BIO: FDA weighs post-pandemic challenges

Pharmaceutical companies and officials at the US Food and Drug Administration are working with unprecedented speed and creativity during the coronavirus pandemic. But there’s little reason to think the workload will abate, or the problems become easier, in the post-pandemic lives of sponsors and regulators, according to panelists who spoke during an FDA Town Hall at the Digital BIO 2020 meeting.

Even amid the pandemic, not all of FDA’s work is centered on COVID-19 vaccines and treatments. “Let’s talk about PDUFA [the Prescription Drug User Fee Act],” said Richard Pops, chairman and CEO of Alkermes, Inc., who moderated the town hall. “First, looking backwards, we have a series of PDUFA goals that you are statutorily obliged to try to meet. How does that look outside of the antiviral and vaccine and COVID-related things?” he asked.

Panelist Peter Stein, director of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER), spoke to CDER’s performance in meeting PDUFA obligations. “We’ve actually been pretty effective at meeting our goals. Obviously it was a worry initially as we were moving to the virtual environment to figure out” how to meet the obligations, he said, noting that “Getting to a review requires a lot of meetings, a lot of key members and collaboration and discussion, so I was a little worried that in this new environment this would be more challenging.”

Stein added that CDER has created internal guidelines that prioritize coronavirus-related work, but that also prioritize serious diseases with unmet needs. “So we do have an organized approach if we do have to delay work -- but I will say so far that we haven’t really had to delay that work,” he said.

Inspections in the era of COVID-19 remain a challenge, Stein said, but the agency has worked “to minimize the impact. All efforts are being made to complete work virtually, but in some cases, “We really do need to visit the inspection site and make sure that it has the appropriate capabilities to manufacture quality products,” said Stein. “So… there will be misses in terms of timelines because of the inspections that will impact us.”

How things change over time remains to be seen: “The hope is that as countries open up, and also as inspectors can begin to get to those sites, [impact on inspection timelines] will be mitigated,” said Stein.

Goal dates for PDUFA are largely being met at the Center for Biologics Evaluation and Research (CBER) as well, said director Peter Marks, though some elective but still important programs, such as initial targeted engagement (INTERACT) meetings have necessarily fallen by the wayside during the pandemic: “Because of all the extra workload coming in, and keeping the stuff that’s in the hopper going at PDUFA rates, it’s been hard to keep up with some of the elective meetings.”

Marks added, “I think we’re able to keep up with our PDUFA goals quite nicely in general. The challenge is that some of these other things, which I think are very important to drug development… they’ve fallen back in time, and it’d be nice to get them back on track.”

What will the clinical trial landscape look like as the regulatory world and regulators emerge from the pandemic? Said Marks, “That keeps me up at night…. What’s going to happen in the post-COVID world?”

Looking at the backlog of trials, and the ways in which data accrual has been impacted by the pandemic worries him deeply, he said: “I see us as having this big bolus in the coming months of vaccines that are going to need approval… and as we clear over COVID 19, I see this pent-up demand for cell and gene therapies, products that have kind of had what I’d almost call stalled development -- not the typical stalled development, but stalled because of a pandemic development.”

In addition to the large volume of these products that will come before CBER, he said, sponsors and the agency will also have to address how COVID-19 has affected ongoing trials. “We’re going to have to be salvaging what we can from phase 3 trials for products, where biopsies may not have been able to get done, levels may not have been obtained -- and yet you have small patient populations where it would be, I would say, unethical not to try to do our absolute best to make every patient count.”

Evaluating the scenario for each trial will be a labor intensive, one-off analysis, said Marks. “You can’t just say, ‘Oh, for all trials, if you do X you can do Y.’ It’s probably going to mean going trial-by-trial and seeing what we can salvage, so I think there’s going to be -- the post-COVID world is going to be very busy, and it may be as or more busy as the pre-COVID world for a little while.”

Pops agreed with this assessment, noting that many sponsors are having to make protocol modifications, or even halt trials completely, even among rare disease patient populations.

Asked for the CDER perspective, Stein concurred with Marks’ analysis of the challenges to come. “There’s no question that there’s going to be extensive missing information, patients that will be gone, COVID-negative patients who have developed COVID, and that impacts their outcomes in the context of a clinical trial.”

Stein said that there’s work now being done at CDER to anticipate some of these issues as trial data come in. “We’re working now on thinking about providing input and guidance oh how to manage these impacts… And all I can say is at the end of the day we certainly recognize the impacts, and we can’t change our substantial evidence standard. But we can be sensible and flexible about how it’s applied and the kind of information that we’re looking at, and to try to be -- again -- as sensible as possible.”

CDER is pursuing whether appropriately employed statistical adjustments, such as sensitivity analyses, can help make the most of available data. The challenge is the balancing act, he said: “We don’t want to see drugs that are potentially very effective delayed, and have to redo trials; on the other hand, if the data simply isn’t sufficient to demonstrate benefit, no matter what sensitivity analysis or additional analysis or whatever else is done, we obviously still can’t approve that drug.”

The agency is taking a forward-thinking, cooperative approach with sponsors through all this, said Stein. “We are going to try to do what can be done to make sure that the data can be put together in a way that is convincing, persuasive, that lets us get to an approval decision. And I can assure you, we will do what we can in terms of exercising flexibility in that regard.”