Regulatory Focus - White paper addresses immuno-oncology's growing pains
Characterizing cytokine release syndrome (CRS) will be key to ensuring broader uptake of advanced cell and gene therapies in the field of immuno-oncology, agreed authors of a newly issued white paper addressing CRS.
Speaking at a webinar hosted by the Friends of Cancer Research, Peter Marks, MD, head of the US Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA’s CBER), also noted that better characterization of manufacturing process must go hand-in-hand with this work as the field grows, however.
“CAR-T cell therapies have really taken off over the past few years,”’ noted Marks, adding that the number of investigational new drug applications (INDs) submitted annually since 2015 has climbed from about 20 to 58 in 2020.
As the field expands and more patients are treated, clinicians and trialists are understanding better the stages and components of CRS, which can range from a transient febrile episode to full circulatory collapse and neurological involvement, including seizures. Genentech’s Bruce McCall, MD, a lead member of the CRS white paper working group, led a discussion to kick off the webinar, asking what can be done to maximize the understanding of these new therapies.
Marcelo Pasquini, MD, of the Medical College of Wisconsin’s Center for International Blood & Marrow Transplant Research (CIBMTR), said that now is the time to harmonize the half-dozen or so CRS ratings systems that exist. “The approach really is to define the main criteria,” said Pasquini. That way, he said, “You don’t have to reinvent the wheel every time there is a new product.”
The white paper points to general clinical areas to be addressed, including fever, abnormal laboratory values, and signs of cardiorespiratory and neurologic involvement. Equally important in developing ratings scales and registries, noted white paper authors, is including a systematic way to track which therapies have been attempted to address which symptoms, and how effective the treatments were.
Marks and others joined a second session of the webinar that focused on manufacturing and other industry considerations. There, Renu Vaish, vice president of regulatory affairs in worldwide cell therapy at Kite, added that the field is now at a point where standardization of chemistry, manufacturing and controls (CMC) is critical; “We want to harmonize potency specifications across the globe as much as possible,” she said. For now, Kite is not alone among industry players in limiting use of these advanced products to centers of excellence that have high levels of expertise with immuno-oncology products.
Asked whether more guidance on these complex therapies is forthcoming from FDA, Marks said, “You’ll see us say a little more in the coming months, or perhaps even a little sooner than that. We’ll continue to work on this.” He added, “This is an area where even guidance that we issue will have to be continually updated,” and a dialog between industry and FDA will be ongoing.
Finding a way to inject more certainty into the manufacture of cell therapies will be critical to the growth of this sector, all agreed. “We don’t have good methods to characterize what’s happening” during manufacture of many cell therapy products, noted Marks. “You can figure out when something’s wrong but you can’t necessarily figure out how to fix it.”
Marks added that “it’s a little easier with allogeneic cells,” in part because the time frame is not as constrained as for autologous cell therapies. In all cases, he said, quality would be improved “if ou had better analytics that you can use in realtime.”
Vaish added that now that developers are looking at combinations of allogeneic and autologous cell therapies, a whole new level of complexity has to be taken into consideration. The back-and-forth between industry and FDA has been helpful to sort out next steps when “the output is not what you expected,” she said, but all players are still very much in the middle of a learning curve.
Mark McClellan, MD, PhD, director of the Duke-Margolis Center for Health Policy and the Margolis Professor or Business, Medicine and Health Policy at Duke University, Durham, NC, brought the need for process improvement back to the clinical arena, noting that the need for process improvements needs to be coupled with “a very good, reliable process for noting what the effects of these modifications are in practice.”
“It gets back to having well understood and well characterized registries,” added McClellan, a former FDA commissioner and administrator of the Center for Medicare and Medicaid Services.