The field of regenerative medicine includes a wide range of products including cell therapies, tissue engineering products, human cell and tissue products (HCT/P), and combinations thereof. It often includes innovative products such as the recently approved KYMRIAH (tisagenlecleucel), a chimeric antigen receptor T-cell (CAR-T cells) therapy for patients with acute lymphoblastic leukemia (ALL). Another example is Carticel® for the treatment of certain cartilage defects, where autologous chondrocytes harvested from the subject are expanded ex vivo and implanted back at the site of injury.

The FDA oversight of these type of therapies has been dictated by the extent of manipulation, where those therapies considered to be minimally manipulated may be outside of FDA’s purview. (There are other considerations of HCT/Ps that further define whether they will solely be regulated by section 361 of the Public Health Service (PHS) Act and 21 CFR Part 1271; these promulgated regulations, which include FDA’s authority to conducts inspections, are based on FDA’s statutory authority in section 361 of PHS Act to prevent the spread of communicable disease. If not solely regulated by section 361, they will be subject to premarket and postmarket regulations of a drug/biologic and/or medical device.) The distinction is not always clear and advances in this field have coincided with an increase in private clinics providing cell and tissue therapies claiming benefits for various ailments without FDA oversight of the safety and efficacy claims that are being made.

This August, FDA announced that it would place more scrutiny on these type of therapies. FDA is seeking to advance a new framework of oversight that will establish clearer guidelines around the definition of minimal manipulation and when these products have sufficient complexity to fall under the agency’s current authority. Further, FDA is planning on issuing a number of new guidances to help define an efficient process for evaluating the safety and efficacy of these products.

Another effort in advancing and overseeing the development of regenerative medicine therapies has been the creation of a “fast-track” designation (so called Regenerative medicine advanced therapy or RMAT) which came into effect under the 21st Century Cures Act in December 2016.

The criteria to meet RMAT designation are:

  • The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under section 361 of the PHS Act and 21 CFR Part 1271.
  • The drug is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition.
  • Preliminary clinical evidence to indicate that the drug has the potential to address unmet medical needs for such a disease or condition.

The advantages of RMAT designation include eligibility for increased and earlier interactions with the FDA, eligibility for priority review and accelerated approval which allows for approval based on surrogate or intermediate endpoints. In addition, the sponsor can satisfy its licensing requirements through commitment to post-approval clinical studies and from real-world data such as those obtained from patient registries and health record analysis.

A request for RMAT designation must be made at the time of an Investigational New Drug (IND) application or as an amendment to an existing IND. If an IND is on hold or is placed on hold during the designation review, the RMAT designation cannot be granted.

The request does not need to contain data sets (primary data) but should provide preliminary clinical evidence that is available, plus brief descriptions of a) any available therapies for the disease or condition, the study design, the population studied and the endpoint(s) used and b) the study results and statistical analyses (e.g. subgroup analyses).

As of May, 17 RMAT submissions were received and four were granted. Two examples of therapies that have been issued RMAT designation are:

  • ATIR101 (Kiadis Pharma N.V.), an adjunctive immunotherapeutic for human stem cell transplantation consisting of a single dose donor lymphocyte infusion with immune cells from a partially-matched family member that contain potential cancer killing T-cells and have been depleted of graft versus host disease (GVHD) causing lymphocytes
  • Ixmyelocel-T (Vericel Corporation), an autologous expanded multicellular therapy for the treatment of a serious cardiovascular disease, dilated cardiomyopathy

Regenerative medicine holds great promise where enhanced regulatory oversight by FDA could promote advancement of these therapies and provide greater assurance of their safety and therapeutic efficacy for consumers. FDA’s commitment to the regenerative medicine field is further exemplified by FDA commissioner Dr. Gottlieb recently calling to expand RMAT designation to include certain gene therapy products that permanently alter tissue and produce a sustained therapeutic benefit.

Do you have any questions? Please reach out to Marinka Tellier, NSF International’s Director of Regulatory Affairs for Pharma Biotech, at mtellier@nsf.org or Andy Papas, NSF International’s VP of Regulatory Affairs for Pharma Biotech, at apapas@nsf.org, or visit our website to learn more about NSF's pharma biotech services.

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