CAR-T Changes Should Boost Uptake, but Challenges Still Remain

Reprinted with AIS Health permission from the July 2025 issue of Radar on Specialty Pharmacy

Less than a year after the FDA approved the first chimeric antigen receptor-T cell therapy without a Risk Evaluation Mitigation Strategy program, the agency has eliminated the REMS for the other six CAR-Ts. At the same time, the FDA loosened other restrictions on patients, moves that should increase uptake of the agents, say industry experts.

“A REMS is no longer necessary to ensure that the benefits of these CAR T cell immunotherapies outweigh their risks and to minimize the burden on the healthcare delivery system of complying with the REMS,” said the FDA on June 26. The programs initially were in place because of the risks of cytokine release syndrome (CRS) and neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), potentially fatal reactions.

Previously, the REMS required that hospitals and their associated clinics needed to be specially certified to administer CAR-Ts and had to have immediate access to tocilizumab (available as Actemra from Roche Group member Genentech USA, Inc.), but the FDA has eliminated these requirements. In addition, the agency approved updated product labeling that decreased:

The requirement for daily evaluations from 10 days to seven days post-infusion;
Monitoring of patients from four weeks to two weeks following infusion;
The amount of time a patient needs to remain within the proximity of a health care facility, not necessarily their treatment facility, after infusion from four weeks to two weeks; and
Driving restrictions from eight weeks to two weeks after infusion.

The FDA cited “established management guidelines and extensive experience” with the agents as the reasons for its decision. The agency approved the first CAR-T, Kymriah (tisagenlecleucel), on Aug. 30, 2017. The agency said it expects the changes to result in broader access to the CAR-Ts, especially for patients residing in rural areas, “while ensuring safe and effective administration to patients who need them.”

The products’ labels still contain a boxed warning about the risks of CRS and neurological toxicities. And manufacturers still must conduct safety monitoring and post-marketing observational safety studies in order to evaluate the risk of secondary cancers, in addition to 15 years of patient follow-up.

The changes apply to all of the BCMA- or CD19-directed autologous CAR-Ts approved before Autolus, Inc.’s Aucatzyl’s (obecabtagene autoleucel) Nov. 8, 2024, approval:

Abecma (idecabtagene vicleucel) from Bristol Myers Squibb and 2seventy bio, Inc.;
Breyanzi (lisocabtagene maraleucel) from Juno Therapeutics, Inc., a Bristol Myers Squibb company;
Carvykti (ciltacabtagene autoleucel) from Johnson & Johnson Innovative Medicine and Legend Biotech USA, Inc.;
Kymriah from Novartis Pharmaceuticals Corp.;
Tecartus (brexucabtagene autoleucel) from Gilead Sciences Inc.’s subsidiary Kite Pharma, Inc.; and
Yescarta (axicabtagene ciloleucel), also from Kite.

This is not the first time the FDA has modified the REMS requirements, notes Rosalie Hoyle, Ph.D., a fellow at Avalere Health Advisory. She points out that in June 2024, the agency “reduc[ed] the education requirements and eliminat[ed] duplicative adverse event reporting in an effort to mitigate the REMS burden on health care systems. The removal of REMS signals that the FDA is willing to reevaluate product requirements as more data becomes available, and the progressive changes to REMS requirements demonstrate some consistency in the approach between administrations.”

Removing the REMS is a “big shift” that will impact patients, providers and CAR-T manufacturers, maintains Kolton Gustafson, a principal at Avalere. For one, “patients eligible for CAR-T treatment have to consider the time, effort and money associated with visiting treatment sites prior to treatment and after treatment,” he tells AIS Health, a division of MMIT. “The FDA decision will reduce some of the perceived and actual barriers those patients face.”

In addition, the lack of a REMS should broaden the amount of treatment sites that can administer the therapies, he says. Indeed, in a press release, Bristol Myers Squibb revealed that it is working to expand “the geographic footprint of cell therapy,” particularly with community cancer centers.

CAR-T manufacturers “will also need to consider the best way to ensure safe and effective use of their products in the absence of REMS; they’ll need to consider the best way to expand their treatment networks and ensure that supply can meet demand,” Gustafson states.

The changes also should “lessen the administrative burden on the hematology and oncology physicians and potentially expand prescribing to additional patients, as well as patients who will have less lifestyle burden due to the lessening of the monitoring requirements,” remarks Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. “However, with this potential enhanced therapy access, this may expand prescribing and have additional financial burden for these therapies with patients and payers.”

While facilities will not be required to have special certification or on-site access to tocilizumab, “hospitals and clinics may choose to continue these requirements per their own protocols,” says Hoyle. “Manufacturers, treatment sites and providers will still need to consider the best way to ensure safe and effective use of their products in the absence of REMS.”

The changes in patient monitoring “basically cut paperwork and logistics, but the treatment site…will still need to follow their patient safety protocol,” says Amy Schroeder, Pharm.D., a principal research scientist at Avalere. “Generally, adverse reactions are observed shortly after CAR-T infusion. For providers and patients open to CAR-T as an option, all of these factors weigh into the choice of the best option for a given patient, in addition to the clinical data for the product and the patient’s clinical situation.”

Previous monitoring requirements “were very burdensome for patients and their caregivers and often required temporary housing and transportation,” points out Szczotka. The modifications should help broaden access to the treatments, especially for patients who do not live close to an administering facility, he tells AIS Health.

Study: ‘Limited Patient Access’ Is CAR-T Barrier

Indeed, studies have raised questions about whether those monitoring requirements were still necessary. For example, an article last year in Blood Advances, a journal of the American Society of Hematology, revealed that side effects were “exceedingly rare” after the first two weeks following treatment with Yescarta, Kymriah and Breyanzi among 475 patients at nine different centers.

The authors noted that “limited patient access” is a barrier to CAR-T treatment, and only 20% to 30% of eligible patients are able to receive it. More than half of patients must relocate during and after treatment, and although “insurance and industry may help defray some of the relocation costs,…much will fall directly to the patient.”

“A flexible monitoring period beyond 14 days appears safe,” they concluded and called for adding community oncology centers to the facilities able to monitor patients who are stable two weeks after infusion. Szczotka notes that most adverse events that occurred after two weeks “were low grade and resolved.”

Asked which of the changes is most significant, Gustafson points to the REMS removal: While providers still need to be ready and able to manage adverse events, the change “could potentially reduce the hesitance some providers have to refer patients for CAR-T. And it could ultimately lead to more treatment sites for these products, which would lower the access challenges some patients face.”

Szczotka cites the loosened monitoring requirements as the most significant change. “The prior monitoring requirements placed a substantial burden on patients for post-infusion monitoring, proximity and lifestyle limitations, potentially limiting access to therapy for patients living in rural areas and away from CAR-T administration facilities.”

The changes are likely to increase the use of CAR-Ts “through greater access in the community center settings, increased patient referrals and higher adoption rates by patients willing to go through the reduced monitoring requirements and lifestyle restrictions,” he says, pointing to an analysis that projects the modifications could “potentially double the current uptake” of cell therapies.

However, Schroeder notes that low CAR-T uptake was not solely due to the REMS but also “clinical comparison to traditional treatment options and innovative treatments (e.g., bispecific antibodies, monoclonal antibodies), reimbursement to treatment centers and affordability for patients.”

According to Gustafson, while the changes relieve some of the burden borne by patients and caregivers, “they don’t solve everything — the treatment odyssey for patients is still complex in the pre-treatment phase, which these changes do not directly address. It’s also worth noting that, in parallel, CAR-Ts are moving up in line of treatment — so overall we would expect more patients to access CAR-T, but the changes made by the FDA are one factor among many.”

As with Aucatzyl, the FDA may not require REMS for future CAR-Ts, says Szczotka. “This may provide a signal to companies developing future therapies that the safety profile of these therapies is gaining confidence and comfort with the FDA with the large number of patients being safely treated and the recent clinical data publications.”

By Angela Maas