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Legal Counsel: Advancing Regenerative Medicine: FDA Implementation of 21st Century Cures Act

The treatment of the skyrocketing number of patients in the United States living with chronic wounds represents an enormous public health challenge, but has also created significant incentives for the development of advanced wound care products. Many believe the future of wound care lies in the promise of regenerative medicine, an emerging, multidisciplinary field involving biology, medicine, and engineering to create therapies that deliver living tissue that stimulates the body’s natural healing process by activating its inherent ability to repair and regenerate. Cutting-edge therapies that are available now, such as bioengineered skin substitutes that heal chronic wounds, will be supplemented by new therapies that aim to heal or reconstruct diseased tissue and support the regeneration of diseased or injured cells and organs. Over the last few years, it has become clear that the U.S. Food & Drug Administration (FDA) needed a fresh approach to regulating this “dynamic and complex” field that would both provide a clear, efficient pathway for companies developing new therapies and allow the FDA to protect patients by ensuring that these breakthrough-type therapies are safe and effective. Against this backdrop came the 21st Century Cures Act,1 which was signed into law in December 2016 following a bipartisan, multiyear effort. One of the primary objectives of the legislation was to improve the FDA’s ability to exercise its crucial oversight function in an efficient, effective manner so that patients can, as quickly as possible, reap the benefits of today’s rapid scientific and biotechnology advances as quickly as possible (with a particular focus on fostering the development and approval of regenerative medicine products). The complexity of the law, a massive piece of legislation running more than 1,000 pages1 and comprising a large, diverse array of health-related initiatives, puts a comprehensive summary beyond the scope of this article. Instead, this discussion is intended to bring wound care providers up to date on the provisions of the act that are most important for regenerative medicine and what they may mean for the future of wound care.   

THE CURES ACT: PATIENT ACCESS TO THERAPIES & INFORMATION

There are four sections of the Cures Act focused specifically on regenerative medicine, two of which are likely to have a relatively immediate impact on the development of innovative therapies. These sections are found in Subtitle D of Title III, entitled “Patient Access to Therapies and Information.” Section 3033, entitled “Accelerated Approval for Regenerative Advanced Therapies,” instructs the FDA to establish a new program to foster the development and approval of such therapies through the new regenerative medicine advanced therapy (RMAT) designation.2 

An investigational regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious condition and if preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such a condition.3 Upon receipt of an RMAT designation, the sponsor of a new product is eligible for increased (and earlier) interactions with the FDA to help facilitate an efficient development program, including discussion of which approval pathways would be appropriate and the size of clinical trials. Section 3034 of the Cures Act establishes that devices used in the recovery, isolation, or delivery of RMATs will be considered moderate risk, unless the FDA determines that the device or intended use requires a higher risk classification. Section 3034 also requires the FDA to issue guidance clarifying how it will evaluate such devices. In addition to these provisions, Section 3035 provides that the FDA must, before March 1 of each year, report to Congress 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. (The first report is due as this article goes to press.) Section 3036 requires the FDA to establish standards and consensus definitions to support the development and review of regenerative medicine therapies, including with respect to the manufacturing processes and controls of such products. Taken together with certain other provisions of the act that are intended to promote and support the development of innovative therapies generally,1 there is reason for great optimism that the Cures Act will spur significant innovation over the next few years in treatments for chronic wounds. For example, the legislation authorizes $4.8 billion in spending over 10 years for new research at the National Institutes of Health to invest in science and medical innovation, provide greater support for outstanding scientists, promote pediatric research for rare diseases and birth defects, and take other steps to help modernize U.S. healthcare research. 

NEW POLICY FRAMEWORK FOR REGENERATIVE MEDICINE PRODUCTS

With the support of the new authorities and funding provided by the Cures Act, the FDA in November announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies.4 The policy framework is “intended to balance the agency’s commitment to safety with mechanisms to drive further advances in regenerative medicine so that innovators can bring new, effective therapies to patients as quickly and safely as possible.” The policy is characterized as building on the FDA’s existing risk-based regulatory approach to support innovative product development while clarifying the FDA’s authorities and enforcement priorities. More specifically, it is intended to clarify applicable premarket regulatory requirements for different types of regenerative medicine products and to set forth an efficient, science-based process for helping to ensure the safety and effectiveness of these therapies. In relevant part, the framework is articulated in two draft guidance documents that elaborate on concepts and mechanisms established by the Cures Act to stimulate and support the development of and access to innovative regenerative therapies. The framework also includes two final guidance documents that had been in the works prior to enactment of the Cures Act. These documents relate to the FDA’s regulation of human cells, tissues, and cell-and tissue-based products (HCT/Ps) and clarify the FDA’s interpretation of the risk-based criteria that manufacturers use to determine whether a product is subject to premarket review. The first guidance5 helps stakeholders better understand how existing regulatory criteria apply to their products by clarifying how the agency interprets certain existing regulatory definitions relevant to determining when a product is subject to the FDA’s premarket approval requirements. The second guidance6 provides greater clarity concerning the circumstances under which cells and tissues are exempt from premarket requirements if they are removed from and implanted into the same individual within the same surgical procedure and remain in their original form. With the issuance of this guidance, the FDA assures stakeholders that it is committed to ensuring that new regenerative medicine therapies can be licensed and made available to patients living with serious conditions as soon as it can be determined that they are safe and effective. Toward that end, the first guidance document describes a set of programs to facilitate development and review of regenerative medicine therapies (including cell therapies, therapeutic tissue-engineering products, HCT/Ps, and combination products using any such therapies or products) intended to address unmet medical needs in those with serious conditions. In particular, the guidance explains that regenerative medicine therapies to treat, modify, reverse, or cure serious conditions will be eligible for the FDA’s expedited programs, including fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation, if they meet the criteria for such programs. The guidance discusses the application of those programs to regenerative medicine therapies and provides additional information about the new RMAT designation program. The second document describes how the FDA intends to simplify and streamline its application of the regulatory requirements for devices used in the recovery, isolation, and RMATs, including combination products. It also addresses the intended uses or specific attributes of RMATs that would result in such devices having Class III status (and thus requiring premarket approval, rather than the simpler premarket clearance); the factors that determine whether a device may be labeled for use with a specific RMAT or class of RMATs; the circumstances under which a device may be limited to a specific intended use with only one particular type of cell; and the application of the least burdensome approach to demonstrate how a device may be used with more than one cell type. The guidance also specifies that devices intended for use with a specific RMAT may, together with the RMAT, be considered to comprise a combination product and sets forth principles for reducing regulatory burdens when separate premarket applications are submitted for the device and biologic components of such a product.  

THE FUTURE OF WOUND CARE

It seems clear that the future of wound therapy lies with bioactive wound healing and soft tissue regeneration. The Cures Act and the FDA’s new regenerative medicine policy framework should spur development of these products and get them into clinics sooner. We are already seeing companies taking advantage of the new framework while others have announced RMAT designations.7 Although many of these designations are not for products intended for dermal wounds, the advances they represent will inevitably find their way into new therapies for chronic wounds. Moreover, products intended specifically for dermal wounds are also taking advantage of the RMAT designation process.8,9 

Naomi J.L. Halpern is a counsel at Arent Fox LLP, Washington, DC. and advises clients on regulatory issues involving the FDA. James R. Ravitz leads the food, drug, medical device, and agriculture practice at Arent Fox.

References

1. Public Law 114–225. United States Congress. 2016. Accessed online: www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf 

2. Regenerative medicine advanced therapy designation. FDA. 2018. Accessed online: www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/ucm537670.htm

3. Regenerative Medicine Advanced Therapy Designation.  FDA. 2018. Accessed online: www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/ucm537670.htm

4. FDA announces comprehensive regenerative medicine policy framework. FDA. 2017. Accessed online: www.fda.gov/newsevents/newsroom/pressannouncements/ucm585345.htm

5. Expedited programs for regenerative medicine therapies for serious conditions - draft guidance for industry. FDA. 2017. Accessed online: www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm585414.pdf

6. Evaluation of devices used with regenerative medicine advanced therapies. FDA. 2017. Accessed online: www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm585417.pdf

7. Humacyte receives FDA regenerative medicine advanced therapy (RMAT) expedited review designation for humacyl in vascular access for hemodialysis. Humacyte. 2017. Accessed online: www.humacyte.com/press/humacyte-receives-fda-regenerative-medicine-advanced-therapy-rmat-expedited-review-designation-humacyl-vascular-access-hemodialysis/

8. U.S. FDA designates mallinckrodt’s stratagraft as regenerative medicine advanced therapy. Mallinckrodt. 2017. Accessed online: www.mallinckrodt.com/about/news-and-media/2286957

9. Abeona receives FDA regenerative medicine advanced therapy designation for EB-101 gene therapy in epidermolysis bullosa. Abeona Therapeutics. 2018. Accessed online: https://globenewswire.com/news-release/2018/01/29/1313576/0/en/Abeona-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-Designation-for-EB-101-Gene-Therapy-in-Epidermolysis-Bullosa.html

Legal Counsel
Naomi J.L. Halpern & James R. Ravitz
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