Precision medicine seeks to provide an individualized therapy for each patient – with the right treatment at the right time – by adjusting for the nuances within an individual’s genetic profile, health records, and lifestyle. These cutting edge drug development programs are increasingly offering new opportunities for life-saving therapies. Yet, with these game-changing technologies come novel issues and new regulatory challenges, as FDA’s regulatory standards evolve behind industry innovation.

The state of cell and gene therapies

Teeing up the J.P. Morgan Fireside Chat over milestones and emerging issues related to the regulation of novel precision therapies, Lowell Zeta, Hogan Lovells partner and member of the pharmaceuticals & biotechnology practice, discussed recent safety concerns related to CAR-T therapies and the overall benefit-risk profile, and how FDA’s approval of the first CRISPR gene-editing therapy can be helpful precedent for other gene-edited technologies in the pipeline. Patient access and high price tags for these emerging medicines are key issues. Auchincloss raised concerns over soaring drug prices for regenerative medicines, including gene therapies. Dr. Bryan echoed these concerns, pointing out that “if we get gene therapies that have an impact on common diseases” – as opposed to the current gene therapies that are approved for rare diseases – then the aggregate cost of treating larger patient populations may be an unacceptably high price, unless these innovative medicines become more affordable.

Blake Wilson, Hogan Lovells partner and member of the medical device practice, questioned the quality of the safety data for novel regenerative medicines under the FDA’s Accelerated Approval Pathway. As FDA continues to leverage the expedited pathway beyond oncology, Dr. Bryan said, “I’m not sure that the agency [FDA] has figured out any sort of standardized approach to accelerated approval,” suggesting that there may be increasing variance among product Centers and review divisions over clinical program design, evidence generations, and oversight of confirmatory studies. Given the prevalence of industry noncompliance with confirmatory studies and the length of time it takes FDA to withdraw a failed drug, Auchincloss suggested that FDA may need to reconsider its approach to how products are removed from the market when they are launched under accelerated approval and confirmatory studies do not bear out the results that were anticipated.

In addition, Auchincloss discussed challenges associated with manufacturing compliance and scale-up, given the nature of human cell therapies and potential variability and safety risks, complex sterile manufacturing process, and global supply chain challenges. While patient safety is paramount, strict compliance with current Good Manufacturing Practice (CGMP) requirements during development and scale-up manufacturing is both time-consuming and expensive. In addition, Wilson suggested there are challenges facing sponsors and academic labs in maintaining an adequate sample amount to permit continued testing suitable for comparability analyses.

Asked about how to respond when study results during manufacturing scale-up differ from prior clinical research data, Zeta and Auchincloss outlined strategies and communication mechanisms to engage with FDA on these complex study data questions.

The future of diagnostics for precision medicine

The development and availability of reliable in vitro diagnostic (IVD) tests are critical for precision medicine. Many IVDs are currently offered as laboratory developed tests (LDTs) without FDA approval or clearance under the agency’s long-standing enforcement discretion policy.

Kicking off the panel’s second discussion topic, Auchincloss outlined how FDA’s regulation of LDTs has been under debate for nearly 20 years, noting the agency’s proposed rule would grant the agency explicit authority to regulate LDTs as devices. She predicted that FDA would continue to push towards final rulemaking in April, as the agency generally does not issue significant rulemaking late in an election year and likely will focus on implementation of agency-wide reorganization commitments. Wilson suggested that Congress likely would not pass LDT legislation, especially after several efforts to pass the VALID Act stalled and the retirement of Sen. Richard Burr, one of VALID's most prominent champions.

Wilson outlined how FDA’s LDT proposed rule aims to avoid the pitfalls of the agency’s 2014 attempt to regulate the tests. Auchincloss similarly recounted how FDA’s 2014 proposal to regulate LDTs may have been overly complex and would have resulted in few LDTs being regulated under that proposal due to grandfathering exceptions (which Wilson noted have been omitted from FDA’s new proposed rule). Litigation including a legal challenge under the Administrative Procedure Act (APA) if the rulemaking were finalized, is widely expected. In addition, the likelihood of success for FDA may be affected by a much anticipated U.S. Supreme Court ruling on legal challenges to the doctrine of Chevron deference, affording deference to a federal administrative agency’s interpretation as long as it was reasonable.

FDA priorities in an election year

Discussing changes being made to FDA’s organizational structure this year, Auchincloss spotlighted how it is critical that these changes are being made during an election year. She contrasted the ongoing structural changes with the lack of change that historically occurs after April-ish of an election year, pointing to increasing focus on structural and programmatic changes in FDA’s inspection office, the Office of Regulatory Affairs (ORA).

Historically, Auchincloss said, ORA has collaborated significantly with FDA’s Centers, but under the reorganization ORA will shift to a more singular focus on inspections. Auchincloss expressed concern over the growing divide between Center directors (who are making decisions based on FDA inspections), and the inspectorate, and the loss of value from a checks and balance system, but also spoke of the potential for significantly increased efficiency and streamlined processes after the reorganization. Zeta, with years of on-site experience at manufacturing facilities around the world, shared these concerns saying, “You really have to see [the site] to understand the ins and outs” of the manufacturing process and risk-based compliance approach to determine the adequacy of GMP compliance.

Zeta also cited persistent concern among start-ups with their inability to interact with CBER. Dr. Bryan recalled how there has been “so much growth in cell and gene therapies” that his former office’s February 2023 expansion to become the Office of Therapeutic Products (OTP) “super office” was “absolutely necessary.” He said this large (and still-expanding) size of the super office points to challenges within CBER to craft uniform decisions. However, Dr. Bryan said CBER has demonstrated a close relationship with the Center for Devices and Radiological Health (CDRH) over the years, suggesting collaboration between these Centers may be helpful for those combination product sponsors.

Responding to audience questions on challenges from lack of uniformity between FDA Centers in their decision-making criteria, Auchincloss cited programmatic challenges and culture differences among the product Centers which can hinder cross-agency coordination and strategic planning efforts by sponsors. Zeta recommended early engagement with FDA calling it “essential” to have a productive relationship with the agency. Wilson similarly emphasized the importance of early engagement with FDA, pointing out that when a combination product or IVD developer waits too long to raise an issue with the agency, FDA may be hesitant to grant a consult at such a late stage. The panel concluded with discussion around strategic communication approaches to engage the agency on tricky issues such as innovative data strategies and enabling technologies, combination products development, and complex manufacturing issues, to provide developers with greater assurance and predictability when making critical product development and investment decisions.