Fallout from Aduhelm Decision Could Undermine FDA Accelerated Approval Process

March 7, 2022 – Newly appointed Food and Drug Administration Commissioner Robert Califf, M.D., who is returning to the position he briefly held during the Barack Obama administration, faces a daunting challenge as he begins anew: coming to terms with how the agency’s controversial accelerated approval of Biogen’s Aduhelm (aducanumab) to treat Alzheimer’s disease affects its reputation and the future appeal of the accelerated approval pathway.

“There has been a lot of ink spilled … on the missteps by FDA in the way that it granted Aduhelm accelerated approval,” according to Prevision Policy Senior Editor Kate Rawson, who spoke last month at a Coalition for Healthcare Communication webinar, “Biden’s Health Policy Priorities: Where We Are and What’s to Come.”

The aftereffects of this decision have called into question “the FDA’s perceived coziness with drug sponsors, its use of advisory committees and its reliance on them, whether or not it actually follows their advice, and the way that it communicates big decisions to the public,” Rawson said.

Before the vote on his confirmation, Califf promised Sen. Ron Wyden (D-Ore.), chair of the Senate Finance Committee, that he would prioritize improvements in the accelerated approval pathway, particularly to ensure that companies do, in fact, complete confirmatory clinical trials after receiving product approvals.

Fulfilling this promise may be even more of a priority for Califf in the face of legislation introduced today by Rep. Frank Pallone (D-N.J.) which would impose serious penalties for companies that fail to complete confirmatory studies. Pallone’s bill would make not doing these studies in a timely manner a violation of the Federal Food, Drug & Cosmetic Act.

In Pallone’s view, “timely” matters – his bill states that drug sponsors that do not complete confirmatory trials within a year of their deadline would be subject to an automatic revocation of their accelerated approval. It is worth noting that Biogen at first seemed to commit to completing these trials in nine years; after a lot of pushback, the company cut that timeframe to four years.

Approval process controversy

The FDA’s accelerated approval pathway, which to date has been used primarily for cancer drugs and drugs to treat several rare conditions, “allows the FDA to approve drugs that treat serious conditions and that fill an unmet medical need based on a surrogate endpoint, which is a marker that is thought to predict a clinical benefit,” the agency states.

In June 2021, the FDA granted accelerated approval of Aduhelm based on the drug’s ability to remove the amyloid from the brain, despite what many term “unconvincing” evidence that this slows Alzheimer’s disease. The FDA did call for a follow-up clinical trial to substantiate the drug’s benefit as part of its approval, but it appeared to ignore its advisory board’s 10-1 vote against approval and there is concern that conversations between the FDA and the company leading up to the approval were not held in a transparent manner. Three of the advisory committee members have resigned as a result of these concerns.

Add to this the drug’s high sticker price (which Biogen recently reduced by half), associated costs with the treatment (e.g., infusion and MRI monitoring costs) and its broad target population and it’s not surprising that there have been calls for investigations from members of Congress and the FDA itself (an Office of Inspector General report is due in 2023) regarding this decision and the use of the accelerated approval pathway for this product.

CMS draft NCD raises ire

What has been quite surprising is the January draft national coverage decision (NCD) from CMS stating that it would not cover Aduhelm or any future Alzheimer’s disease therapies in the same class, which, Rawson shared, essentially renders it back to investigational status.

“You think you’ve seen everything,” she said in reference to CMS’ “holy cow” draft NCD. “CMS has typically covered accelerated approval drugs … pretty much to the label. It’s an alarming decision.”

She remarked that “you could argue that this draft decision is sort of an unprecedented, one-off situation surrounding a very specific drug,” but it could be part of a larger conversation that may not pan out well for industry. Indeed, she noted that the Medicare Payment Advisory Commission (MEDPAC), which advises CMS on coverage issues, recently raised a question in a public meeting about whether the FDA should be the “sole proxy” for deciding which products qualify for CMS coverage.

“MEDPAC suggested that CMS take FDA approval decisions into consideration, but not automatically defer to them,” which Rawson stated would be a “major change in policy” and “could put a chill” on the accelerated approval process in general.

“If there’s no guarantee that CMS is going to cover an accelerated approval product, then why would you use that pathway?” she queried. “It could delay products coming to the market in the worst-case situation.”

Response to the CMS draft NCD has been swift and significant, with CMS receiving roughly 10,000 comments to date – one of them from 78 House Republicans, which urged CMS to consider revising the NCD when it is issued in final form. “This could signal the type of oversight that could come from the House if Republicans win in the midterms,” Rawson commented.

The final NCD is expected to be issued by CMS in April. In the meanwhile, what Califf does or does not do to mitigate the situation or improve the FDA’s reputation should be of great interest to industry.

To view Rawson’s slides from the recent webinar, click here.