumab on June 7, 2021. As of July 8, 2021, the FDA revised aducanumab’s label – its recommended use criteria now reflect the data that was collected in the Phase III trials. This revision narrows the intended patient population from all Alzheimer’s patients to patients with milder forms of the disease. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.
On July 9, 2021, acting Commissioner Janet Woodcock asked the independent Office of Inspector General to investigate how agency staff interacted with Biogen in the run-up to the approval of aducanumab. As noted in an article from STAT released on July 9, 2021, Woodcock wrote in a letter to acting Inspector General, Christi Grimm, that “there continue to be concerns raised … regarding contact between representatives from Biogen and FDA during the review process, including some that may have occurred outside of the formal correspondence process. To the extent these concerns could undermine the public’s confidence in the FDA’s decision, I believe it is critical that the events at issue be reviewed by an independent body such as the Office of Inspector General to determine whether any interactions that occurred between Biogen and FDA review staff were inconsistent with FDA policies and procedures.”
A month later, and daily headlines regarding the approval of aducanumab continue to surface, demonstrating the substantial impact this drug approval has over the industry.
“As a regulatory affairs professional, this gives me great pause and leads me to think this decision will have a tremendous impact on the continued use of the accelerated approval pathway and the approach to developing new drugs under expedited pathways,” shared Niki Gallo, Associate Principal Consultant in Halloran’s Regulatory Affairs group. The accelerated approval pathway is an innovative expedited drug development pathway for therapies targeting serious conditions for which there is an unmet medical need. Accelerated approval is based on a surrogate or intermediate endpoint that is thought to be a predictor of clinical benefit.
In aducanumab’s case, the reduction in amyloid plaques in the brain is thought to confer clinical benefit to Alzheimer’s disease patients and the approval was felt to be supported by two Phase III trials in which one trial met the primary endpoint by showing a reduction in clinical decline, while the other study failed to meet its primary endpoint. “To be blunt, we do not know the clinical benefits patients will receive from aducanumab, as it is too early to tell. The clinical dataset needs to mature, the clinical benefit needs to be validated, and the use of the surrogate endpoint of reduction in amyloid plaques need to be proven to ensure clinical benefit to Alzheimer’s patients,” confirmed Niki Gallo.
The aducanumab confirmatory clinical trials that are to be completed within nine years will be very telling. Historically, the accelerated approval pathway has been commonly used in the oncology, immune-oncology space, especially in the realm of check-point inhibitors. In April 2021, the Oncology Drugs Advisory Committee (ODAC) convened to review recent confirmatory data from checkpoint inhibitors that were approved under the accelerated pathway to determine if the approval still stands. Broadly, the data from confirmatory trials involving checkpoint inhibitors did not substantially improve survival outcomes, however, the seriousness of unmet needs still carried substantial weight in permitting checkpoints inhibitors to be approved in multiple indications.
The jury may still be out on the utility of surrogate endpoints in the accelerated approval pathway and the aducanumab approval is going to bring even more attention. Ultimately, this industry wants to impact human health successfully, safely, and meaningfully, and though the accelerated approval pathway allows our industry to bring that impact to patients sooner, it is often on an immature dataset with significant unknowns.
Niki Gallo shared, “moving forward, more dialogue and collaboration with the FDA in vetting and determining the appropriate surrogate endpoint for a given serious life-threatening disease will be needed to enable access to meaningful innovative therapies that confer the prospects of clinical benefit.”
The Ethics Perspective – Will the Advisory Committee Role Evolve?
It is not unheard of for the FDA and the applicable Advisory Committee to disagree on the approval or rejection of a new drug. “However, I do think this is the first where 100% of the Advisory Committee voted ‘no’ and the FDA approved aducanumab anyway, albeit under the accelerated approval pathway that was not discussed with the Advisory Committee,” stated Niki Gallo.
It has become clear that the Advisory Committee was asked to evaluate the safety and effectiveness of aducanumab via a traditional drug approval pathway and not the accelerated approval route under which the FDA granted approval. A recent podcast from NPR’s Short Wave notes that it was clear that the FDA had already made up their mind and the approval was “foreordained,” so the Advisory Committee’s recommendation didn’t have a chance. “It seems the FDA encouraged Biogen to not give up on the development of aducanumab and it could be possible that the FDA and Biogen established criteria for aducanumab to be portrayed as a success,” noted Kim Raymer, Vice President of Regulatory Affairs at Halloran.
So, will this experience change the way Advisory Committees are used? Kim Raymer shared: “we may see a change where Advisory Committees ensure a more in-depth, advance understanding of the regulatory pathways for the programs they’re assessing and how it plays into an eventual approval, especially considering the Advisory Committee was originally asked to assess the aducanumab program based on the traditional approval pathway.”
Normally, emerging biopharma companies developing their first asset and preparing for FDA approval are also tasked with preparing for a wide-ranging, intense, and sometimes contentious Advisory Committee meeting with the preparation of six months to a year in advance. “Will this situation changes this time-consuming tradition and maybe lessen the burden and focus the discussions on the Advisory Committee?” was a question posed by John Ferraro, West Coast Site Head & Innovation Lead at Halloran. Time and experience will tell.
The Health Economics Perspective – High Price Tag and its Impact
Looking at this drug approval, the large patient population it serves (estimated at 6.2M Americans), and the fact that this is the first Alzheimer’s disease-modifying drug to enter the market, there is a vast negative commentary on the price and the effect this will have on the health economic system. Though this cost is shared by everyone in the health care system, when there’s a drug that’s priced quite high ($56,000 per year), industry concerns are focused on how a drug could be priced this high with limited yet conflicting evidence of efficacy. This cost does not include those that may be associated with administration and monitoring.
Sheila Gwizdak, Vice President of Quality at Halloran, said “this can be devastating to the patient population. The patients and their families felt this big high with the drug approval, but if they can’t pay for it, that’s such a devastating challenge.”
ICER (The Institute for Clinical and Economic Review) issued a statement on this approval. They noted: “ICER believes the FDA in approving aducanumab has failed in its responsibility to protect patients and families from unknown harms.” ICER is not known for critiquing the FDA in public forums, so this statement is especially impactful. ICER also did a comparative analysis on the fair market value, and they wrote “in their modeling framework, the list price should be multiples lower than what Biogen has it listed for.”
Matt Cardinal, head of the Strategy and Program Leadership unit at Halloran stated, “when you’re working on development planning and clinical trial design, the economic aspect is critical to examine and evaluate as they have an impact on the health care system at large.”
The Patient Perspective – an Insider’s Look at Patient Centricity
Anmol Grover, a consultant in Halloran’s Strategy and Program Leadership group, observed “those that are suffering are desperate for treatment, and there has not been an approved disease-modifying therapy on the market until now, despite industry effort. There is so much grief felt by those that are affected, which shines a light on why there was so much support from patient advocacy groups to approve this drug to give hope to patients and their families.”
While there is an urgent need for an effective disease-modifying Alzheimer’s product, there are some concerning side effect concerns with aducanumab. “Patients are at risk of Amyloid-related imaging abnormalities (ARIA), such as hemorrhage and edema, which may or may not be symptomatic,” noted Anmol Grover. He also shared that “a significant proportion of treaters and caregivers are willing to try Aducanumab given the significant burden of the disease and knowing that side effects can be managed by lowering the dose and frequent monitoring of the patients. Unfortunately, the effectiveness of Aducanumab was only seen with higher doses.”
Sheila Gwizdak also noted “perhaps what we are seeing is that agencies are feeling pressure to approve, while we’re also seeing incredible support and pressure from patient advocacy groups. Patients, or in this case families, are often desperate for anything that has the potential to improve the lives of their loved ones especially when they are suffering from such a heartbreaking disease.”
So, where is the line drawn with patient centricity? It’s clear that patient advocacy groups are influential – they put pressure on governments and trial sponsors, particularly because of the harrowing experiences felt by families and patients. “It appears little consideration has been given to the impact this drug will have on the caregiver, such as the monthly in clinic infusions and periodic MRI requirements for monitoring purposes, all in addition to the cost of therapy. This will be a challenging model for caregivers to maintain going forward,” said Sheila Gwizdak.
How and Why Did This Happen? A Mix of Business Acumen and Hope
Matt Cardinal mentioned that “the driving force is multifactorial. Biogen is just doing what they need to form a business perspective – they’re a multinational biotech company returning value to their investors and developing products to meet the needs of patients. It’s the accelerated approval regulations that also helped to pave their way.”
“The patient advocacy groups also had the main goal. This is a devastating disease, and the glimmer of hope is also what drove this approval. These groups are getting a stronger voice with the FDA,” said Kim Raymer.
Eli Lily recently announced receipt of a breakthrough designation for donanemab and plans to submit its BLA for accelerated approval based on its phase II study results that included a robust reduction in brain amyloid and a positive hit on its primary efficacy endpoint while missing on key secondary endpoints. It may be likely that others are now more likely to follow suit and we, as an industry, will be hopeful and observant.
Halloran’s Collective Perspective:
Halloran will continue to watch how this approval unfolds and new data emerge from future aducanumab trials. It is safe to say that though the approval of aducanumab is a seeming win for the Alzheimer’s community, this approval is at odds with the agency’s historic review and approval process, signaling potential changes ahead especially for underserved patient populations.