Meet the Regenerative Advanced Therapy Designation

FDA recently put forth its first interpretation of the Regenerative Advanced Therapy (“RAT”) designation program, which was established by section 3033 of the 21st Century Cures Act. Although it consists of just a few short paragraphs on FDA’s website (here), the guidance confirms that FDA will use its standard definitions found in its Expedited Programs Guidance for terms like “serious or life-threatening,” and it signals that FDA has begun the lengthy process of implementing the new designation program. For a healthy dose of nostalgia, recall a simpler time, when breakthrough therapy designation was the newest tool in FDA’s expedited programs kit (here).

Background

Section 3033 of the 21st Century Cures Act provides that a drug is eligible for RAT designation if:

• “(A) the drug is a regenerative medicine therapy [which] includes cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act and part 1271 of title 21, Code of Federal Regulations;
• (B) the drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
• (C) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs.”

FDA’s website clears up any potential confusion related to the “includes” clause in the first prong by stating that “regenerative medicine therapy . . . is defined as a cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act and part 1271 of title 21, Code of Federal Regulations.” (Emphasis added.)

Given the definition of RAT, it’s useful to recall that, per 21 CFR 1271.10(a), 361 human cells, tissues, or cellular or tissue-based products (“HCT/Ps”):

• Are minimally manipulated;
• Are intended for homologous use (as reflected in labeling and advertising);
• Are not manufactured by combining cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent; and
• Do not have a systemic effect nor are they dependent upon the metabolic activity of living cells for their primary function, with certain limited exceptions.

If any of these requirements are not met, the HCT/P is still subject to regulation under 21 C.F.R. Part 1271, but in addition is likely subject to biologic, drug, or medical device regulation.

In practice, many of the HCT/Ps in regenerative medicine that do not qualify as 361 HCT/Ps are regulated as biologics subject to section 351 of the PHS Act and approved via a biologics license application (BLA). The BLA process is perhaps the most burdensome and lengthy premarket review process that FDA imposes. To address this, Congress created the RAT designation.

Evolving Definition of Regenerative Therapy

The definition of RAT established by 21st Century Cures is considerably broader than the one recently provided by FDA in a presentation on regenerative medicine and regulatory science. In a October 2016 presentation, FDA stated that regenerative medicine products are generally for repair, replacement, or regeneration and usually are a combination of a biological product with a medical device (e.g., a 3D, cell-scaffold product).

Instead of focusing on function, a la “repair, replacement, or regeneration,” the 21st Century Cures definition puts greater emphasis on product type (e.g., whether it is a therapeutic engineering product), as opposed to intended use. After all, a RAT need only be “intended to treat . . . a serious or life-threatening disease or condition.” (Emphasis added.) This intended use is in no way unique to regenerative medicine, and the Agency may seek to narrow the intended uses that qualify as RATs in future guidance.

RAT Designation Process

Requests for RAT designation can be made concurrently or at any time after submission of an IND. FDA is required to respond within 60 days. If CBER’s Office of Tissues and Advanced Therapies (“OTAT”) determines that a RAT designation request is incomplete or that the drug development program does not meet the criteria for designation, it will inform the sponsor and include a written description of the rationale for its determination. FDA’s RAT website also provides that:

• Sponsors should refer to FDA’s Expedited Programs Guidance for FDA’s interpretation of whether a disease or condition is “serious or life-threatening” and whether a drug is “intended to treat a serious disease or condition.”
• Consistent with fast track and breakthrough therapy designations, FDA does not expect that sponsors submit primary data. Instead, FDA requests that sponsors describe the preliminary clinical evidence.
• Sponsors should provide a brief description of any available therapies for the disease or condition, the study design, the population studied, and the endpoint(s) used, and a description of the study results and statistical analyses (e.g., subgroup analyses).
• Requests for RAT designation should be submitted to OTAT.
• The cover letter for a request should clearly specify that the submission contains a “REQUEST FOR REGENERATIVE ADVANCED THERAPY DESIGNATION” in bold, upper case letters.

Benefits of RAT Designation

RAT designation affords the following benefits to sponsors:

• Expedited development and review by FDA (i.e., the same actions as for breakthrough therapy designation);
• Early interactions “to discuss any potential surrogate or intermediate endpoint to be used to support the accelerated approval of the product;” and
• Eligibility for accelerated approval under current FDA preapproval standards but with new postapproval requirements.

Signaling for Expanded Use of Accelerated Approval

The new postapproval requirements are a key differentiating factor from the breakthrough therapy designation. Sponsors of RAT-designated products approved via the accelerated approval pathway have additional options to meet post-approval requirements beyond the standard, controlled clinical trial. Post-approval requirements can be met through:

• Clinical evidence, clinical studies, patient registries, or other sources of real world evidence, such as electronic health records;
• The collection of larger confirmatory data sets; or

Postapproval monitoring of all patients treated with such therapy prior to approval of the therapy.

The new designation, therefore, encourages FDA to further develop and utilize the Subpart H/accelerated approval pathway. For a comprehensive review of FDA’s use of accelerated approval, refer to our paper, here.

Notably, the January 2015 House version of 21st Century Cures at section 2041 addressed regenerative medicine from a different angle. It directed FDA to issue a guidance document on surrogate and intermediate endpoints for accelerated approval of regenerative medicine products. Although this original approach was less ambitious, it also highlighted the need for accelerated approval to bring to market products in the budding field of regenerative medicine.