Cell And Gene Therapies: Regulatory Opportunities In 2024

By Life Science Connect Editorial Staff

A 2023 Cell & Gene Live event welcomed Dr. Adora Ndu, Chief Regulatory Affairs Officer at BridgeBio, and Dr. Nina Hunter, Vice President of Corporate Strategy at REGENXBIO, to join host Erin Harris to discuss the top three regulatory issues impacting the cell and gene therapy sector.ⁱ Drawing from that discussion, this article examines the shifting regulatory landscape around cell and gene (C&G) therapies, as well as the opportunities created by new or updated regulations.

Despite the promise of C&G therapies, the regulations governing them seem to lag, hindering the clinical translation of these novel medicines. But pharmaceutical/biopharmaceutical sponsors and industry groups can work with the FDA and other regulatory agencies to improve communication, promote regulatory clarity, and even help to shape policy — accelerating development and approval of these products.

Opportunity 1: Fulfilling RMAT’s Promise

A key opportunity area for regulatory advancement is smoother utilization of the FDA’s Regenerative Medicines Advanced Therapies (RMAT) designation, established to support accelerated and expedited development of regenerative medicines. RMAT designation establishes that preliminary clinical evidence suggests a product has potential to address unmet medical needs for serious diseases. Products with this designation benefit from increased regulatory flexibility and additional discussions with CBER leadership.

However, RMAT designation has not been leveraged to its fullest potential. In the five-year period following its 2017 implementation, only three RMAT products were approved. A similar designation, breakthrough therapy, approved 94 products in its first five years. Moreover, RMAT denials outpaced RMAT approvals during that five-year timeframe, hinting that the problem was not a shortage of applications.

We as an industry must examine the barriers more closely: how can we work with FDA to clarify the requirements to achieve RMAT designation for specific products (e.g., workshops or pre-meetings, like those in place for breakthrough therapy designated programs)? The conversation must focus on clear actions that can make RMAT a more efficient process with clearer thresholds. 

For example, a pre-meeting to discuss whether your product would qualify for RMAT, based on currently accumulated data, would save both sponsors and regulators a significant amount of time. Sponsors would assemble fewer premature RMAT applications, and the FDA would have to review fewer RMAT requests that are not yet ready for submission.

Obviously, the regulatory path depends on the disease, as well as considerations around benefit/risk profile, the mechanism of action, route administration dose, and other factors. In terms of regulatory considerations, it is impossible to make general policy across the spectrum for novel therapies. So, close collaboration — early and often — and prioritizing engagement between sponsors and regulators goes a long way toward addressing challenges.

Opportunity 2: PDUFA VII Opens New Doors

By 2030, 60 C&G therapies are expected to reach regulatory approval.ⁱⁱ Reauthorization of the Prescription Drug User Fee Act (PDUFA VII)ⁱⁱⁱ through 2027 provides resources for the FDA and CBER to deliver more in-depth and frequent feedback on development, review submitted applications more promptly, and fund a host of other critical activities. Many of these are applicable to all drugs and biologics, but some are specific to C&G therapy.

These resources are intended to strengthen the agency’s staff capacity to meet increasing demand, allowing personnel to spend more time on meetings and submission reviews, so sponsors can enjoy a more significant level of engagement. Compare C&G therapy models to areas like oncology, where extensive engagement and collaboration has facilitated more diverse options for patients.

For example, patient-focused drug development meetings are especially important to incorporate perspectives on product development, including cell mediated gene therapy. These are not specific to C&G therapy; they're highly relevant to challenges faced by many sponsors. One such challenge is the disease condition. Gene therapy often targets well-understood disease pathophysiology, therefore the use of surrogate endpoints as clinical trial endpoints that could be the basis for approval is promising. PDUFA VII includes provisions like early consultation between review teams and sponsors when the sponsor intends to use a biomarker as a surrogate endpoint.

CBER is in a position to add over 200 staff under PDUFA VII and has undergone a reorganization (OTA is now the Office of Therapeutic Products). As new employees are added, from reviewers to product managers, the right structure and training must be in place to ensure those employees are assets as soon as possible.

During the COVID-19 pandemic, CBER was at the center of vaccine reviews, stretching the agency thin and deprioritizing C&G therapies. As a result, a significant number of meeting requests were and still are automatically converted to “written response only.” Even with FDA adding staff, continuing predominantly with written-only responses robs new employees of the benefit of live conversations with sponsors to talk through key issues.

CBER has been responsive, though, reaching out to several sponsors to get feedback on communications challenges, as well as through organizations like the American Society of Gene & Cell Therapy (ASGCT).^iv Still, it remains a best practice, when assembling submission packages, to keep them very focused. Ask precise questions so the answers are not difficult to interpret, since there may be little opportunity for follow-up. This also entails limiting the number of questions you ask.

And always bear in mind that engagement with the FDA cannot start soon enough. The INTERACT program, for example, enables sponsors to gather invaluable early feedback from the agency, confirming their product development plan is headed in the right direction. Under PDUFA VII, INTERACT is a meeting that can be requested, complete with associated timelines. FDA also has issued an SOPP on INTERACT.^v

Opportunity 3: All Stakeholders Must Drive Harmonization

While the U.S. government’s 2024 omnibus spending bill does not appear to contain provisions significantly impacting C&G therapy development,^vi the 2023 iteration contained several,^vii including a stipulation to summarize activities relating to approving and licensing drugs used to treat rare diseases.

For example, provisions were added to strengthen accelerated approval, a tool that allows for patient access to therapeutic options that have demonstrated an effect on the surrogate or an intermediate clinical endpoint that's reasonably likely to predict clinical benefit. Accelerated approval now requires the FDA to specify conditions or require post-approval studies for drugs approved under the program. These conditions may include enrollment targets and milestones, including the target date for study completion by the time the drug is approved.

Additionally, human cells, tissues, and cellular and tissue-based therapies are regulated, in part, under sections 351 and 361 of the Public Health Service (PHS) Act,^viii as well as the Food, Drug, and Cosmetic (FDC) Act.^x In the past few years, the FDA made a concerted enforcement effort, trying to define which products need to be regulated versus those exempt from pre-market review, resulting in the issuance of warning letters to some manufacturers.

The FDA currently is working to clarify the regulatory framework around those products. In December 2023, the agency released an updated guidance document, Rare Diseases: Considerations for the Development of Drugs and Biological Products.^x But how do we proceed from these anchoring points to the next level of cooperation and clarity?

A good start is by contracting with science associations (e.g., National Academies of Sciences, Engineering, and Medicine). This collaboration allows industry stakeholders to better compare rare diseases, as well as the the safety and efficacy of various therapies across the U.S. and E.U., to aid in mutual understanding of rare diseases and harmonization of the rules applied to developing and marketing therapies.

Most trials are multinational, so having regulatory requirements that differ vastly from country to country adds a significant burden. In that same vein, sponsors being able to rely on reviews performed by other health authorities to support broader global approval would be an immense step forward. Some of this can be streamlined through mechanisms such as Project Orbis^xi (intended “to provide a framework for concurrent submission and review of oncology products among international partners,” but not yet implemented at CBER).

The FDA also would benefit by seeking out more input from hands-on scientists and experts within sponsor and industry organizations. But that should build on avenues already available: comment on regulations and guidances when they are issued. The more we submit those letters to FDA, the more the agency can consider implementation issues from a stakeholder perspective. Become active in organizations that can help facilitate interactions with FDA. These entities often submit industrywide comments to the FDA or hold meetings with the agency to talk through broader industry challenges.