This is Not a Test: RMAT Designation Goes Live

By: Peter Marks, M.D., Ph.D.

The field of regenerative medicine encompasses a wide scope of innovative products including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products using such therapies. Examples include genetically-modified cellular therapies, such as chimeric antigen receptor T-cells (CAR-T cells) and human tissues grown on scaffolds for subsequent use. These products hold great promise in addressing serious unmet medical needs. For example, data from a number of different published studies indicate the potential for CAR-T cells to treat certain relapsed or refractory blood cancers.

Peter MarksRecognizing the importance of this field, Congress included several provisions related to regenerative medicine in the 21st Century Cures Act, signed into law on Dec. 13, 2016. Building on the FDA’s existing expedited programs available to regenerative medicine products, one of these provisions established a new program to help foster the development and approval of these products: Regenerative Medicine Advanced Therapy (RMAT) Designation.

Sponsors of certain cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products may obtain the RMAT designation for their drug product if the drug is intended to treat serious or life-threatening diseases or conditions and if there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for that disease or condition. Sponsors may make such a request with or after submission of an investigational new drug application and the agency then will take action on the requests within 60 calendar days of receipt.

Sponsors of RMAT-designated products are eligible for increased and earlier interactions with the FDA, similar to those interactions available to sponsors of breakthrough-designated therapies. In addition, they may be eligible for priority review and accelerated approval. The meetings with sponsors of RMAT-designated products may include discussions of whether accelerated approval would be appropriate based on surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

Once approved, when appropriate, the FDA can permit fulfillment of post-approval requirements under accelerated approval through the submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records; through the collection of larger confirmatory datasets; or through post-approval monitoring of all patients treated with the therapy prior to approval.

The FDA’s Center for Biologics Evaluation and Research is committed to helping make regenerative medicine advanced therapies that are shown to be safe and effective available as soon as possible, particularly for patients with serious or life-threatening diseases or conditions lacking other treatment options.

We have started receiving RMAT designation requests and expect that, as with Breakthrough Therapy Designation, early and frequent communication facilitated by the RMAT designation will help reduce overall product development times. We very much look forward to continuing to work with sponsors of these products and other stakeholders to help make these exciting new therapies available to those in need.

Peter Marks, M.D., Ph.D., is the director of the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.

Sentinel: Harnessing the Power of Databases to Evaluate Medical Products

By: Michael D. Nguyen, MD

Clinical trials are designed to evaluate the safety and effectiveness of medications. But the number of participants in clinical trials represents only a fraction of the number of people who will ultimately use the product after FDA approves it. Occasionally, rare and unexpected health problems (which we call “adverse events”) become apparent only after a medical product is on the market and many more people use it. That’s why it’s so important for FDA to continue to monitor the safety of medical products, a practice called surveillance.

Michael NguyenMost safety surveillance systems are passive: They rely on health care professionals and consumers to notice and report adverse events. Although these passive systems remain essential, they have certain limitations. For example, health care professionals and consumers might not recognize that the product is the cause of an adverse effect and not report it to FDA. Or, they might report a suspected adverse event that’s not truly the cause of a problem the consumer experiences.

Now imagine if we could actively search more than 100 million health insurance records to uncover possible adverse events, rather than relying on doctors and patients to report them. Such a system would enable us to get continuous feedback on the use of medicines under real-world conditions – feedback that might help us to discover unexpected patient reactions or unexpected drug interactions.

FDA scientists have partnered with the Harvard Pilgrim Healthcare Institute to create such a surveillance system, called Sentinel. Within Sentinel, FDA has supported the development of software that analyzes information from health insurance and health record databases to search for evidence that certain products are linked to specific adverse effects. Although these data are protected behind tight firewalls and remain under the control of the original health insurance plans that created them, the software makes it possible to analyze the information without disclosing identifying information in order to strictly maintain patient privacy.

FDA and Harvard Pilgrim Healthcare Institute are using this surveillance system to determine whether a certain type of immune therapy is associated with heart attacks or strokes, and to better define the true rate of acute lung injury after transfusions of certain blood components.

More recently, FDA completed its first study using the Sentinel system, which evaluated the safety of the two current vaccines (RotaTeq and Rotarix) that prevent rotavirus infection (the leading cause of severe diarrhea and dehydration in infants). The new study revealed that these rotavirus vaccines slightly raise the risk of a rare bowel problem (intussusception) that previously caused a prior rotavirus vaccine (Rotashield ) to be voluntarily withdrawn from the market by its manufacturer. But the Sentinel study showed that the newer vaccines have a much lower rate of this bowel problem and are safer, with the benefits outweighing the risks, including the risk of intussusception, associated with vaccination.

The Sentinel rotavirus vaccine and immune therapy studies are examples of how FDA scientists are harnessing the power of big electronic databases to ensure the safety of the medical products we use every day.

Michael D. Nguyen, MD, is the Acting Director of the Division of Epidemiology in FDA’s Center for Biologics Evaluation and Research