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Gene and cell therapy have moved from the realm of science fiction to medical reality. These new therapies have the potential to permanently correct genetic disorders with a single administration.

But for the potential of gene and cell therapy to be fully realized, all sectors of the health care system need to work together.

Orchard Therapeutics is a company whose vision is to end the devastation caused by genetic and other severe diseases by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. To make this happen, a regulatory framework with the capacity and technical ability to assess these technologies in a timely way is needed.

Every five years, Congress considers legislation that extends the Prescription Drug User Fee Act (PDUFA) and similar laws that provide the Food and Drug Administration (FDA) with funding for its regulation and evaluation of new therapies. The latest iteration, PDUFA VII, will be considered in 2022, and the FDA’s recent PDUFA VII commitment letter puts the regulatory framework for gene and cell therapies front and center.

The 2022 PDUFA legislation will provide an opportunity to assure that staffing and policies at the FDA are maximally supportive of advancing gene and cell therapy development and timely regulatory assessment. In the PDUFA VII commitment letter, several provisions would provide for the efficient development and regulatory review of gene and cell therapies.

Upward of 60 gene and cell therapies are projected to reach regulatory approval in the U.S. by 2030, according to the MIT NEWDIGS collaborative. Now is the time to ensure that regulatory systems have the capacity necessary to accommodate the coming wave of cell and gene therapies.

Increased staff resources at CBER

A key challenge is not only the level of staffing needed, but also the extraordinarily high level of knowledge and understanding required for gene and cell therapy development. It takes years for medical and scientific experts to develop this knowledge. The FDA not only needs more people focused on gene and cell therapy, but also people with specific knowledge of the field.

The FDA’s PDUFA VII commitments would nearly triple staff for the Center for Biologics Evaluation and Research (CBER). This new staff would offer increased capacity and expertise to evaluate the influx of new gene therapy candidates approaching regulatory review. One specific hope for the increased staffing resources is that CBER would opt for more face-to-face meetings to discuss time-sensitive clinical development issues. As the gene therapy clinical development pathway continues to evolve, there will be more complex and never-before discussed topics that will often need immediate attention so as not to unnecessarily slow down the clinical development process. Direct and interactive meetings that can be scheduled more quickly would be more efficient and productive for CBER and the sponsor. 

Expanded use of real-world evidence

To date, real-world evidence (RWE) has not been consistently utilized in the clinical development and regulatory review process. But given the small patient population sizes of most of the conditions that gene therapies aim to treat, the use of RWE is essential.

The appropriate use of RWE could be leveraged to bolster the data supporting applications, including new indications or post-approval studies. FDA has long demanded placebo-controlled trials for new therapies, but increased acceptability and confidence in reliable RWE could provide sufficient basis for moving forward with therapies in lieu of placebo-controlled studies, especially in situations where the course of disease is rapidly progressive, irreversible and ultimately fatal.

In its commitment letter, the FDA has indicated its intention to “explore the use of real-world evidence for use in regulatory decision-making,” signaling a growing appreciation for the complexities of rare disease development. The agency should continue to partner with sponsors, patients, providers, and other stakeholders to determine how to better utilize RWE to bring needed therapies to patients as expeditiously as possible. 

New rare disease pilot program

Increased communication with the FDA on the development of efficacy endpoints is critical, particularly for genetic and other severe diseases — many of which are rare or ultra-rare. Navigating the clinical development pathway for a new therapy for an ultra-rare patient population is highly challenging, with some trials having fewer than 20 patients. Sponsors often need ongoing guidance from the experts at FDA whose evaluation of the data will ultimately determine the fate of the therapy. Multiple communications are needed to explore endpoints under consideration, but this has not always been possible.

With the Rare Disease Endpoint Advancement Pilot Program being proposed in PDUFA VII, sponsors will have the opportunity to submit a proposal for additional novel endpoints before or during a new drug application. The agency will then select a limited number of qualified proposals for admission into the pilot program. This pilot program could be an opportunity for validating endpoints which may have utility across multiple rare diseases and could help pave the way for clinical development and regulatory reviews that best meet the needs of people living with rare diseases.

CMC guidance

Given the foundational importance of manufacturing processes in the development and delivery of gene therapies, the FDA’s proposed increases to Chemistry, Manufacturing and Controls (CMC) guidance, public workshops and lessons learned would be welcomed steps toward better collaboration between FDA and sponsors. The agency acknowledged in its commitment letter that gene therapies with “accelerated clinical development activities often face challenges in expediting CMC development activities to align with the accelerated clinical timelines.” Meeting patient access goals of an accelerated program usually requires multiple and prompt interactions with CBER to ensure CMC keeps pace with the clinical development program.

As part of its commitment to promote the development of cell and gene therapies, the FDA plans to issue FAQs to disseminate policy guidance more rapidly. This would offer a flexible and expedited process and will better accommodate the rapidly changing and growing field of gene therapy with a hopeful appreciation for science and risk-based regulatory approaches.

An eye toward the future

Upward of 60 gene and cell therapies are projected to reach regulatory approval in the U.S. by 2030, according to the MIT NEWDIGS collaborative. Now is the time to ensure that regulatory systems have the capacity necessary to accommodate the coming wave of cell and gene therapies, as well as the notable attention that rare disease drug development requires —particularly in ultra-rare pediatric conditions where the medical needs are incredibly high. The PDUFA VII commitment letter and the reauthorization process come at a time when the opportunity is ripe for regulatory review to keep pace with gene therapy innovations and to enable the efficient development and prompt review of these therapies for patients.

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