Accelerated Approval Not the Finish Line, Says FDA Commissioner

Drugmakers will no longer be able to slow-walk their accelerated approvals to full regulatory approval, said FDA Commissioner Robert Califf, MD, during the J.P. Morgan Healthcare Conference on Tuesday, while also fielding questions on gene therapies and the modernization of clinical trials, among other topics.

Accelerated Approval

When asked about the kind of data needed to warrant an accelerated approval decision, Califf said it would depend on the clinical condition and what other treatments are available.

Criteria for accelerated approvals are already "pretty well laid-out," he noted, but there has been one "big change." A provision of the Inflation Reduction Act now requires companies to "move quickly to either verify or disprove the concept that the treatment's benefits outweigh its risks."

Califf called this reform important, adding that it has been needed for a long time due to the inherent uncertainty in the accelerated approval pathway.

Instead of a risk-benefit calculus, the FDA makes decisions based on "likely risks" and "likely benefits," he said. He also agreed that there has been "fair criticism" of the FDA for not requiring that definitive studies be done quickly after a drug's approval.

"So, I think the message to drug developers is ... from day one, you need to be thinking about what is the structure or the evidence that we're going to need, not just to get through that first hurdle at FDA, but to get the definitive study done, and to meet the needs of the payers who are going to have to decide whether it gets done," he continued. "And the sooner that's considered in the framework of the plan for evidence development, the better off you're going to be."

Gene Therapies

Asked whether surrogate endpoints might be used to gain accelerated approval of gene therapies -- an idea that Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, allegedly favors, according to the discussion moderator -- Califf again said the answer depends on the circumstances and on the disease.

The FDA hasn't laid out "an absolute clear pathway" for the accelerated approval of gene therapies, he noted, adding that there are lots of rare genetic diseases for which large clinical trials aren't feasible.

He said the agency is looking to develop methodologies in this space. In particular, he highlighted the Bespoke Gene Therapy Consortium, a public-private partnership between the FDA, NIH, pharmaceutical companies, and other nonprofits, which is investigating cases rare enough to be "an 'n' of one each time you do it."

On the other hand, companies looking to use gene modification to address more common diseases, such as coronary artery disease, would need larger trials to advance their products, given that there are already effective treatments in that space.

Whether a new therapy applies to a rare disease or a common one, follow-up will be critical, Califf stressed.

"When you modify the gene of an infant or in utero developing person, the idea would be to follow the person for decades because we don't know the summative effects of gene modification," he explained. "It's well known that the impact of other combinations of genes could change when you modify a gene which is very important to biology. So, there are going to be unknowns. That shouldn't hold us back."

However, "we can't act like there is no risk. We need to follow up and get the data," he added.

Modernizing Clinical Trials

Clinical trials still do not routinely leverage electronic health records, which Califf argued would not only reduce costs, but would provide more relevant data.

"It's not hard to imagine that the combination of the patient's medical record and the use of digital technologies at home would give a much better portrayal of what's going on with a human being than going to a research clinic once every 3 months and having a study coordinator try to figure out what happened during that intervening period," he said.

However, so far, these kind of studies aren't happening, he added.

It isn't in an individual company's interest to invest in validating those technologies, he noted. As a result, there are "halfway validated technologies that have a lot of promise," but nothing that has definitively been proven to work.

Califf also advised companies seeking Investigational New Drug Applications to advance to the clinical trial stage, in light of new modalities.

Everything moves more quickly if the technologies are "well-developed" and "well-understood," and there is clear oversight, he said. But any time a company proposes a process that "has a big impact on biology," there's going to be more scrutiny.

He also issued a firm warning to start-ups to be transparent about their work. Given his own experience in the industry, he said he understands the pressure companies are under when they've invested a lot of money in one idea and are worried their business will fail if the idea does. "But hiding things from FDA? Not a good idea," he added.

Inclusivity in Research, Misinformation

During his talk, Califf also touched on the importance of expanding populations enrolled in clinical trials, noting that the Biden administration has allocated funding for high-speed internet in rural communities.

Once states have rolled out this technology, there can be "no excuse" for not enrolling people living in rural areas or others who lack easy access to transportation in clinical trials, he said.

Furthermore, he argued that healthcare systems contribute to inequities in clinical research participation. For example, "if all the doctors who are specialists in diabetes are located in urban areas close to academic medical centers, it's very hard to say, 'we're going to do high specialty diabetes research in areas where those doctors don't exist.'"

Califf said he is "100% in favor" of doing everything that can be done to address inequities in clinical trial enrollment, but it's important to also look at the healthcare system to determine what the problems are.

Finally, in highlighting the problem of widespread misinformation, Califf said he has tapped every expert in the world for ideas. "And I haven't found a one who feels like there is a recipe book for how to fix it," he said.

"I want to urge all of you to spend a little bit of time every day ... on this topic, because your friends and neighbors are being very much influenced by factors ... happening in the interaction with their social media devices," he added.

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