Over the past few years, the Food and Drug Administration has come increasingly under scrutiny for its program to grant speedy approvals to drugs that show early signs of benefiting patients with life-threatening diseases.
These so-called accelerated approvals have ushered in many new therapies, particularly for cancer. But they have also ginned up substantial controversy in several cases, such as with Biogen’s new Alzheimer’s medicine Aduhelm, because they brought to market high-priced therapies that weren’t proven to help people.
Drugmakers have also faced criticism for dragging their feet on the follow-up studies meant to definitively show their medicines work.
Soon, the FDA could receive new authority to compel pharmaceutical companies to follow through with these confirmatory studies and to order withdrawal of drugs that fall short of their initial promise. Draft legislation in Congress, as well as a budget proposal from the Biden administration, would both require companies begin trials to confirm drugs’ benefits earlier than is now mandated by law.
Changes appear more likely this year as Congress must reauthorize the user fee law, called PDUFA, that funds much of the FDA’s budget. A House panel is this week expected to review and vote on PDUFA renewal legislation, which contains changes to the accelerated approval program.
“The fact it is a PDUFA year gives them a ready-made, must-pass vehicle, which makes passage of something much more likely,” said Rick Weissenstein, an analyst for Cowen.
However, drugmakers might have dodged more damaging modifications as the draft bill, released last week by a key Congressional committee, omitted a measure that would have set an expiration date on accelerated approvals.
An evolving program
Congress created the accelerated approval pathway in 1992 in response to the HIV epidemic, aiming to provide quicker access to drugs to treat what at the time was a fatal disease. The first drug cleared this way was a Roche antiviral called Hivid.
But in the years since, the FDA has more commonly granted accelerated approvals for cancer treatments and rare disease drugs. Over the past decade, 85% of accelerated approvals awarded by the FDA were in oncology, according to a recent article by two top agency officials.
This trend has helped fuel the rapid expansion of immunotherapies and targeted treatments for cancer into new uses over the past decade. But those drugs can cost more than $100,000 a year and, in some indications, haven’t yet been proven to extend survival
“We have some examples of how accelerated approval has worked to benefit patients,” said Mikkael Sekeres, hematology division chief at University of Miami Health System’s Sylvester Comprehensive Cancer Center.
“Then we have situations where it hasn’t worked as well,” he added. “It’s incumbent on us to review those drugs and see if they should stay on the market, and whether they are offering hope or false hope.”
Accelerated approvals are typically based on what’s called a “surrogate” measure, an effect researchers believe can predict clinical benefits that may take longer or be harder to assess. In cancer, a common surrogate measure is how well a new treatment can shrink tumors.
Yet, to keep a drug on the market and win full approval, companies must complete a follow-up trial that more definitively confirms a benefit to treatment. For cancer drugs, that’s often whether they can forestall disease progression or extend the lives of treated patients.
The link between surrogate measures and confirmed benefits isn’t always clear, however. And even if it is, small but statistically significant changes might not lead to noticeable improvements in patients’ lives.
For example, Sarepta Therapeutics won accelerated approval for a Duchenne muscular dystrophy drug in 2016 that critics said offered little real benefit. The FDA overruled its own advisers in clearing the medicine.
Accelerated approvals have also become controversial when the confirmatory trial is slow to deliver results or fails to do so, in part because the FDA lacks strong powers to order drugs off the market. A 2021 analysis by the Institute for Clinical and Economic Review, a nonprofit watchdog group, found that 13% of drugs cleared on an accelerated basis weren’t converted to full approval five years later.
Three years after Sarepta's drug’s approval, the company again faced criticism when it hadn’t begun the required confirmatory trial.
More recently, the FDA in 2021 granted an accelerated approval to Aduhelm in a controversial decision that sparked renewed attention on the program, Congressional inquiries and an inspector general investigation. The agency received further blowback by giving the company until 2029 to finish the confirmatory trial. (Biogen has since said it will finish the study in four years.)
Room for reform?
While the FDA has been criticized for some of its approval decisions, it’s also shown interest in reform, too.
The agency last year convened a meeting of outside experts to review six accelerated cancer drug approvals after several had failed in confirmatory testing. Since then, FDA officials have made clear they aim to focus on resolving these “dangling approvals.” A number of drugmakers have proactively withdrawn previously approved drug uses or applications in response.
“This is my jihad. It’s going to continue,” Richard Pazdur, the FDA’s top cancer official, said in a December conference organized by the analysis firm Prevision Policy. The FDA didn’t make Pazdur available for an interview.
Without confirmation of a drug’s benefit, “I can’t look my patient in the eye and say I think this drug is going to help you live longer,” said Sekeres, who is chair of the American Society of Hematology’s communications committee and a former chair of the FDA’s oncology advisory committee.
The National Organization for Rare Diseases, which is generally supportive of the accelerated approval program, views the current controversy as jeopardizing access, particularly when insurers push back as they have with Aduhelm. In Oregon, meanwhile, the state’s Medicaid program has requested permission to deny coverage for accelerated approval products in some circumstances.
“I think that there’s a lot that can be done with post-market confirmatory trials and transparency around them,” said Heidi Ross, NORD’s vice president of policy and regulatory affairs.
The group is recommending more frequent reporting from drugmakers and for the FDA to make these records publicly accessible, Ross said.
The agency could have new tools to prevent “dangling” approvals beginning in October, if Congress votes to include accelerated approval reform in the PDUFA reauthorization legislation, which is renewed every five years.
The Pharmaceutical Research and Manufacturers of America, a powerful industry lobby, argues changes aren’t necessary.
“America’s biopharmaceutical research companies are committed to supplying patients with safe, effective and high-quality innovative therapies and accelerated approvals must meet the same standards of safety and efficacy for approval as all other medicines,” a spokesperson wrote in an email.
The House of Representatives draft bill, which would serve as a PDUFA reauthorization document, would allow the FDA to require drugmakers begin confirmatory trials before an accelerated approval is granted. The agency would also gain strengthened authority to have a drug withdrawn from the market if a company doesn’t follow through or if the trial fails.
The bill doesn’t take more drastic steps included in legislation authored by the Energy and Commerce Committee’s chairperson, Frank Pallone, D-N.J., that would have made accelerated approvals automatically expire after five years. Pallone’s position as the committee’s chair could mean the idea remains a point of negotiation, however.
To Michael Carome, director of non-profit consumer advocacy organization Public Citizen’s Health Research Group, a firm deadline is necessary. “Often these studies are slow getting off the ground [and] they miss their planned deadlines for completion, if they ever get completed at all,” he said.
Other groups aren’t as supportive. The American Society of Clinical Oncology, for instance, is opposed, as cancer drug trials are typically based on events like disease progression or death rather than how long a patient is on treatment. “I wouldn’t like it to be based on when a study is scheduled [to report],” said Julie Gralow, ASCO’s chief medical officer.
The PDUFA reauthorization draft would also clarify the FDA’s process for withdrawing an accelerated approval based on negative clinical data or poor trial execution, including specifying how the agency should notify drugmakers, open a public comment period and give companies an opportunity to appeal.
Strengthened powers to order withdrawal of drugs could be an important step forward, Carome said. He noted the example of Makena, a drug designed to prevent premature birth that won accelerated approval in 2011. While a confirmatory trial failed to prove it works, the medicine remains on the market three years later.