This article examines US regulations and guidance documents for regenerative medicine advanced therapies (RMATs). The author describes the field of regenerative medicine, noting that it is expanding at an accelerated pace, and outlines some of the common terms associated with it. He also addresses the application process for these therapies, accelerated regulatory pathways, market access, and the outlook for RMATs. The author cautions that, as exciting as these therapies are, they require a rigorous and carefully planned approach to ensure a seamless progression to regulatory approval and commercial success. Introduction Regenerative medicine is a rapidly expanding field, offering the potential to treat serious and life-threatening conditions by replacing, or regenerating, human cells, tissues, or organs that have been damaged by disease, trauma, or congenital defects.1 With more than 200 investigational new drug (IND) applications anticipated by the US Food and Drug Administration (FDA) in 2020,2 regenerative medicine should yield many new therapies with enormous benefits to patients, especially those with unmet medical needs. Navigating the complex regulatory environment of regenerative medicine requires companies to engage with the FDA early and often throughout the drug development process to identify and overcome potential obstacles to approval. Many of these therapies are developed by scientific institutions and medical research groups with limited inhouse regulatory resources, so it is advisable to seek external regulatory support early in the planning process. Regenerative medicines defined Regenerative medicines, as defined by the FDA, include cell therapies (non- and genetically modified), therapeutic tissue-engineering products, human cell and tissue products, and combination products using these biologic components, which lead to a sustained effect on cells and tissues. In addition, a combination product (biologic device, biologic drug, or biologic device-drug) can be eligible for regenerative medicine advanced therapy (RMAT) designation when the biological product constituent part is a regenerative medicine therapy and provides the greatest contribution to the overall intended therapeutic effects of the combination product (i.e., the primary mode of action of the combination product is conveyed by the biological product constituent part). In January 2020, the FDA released six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance.3 The FDAs policy to advance the development of safe and effective cell and gene therapies can be found here.4 This article explains some of the terminology and covers the key US regulations and guidance documents. Discussions of a select number of these documents will be published in separate articles in Regulatory Focus. Terminology Cellular & gene therapy products5 Cellular therapy products include cellular immunotherapies, cancer vaccines, and other types of autologous and allogeneic cells, including hematopoietic stem cells and adult and embryonic stem cells, for certain therapeutic indications. Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. The FDAs Center for Biologics Evaluation and Research (CBER) has approved both cellular and gene therapy products.5 Gene therapy6 Gene therapy is a technique that modifies a persons faulty genes treat or cure disease and is most often applied to cancer, genetic diseases and infectious diseases. Gene therapies can work by several mechanisms:

The following figureshows CBERs organisation for pre and postmarket regulation35

Market access and outlook As of May 2019, the FDA had granted 34 products FDA regenerative medicine advanced therapy designations.36 In all, 68 of the 100 designation applications were cell therapy products, 20 of the 34 RMAT granted products have orphan product designation, and 11 of the 34 have fast track designation. While the promise of regenerative medicines to cure disease is driving the field forward at an accelerated pace, developing these therapies require a rigorous and carefully planned approach to ensure a seamless progression to regulatory approval and commercial success. Abbreviations ANDA, abbreviated new drug application; CBER, Center for Biologics Evaluation and Research; FDA, Food and Drug Administration; HCT/P, human cell, tissue, and cellular and tissue-based product; IND, investigational new drug; PDUFA, Prescription Drug User Fee Act; rDNA, ribosomal DNA; RMAT, regenerative medicine advanced therapy. References All references were accessed 23 July 2020.

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US regulations for regenerative medicine advanced therapies - Regulatory Focus