FDA 2nd Complete Response on BLA for Atara Cell Therapy

FDA has issued Pierre Fabre Pharmaceuticals a second Complete Response Letter rejecting its BLA for Atara Biotherapeutics’ investigational cell therapy for a rare and often fatal post-transplant cancer, citing the need for additional clinical evidence. The rejection appears to be one of the first rejections under a new CBER policy that raises the approval bar for such products.

Under a global partnership, Pierre Fabre handles the development, manufacturing, and commercialization of Atara's T-cell therapy, Ebvallo (tabelecleucel), in most markets, including the U.S. The therapy is intended to treat patients with Epstein-Barr virus–positive post-transplant lymphoproliferative disease (EBV+ PTLD) who have failed standard treatment options.

The FDA letter informed the company that it could not approve the biologics license application for tabelecleucel in its current form. Pierre Fabre says it was “surprised and deeply disappointed” by the decision, noting that patients with EBV+ PTLD after transplant have no FDA-approved therapies and often face a life expectancy measured in weeks to months.

The application had been resubmitted after what the company described as alignment with FDA on the criteria for resubmission following an earlier complete response letter issued 1/2025. That earlier letter identified a single good manufacturing practice deficiency and raised no concerns about safety, efficacy, or trial design, the company says. After accepting the resubmission 7/2025, the agency reportedly considered the BLA for accelerated approval.

In the latest letter, however, the agency says that while the manufacturing issue had been resolved and no safety concerns were identified, it no longer considers the single-arm ALLELE study sufficient to support accelerated approval and is requesting a new study. Pierre Fabre says the decision represents an unexpected shift from the FDA’s prior position following years of discussions.

This “shift” is presumably related to a new policy announced by CBER director Vinay Prasad  last month that FDA is moving away from reliance on single-arm studies toward randomized controlled trials (RCTs) that demonstrate superiority over existing treatments. Writing in a new JAMA Perspective piece, Prasad and other Center officials say that many new CAR-T therapies will now be expected to show that their products outperform (superiority) standard-of-care treatments. This marks a departure from the approach used since the agency approved Novartis’ Kymriah in 2017, which largely relied on single-arm trials.

Writing in JAMA, Prasad et al said the agency’s goal is to maintain high evidentiary standards while using regulatory flexibilities when appropriate. They recommend that initial approvals for CAR-Ts be based on RCTs with clinically meaningful endpoints such as overall survival or acceptable time-to-event measures.

The company warns that the agency’s stance could have broader implications for drug development in ultra-rare diseases, where conducting large or randomized trials can be impractical and may delay patient access to therapies. Pierre Fabre says it plans to work with FDA and Atara to identify a path forward toward approval.

Atara describes tab-cel as an allogeneic, EBV-specific T-cell immunotherapy designed to target and eliminate EBV-infected cells. The BLA is supported by data from more than 430 patients treated with tab-cel across multiple life-threatening diseases, including the latest pivotal ALLELE study data that demonstrated a statistically significant 48.8% objective response rate and favorable safety profile consistent with previous analyses, it says.