Few government agencies were as front and center in the public eye last year as the Food and Drug Administration, which came under immense pressure to authorize unproven drugs as the world grappled with the pandemic and conducted high-stakes reviews of two coronavirus vaccines.
As COVID-19 cases continue to soar in the U.S., most of those pressures haven't gone away. But the inauguration next week of Joseph Biden as president will almost certainly bring new management to the agency, a change that can often result in policy shifts both subtle and far-reaching.
There will also be new faces at the FDA's parent agency, the Department of Health Human Services, which has battled FDA leadership at several points during the Trump administration. Even now, with days left to Trump's term in office, HHS officials are reportedly attempting to ram through several new policies that impact the FDA.
The pace and frequency of drug approvals, meanwhile, has quickened in recent years, prompting some to question whether reviewers are showing enough caution. Depending on who's appointed commissioner, the Biden administration could pull the reins somewhat.
"I think after so many years of faster, faster, faster, we're going to see a little bit of a pendulum shift," Remy Brim, co-lead of the health and life sciences practice at lobbying firm BGR Group, said Dec. 14 during the virtual Biopharma Congress sponsored by Prevision Policy.
"FDA, especially under Democratic administrations, really feels that a product is not safe and effective until it's shown it's safe and effective," Brim said. "It doesn't necessarily take the stance that a six -month or a one-year delay is detrimental."
Here are five issues before the FDA that will define its first year under a Biden administration:
Who will Biden nominate to be commissioner?
The FDA commissioners under President Donald Trump, Scott Gottlieb and Stephen Hahn, have been relatively steady leaders. Even though Hahn yielded to pressure from Trump to grant some controversial coronavirus drug authorizations, he became a fierce defender of the agency's review process for vaccines developed by Moderna and partners Pfizer and BioNTech.
While Hahn offers continuity amid the pandemic, the Biden administration is almost certain to appoint a new commissioner. The appearance of David Kessler, an FDA commissioner under Presidents George H.W. Bush and Bill Clinton, on the Biden transition team raised eyebrows. Two other Obama administration-era FDA officials, Luciano Borio and Lisa Barclay, are also members of the team.
Kessler, however, is reportedly out of the running for a FDA commissioner appointment, according to BioCentury.
Other names that have emerged include Gottlieb and two former commissioners, Margaret Hamburg and Mark McClellan. From within the agency, Amy Abernethy, the principal deputy commissioner whose name surfaced the last time there was a vacancy, has also been mentioned, as has a past holder of Abernethy's post, Joshua Sharfstein, now at Johns Hopkins University.
In a Nov. 16 note to clients, Cowen analyst Rick Weissenstein wrote Sharfstein's continued involvement in agency issues since leaving a decade ago makes him the best nomination for the sector. "We see a pick like Sharfstein as the best possible outcome as it would mean continuity at the FDA and maintain a positive environment for drug developers," he wrote.
A heavy coronavirus workload
Authorizing two coronavirus vaccines in two weeks last December was a monumental task, but the job isn't done. Three more vaccines could soon have late-stage study results supportive of authorizations, too, while testing continues for new experimental antivirals and antibodies that aim to help infected patients stay alive and out of the hospital.
If the latest vaccines succeed in the clinic, the FDA would likely convene an advisory committee meeting for each one as it did with the Pfizer and BioNTech and Moderna vaccines, a time-consuming task that is nonetheless considered important for building public trust.
Meanwhile, drugmakers that developed coronavirus treatments now cleared for emergency use, including Regeneron and Eli Lilly, may seek to convert their authorizations into full approvals.
The job of reviewing all of them will be made more complicated by the companies' efforts to expand the populations in which they can be used. Both the Regeneron and Lilly antibody drugs were authorized after results in comparatively small numbers of patients. Data from larger groups could change the conclusions of the drugs' effectiveness and pose thorny questions for reviewers.
Powerful examples in adapting clinical trial design
The massive trials to push coronavirus vaccines through from design to emergency authorization in less than a year, and a separate one to quickly evaluate treatments of hospitalized patients, have proven that big studies do not necessarily need to be multi-year affairs. The RECOVERY trial in the U.K., in particular, showed how a simple trial asking only one or two urgent public health questions can yield answers within weeks or a few months. The U.S. government's COVE trial, which tested Moderna's vaccine, did something similar.
The public health emergency of 2020 no doubt inspired agency reviewers to be more flexible about clinical trial design and the speed at which they were conducted. While normal times won't bring the same pressure, the experience could have lessons for regulators' oversight of trials in the future.
Particularly in cancer and rare diseases, the FDA has shown that it's willing to work with drug developers to design trials that can determine whether or not treatments work in short order. RECOVERY and COVE point toward a way to do the same for broader public health questions, and the agency may need to consider how the study of new drugs for major conditions like diabetes or cardiovascular disease could be sped up.
Regulating a wave of genetic medicines
The FDA's surprise rejection of BioMarin Pharmaceutical's hemophilia gene therapy Roctavian, along with scrutiny of manufacturing processes for other gene therapy developers, has led some to argue the FDA has raised standards. But Wilson Bryan, head of the agency's gene therapy review center, has argued the tough oversight is tied to "an increase in activity in the field."
Roctavian's rejection was unexpected, as two previous gene therapies, Roche's Luxturna and Novartis' Zolgensma, had largely non-controversial approvals. (The clearance for the latter, however, was marred by a post-approval data manipulation scandal.)
The FDA's concern, according to BioMarin, was that early data from later-stage testing showed a somewhat weaker treatment effect than a smaller, early study, raising questions about the durability of Roctavian's benefit. And in hemophilia, patients have many existing drug options available to them, which may have changed the agency's risk-benefit calculation.
"What does unmet need mean, when you have a gene therapy versus other products on the market?" Brim said at the Biopharma Congress session. "Once a patient takes [a gene therapy], they can't untake it."
More than 1,000 Investigational New Drug applications for gene therapies have already been submitted to the FDA, according to Bryan, meaning the demands on the agency will only grow with time.
The laws authorizing the user fees that partially fund FDA drug reviews — known in shorthand as PDUFA — sunset every five years, requiring Congress to pass a new one to sustain the program. The current edition is set to expire Sept. 30, 2022, so work is already underway to set the agenda for the seventh iteration of the law.
In the past, reauthorization of the PDUFA program has forced the agency to set firmer deadlines for drug approval decisions and has created expedited approval pathways such as the Breakthrough Therapy designation. The laws can also become a vehicle for Congress to achieve changes within the agency, which has been under the microscope during the coronavirus pandemic.
"How FDA handles itself on COVID is going to play into what type of policy riders we're going to see," Brim said.
A chief FDA request has been for more resources to beef up the staffing in its gene and cell therapy division. The agency, meanwhile, may be called upon to expand its work on new models of clinical trials, such as adaptive studies, that can shorten the amount of time experimental drugs spend in development.
Drugmakers could also seek to streamline the manufacturing paperwork involved in expedited review pathways to further shorten timelines.