The 21st Century Cures Act enacted the Regenerative Medicine Advanced Therapy (RMAT) designation in recognition of the growing importance of regenerative therapies. Qualifying for RMAT designation conveys significant regulatory benefits, and the number of products that have qualified since the inception of RMAT designation continues to increase. In this WSGR Alert, we discuss the requirements to obtain RMAT designation, discuss the benefits associated with RMAT designation, and present selected examples of investigational therapies that have been RMAT-designated.

RMAT Eligibility

Investigational drugs are eligible for RMAT designation if they:

1. meet the definition of a regenerative therapy medicine;
2. are intended to treat, modify, reverse, or cure a serious condition; and if
3. preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address an unmet medical need.¹

A "regenerative therapy" includes cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using these components.² Combination products (e.g., biologic-device, biologic-drug, or biologic-drug-device) can be RMAT-designation-eligible if the biological component provides the "greatest contribution to the overall intended therapeutic effect(s)."³ Gene therapies, including genetically modified cells that "lead to durable modification of cells or tissues" may meet the definition of a regenerative therapy medicine. Therapies regulated solely under Section 361 of the Public Health Service Act and 21 C.F.R. part 1271—so called human cells, tissues, or cellular or tissue-based products (HCT/Ps)—do not qualify as regenerative therapy medicines.⁴

A "serious disease or condition" is one that is associated with morbidity and that has a substantial impact on day-to-day-functioning. Life-threating diseases are serious diseases or conditions. The FDA considers a drug to be intended to treat a serious condition when the drug is intended to "have an effect on a serious disease or condition, or a serious aspect of a serious disease or condition."⁵

An "unmet medical need" is a condition whose treatment or diagnosis is not addressed adequately by a currently available therapy.

Benefits of an RMAT Designation

RMAT designation carries all of benefits of Breakthrough and Fast Track therapy designations, including intensive interaction with the FDA on an efficient drug development program—beginning as early as Phase 1; organizational commitment involving senior managers from the FDA; and rolling review. RMAT-designated products may also be eligible for priority review if supported by clinical data at the time of marketing application submission.⁶ Additionally, the statute addresses potential ways to support accelerated approval and satisfy post-approval requirements.

RMAT designation does not provide additional exclusivity because the RMAT-designated candidate is a biologic—and biologic exclusivity is 12 years.

Examples of RMAT-Designated Investigational Therapies

As of September 2017, 10 investigational therapies were granted RMAT designation. At least four additional RMAT designations were granted in 2018. Examples of RMAT-designated investigational therapies include:

• AST-OPC1 (oligodendrocyte progenitor cells manufactured from a pluripotent embryonic stem cell platform);
• MiltiStem (a stem cell product for the treatment of diseases and conditions in the inflammatory and immune, neurological, and cardiovascular disease areas); and
• JCAR017 (a CAR-T cell targeted for lymphoma).

When to Apply for RMAT Designation

RMAT designation requests can be made concurrent with filing an Investigational New Drug (IND) Application or any time after IND submission. RMAT designation requests should be submitted to the Center for Biologics Evaluation and Research (CBER) in the IND or in an IND amendment. CBER notes that RMAT designation requests will not be processed for inactive INDs or INDs on hold status.⁷

Importantly, because RMAT designation requires preliminary clinical evidence, many RMAT designation requests will be submitted in IND amendments. Guidance issued by the FDA suggests submitting the RMAT designation request no later than an end-of-phase 2 meeting.

RMAT Designation Request Content

RMAT designation requests should contain a cover letter with a bolded, all-caps title as described in the guidance. Requests also should also include:

1. a rational for why the investigative drug meets the definition of a regenerative medicine therapy;
2. a discussion to support that the investigative drug is intended to treat the serious disease or condition, or a serious aspect of the disease or condition;
3. a summary of the risks and benefits of therapies, if any, available for the condition;
4. a description of the unmet medical need; and
5. preliminary clinical evidence that the product has the potential to address the unmet medical need.

Time for Determination of RMAT Designation

The guidance notes that CBER will notify the IND sponsor whether the RMAT designation is granted no later than 60 calendar days after receipt of the designation request.⁸ RMAT designations for investigational drugs that fail to continue to meet the qualifying criteria can be withdrawn.

Conclusion

RMAT designation carries significant benefits, and the number of RMAT-designated therapies continues to increase. Companies developing regenerative therapy medicines should consider seeking RMAT designation as part of a comprehensive regulatory strategy.