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The ever-increasing demand for healthcare advances has prompted legislators to consider means of facilitating the development of potentially life-saving new therapies. In this guest column, Alison Wilson will review the definition of a regenerative medicine advanced therapy (RMAT) and how this designation can facilitate speed to market for these innovative therapies. Alison is an independent regulatory affairs consultant specializing in human cell and tissue-based advanced therapies.
In December 2016 the US Congress enacted the 21st Century Cures Act1, which provides for >US$6 billion in funding intended to facilitate, among other things, action against the misuse of opioids and promotion of measures to increase health insurance protection for mental health issues. Of specific interest to the advanced therapy industry, the Act required FDA to facilitate an efficient development program for, and expedited review of, new medicines meeting the definition of a regenerative advanced therapy (RAT) (Section 3033). The RAT designation in the legislation is now referred to as the Regenerative Medicine Advanced Therapy (RMAT) designation. Such therapies are defined as a:
cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition
Cell and tissue-based products regulated solely under Section 361 of the Public Health Service Act and 21 CFR part 12712 are excluded from the definition: broadly these are minimally manipulated human cell/tissue products for which claims are restricted to homologous functions, such as decellularized skin or demineralized bone matrix.
Details of the RMAT designation are set out on the relevant CBER webpage3. Sponsors can find help on interpretation of the terms “serious disease or condition” and “unmet medical need” in FDA’s guidance document on fast-track expedited programs4.
Requesting RMAT Designation
Sponsors of drug products meeting the above criteria can request RMAT designation from the Office of Tissues and Advanced Therapies (OTAT) when submitting an Investigational New Drug application (IND), or after one has been submitted. This implies that the Agency will accept early non-US clinical data, since the designation requires preliminary clinical evidence that the new therapy may address an unmet medical need. However the IND must be active, and not on hold; if the IND part of a combined submission is placed on hold the RMAT designation will not be issued.
RMAT designation requests do not require submission of full clinical data; instead sponsors must describe the preliminary clinical evidence on which the request is based. This should include a brief description of any available therapies for the disease or condition, the study design including population studied and endpoint(s) used. A description of the study results and statistical analyses should be provided. The Agency has 60 days to review the request for RMAT designation; if it is denied OTAT will provide a justification for not assigning the designation.
Benefits of RMAT designation
The RMAT designation gives the sponsor of a new drug access to increased meeting opportunities with FDA, in a manner comparable to those offered to sponsors of breakthrough-designated therapies. In fact the RMAT may be considered as analogous to the breakthrough designation for regenerative medicine drugs. Because the designated products meet the criteria for unmet medical need in the treatment of a serious condition, they may be eligible for priority review, in which the initial assessment of the BLA is reduced from 10 months to 6 months, and accelerated approval, which bases approval on an effect on a predictive surrogate endpoint or an intermediate clinical endpoint. RMATs qualifying for accelerated approval may be able to satisfy licensing requirements through commitment to post-approval clinical studies as well as real-world data such as patient registries and health record analysis: as a consequence of the 21st Century Cures Act, FDA are now required to take account of clinical evidence beyond controlled clinical trials. The eligibility of the RMAT-designated product for these expedited programs can be discussed with FDA at specific development meetings. The increased access to FDA during early development is a significant benefit for sponsors, because the typical Type B development meetings are normally restricted to one each at pre-IND, end of Phase II/pre-Phase III and pre-BLA submission. In addition, the option to qualify for fast-track approval, also based on the potential to serve an unmet medical need in the treatment of a serious condition, allows for a so-called “rolling review” of parts of the BLA, which can be submitted for assessment following agreement of a review timetable with CBER.
Recent Approvals
Several products have already achieved RMAT designation since the program’s inception, including:
Outlook
It appears that the RMAT designation has caught the attention of advanced therapies. The opportunity for early and more frequent interactions with FDA during critical development stages is understandably very attractive to the companies involved in advanced therapy development, many of whom are small, clinician-led enterprises with little experience of conventional drug development pathways. The extent to which we can shift the balance of evidence from licensing to the post-marketing phase is something that regulators and sponsors are exploring in many expedited development programs, and this takes on an urgent appeal when considering the life-threatening nature of many of the conditions these regenerative medicines are intended to address. The flexibility granted to FDA in considering forms of clinical evidence other than the usual randomized controlled clinical trials could facilitate pragmatic decision-making and the possibility of bringing key new therapies to market more quickly, or represent a weakening of the requirements and reduction in patient protection depending on your viewpoint. More RMAT designations are anticipated; it will be several years before we see whether this initiative is achieving its goal of facilitating faster development whilst maintaining rigorous standards of safety and efficacy.
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