NEW YORK – Industry experts are optimistic about a new pilot program from the US Food and Drug Administration that is exploring whether increased and rapid communication with agency staff speeds gene and cell therapy development in the rare disease space.
The FDA this fall said it will begin accepting applications next year for a pilot program aimed at making the development process for rare disease therapeutics more efficient and responsive. Insights from the pilot, dubbed Support for clinical Trials Advancing Rare disease Therapeutics, or START, could inform new regulatory approaches that expedite promising rare disease drugs through clinical trials to market approval, the agency said.
The FDA's Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) are co-leading the pilot, and each center will select up to three drug sponsors to participate in the pilot based on different eligibility criteria.
To qualify for CBER's arm of the pilot, for instance, sponsors must be developing a gene or cell therapy for a serious condition likely to lead to significant disability or death within the first 10 years of a patient's life. The product must be in clinical trials, and the development program should be headed toward commercialization.
Rare disease therapies and precision medicines are difficult to develop because sponsors have to prove their drugs' safety and efficacy, and unravel complex drug response and disease biology questions, based on data from a small patient population. Trial designs, statistical approaches, and endpoints, therefore, often need to be adjusted to accommodate this challenge. Concerns about the reality of return on investment also leads many drugmakers to shy away from the challenge, given that the complex medications they develop will only be marketed to a small patient population.
To Bambi Jo Grilley, an associate professor of pediatric hematology and oncology in Baylor College of Medicine's Center for Cell and Gene Therapy, the launch of this pilot shows growing understanding within the FDA that its regulatory processes must evolve in step with changes in the world of drug development. "This is really an exciting development," Grilley said of the FDA's pilot. "They're really getting out of their comfort zone doing this."
Within the program, the FDA will facilitate frequent and even ad hoc communication between sponsors and agency staff in an effort to quickly address clinical development issues, such as providing advice on clinical trial design, sample size, or the enrolled patient population, which might otherwise delay a promising product from advancing toward the market. To apply, sponsors must submit a request to participate in the pilot as an amendment to an IND application and specify the development issue they need the FDA's input on.
Agency officials felt developers of gene and cell therapies may find that type of support helpful, according to CBER Director Peter Marks, since gene and cell therapy developers often use novel biomarkers and implement study designs other than the "gold standard" randomized clinical trial. These additional interactions between the agency and sponsors "about the endpoint, the trial design, the manufacturing … could shave months off of the development process," Marks said.
While other FDA programs also allow for early or more frequent communication, this pilot is "fundamentally different," Marks explained.
When sponsors garner fast-track designation for drugs designed to treat serious conditions with unmet medical need, for example, they can also have additional meetings with the FDA. These tend to be formal meetings, however, Marks said. Sponsors participating in the START pilot will be able to bypass having to request formal meetings and reach out directly to a project manager at the FDA.
The START pilot "demonstrates a proactive effort by FDA to accelerate development of much-needed products," agreed David Barrett, CEO of the American Society of Gene & Cell Therapy, a group that has advocated for speeding up development of these agents. "From the developer perspective, it’s much easier to make sure a clinical research program is on the right track when you have opportunities to ask questions along the way."
It's a "big step forward" in helping sponsors in the rare disease space, said Ben Yerxa, president and CEO of Opus Genetics, which is developing gene therapies for inherited retinal diseases. According to Yerxa, Opus is considering applying for the START pilot.
The "normal types of prespecified FDA meetings require substantive briefing documents and fairly long lead times to get to a meeting, which may be problematic when addressing an emerging issue," he said. "This leaves sponsors in a quandary about how to engage with FDA on quickly emergent issues that fall outside traditional development-stage meetings."
The pilot has a shot at "moving the field forward," said Abla Creasey, VP of therapeutics development at the California Institute for Regenerative Medicine (CIRM). The institute funds stem cell research and clinical trials in the state, and about half of the institute's grants to date have been in the rare disease setting. Creasey is interested in seeing if a CIRM grantee will be able to participate in the pilot and said she is keeping an eye out for more detailed information about the selection criteria.
In Creasey's view, additional drug development feedback from the FDA could be especially useful for companies conducting trials with novel endpoints so they can ensure early on that they're measuring what the agency wants to see.
The industry is at an "inflection point" for rare disease therapeutics, Grilley added. The ability to diagnose patients with increasing specificity based on molecular biomarkers could redefine many ailments into rare diseases, she said.
For example, as more targetable tumor alterations are discovered in lung cancer, patients are increasingly diagnosed with not just non-small cell lung cancer or small cell lung cancer, but with EGFR-mutated or ROS1-rearranged NSCLC. And the tests that determine these biomarkers have become an important part of the work-up NSCLC patients receive, since the results can inform what therapies they receive.
"It's really important that we consider that … the FDA traditionally has built [processes] around treatments of thousands of patients," Grilley said. But "this change in the ability to diagnose disease and really dig in [to disease biology] has meant that diagnostic groups are getting smaller and smaller."
Grilley pointed out, however, that while the START pilot is exciting, it could take years to find out if the process truly leads to faster drug approvals.
The pilot could inform a variety of activities at the FDA, depending on feedback and the program's outcomes, Marks said. A sponsor's participation in the pilot will conclude when the product has reached a prespecified regulatory milestone, such as starting a pivotal trial.
If the agency finds that the advice gained through this pilot spurred sponsors to move their product toward market authorization significantly faster than expected, the FDA might ask Congress to give it the authority to expand this process to all rare disease products. If this initial effort is modestly successful, the agency might launch a second, larger iteration of START to further refine the program.
The START pilot is one of a few moves the FDA has made in the rare disease space in recent months, an area which Marks has repeatedly said is a priority for the agency.
In September, the FDA issued a request for information (RFI) soliciting feedback on scientific challenges and opportunities in advancing personalized gene and cell therapies for extremely small disease populations. And the agency last week launched an online campaign to "crowdsource" input from industry players on the future of biologics, which, while broader, Marks described as a complementary effort to the RFI.
Unlike a standard RFI, those who comment on the crowdsourcing platform are encouraged to submit any relevant ideas and suggestions for where the FDA should be focusing its attention, Marks said. Commenters can also interact with others' suggestions, rather than submitting a formal letter to a docket. It's the first time CBER has used this more informal approach to solicit feedback from the public.
The FDA in September also said that in the coming months it would publish "a number" of gene and cell therapy guidance documents. That's "very positive," said Julie Allickson, director of Mayo Clinic's Center for Regenerative Biotherapeutics, as it will make it clearer to sponsors what the FDA's expectations are.
"The FDA is trying very hard to help sponsors when we have the scientific and safety data to move forward," she said. In the future, she said she hopes to see additional programs, resources, and guidance from the FDA on challenges in the preclinical development phase, as well, to help sponsors looking to proceed into their first in-human trials.
The FDA will accept applications for the START pilot program from Jan. 2 to March 1, 2024.