Regenerative (Medicine) Advanced Therapy: from RAT to ART to RMAT

In the United States, the government can promote or incentivize the drug development in certain areas through its policies. In FDA, there are different kind of designations, each providing specific benefits or incentives for speeding up the drug development in specific areas. Here are some of the designations/vouchers,… all with purpose to stimulate the drug development in certain areas.

Orphan Drug Designation	For granting special status to a drug or biological product (“drug”) to treat a rare disease or condition upon request of a sponsor. This status is referred to as orphan designation (or sometimes “orphan status”). Orphan designation qualifies the sponsor of the drug for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing. A marketing application for a prescription drug product that has received orphan designation is not subject to a prescription drug user fee unless the application includes an indication for other than the rare disease or condition for which the drug was designated.
Fast Track	Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
Breakthrough Therapy	A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
Accelerated Approval	These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
Priority Review	A Priority Review designation means FDA’s goal is to take action on an application within 6 months.
Rare Pediatric Disease Priority Review Voucher	Under Section 529 to the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA will award priority review vouchers to sponsors of rare pediatric disease product applications that meet certain criteria. Under this program, a sponsor who receives an approval for a drug or biologic for a "rare pediatric disease" may qualify for a voucher that can be redeemed to receive a priority review of a subsequent marketing application for a different product.
Neglected Tropical Disease Priority Review Voucher	Authorizes the FDA to award priority review vouchers to sponsors of certain tropical disease product applications that meet the criteria specified in that section
Generating Antibiotics Incentives Now (GAIN)	With incentives to help bring new antimicrobials to market. Antimicrobials or antibiotics drugs can be approved after being designated as a Qualified Infectious Disease Product (QIDP) under the GAIN Act. As part of this QIDP designation, FDA’s review of the drug application is expedited. The designation also qualify the drugs for five years of marketing exclusivity to be added to certain exclusivity already provided by the FDA.

With 21^st Century Cure Act passed last December, we now have a new designation – Regenerative Advanced Therapy. It is interesting that Regenerative Advanced Therapy can be abbreviated as RAT – which is not a good name.In one of the webinars, Dr Frank Sasinowski questioned the term and suggested the use of Advanced Regenerative Therapy (ART). Nobody wants to have their innovative therapy being labelled as RAT, everybody wants to have their innovative therapy being labelled as ART.

Yesterday, FDA issued its first Regenerative Advanced Therapy designation to Humacyte - a company in Research Triangle Park, North Carolina for their tissue engineered vessel or human acellular vessel. In its issuance, neither RAT nor ART is used by FDA. Instead, the term is called RMAT (Regenerative Medicine Advanced Therapy). I guess that FDA realizes the term RAT is not a good one. 

With RMAT designation, the sponsor will have the breakthrough and priority review benefits as well as one aspect of fast track (rolling submission). In addition, with RMAT designation, the sponsor will have an opportunity for accelerated approval on basis of invalidated surrogate endpoint and the sponsor will have reduced phase 4 requirements if the product is approved. 

Below are some specific sections from 21^st Century Cure Act regarding the Regenerative Advanced Therapy designation:

 (g) Regenerative Advanced Therapy.—

 “(1) IN GENERAL.—The Secretary, at the request of the sponsor of a drug, shall facilitate an efficient development program for, and expedite review of, such drug if the drug qualifies as a regenerative advanced therapy under the criteria described in paragraph (2).

 “(2) CRITERIA.—A drug is eligible for designation as a regenerative advanced therapy under this subsection if— 

“(A) the drug is a regenerative medicine therapy (as defined in paragraph (8)); 

“(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 for such a disease or condition.

 “(5) ACTIONS.—The sponsor of a regenerative advanced therapy shall be eligible for the actions to expedite development and review of such therapy under subsection (a)(3)(B), including early interactions to discuss any potential surrogate or intermediate endpoint to be used to support the accelerated approval of an application for the product under subsection (c).

 “(6) ACCESS TO EXPEDITED APPROVAL PATHWAYS.—An application for a regenerative advanced therapy under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act may be— 

“(A) eligible for priority review, as described in the Manual of Policies and Procedures of the Food and Drug Administration and goals identified in the letters described in section 101(b) of the Prescription Drug User Fee Amendments of 2012; and 

“(B) eligible for accelerated approval under subsection (c), as agreed upon pursuant to subsection (a)(3)(B), through, as appropriate— “(i) surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit; or “(ii) reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites, as appropriate. 

“(7) POSTAPPROVAL REQUIREMENTS.—The sponsor of a regenerative advanced therapy that is granted accelerated approval and is subject to the postapproval requirements under subsection (c) may, as appropriate, fulfill such requirements, as the Secretary may require, through— 

“(A) the submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence, such as electronic health records; 

“(B) the collection of larger confirmatory data sets, as agreed upon pursuant to subsection (a)(3)(B); or 

“(C) postapproval monitoring of all patients treated with such therapy prior to approval of the therapy.

 “(8) DEFINITION.—For purposes of this section, the term ‘regenerative medicine therapy’ 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.”.    

SEC. 3034. GUIDANCE REGARDING DEVICES USED IN THE RECOVERY, ISOLATION, OR DELIVERY OF REGENERATIVE ADVANCED THERAPIES.(a) Draft Guidance.—Not later than 1 year after the date of enactment of the 21st Century Cures Act, the Secretary of Health and Human Services, acting through the Commissioner of Food and Drugs, shall issue draft guidance clarifying how, in the context of regenerative advanced therapies, the Secretary will evaluate devices used in the recovery, isolation, or delivery of regenerative advanced therapies. In doing so, the Secretary shall specifically address— 

(1) how the Food and Drug Administration intends to simplify and streamline regulatory requirements for combination device and cell or tissue products; 

(2) what, if any, intended uses or specific attributes would result in a device used with a regenerative therapy product to be classified as a class III device; 

(3) when the Food and Drug Administration considers it is necessary, if ever, for the intended use of a device to be limited to a specific intended use with only one particular type of cell; and 

(4) application of the least burdensome approach to demonstrate how a device may be used with more than one cell type. (b) Final Guidance.—Not later than 12 months after the close of the period for public comment on the draft guidance under subsection (a), the Secretary of Health and Human Services shall finalize such guidance.  

SEC. 3035. REPORT ON REGENERATIVE ADVANCED THERAPIES.(a) Report To Congress.—Before March 1 of each calendar year, the Secretary of Health and Human Services shall, with respect to the previous calendar year, submit a report to the Committee on Health, Education, Labor, and Pensions of the Senate and the Committee on Energy and Commerce of the House of Representatives on— 

(1) the number and type of applications for approval of regenerative advanced therapies filed, approved or licensed as applicable, withdrawn, or denied; and 

(2) how many of such applications or therapies, as applicable, were granted accelerated approval or priority review. (b) Regenerative Advanced Therapy.—In this section, the term “regenerative advanced therapy” has the meaning given such term in section 506(g) of the Federal Food, Drug, and Cosmetic Act, as added by section 3033 of this Act.  

SEC. 3036. STANDARDS FOR REGENERATIVE MEDICINE AND REGENERATIVE ADVANCED THERAPIES.

Subchapter A of chapter V of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351 et seq.) is amended by inserting after section 506F the following: 

“SEC. 506G. STANDARDS FOR REGENERATIVE MEDICINE AND REGENERATIVE ADVANCED THERAPIES. “(a) In General.—Not later than 2 years after the date of enactment of the 21st Century Cures Act, the Secretary, in consultation with the National Institute of Standards and Technology and stakeholders (including regenerative medicine and advanced therapies manufacturers and clinical trial sponsors, contract manufacturers, academic institutions, practicing clinicians, regenerative medicine and advanced therapies industry organizations, and standard setting organizations), shall facilitate an effort to coordinate and prioritize the development of standards and consensus definition of terms, through a public process, to support, through regulatory predictability, the development, evaluation, and review of regenerative medicine therapies and regenerative advanced therapies, including with respect to the manufacturing processes and controls of such products. 

“(b) Activities.— 

“(1) IN GENERAL.—In carrying out this section, the Secretary shall continue to— 

“(A) identity opportunities to help advance the development of regenerative medicine therapies and regenerative advanced therapies; 

“(B) identify opportunities for the development of laboratory regulatory science research and documentary standards that the Secretary determines would help support the development, evaluation, and review of regenerative medicine therapies and regenerative advanced therapies through regulatory predictability; and 

“(C) work with stakeholders, such as those described in subsection (a), as appropriate, in the development of such standards. 

“(2) REGULATIONS AND GUIDANCE.—Not later than 1 year after the development of standards as described in subsection (a), the Secretary shall review relevant regulations and guidance and, through a public process, update such regulations and guidance as the Secretary determines appropriate. “(c) Definitions.—For purposes of this section, the terms ‘regenerative medicine therapy’ and ‘regenerative advanced therapy’ have the meanings given such terms in section 506(g).”.