CAR-T boxed warnings: regulatory precedents and opportunities

Regulatory-blog-image_100x100.jpgThis blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.


The recent FDA mandate regarding boxed warnings for CAR-T therapies has implications for sponsors with approved therapies, as well as those in development. Dr Mwango Kashoki, former Associate Director for Safety in FDA’s Office of New Drugs, shares insights and guidance to navigate this new regulatory expectation.

The FDA recently required the manufacturers of six licensed BCMA- and CD19-directed CAR-T cancer treatments to add boxed warnings to their product labels. These warnings are intended to inform healthcare providers and patients about the risk of T cell malignancies associated with these therapies. The decision to require these labeling changes is based on findings from postmarketing adverse event reports and clinical trial reports.

Why class-wide safety labeling changes?

The boxed warning requirement aligns with the FDA's responsibility to routinely monitor the safety of approved products and take appropriate action, like requiring labeling changes, when new safety information emerges. In the case of autologous CAR-T products, the FDA has determined that the risk of T cell malignancies applies to the entire class of drugs, hence the requirement for boxed warnings across all approved products.

There are many examples of FDA-required class-wide safety labeling changes. For example, in 2023, the FDA mandated updated warnings for immediate- and extended-release opioids, which included adding new risk information about opioid-induced hyperalgesia based on new postmarketing reports. The FDA issues and approves drug safety labeling changes frequently, and these are captured in its Drug Safety-related Labeling Changes (SrLC) database.  

What some may consider a “different” aspect to the FDA’s requirement for class-wide boxed warning for CAR-T products is that it is based on 22 reported cases of secondary T-cell cancers associated with CAR-T therapies. These events have been reported in a relatively short period (approximately six years) since these products first entered the market.

However, postmarketing adverse event reports play a crucial role in providing new safety information and can serve as the basis for safety labeling changes. The plausibility of a causal relationship, the strength of the evidence from aggregated cases, and the severity of the adverse event inform the FDA's decision to require safety labeling changes. In the case of CAR-T therapies, with their novel mechanism of action, the potential for the development of new cancers is a significant risk for patients. The FDA is therefore acting to inform patients and healthcare providers about the risk, so they can make better-informed treatment decisions; and, as a result, the agency intends to mitigate this risk.  

The FDA has also issued postmarketing requirements (PMRs) for each CAR-T sponsor to conduct long-term observational studies to further evaluate and understand the risk of malignancies associated with their drugs. The PMRs are identical for all sponsors, and the details of the study designs were determined through negotiations with the FDA.

Implications for investigational CAR-T products 

As we consider the implications for CAR-T therapies that are still in development, it is reasonable to expect that future approved autologous CAR-T products will also require boxed warnings in their product labeling. However, if a sponsor can adequately demonstrate, based on pre-approval investigations or other data, that their specific product does not pose the same risks, then the FDA may consider not including the boxed warning in that product’s labeling. Nevertheless, the evidentiary standards for such an exemption would likely be substantial.

It is worth noting that the FDA's requirements and considerations may differ for allogeneic CAR-T therapies or CAR-T products engineered using non-integrating methods, since secondary T-cell cancers have only been observed with autologous CAR-T products.

Next steps for CAR-T sponsors

The FDA has indicated that it will continue to gather more information about reported T-cell malignancies, and will provide updates as substantive new information becomes available. This means that CAR-T sponsors need to consider various options going forward, both for approved products and those being developed. 

Ideally, additional information obtained through ongoing studies would refute the safety risks or provide a more nuanced understanding of the concerns. In such cases, the FDA may remove the boxed warning or adjust the language to better reflect the risk. Precedents exist for such updates, such as when the FDA removed the boxed warning about the risk of amputation with the diabetes drug canagliflozin.

Furthermore, by elucidating the mechanisms responsible for the observed T-cell malignancies, manufacturers could potentially reduce the risk of secondary malignancies. However, this would be a challenging task. Nevertheless, the additional information generated may enable the FDA to provide more specific labeling recommendations on how to minimize the risk through appropriate dosing, patient selection, and monitoring. This would involve class-wide safety labeling changes.

Additionally, CAR-T sponsors should carefully consider the specific outcomes and risk mitigation measures to fully characterize the risks associated with secondary T-cell cancers. As CAR-T sponsors collect and analyze safety data with their products, they should aim to efficiently evaluate these outcomes while minimizing the burden on patients.

As CAR-T therapy expands beyond oncologic indications into non-oncologic areas, such as autoimmune disease, the FDA's ongoing investigation into the risk of secondary T-cell malignancies becomes even more important. The benefit-risk considerations for CAR-T therapy in these new target populations, which already differ significantly from oncologic patient groups, could be further impacted by the knowledge of a higher potential risk for secondary malignancies. Sponsors of CAR-T therapies targeting non-oncologic areas should closely monitor the developments in T-cell malignancy investigations for oncologic indications.

The FDA's requirement for a boxed warning in the labeling for CAR-T products represents an important step towards continuing to ensure patient safety by informing patients and healthcare providers about potential risks. By navigating the regulatory landscape effectively and proactively assessing the short- and longer-term risks of CAR-T products, sponsors can continue to develop these promising therapies while minimizing patient risk.

Ready to discuss the implications of the FDA requirement on your CAR-T therapies? Our experts are always available for a conversation. Please contact us.

Return to Insights Center