The Food and Drug Administration finally looks set to get a new commissioner in early 2022, and the face should be familiar to many in White Oak: Robert Califf, who led the agency in the final year of Barack Obama's presidency.
New commissioners always face a long to-do list, especially when the position goes unfilled for as long as it did this time. Janet Woodcock, who has served as acting commissioner, is an experienced leader and known quantity for her colleagues. But lacking the backing of a presidential appointment and Senate confirmation, she wasn't in as strong a position to carry forward longer-lasting policy changes as Califf will be, if confirmed.
Califf's commitment to review FDA decision making on addictive opioid painkillers — an issue that may have kept Woodcock from consideration for the permanent appointment — will be tested almost as soon as he takes office. But other urgent matters will cross his desk in the coming months, on top of the usual cadence of drug approval decisions and the ongoing reviews of COVID-19 vaccines and treatments.
The continuing pandemic is a constant reminder of the position's importance. "This administration has left the FDA commissioner position open since January 20, almost a full year, in the middle of a pandemic," Richard Burr, R-N.C., the senior Republican on the Senate Health, Education, Labor and Pensions Committee, said during Califf's nomination hearing. "I'm disappointed that it took so long but I'm glad to see you here again sitting before this committee."
What direction will Califf take the FDA?
Califf will benefit from his previous stint in a way that a fresh appointee might not. Yet he was in office as commissioner less than a year, and came from an academic background rather than one of long government service. His main government experience before his first term as commissioner came as head of the FDA's Office of Medical Products and Tobacco for less than a year.
That outsider viewpoint can be as much an advantage as an obstacle. Califf is well-known as an advocate for innovation in clinical trials, pushing for faster and simpler data collection as well as promoting electronic information gathering. He's also advocated for greater trial diversity and pragmatic study designs.
The FDA has been under pressure to modernize its views on clinical trials for years, and having an advocate in the commissioner's office may push the agency further in that direction.
Califf's recent role as an executive at Alphabet's health-data group Verily will likely have shaped his views on these issues, although his time there has also been criticized as another example of his ties to industry. (Califf also served as a consultant and board member for pharmaceutical companies, and some lawmakers, such as Sen. Bernie Sanders, I-Vt., have cited that as a reason for not supporting his nomination.)
Will the FDA press harder on confirmatory trials?
The FDA typically grants accelerated approvals to important or potentially life-saving new drugs based on a relatively small amount of data, often using proxy measures such as patient responses. And in the past two years, the pace of these approvals has picked up. About a quarter of new medicines cleared in 2021 and 2020 received an accelerated OK, up from a fifth in 2019 and less than a tenth in 2018.
In exchange, the FDA requires drugmakers run confirmatory trials that compare the new treatment to a placebo or active therapy, using more rigorous yardsticks such as survival rates.
For many drugs and disease types, those confirmatory trials haven't been completed, and in 2021 drugmakers, under FDA pressure, withdrew several accelerated approvals. More remain unconfirmed, however, and the FDA appears set on pressing the issue further. Richard Pazdur, director of the FDA's Oncology Center of Excellence, recently told an industry audience that so-called "dangling" approvals will become a regular agenda item for the agency's panel of outside advisers.
"This is my jihad. It's going to continue," Pazdur said during the Biotech Virtual Congress organized by the analysis firm Prevision Policy, without naming specific drugs.
The process for withdrawing drugs can be cumbersome. But Pazdur indicated the oncology review office has come up with a way to hurry things along by first publishing an article outlining points of concern in a peer-reviewed journal and then laying out unfulfilled trial obligations in advisory committee briefing documents — a series of events that prompted some drugmakers to withdraw their products before the committee met.
This may be a pattern that gets repeated in the future. "People realized that there was a greater issue at stake, and that is the integrity of the program," Pazdur said, speaking on pre-meeting withdrawals in 2021. "The FDA is under scrutiny here."
How will controversy over Aduhelm impact the agency?
While Pazdur and the FDA's cancer drug office contemplate a new approach, the high-profile controversy over the agency's accelerated approval of Biogen's drug for Alzheimer's disease, Aduhelm, has shaken confidence in the program and the overall rigor of the FDA's reviews.
FDA officials and Biogen staff worked unusually closely on Aduhelm's review, and the agency's eventual approval went against the recommendation of its own advisers, raising questions about the FDA's decision-making process.
Several of those advisers resigned as a result of the approval, which is now the focal point for a review of the entire accelerated approval pathway by the inspector general of the Department of Health and Human Services.
This year, the FDA will find itself in a similarly difficult position as it reviews Alzheimer's drugs from Eli Lilly and Eisai that work similarly to Aduhelm and were also submitted for accelerated approval. (Eisai is partnered with Biogen.) If the agency takes a harder line with either Lilly or Eisai's drug, it risks undermining the approval precedent it set with Aduhelm. If the agency greenlights both, it risks further criticism of relying too heavily on an unproven surrogate measure of benefit.
Heightening the stakes will be the inspector general's review, which will examine past accelerated review practices in an attempt to determine whether FDA officials complied with relevant laws and regulations. The issue won't be going away soon, either, as the inspector general's office isn't expected to publish its report until 2023.
Will the planned PDUFA renewal go as planned?
The FDA's user fee program, which funds a significant portion of its drug review budget, is subject to renewal every five years when the law governing it, abbreviated as PDUFA, expires. In the past, renewals have been used as opportunities to set performance goals, such as deciding on 90% of drugs submitted under standard review within 10 months of submission, or new programs, such as the Breakthrough Therapy designation.
The legislation needs to pass by Sept. 30 in order to keep PDUFA programs alive, but the process for renewal tends to be orderly and negotiated between the FDA, the industry, and patient and practitioner groups. The agreement, outlined in a "commitment letter" released last August, included some enhancements to drug review.
Among them were commitments to reinforce cell and gene therapy review staff; accelerate review procedures for already approved therapies being tested in new diseases; increase collaboration between the FDA and drugmakers in designing rare disease clinical trials; expand the use of "real-world" evidence; and improve alternative inspection practices for overseas manufacturing facilities.
The recommendations from FDA's letter will be submitted to Congress by Jan. 15, after which legislators will draft a bill and push it into hearings and votes. Although the passage of PDUFA renewal legislation tends to be routine, lawmakers could seek to add new agency obligations, particularly if new controversies emerge over the next nine months.
Has the FDA become tougher?
Aduhelm's approval notwithstanding, a series of drug rejections by the FDA last year, along with new warnings for several autoimmune medicines, have raised questions of whether agency review offices are taking a stricter line.
In 2021, FDA rejected such closely watched drugs as FibroGen's roxadustat, Acadia Pharmaceuticals' Nuplazid in dementia-related psychosis and Provention Bio's teplizumab. The agency also added new restrictions to drugs from Pfizer, AbbVie and Eli Lilly.
In all three rejections, drug reviewers took issue with technical aspects of the companies' applications. But they also appeared to signal to industry watchers a "more active and rigorous stance at the FDA, particularly with respect to safety," according to SVB Leerink analyst Geoffrey Porges. Others, including executives at Acadia, have criticized the agency for moving its review goalposts.
As Califf takes office, drugmakers will be watching the FDA's decisions closely. Of note is Akebia Therapeutics' vadadustat, a competitor to FibroGen's drug which also has mixed data.
The events of 2021 haven't discouraged Bruce Booth, a well-known biotech venture capitalist, who noted in a review video for the year that the rejections "objectively had issues."
"Importantly the FDA as a whole has been incredibly facilitating and engaged with innovators," he said of the outlook for future drug evaluations.