A major shift is unfolding in the world of CAR-T-cell therapy, and it didn’t come through a formal FDA guidance or regulation. Instead, it arrived as a “perspective” article in a top medical journal, authored by the FDA’s CBER leadership. Beneath its calm academic tone lies a seismic message: the era of open-label CAR T approvals could be coming to an end.
The FDA’s newly published JAMA Perspective on CAR-T-cell therapy development may not carry the formal weight of a guidance document, but its authorship speaks louder than any regulatory stamp. When the director of CBER and senior FDA officials tell the world how CAR-T trials “should” now be designed, the industry must listen and adapt. And what they have outlined is nothing short of a major policy pivot that will reshape the development of nearly every new CAR-T product in the pipeline.
For the last decade, CAR-T therapies have been approved primarily on the basis of single-arm, open-label trials showing high response rates in relapsed or refractory disease. That approach made sense in a groundbreaking field with small patient populations and life-threatening conditions. But now the FDA is signaling that this era is over: randomized controlled trials (RCTs), with survival or time-to-event endpoints, will be the expected standard for licensure of new CAR-T products.
This shift represents a dramatic increase in the burden of proof for sponsors. Conducting RCTs in rare diseases, rapidly progressing cancers, or heavily pretreated patients is complex, expensive, and in some cases ethically fraught. Yet the FDA’s message is clear: the bar is rising, and open-label designs will no longer routinely support traditional approval. Even accelerated approvals will face tighter scrutiny, with response-rate–based single-arm trials generally relegated to that pathway and confirmatory RCTs required.
What makes this especially consequential is that already-approved CAR-T therapies remain on the market, and new products will now have to outperform them, or prove noninferiority with extensive justification. For many emerging CAR-T developers, this shifts the competitive and regulatory landscape sharply. The implicit effect is a de facto advantage for existing products while placing a heavier evidentiary burden on new entrants, a classic case of regulatory drift with major commercial impact.
Importantly, the article stops short of being a formal rulemaking document. Yet in regulatory practice, perspectives authored by top FDA leadership often function as informal policy directives. Industry stakeholders understand that once the agency publicly articulates expectations, sponsors are expected to fall in line, even without a guidance document. That’s what makes this publication so significant: it quietly rewrites the rules of engagement for CAR-T development without invoking the formal machinery of regulation.
Beyond trial design, the FDA also reiterates the need for long-term safety monitoring, enhanced mechanistic understanding of new toxicities, and greater justification for unmet-need claims in accelerated approval requests. But the headline remains unchanged: controlled trials are the new currency of CAR-T evidence.
This seemingly modest journal article represents a sweeping shift in the regulatory philosophy governing CAR-T therapies. By raising the evidentiary bar and favoring randomized trials, the FDA is signaling a new, more stringent era for cell therapy development. Whether this drives better science or slows innovation, one thing is clear: the ground has shifted, and every CAR-T developer must now recalibrate their strategy.
