FDA to tighten approval requirements for CAR T-cell therapies

Top officials at the US Food and Drug Administration’s (FDA) Center for Biologic Research and Evaluation (CBER) say the agency will generally require randomized controlled trials (RCTs) to support the approval of chimeric antigenreceptor (CAR) T-cell therapies to treat cancer, except in certain circumstances, such as treatments for rare or multiple relapsed or refractory populations.

CBER Director Vinay Prasad and other center officials published an article in the JAMA outlining FDA’s experience regulating CAR T-cell therapies and how the agency plans to regulate the products from now on. The authors said that the agency has so far approved seven CAR T-cell therapies for 18 indications and noted that seven of the original biologic license applications were based on single-group trials with response rate as the primary end point and conducted in relapsed refractory setting. Moving forward, however, they said CAR T-cell therapies using RCTs with a survival or acceptable time-to-event end point will be given preference.

“The selection of a control group in an RCT is critical and must take into account the available standard treatments including approved CAR T-cell therapies, ethical considerations, and most importantly the ability to reliably distinguish the outcome caused by an investigational product from the outcomes caused by other factors such as natural history of disease, observer or patient expectations, or other treatments,” said the authors. “Evidence should generally demonstrate superiority of the investigational CAR T-cell therapy compared with control.

“Any plan to establish effectiveness of a new CAR T-cell product compared with an approved CAR T-cell therapy based on demonstration of equivalence or noninferiority must be adequately justified and discussed with the FDA,” they added.

The CBER officials said that sponsors should discuss with regulators the confirmatory evidence they intend to gather in at least one adequately controlled study. They noted that such evidence could be related to the patient’s condition, relevant mechanistic or pharmacodynamic evidence, nonclinical data, evidence from other products of the same pharmacological class, natural history evidence, or real-world evidence (RWE).

While the authors said that overall survival is considered most directly beneficial to patients when assessing CAR T-cell therapies, the agency will consider other end points such as global quality of life, delays in toxic subsequent therapy, durable remission, and cure. They said crossover of patients in the RCTs will be considered and evaluated based on the existing regulatory framework. They also acknowledged that when treating indolent cancers, overall survival data may take too much time, and the agency may consider the use of surrogate endpoints.

“The FDA will consider on a case-by case basis the use of biomarkers such as minimal residual disease as a surrogate end point to support either a traditional or an accelerated approval when sufficient data are provided to demonstrate that such a biomarker is known to be valid or reasonably likely to predict a clinical benefit,” the authors said.

While the preference is for RCTs, the CBER officials said they will also consider single group trials for rare cancers and in multiple relapsed or refractory patient populations where RCTs may not be feasible or ethical.

“Although high and durable response rate has previously supported traditional approval of CAR T-cell therapies in relapsed refractory aggressive hematologic malignancies, the response rate supported by durability from a single-group trial will generally be considered for an accelerated approval,” they added. “Traditional approval will generally require evidence of effectiveness on a direct clinical end point such as overall survival from an RCT.”

The authors also detailed when FDA will grant accelerated approval to CAR T-cell therapies, noting that the product will need to be for serious or life-threatening cancers that have shown promise in addressing an unmet need. However, they emphasized that the onus is on the product sponsor to justify the unmet need.

“Unmet need could be justified based on either lack of available therapies or, when there are available therapies, based on improved effect on serious outcome of the condition, improved safety, or other clinically meaningful therapeutic advantage over available therapies,” said the CBER officials. “While the accelerated approval pathway helps bring promising therapies to patients in need faster, it introduces risk and uncertainties to the patients until the clinical benefit is confirmed.

“If an accelerated approval is granted based on results from a nonrandomized trial, the FDA expects that sponsors conduct an RCT to confirm the clinical benefit,” they added.

JAMA

FDA to tighten approval requirements for CAR T-cell therapies

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