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STAT News – Will controversy over new Alzheimer’s drug spell the end for the FDA’s faster approval process?

STAT News – Will controversy over new Alzheimer’s drug spell the end for the FDA’s faster approval process?

WASHINGTON — For most of its history, the Food and Drug Administration’s shortcut pathway for approving certain medicines was hardly contentious among anyone but the most diehard agency nerds; for years, only a handful of drug makers even used it.

Now, however, just as the accelerated approval program is reaching peak popularity, key supporters, including Oncology Center of Excellence Director Rick Pazdur, are warning that it’s “under attack.” 

The pathway is under intense scrutiny after the FDA used it to greenlight Biogen’s controversial new Alzheimer’s drug, aducanumab, known by its brand name Aduhelm. That move prompted a new swirl of criticisms in prominent medical journals and major newspapers. The spotlight got even brighter last week, when the federal health department’s investigative arm announced it is probing the FDA’s process for utilizing the pathway. 

Insurers and their allies are also becoming increasingly vocal about how such approvals outsource the FDA’s job of figuring out whether drugs work, forcing insurers to decide whether to pay for those drugs. Medicaid directors, in particular, are beginning to speak out because their programs must cover the drugs regardless of whether they work or not. 

Drug makers say the pathway saves lives by letting them more quickly launch promising drugs for previously untreatable conditions. Critics, meanwhile, say the pathway gives drug makers permission to sell largely unproven drugs, often at high prices, with minimal oversight. And they argue that nothing makes their case clearer than Biogen’s drug. 

“Aducanmab is, in a sense, a poster child for some of the issues around accelerated approval that people have been talking about,” said Steve Pearson, the president of the Institute for Clinical and Economic Review. “You take these general [problems], and you can basically pin the tail on the donkey with every one of them with aducanumab.”


Any major changes to accelerated approval would likely require congressional action, and even the pathway’s fiercest critics were doubtful an overhaul would come quickly. Most of the reforms gaining any traction in Washington also have little to do with limiting the FDA’s ability to fast-track drugs — instead, they’re focused on reimbursement for those therapies. But nonetheless, proponents of accelerated approval are increasingly concerned that anger over Aduhelm will prompt lawmakers to push for wholesale changes to the program. 

“It worries me that there are discussions being had about accelerated approval that are taking it out of context from the totality of the program … independent of the benefits that have been seen for several decades,” said Jeff Allen, the president of Friends of Cancer Research, one of the biggest backers of the program.

Below, STAT walks through why accelerated approval is so important to drug makers, what reforms are on the table, and why Aduhelm has prompted such a debate.

What is accelerated approval and why is it so important to drug makers?

Accelerated approval is a special FDA pathway that allows the agency to approve drugs based on their impact on so-called surrogate endpoints — intermediate measures that look, for example, at whether a drug shrinks a tumor rather than its impact on a patient’s cancer progression itself. The FDA approved Aduhelm based on its ability to reduce accumulation of plaques in patients’ brains rather than its ability to slow the progression of Alzheimer’s disease. 

In exchange for a fast track to market, drug makers must complete follow-up studies to prove that their drugs actually provide a clinical benefit. Drugs that fail those studies are supposed to be taken off the market. 

The pathway was created in 1992 in response to the AIDS crisis, and its backers say it’s been a resounding success. An FDA review of the accelerated approval pathway, which was published in the Journal of the American Medical Association, found that the majority of cancer drugs approved using accelerated approval between 1992 and 2017 eventually showed clinical benefit. 

The pathway’s popularity has ballooned in recent years. A STAT analysis of FDA data found that 2020 was the most popular year for accelerated approval on record. Twenty-three percent of the new drugs approved by the FDA’s drug center went through the accelerated approval pathway, according to a recent FDA report.

“The accelerated approval pathway is a critical tool for patients and regulators, and the biopharmaceutical industry supports its continued usage,” said Andrew Powaleny, spokesperson at PhRMA, in a statement. Powaleny added that the pathway “has helped speed the availability of treatments for patients with serious or life-threatening disease and where there is significant unmet medical need.”

The pathway is also attractive to drug makers because it lets them sell their drugs more quickly, freeing up capital, explained Joseph DiMasi, the director of economic analysis at the Tufts Center for the Study of Drug Development.

“Accelerated approval is attractive because time is money,” DiMaisi said. “Getting your money sooner means that it can be spent sooner or invested longer.” 

Why is Aduhelm the new poster child for accelerated approval?

For those critical of accelerated approval, Aduhelm is a perfect example of the program’s flaws. 

For years, critics have complained that the program allows the FDA to approve drugs based on shoddy endpoints that don’t actually make an impact on patients’ lives. 

The accelerated approval statute technically requires that a surrogate endpoint be “reasonably likely to predict clinical benefit,” but there’s often fierce debate between advocates regarding the benefits of different surrogates. 

Critics say that the surrogate endpoint that the FDA used to approve Aduhelm is particularly shocking. They note that there’s been widespread debate in the scientific community about whether stopping amyloid plaque formation in the brain actually has anything to do with slowing the progression of Alzheimer’s. 

“The Alzheimer’s drug, from the outside, was giant steps beyond the mistakes they constantly make in oncology,” said Fran Visco, the president of the National Breast Cancer Coalition, which has been outspoken for years against the use of surrogate endpoints and accelerated approval in cancer treatment. 

The FDA, for its part, has said that “the reduction in amyloid plaque correlates with slowing of disease progression and is reasonably likely to predict clinical benefit.”

For insurance companies, Aduhelm also is an example of the bind the pathway puts them in. Aduhelm costs $56,000 per year, and insurers will be forced to choose whether to pay for the drug with only minimal information on whether the drug actually helps patients. 

AHIP, the lobby for health insurers, declined to comment on the accelerated approval pathway for this story. However, Pearson, the president of ICER, noted that when his group’s Policy Leadership Forum — a group of roughly 30 payers, middlemen and drug makers — decided to address the issue of accelerated approval, it was “more on the payers’ minds.”

“The payers, they want better evidence, partly because it helps them create rational, appropriate coverage policies and because they think it helps them also limit what they might view as use not supported by evidence, but they need that evidence to be able to help draw those lines responsibly,” said Pearson. 

The burden falls even harder on Medicaid directors, who are required to cover virtually every drug on the market.

Jack Rollins, the director of federal policy at the National Association of Medicaid Directors, said Aduhelm is “really is one of these perfect examples of all of the issues that have been apparent with the accelerated approval pathway.”

“I don’t think you could find a better example to shine a light on all the concerns that we’ve had,” Rollins added. 

What changes are reformers pushing?

A select few critics of the accelerated approval pathway, like Visco of the National Breast Cancer Coalition, want to see the pathway abolished entirely. Others are content with much smaller changes. None see them happening fast. 

“I’m not that hopeful that it’s going to change, although I don’t know what more evidence we need that it needs to change,” said Visco. “The forces in support of accelerated approval are incredibly strong. They are the vast majority of the patient groups, the pharmaceutical industry, the FDA itself.”

ICER, the drug pricing watchdog, laid out a slew of options for reforming the pathway in an April white paper. Those proposals range from increasing FDA enforcement against drug makers that don’t complete required follow-up trials to requiring that drugs that rely on the pathway have a separate warning on their label. 

Medicaid directors have also been pushing for the flexibility to deny beneficiaries access to certain accelerated approval drugs. Massachusetts’ Medicaid program, for example, unsuccessfully petitioned CMS in 2017 for the ability not to cover certain drugs, including accelerated approval drugs. The state, instead, proposed to work with the University of Massachusetts Medical School to review the evidence supporting accelerated approval drugs before covering them.

A panel of federal advisers on the Medicaid program recently endorsed a second option, recommending in June that drug makers give Medicaid programs bigger rebates on drugs approved with accelerated approval until the manufacturers complete the follow-up studies meant to prove that their drugs actually benefit patients. 

That proposal, which Congress would have to pass into law, already has drug makers on guard. One coalition said it would “counter the economic incentives to pursue accelerated approval drugs, disincentivizing drug developers from pursuing development of therapies in otherwise intractable disease areas” and would “punish patients who are forced to suffer as their disease progresses while continuing to wait for a treatment.”

What reforms can proponents of the pathway live with?

Backers of the accelerated approval pathway insist they’re open to having conversations about reforming the pathway, too, but their proposed tweaks are much more modest than those pushed by ICER or even the congressional Medicaid advisers.

Friends of Cancer Research, for example, has proposed a number of modest changes to the pathway, focused largely on helping to validate the use of surrogate endpoints and making it easier to conduct the confirmatory trials needed to be done. 

They have proposed, for example, that the FDA provide additional guidance on how it determines whether a surrogate endpoint is “reasonably likely to predict clinical benefit.” They’ve also suggested requiring that follow-up trials start when drug makers file their applications with the FDA.

“I think it’s good [to] have periodic discussions in order to make sure that the program is still meeting the original goals and the benefits that it’s provided over the years,” said Friends of Cancer Research’s Allen. “We have to be a little bit careful to try and make those enhancements where they need to be made, but not get so wrapped up in one case study.”