From The Editor | December 9, 2019

Challenges, Short-Term Outlook Facing the Cell and Gene Sector's Regulatory Landscape


By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1


In 2018, the FDA issued six draft guidance documents for cell and gene therapy products. In February 2019, two additional guidance documents were issued. To say the sector’s regulators are moving quickly yet judiciously to craft essential regulations is an understatement. I caught up with Dr. Jiwen Zhang, VP, regulatory affairs at Passage Bio to gain a better understanding of just how rapidly regulators must move to keep pace with the sector’s ever-evolving regulatory landscape and what industry professionals should do to stay ahead of the curve.

Zhang says that beyond the U.S., E.U., and Japan, other areas of the world, including Canada, Australia, and South Korea already have regulatory framework and guidance documents focused on cell and gene therapies in place, as well. Other countries, including Singapore, Philippines, Malaysia, Taiwan, Russia, and Brazil, have released — or are close to releasing — regulations.

She notes other factors impacting the regulatory landscape stem from the industry’s activities. After Kymriah (Novartis), Yescarta (Gilead), and Luxturna (Spark) were approved in the U.S. in 2017, they were subsequently approved in the E.U in 2018. Kymriah also has received approval in Australia and additional indication in the U.S. 2019 has seen the approval of Zolgensma (Novartis) in the US, a gene therapy to treat a rare genetic pediatric disease, spinal muscular atrophy (SMA) and Zynteglo (Bluebird) in the EU for the treatment of transfusion-dependent β-thalassemia (TDT). Meanwhile, a significant number of cell and gene products are under development with close to 100 in late-stage development based on ARM’s industry briefing released earlier this year. In a January 2019 statement by the former FDA commissioner Dr. Scott Gottlieb and CBER Office Director Dr. Peter Marks, by 2020, the FDA anticipates it will receive more than 200 IND applications per year. By 2025, 10 to 20 cell and gene therapy products will be approved annually.

Further, “New technologies are evolving that can help improve cell and gene product development and manufacturing — particularly manufacturing technologies that can help with productivity, consistency, and analytical technologies to ensure product quality and testing accuracy,” states Zhang. “All these efforts lead to knowledge and experiences, which will help with a regulator’s comfort level with cell and gene products, progressing regulatory standards.”

Challenges Facing the Regulatory Outlook

From policy and regulation to regulatory requirements and new data triggering new sets of questions to address during development means unpredictability from regulators, which results in uncertainty for cell and gene developers. “For example, in 2018, two studies published in Nature Medicine raised potential concerns of cancer risks associated with CRISPR gene editing,” explains Zhang. “With CRISPR technology still being relatively new, it is difficult to discern how these theoretical concerns should be addressed during development for products utilizing CRISPR and how regulators may or may not request additional data to mitigate such potential risks.”

Zhang explains that the science and technology associated with cell and gene therapies are advancing faster than regulators have become accustomed to. She notes that while the first CAR-T products only received regulatory approval in 2017, the next generation of CAR-Ts are already being explored. The same is happening with the AAV based gene therapy technologies. “It is fascinating to watch the ingenuity of molecular engineering to attempt to refine cell and gene products to further improve their safety and efficacy,” she says. “On the flip side, new technologies and product platforms implicate new uncharted regulatory paths for product development and approval.”

How Regulatory Experts Plan to Overcome These Challenges

In order to overcome these challenges, it’s imperative to keep up with new regulations and guidances. She advises sector professionals to research recent approvals and agency-review documents that showcase regulators’ current thinking, making regulatory guidance more meaningful and digestible. In addition, “keep up with science and technology advancement, monitor research publications that may raise new questions or shed new light on existing issues, stay current with new technologies that will help address manufacturing and testing challenges but may also pose development and regulatory hurdles; be comfortable with ambiguity and uncertainty, and stick to fundamentals and principles of regulatory framework but be prepared for evolving regulatory thinking and specific regulatory requirements associated with product development.”

Zhang recommends joining industry and professional groups, learning from peers, and contributing to the collective knowledge and experiences that will benefit the whole field.

The Near-Term Outlook for the Regulatory Landscape

With more countries establishing regulatory frameworks for cell and gene products, clinical studies can be conducted in more countries and regions to help accelerate development, which also drives the need for regulatory convergence, particularly, convergence in regulatory requirements and standards. “Led by the U.S. with federal funding and support for standards development embodied by the Standards Coordinating Body, regulatory and technical standards will be developed to facilitate product development, reduce cost, and enable global development and approval,” states Zhang. “All these advancements will drive the sector’s growth as well as help define the regulatory landscape and expectations for successful product development and commercialization.”

Key Regulatory Actions for Industry

Regulators are open and willing to help cell and gene innovators bring these therapies to patients. Specific regulatory mechanisms such as the RMAT (regenerative medicine advanced therapy) designation in the U.S. and INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER products) meetings for early dialogues with the FDA should be fully leveraged when possible to seek clarity and feedback on development.

Zhang suggests employing innovative clinical trial designs such as those explored in the NEJM article by Peter Marks and Scott Gottlieb, “Balancing Safety and Innovation for Cell-Based Regenerative Medicine.” There are several FDA guidance documents that discuss novel clinical trial designs, including those on expansion cohorts (“Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry”, August, 2018) and master protocols (“Master Protocols: Efficient Clinical Trial Design Strategies To Expedite Development of Oncology Drugs and Biologics”, March, 2019). In September 2019, the FDA also issued a draft guidance, “Interacting with the FDA on complex and innovative clinical trial designs for drugs and biological products.” Also, using real-world data (RWD) and real-world evidence (RWE), will be gaining more ground for successful cell and gene product development.

The Patient Perspective

In the coming years, patients who may have exhausted all their treatment options will likely see many new opportunities in the form of cell and gene therapies.  According to Zhang, this increase in cell and gene products will be particularly meaningful for children because more than half of the cell and gene products in development are for rare diseases — and more than half of rare diseases affect children. “Currently at Passage Bio, two out of three development programs are for pediatric patients,” explains Zhang. “In the future we plan to initiate clinical trials for a program focused on patients with the infantile type of GM1 gangliosidosis, which is the most common and severe form of the disease. However, it is important to keep in mind that even for approved products, long-term data is still being collected to demonstrate the durability of treatment effect and monitor any potential risks. Therefore, there are regulatory requirements related to long-term follow-up.”

On the manufacturing front, Zhang stresses that industry professionals should continue to investigate and adopt new manufacturing and analytical technologies that will impact cell and gene therapy production and delivery. And, there is an ongoing need for continued dialogue between regulators with individual sponsors and consortia for the advancement of scientific and technological solutions.”