Expediting the Development of Advanced Therapies such as CAR-T cells by making use of FDA’s RMAT designation

by Annegret Vaggelas

How does RMAT work and which products are considered for the designation?

In 2017, the first CAR-T cell therapies (Kymriah, Yescarta) have been approved by FDA. End of June 2018, EMA followed by recommending marketing authorizations for both of them in the EU. These first in class medicines hold enormous potential to cure some of the deadliest and largely untreatable cancers and are expected to shift the focus of medicine from treating symptoms or delaying progression to curing diseases. Further CAR-T cell therapies are under development and are expected to reach the market not too far from now.

The development of CAR-T cells and other cell and tissue engineered products is frequently associated with challenges due to their complex and unique nature. In addition, these types of products are often developed by small- and medium-sized enterprises who are not as familiar as big players with drug development and regulatory processes. The US FDA has responded to this challenge beginning of 2017 by launching the Regenerative Medicine Advanced Therapy (RMAT) designation, an expedited program dedicated to regenerative medicines, in order to accelerate the speed to market for these innovative therapies by providing frequent interactions with the agency and intensive guidance on efficient drug development. The RMAT program is open to companies developing cell- and tissue-based therapies, tissue-engineering products, and combination treatments including genetically modified cells, that lead to a durable modification of cells or tissues. Until June 2018, 18 products have been granted RMAT designation including Juno’s CAR-T cell therapy JCAR017 (recently acquired by Celgene). Regulatory tools, like RMAT, are precious as timely engagement with regulators can be crucial for the development process and thus provides the potential to shorten the development time. The RMAT designation should be considered as part of the integrated development and regulatory strategy for advanced therapies in the US. Figure 1 provides an overview when to consider RMAT and other US tools:

Figure 1:  Regulatory tools to consider and integrate into overall US development strategy

Abbreviations: LCM: Life Cycle Management; R&D: Research and Development; CMC: Chemistry Manufacturing and Control development; NC: nonclinical development; I: phase I clinical development; II: phase II clinical development; III: phase III clinical development; A: approval/authorization; L: Launch

In our recent publication called “Expediting Drug Development: FDA's New Regenerative Medicine Advanced Therapy Designation” for the Therapeutic Innovation & Regulatory Science (TIRS), we have presented the RMAT designation in detail, outlined other existing FDA regulatory tools aiming at expediting approval and discussed the overall value of these programs. Additionally, we provided recommendations for companies developing these very specific and complex therapies on how and when to consider these tools for an integrated development and regulatory strategy. If you are interested, please do not hesitate to check it out HERE. If you would like to receive the full publication, please get in contact with us.

Besides expedited programs also detailed guidance documents can help facilitate the development of these new and rapidly evolving technologies. Alone in 2017, FDA has generated 5 new guidance documents on gene and cell therapies and announced at BIO 2018 that they intend to release six new sets of guidance in July focusing on product-related issues as well as on accelerated clinical endpoints. Moreover, FDA introduced a new program within the CBER, called 'Interact,' for pre-clinical, early engagement for cell-based and regenerative therapies. This program should advise companies on how to get products into the IND stage, help solve CMC issues and focus on the requirements for preclinical testing. This demonstrates that FDA is committed to making these game-changing therapies available to patients. It was also announced after the European Commission/EMA–FDA bilateral meeting in June that regulators on both sides of the Atlantic plan to closely collaborate by encouraging early parallel scientific advice in order to develop common scientific approaches in the regulation of these medicines. These could facilitate the preclinical and clinical development, and the way data collection on these types of medicines can be optimized after authorization. We believe that if regulators accept their new role as enabler between science and healthcare systems this will allow them to create appropriate regulatory requirements, which ultimately benefit patients.

The EMA’s response to the FDA’s breakthrough and RMAT designation is the so called PRIME status, which both, Kymriah and Yescarta, received in 2016. PRIME stands for Priority Medicines and aims to support the development of medicines targeting a high unmet medical need. Though the PRIME scheme is open to all of product categories, a lot of advanced therapy medicinal products were among the designated products, underlining the great potential of this product class. For more information on the PRIME scheme, please refer to one of our other publications HERE.

We at Biopharma Excellence have the specialized knowledge on how to accelerate the development and approval of cell, tissue and gene therapies including the use of applicable regulatory tools. Do not hesitate to contact us for more information.