On November 16, 2017, FDA released a comprehensive policy framework for how the Agency intends to apply existing laws and regulations that govern regenerative medicine products, including human cells, tissues, and cellular and tissue-based products (HCT/Ps). The policy framework is set forth in a series of four guidance documents (2 final, 2 draft) that build upon the regulatory framework for these products, which was completed in 2005. A guidance document cannot alter a regulation, but can clarify how FDA intends to enforce the regulation.
In a self-described balancing act, Commissioner Gottlieb notes that FDA hopes to foster new and innovative treatment options for patients, while creating a clearer regulatory framework that will allow for greater enforcement ability against those that fall outside of the framework (statement available here). In addition, the policy framework also serves to implement regenerative medicine-related provisions of the 21st Century Cures Act, including the Regenerative Medicine Advanced Therapy (RMAT) designation program (see previous coverage here). Recall, under Section 3033 of the 21st Century Cures Act, which added Section 506(g) to the Federal Food, Drug, and Cosmetic Act (FDC Act), a drug or biological product is eligible for RMAT designation if:
- It meets the definition of a regenerative advanced therapy: “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 [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;
- The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
- Preliminary clinical evidence indicates the drug has the potential to address an unmet medical need.
The effect of designation means that FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval, would be subject to a confirmatory study.
The final guidance documents, which were addressed in a previous accompanying blog post (here), are:
- Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use;
- Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception.
The two new draft guidances, which are the subject of this blog post, are intended to aid in bringing innovative, safe, and effective products to patients as efficiently as possible:
- Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (“Expedited Programs for RMAT”);
- Evaluation of Devices Used with Regenerative Medicine Advanced Therapies (“Devices Used with RMAT”).
Draft Guidance #1: Expedited Programs for Regenerative Medicine Therapies
The “Expedited Programs for RMAT” draft guidance (RMAT draft guidance) describes several established programs, including Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority review designation, all of which are detailed in the more generally applicable guidance document entitled “Expedited Programs for Serious Conditions – Drugs and Biologics,” (May 2014) (see previous coverage here) as well as the newly established RMAT designation.
This draft guidance does not change the meaning of established terms such as “serious disease or condition,” “unmet medical need,” “surrogate endpoint,” “intermediate clinical endpoint,” and “clinically significant endpoint,” which were defined in the May 2014 Expedited Programs guidance. This new draft guidance does, however, address how CBER will apply the qualifying criteria for these expedited programs to regenerative medicine therapies, largely through examples.
Definition of RMAT
The RMAT draft guidance notes that regenerative medicine therapies are defined in section 506(g)(8) of the FDC Act, as “including cell therapies, 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 (PHS Act) (42 U.S.C. 264) and [21 C.F.R. Part 1271].” RMAT draft guidance at 2. In this draft guidance, FDA interprets section 506(g) to apply to gene therapies, including genetically modified cells, if they lead to a durable modification of cells or tissues (this policy was first announced by Commissioner Gottlieb in August 2017 – see previous coverage here). FDA also interprets section 506(g) to permit RMAT designation of a combination product (biologic-device, biologic-drug, or biologic-device-drug) when the biological product component provides the greatest contribution to the overall intended therapeutic effects of the product (i.e., the primary mode of action is conveyed by the biological product component).
RMAT Benefits & Qualifying Criteria: Borrowing & Building upon Concepts from other Expedited Programs
The RMAT draft guidance clearly sets out the benefits and requirements of the RMAT designation by comparing and contrasting it to other, more-established expedited programs. With regard to benefits of RMAT designation – that FDA must take actions to expedite development and review of the product – the draft guidance interprets these statutory benefits as equatable to the benefits of the Fast Track and Breakthrough Therapy designation programs, which consist of:
- Opportunities for frequent interactions with the review team;
- Intensive guidance on an efficient drug development program;
- Organizational commitment involving senior managers; and,
- Consideration for rolling review of the BLA.
Then, with regard to the qualifying criteria for RMAT designation, the RMAT draft guidance establishes a broader approach to what qualifies as “preliminary clinical evidence” than FDA set out in the May 2014 Expedited Programs guidance. In addition to accepting more traditional clinical trials as preliminary clinical evidence, the RMAT draft guidance explicitly allows for well-designed retrospective studies and clinical case series that provide data systematically by treating physicians. In addition, the RMAT draft guidance distinguishes what level of evidence is needed from Breakthrough Therapy designation, noting that RMAT does not require evidence that indicates the drug may offer substantial improvement over available therapies, which is a higher evidentiary bar. This evidentiary flexibility comes with a key qualification. The RMAT draft guidance requires the evidence to be generated using the actual product that is planned for clinical development, and not a related product.
RMAT-Specific Accelerated Approval
The RMAT draft guidance sets out that programs with RMAT designation are eligible for Accelerated Approval based on either (a) “previously agreed-upon surrogate or intermediate clinical endpoints that are reasonably likely to predict long-term clinical benefit” or (b) “reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites, as appropriate.” RMAT draft guidance at 9. While (a) is the traditional standard for Accelerated Approval under Subpart E, (b) is new and specific to RMAT-designated products, and the RMAT draft guidance specifies that this will depend on “whether the evidence of effectiveness is likely to be affected by a site-specific or investigator-specific bias, such that any conclusions regarding the product’s effectiveness could not be reliably generalized to other sites.” Id. This type of Accelerated Approval would likely result in requirements for post-approval clinical evidence about the product through expansion to additional sites.”
The other RMAT-specific Accelerated Approval provision that the RMAT draft guidance implements is the ability for such products to satisfy post-approval requirements via:
- The submission of 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 as agreed upon during product development; or
- Post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.
RMAT draft guidance at 10.
Considerations in Clinical Trial Design
Moving beyond the formal expedited programs, the RMAT draft guidance, in recognition that many regenerative medicines are being developed to address unmet medical needs in patients with serious conditions, including rare diseases, mentions innovative clinical trial designs that can support a BLA. Specifically, the RMAT draft guidance states that CBER will consider clinical trials that incorporate adaptive designs, enrichment strategies, and/or novel endpoints.
While this has already been done in other areas such as oncology drug development, the draft guidance proposes that, given the limited number of affected individuals in rare diseases that can participate in clinical trials, that several different investigational products may be compared to each other and a common control in a single study.
When selecting endpoints for clinical development, the draft guidance encourages sponsors to obtain input from the affected patient communities about endpoints that might be clinically meaningful – a principle supported by FDA’s Patient-Focused Drug Development Initiative (see previous coverage here). As an example of such a patient-centric endpoint, the draft guidance discusses how improvement in performance of tasks that require visual function might be more appropriate than traditional measures of visual impairment in conditions that lead to advanced visual impairment; this is an apparent call-out of the endpoint Spark Therapeutics developed for its gene therapy program (see previous coverage here).
GMP Manufacturing Compliance Appears to be Waived
The RMAT draft guidance suggests that clinical trial data can be shared buy multiple clinical sites utilizing a common protocol if any individual site intends to seek BLA approval. While noting that the sites would also need to share a common manufacturing protocol, the RMAT draft guidance fails to address or even mention whether it expects to obtain comparability data for products manufactured at different sites (as it would for a commercial BLA), or whether it expects the clinical sites to expend the very substantial resources that would be needed to assure compliance with Good Manufacturing Practices (GMPs). While FDA is to be applauded for its efforts in being creative, the resulting regulatory paradigm cannot result in disparate treatment of parties seeking BLA approval.
Draft Guidance #2: Devices Used with RMATs
The “Devices Used with RMAT” draft guidance (Device Evaluation draft guidance) was developed to satisfy the requirement set out in Section 3034 of the 21st Century Cures Act that FDA issue guidance clarifying how FDA will evaluate devices used in the recovery, isolation, or delivery of regenerative medicines. Accordingly, this guidance discusses what FDA will consider when evaluating the devices used with RMATs.
Applying the Medical Device Regulatory Framework
The Device Evaluation draft guidance largely summarizes the existing medical device regulatory framework, asserting that devices used with RMATs are subject to the same processes and standards. For example, according to the draft guidance, like any other device, FDA has no predetermined list of intended uses or specific attributes that would result in a device used with an RMAT to be classified as a Class III device. Also, FDA intends to apply the same regulatory principles to the development of devices used with RMATs, including the applicability of the “least burdensome” principle and determination of premarket pathway (e.g., 510(k), de novo, PMA, HDE).
Combination Device-RMAT Products
The Device Evaluation draft guidance attempts to simplify and streamline the application of regulatory requirements for combination device and cell or tissue products. The document articulates FDA’s intent that devices to be used with a specific RMAT may, together with the RMAT, be considered to be a combination product and be evaluated under a BLA at CBER. However, stand‑alone devices that can be used for the recovery or delivery of approved RMATs (e.g., surgical tools, syringes) may be evaluated independently using premarket submission pathways for devices. And, as such, FDA commits to apply the least burdensome principle to determine the “minimum required information” necessary for marketing authorization of that device.
Finally, in instances where the RMAT and specified delivery devices are separately packaged but labeled for use together, the two products may comprise a combination product. Where the delivery device may be used with multiple similar RMATs, separate marketing applications for each product may be required, however FDA intends to similarly simplify and streamline the regulatory requirements by reducing redundancy in data requirements (e.g., use RMAT IND studies to support approval or clearance of the device).
Use of a Device with One or More Types of Cell-Based RMATs
Because cell-based RMATs are likely to differ with regard to characteristics that can impact the way the RMAT interacts with different device materials (and, therefore, potentially impact its safety and effectiveness), such as cell viability, differentiation potential, activation state, and ability to respond to stimuli after administration, the Device Evaluation draft guidance discusses factors to consider when a device can be used with only one particular type of cell-based RMAT versus more than one type. Factors include (a) physical characteristics of the RMAT (e.g., cell size and sensitivity to shearing forces) and (b) demonstrated performance and compatibility.
Similarly, if during development, a given RMAT is demonstrated to have characteristics and use requirements that allow it to be administered with a class or subset of delivery devices without compromising safety and effectiveness, the RMAT may be approved on its own with appropriate labeling for use with devices. The draft guidance anticipates this will become more common as experience is gained over time with a specific RMAT or class of RMATs in different use settings.