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Biogen Alzheimer Drug Row Augers Flux in Fast FDA Approvals (1)

Feb. 14, 2022, 10:35 AMUpdated: Feb. 14, 2022, 2:53 PM

Lawmakers could revamp the fast-track FDA process used to approve Biogen’s Alzheimer’s drug under must-pass legislation to reauthorize the agency’s user fees.

The House is weighing a proposal to renew the Prescription Drug User Fee Act, which allows the Food and Drug Administration to collect fees from brand-name pharmaceutical companies to help fund agency operations. Lawmakers spent much of the first hearing on the matter focused on the Aduhelm approval that had attracted renewed scrutiny to the accelerated pathway program.

“I would not be surprised at all to see some reforms to the accelerated approval process as part of the PDUFA legislation,” Rachel Sachs, a law professor at Washington University in St. Louis whose specialties include FDA and health law, said in an interview.

At the heart of the Aduhelm controversy was the FDA’s decision to put the drug on the market based on questionable evidence and against the recommendation of its scientific advisory panel. The accelerated approval mechanism isn’t directly related to the rates the FDA negotiates with industry, but PDUFA often includes policy riders that go beyond user fees.

Potential changes include improving the clinical trial endpoints used under accelerated approval, beefing up the FDA’s ability to enforce post-market requirements, and making the decision process more transparent.

The House Energy and Commerce Committee plans to continue hearings on PDUFA next month. Congress must pass the five-year agreement before the current authorization expires at the end of September.

Concern Not Going Away

The FDA has faced criticism of the accelerated approval pathway long before Aduhelm. A top concern is whether the program is making drugs available without certainty that they will show a definitive clinical benefit down the line.

“I don’t think this concern is going to go away,” said Kay Holcombe, who worked on every PDUFA negotiation prior to the one currently being deliberated as a former senior vice president for the Biotechnology Innovation Organization.

“Sadly, this always is something that happens because of one product that people have decided was done the wrong way, or got screwed up somehow. Then it grows from there, and it becomes this huge mushroom cloud,” she said.

Accelerated approval first became available in 1992 amid the HIV crisis. At the time, an FDA review on a drug application averaged three years. The agency can now do it in six to 10 months, in large part due to user fees. The pathway aimed to shorten the time to clear drugs for diseases with an unmet medical need by relying on surrogate endpoints, which are laboratory measurements that can stand in for a clinical endpoint—a direct measurement of whether a patient feels or functions better or lives longer. Clinical endpoints offer a stronger indicator of effectiveness but can take much longer to demonstrate.

For example, tumor shrinkage is a surrogate endpoint for survival rate, which in turn is a clinical endpoint that typically requires waiting at least five years.

“Accelerated approval in one sense is not about accelerating the approval. It’s about looking at a different kind of endpoint,” Holcombe, who’s now a senior adviser to the Milken Institute Center for Public Health as well as secretary and treasurer of the Reagan-Udall Foundation for the FDA, said. Drug companies still have to demonstrate clinical benefit with post-market studies.

But with more than 250 drugs now cleared through accelerated approval, questions have arisen about whether the surrogate endpoints used to approve these drugs are good predictors of clinical benefit.

A Commonwealth Fund report found some drugs linger on the market without the required follow-up studies. These drugs tend to have higher price tags and contribute significantly to Medicare’s spending on drugs.

While accelerated approval often speeds up the process, Holcombe noted that sometimes a drug won’t hit the market any faster than with a traditional approval. Speed depends on a number of factors including what the surrogate endpoints are, what the product is, and what the disease is.

“The argument is much more complicated than one drug got on the market too fast,” she said.

Standardizing Endpoints

Oncology drugs account for about 65% of the drugs approved under the accelerated mechanism. The surrogate endpoints in oncology are more established than in other areas, such as tumor shrinkage as a marker for survival from a cancer. There’s also been a collaborative approach in oncology research to standardize the criteria that’s used in clinical trials.

Standardizing and applying surrogate endpoints consistently are critical in other therapeutic areas as well, Jeff Allen, president and CEO of Friends of Cancer Research, said. “That in turn will will improve the confidence that you can have in those measures,” he said.

Congress in the user fee legislation could “create a more rigorous step for identifying and accepting and using a surrogate endpoint,” said Jeremy Sharp, a former FDA deputy commissioner who’s now at Waxman Strategies, the public affairs firm founded by former congressman Henry Waxman.

The FDA can further improve biomarkers by saying, “if you increase the user fees by X percent, we can use some of those resources to allocate more staff time to that development,” Sharp said.

Lawmakers could also use the user fee plan to better hold companies accountable for complying with the accelerated approval pathway’s post-market requirements to submit clinical trial data confirming a drug’s anticipated clinical benefit, Sharp added.

The FDA plans to devote a portion of drug industry funding over the next five years to early consultation between review teams and sponsors to develop new surrogate endpoints that can better predict a treatment’s clinical benefit, according to its PDUFA commitment letter.

The FDA also committed to creating a pilot program to look at novel endpoints for rare diseases.

“I just was struck by the sort of philosophical connection between that and the flap over accelerated approval, which is also about looking at a different set of endpoints,” Holcombe said.

Beefing Up Enforcement

Lawmakers could also strengthen the FDA’s authorities to enforce its accelerated approval requirements, Sachs said. “There certainly is a question about whether FDA is enforcing their existing authorities as strongly as they could be,” she said.

Senate Finance Committee Chair Ron Wyden (D-Ore.) raised concerns in a Feb. 4 letter that “some companies have taken advantage of the Accelerated Approval Pathway” and that the FDA has fallen short in “using its authority to hold drug companies accountable for fulfilling their obligations.”

The FDA is typically less likely to take action against a drugmaker once its product is already on the market through the accelerated approval pathway, Sharp said.

“When FDA positions itself as the person taking away your product or denying you your product, it goes under intense political criticism and pressure, which makes it harder for it to do its job,” he said.

The process for removing a drug from the market is complicated and time consuming for a resource-constrained agency, Sachs said. “It’s understandable that [FDA] would request a simplified process, even if there might be arguments that they’re not using their existing authorities to the fullest extent.”

Jonathan J. Darrow, an assistant professor at Harvard Medical School who focuses on the intersection of law, innovation, and pharmaceuticals, said he doesn’t anticipate changes to undo the flexible nature of the accelerated approval process.

“Congress has instructed the FDA to be more flexible in its acceptance of clinical trial design, and the FDA has responded. So I would be surprised to see Congress reverse its position and say that FDA should be less flexible,” Darrow said.

But it’s likely the pathway will see some change as the user fee agreement moves through Congress and pits “different political motivations against each other,” Sharp said.

It’s “cost of health care versus the access to innovation, innovative care,” he said. “And the question will be which one is more front of mind for” lawmakers this summer.

(Updates with comment on speed approval factors in the 15th and 16th paragraphs. An earlier version corrected definitions of surrogate and clinical endpoints.)

To contact the reporters on this story: Celine Castronuovo at; Jeannie Baumann in Washington at

To contact the editor responsible for this story: Alexis Kramer at