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US FDA pulled a rabbit out of a hat with its surprise use of the accelerated approval pathway for aducanumab.(Source:Alamy)

The US Food and Drug Administration’s accelerated approval of Biogen, Inc. and Eisai Co., Ltd.’s Alzheimer’s drug Aduhelm (aducanumab) on the basis of a surrogate endpoint is destined to further inflame the debate over the agency’s use of the expedited pathway and leaves a host of challenges in its wake.

On 7 June, the agency granted accelerated approval to aducanumab, an amyloid beta-directed antibody, for treatment of Alzheimer’s. The FDA concluded there is substantial evidence that aducanumab reduces amyloid beta plaque in the brain and this surrogate endpoint is reasonably likely to predict clinical benefit, even though the drug failed the primary clinical efficacy endpoint in one of two similarly designed Phase III trials.

“Detailed and thorough analysis of the data from the Aduhelm development program provided evidence that the reduction in amyloid plaque is reasonably likely to result in clinical benefit, reducing the progressive loss of brain function in patients with Alzheimer’s.” – FDA’s Patrizia Cavazzoni

Evidence from the Biogen clinical trials regarding amyloid plaque reduction “fully support approval using the accelerated approval pathway, although the evidence from these trials regarding delay in cognitive and functional decline did not satisfy the criteria for traditional approval,” Center for Drug Evaluation and Research director Patrizia Cavazzoni said during a press call on the approval.

“In all studies in which it was evaluated, Aduhelm consistently and convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Cavazzoni said. “Detailed and thorough analysis of the data from the Aduhelm development program provided evidence that the reduction in amyloid plaque is reasonably likely to result in clinical benefit, reducing the progressive loss of brain function in patients with Alzheimer’s.”

The accelerated approval action caps the drug’s tumultuous regulatory review in the US and cements its status as one of the FDA’s most controversial approval decisions. (US FDAs Most Controversial Drug Approval Decisions From A To Z)

With FDA approval behind it, Biogen now faces the task of commercializing a drug with a $56,000 annual price tag amid payer skepticism about the robustness of the efficacy data.

Accelerated Approval Not An Issue At Adcomm

The approval flies in the face of the Peripheral and Central Nervous System Drugs Advisory Committee’s highly negative review of aducanumab in November. Ten of 11 panelists voted that the lone successful Phase III trial could not serve as primary evidence of aducanumab’s effectiveness, with one panelist saying he was uncertain.

Committee members said they could not divorce the results of the successful EMERGE study from the negative results from the identically designed ENGAGE study. (Biogens Aducanumab Falls Hard At Panel Review Leaving US FDA In A Tight Spot)

The vote followed panelists’ harsh critique of the robustness of the data and the FDA review division’s close interaction with the sponsor to get the drug over the finish line, which included reliance upon various exploratory and post hoc analyses. (What Did US FDA Do Wrong In Its Review Of Aducanumab AdCom Members Have A List)

Though not outside the realm of possibility, use of the accelerated approval mechanism was surprising because the advisory committee was not specifically asked to consider whether the drug’s effect on a surrogate endpoint or an intermediate clinical endpoint could support approval under the expedited pathway.

Office of Neuroscience director Billy Dunn, who argued the case for approval at the advisory committee, explicitly said the agency was not using the drug’s effects on amyloid “as a surrogate for efficacy.” (Biogens Aducanumab Why Accelerated Approval Might And Might Not Be An Option For US FDA)

The closest the committee came to weighing in on the drug’s effects on a surrogate endpoint was when five of 11 committee members voted that there was strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology; the remaining six panelists said they were uncertain.

Several advisory committee members said that while aducanumab appeared to have an effect on beta-amyloid in the brain, there was a disconnect between this biomarker data and the clinical efficacy results. They agreed with the dissenting review of the agency’s statisticians, who said dose-dependent changes in amyloid seen with aducanumab do not appear to correlate with or predict long-term cognitive and functional changes as measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB), which was the primary efficacy endpoint in the Phase III trials.

In materials announcing the approval, the FDA acknowledged that accelerated approval did not come up at the panel review. “After the advisory committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for accelerated approval,” the agency said.

Replicating The Oncology Model

CDER’s Cavazzoni suggested the aducanumab approval could open the door to more widespread use of accelerated approval in neurodegenerative diseases.

“The accelerated approval pathway has been an incredibly useful tool in oncology,” Cavazzoni said. “For those of you who have followed the dramatic leap forward in the cancer space in the last 20 years, we believe it serves as a model that we hope can be replicated with more degenerative diseases.”

In the near term, aducanumab’s approval seems likely to renew questions about the prospects for accelerated approval of Eli Lilly and Company’s anti-amyloid antibody donanemab on the basis of the Phase II TRAILBLAZER-ALZ study. (Lilly Tries To Keep Investors Focused On The Pipeline Not Performance)

UsAgainstAlzheimer’s, which advocated for aducanumab’s approval on behalf of people living with the disease and their caregivers, said the FDA’s action will have a positive ripple effect on pharmaceutical innovation far beyond this one drug and will spark additional investment in disease-modifying treatments and therapies. “We believe that the pathway to the best-in-class drug – and ultimately a cure – must start with a first-in-class drug,” the group said. “With approval of this first drug therapy, we believe that development and approval of drugs two, three and four will follow at a faster pace.”

Frank Sasinowski, a director at Hyman Phelps & McNamara, said the aducanumab decision was a “potential sea change” in the use of accelerated approval and could be a harbinger for future agency actions, especially in neuropsychiatric diseases.

The decision signals an expansion of the FDA’s use of accelerated approval when circumstances warrant regulatory flexibility, he said. “Given the flexibility that FDA has shown here, there is a reasonable expectation that more flexibility will be shown to other therapies, especially for serious diseases with an unmet medical need.”

Ammunition For Critics

However, others were less sanguine about use of accelerated approval in this situation, instead seeing it as a move by the agency to get around shortfalls in the clinical efficacy data.

“Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval,” tweeted Aaron Kesselheim, professor at Harvard Medical School and faculty member at Brigham and Women’s Hospital. Kesselheim was a member of the advisory committee that reviewed aducanumab, and he has been a frequent critic of use of the expedited pathway, particularly the failure of sponsors to timely conduct confirmatory trials. (Accelerated Approval US FDA Panel To Reconsider Six Indications For Checkpoint Inhibitors)

“I think it’s yet another surprise in the story, another curious development,” said Caleb Alexander, professor of epidemiology and medicine at the Johns Hopkins University Bloomberg School of Public Health and a member of the advisory committee. “The evidence to approve the product based on clinical outcome was hardly persuasive,” so the agency went with the accelerated pathway on the basis of amyloid as a reliable surrogate. However, “the jury is still out on what is a valid surrogate.”

Rachel Sachs, a law professor at Washington University, said her primary concerns with using the accelerated approval strategy is not only that it was not part of the advisory committee discussion, but also that confirmatory trials “take years to complete, and even after they are completed the FDA finds it very difficult to remove these products from the market if they turn out not to have the anticipated clinical benefit.”

“In general, the approval of this product will add ammunition for critics of the accelerated approval program and it will empower insurers to push back against any requirements that they cover this product,” Sachs said.

Nine-Year Timeframe For Confirmatory Data

In granting the accelerated approval at this time, the FDA opted not to demand that the confirmatory trial be fully enrolled, or at least well underway, at the time of approval –  an expectation that the oncology office and some other FDA review divisions have adopted. Rather, the aducanumab decision more closely resembles the 2016 accelerated approval of Sarepta Therapeutics, Inc.’s Duchenne muscular dystrophy drug Exondys 51 (eteplirsen), the confirmatory trial for which has been repeatedly and substantially delayed.

For aducanumab, accelerated approval as the first disease-modifying therapy for Alzheimer’s in a broad, unrestricted patient population has the potential to create significant feasibility challenges in conducting a confirmatory study.

Biogen CEO Michel Vounatsos told CNBC the company “will be in a position to generate real-world evidence data that hopefully will substantiate the mechanism of action” during the nine years it has to deliver the final results from the confirmatory trial.

The FDA is requiring Biogen to conduct a “new randomized, controlled clinical trial” to verify the drug’s clinical benefit. The approval letter outlines what appears to be a generous timeline to satisfy the accelerate approval requirements, including more than a year to finalize the protocol and nearly nine years to submit the study. (See box.)

Confirmatory Trial Timeline

Draft Protocol Submission: October 2021

Final Protocol Submission: August 2022

Trial Completion: August 2029

Final Report Submission: February 2030

In an interview with CNBC, Biogen CEO Michel Vounatsos said the company is committed to deliver the deliver the data as soon as possible and also “will be in a position to generate real-world evidence data that hopefully will substantiate the mechanism of action.”

The agency told the Pink Sheet it will work with the sponsor “to assure a robust, global study design that can address the scientific issue – that is, capable of confirming benefit – but that can be implemented efficiently so as to support satisfying PMR requirements in a timely manner.”

On the press call, Office of New Drugs director Peter Stein said he expects there will be patients and clinical sites within the US interested in participating in a confirmatory trial despite the drug’s availability under accelerated approval. “There remains some uncertainty with regard to ultimate clinical benefit. There will be patients who are agreeable to participate knowing that.”

In addition, “there will be sites in many regions of the world where the drug might not otherwise be available, and so we expect that this will be a trial that can be implemented and completed and obviously we’ll be tracking that very carefully,” Stein said.

Maria Carrillo, chief science officer at the Alzheimer’s Association, said whether the confirmatory trial is going to be difficult to recruit remains to be seen, but commercial reimbursement hurdles for the drug could play a part in individual patients’ willingness to enroll.

“It’s important to remember that even though there will be coverage for this drug there may be out-of-pocket costs that could be considerable for many Americans,” Carrillo said. “If you are participating in a clinical trial, you may have those costs covered and you may have access to actually higher touch care, more frequent health care. So there are lots of benefits to participating in a clinical trial, and I think it's going to be important for families just to make that decision and to see what works best for them.”

Market Removal A Daunting Prospect

In its announcements about the aducanumab approval, the FDA highlighted the “regulatory procedures in place” that could lead to the drug’s removal from the market if the confirmatory trial fails to verify clinical benefit. However, it appears there is no special agreement with Biogen on withdrawal. Rather, the agency would have to seek withdrawal pursuant to its accelerated approval regulations, which could end up becoming a years-long, resource-intensive process if Biogen resists.

In 2011, Genentech, Inc. became the first product sponsor to have an accelerated approval revoked under this public hearing process when it challenged CDER’s proposal to withdraw the metastatic breast cancer claim for Avastin (bevacizumab). That experience, which included vociferous patient opposition to removing the claim, led some FDA officials to call for an expedited withdrawal pathway for accelerated approval drugs that fail to verify clinical benefit.

The agency currently is in the midst of another bid to remove an accelerated approval drug from the market against the sponsor’s wishes. CDER has proposed withdrawal of AMAG Pharmaceuticals Inc.’s preterm birth prevention drug Makena (hydroxyprogesterone caproate), which failed its confirmatory trial. AMAG has opposed withdrawal and requested a public hearing. (Accelerated Approval US FDA Request For Makenas Withdrawal Goes Beyond Failed Confirmatory Trial)

And while they haven’t reached an adversarial stage, the FDA Oncology Center of Excellence currently is reconsidering a host of “dangling” accelerated approval indications for PD-1/L1 inhibitors that failed their confirmatory trials. (ODAC Report Card Six Takeaways From Accelerated Approval Reviews Of Checkpoint Inhibitors)

Once a drug receives accelerated approval, it is “devilishly hard to get it off the market,” said Peter Lurie, president of the Center for Science in the Public Interest and former FDA associate commissioner.

“If this trial fails to demonstrate benefit, we will move very quickly to do what is within our authority and through the procedures that we have to look to remove this drug from the market.”– FDA’s Peter Stein

Given the experience to date with withdrawal proceedings for both Avastin and Makena, the prospect of having to remove a drug that would be used by millions of Alzheimer’s patients is daunting.

Stein said the FDA expects the forthcoming postmarketing trial will confirm aducanumab’s clinical benefit, “but … the trial could turn out not to do so. It’s important to recognize that when we see a trial, we’re going to always look at the data very carefully and make sure that within that dataset there’s not evidence to believe that the drug” actually worked as expected.

“If this trial fails to demonstrate benefit, we will move very quickly to do what is within our authority and through the procedures that we have to look to remove this drug from the market,” Stein said. “We expect that the sponsor, recognizing a responsibility to assure that a drug that’s being approved through accelerated approval which fails to demonstrate the benefit that’s expected to be seen, will agree and will support the removal of drug from the market.”

Derrick Gingery, Mandy Jackson and Brenda Sandburg contributed to this story.

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