Magazine Article | November 27, 2019

Challenges Facing The Cell And Gene Sector's Regulation Landscape

Source: Life Science Leader

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In 2018, the FDA issued six draft guidance documents for cell and gene therapy products.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 regulation landscape and what industry professionals should do to meet requirements.

Zhang says that beyond the U.S., EU, and Japan, other areas of the world, including Canada, Australia, and South Korea, already have regulatory framework guidance documents focused on cell and gene therapies. 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 2018 in the EU. Kymriah also has received approval in Australia and an additional indication in the U.S. RECELL, by Avita, received approval in the U.S. in 2018. 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.

“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.”


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 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 can keep up. She notes that while the first CAR-T products only received regulatory approval in 2017, the next generation of CAR-Ts is already being discussed and explored. “It is fascinating to watch the ingenuity of molecular engineering to attempt to refine CAR-T 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.”


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. “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 challenges, be comfortable with ambiguity and uncertainty, and stick to fundamentals and principles of regulatory frameworks, but be prepared for evolving regulatory thinking and specific regulatory requirements associated with product development.”

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


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. “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 the regulatory path for successful product development and commercialization.”


Regulators are open to 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 dialogue with the FDA should be fully leveraged when possible. Furthermore, you should plan and initiate frequent dialogues with regulators during development to seek clarity and input on development.

"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 development to facilitate product development, reduce cost, and enable global development and approval."

Dr. Jiwen Zhang, VP, Passage Bio

Zhang suggests employing innovative clinical trial designs, such as those explored in the NEJM article by Scott Gottlieb and Peter Marks, ”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). The FDA also plans to issue a draft guidance on interacting with the FDA on complex and innovative clinical trial designs for drugs and biological products.

Using real-world data (RWD) and real-world evidence (RWE), as well as newer technogies such as genomic sequencing, can increase the likelihood of success in cell and gene product development. Zhang adds that development and adoption of standards also will help advancement, as will stakeholder engagement and collaborations. “Alliance groups, public-private partnerships, and consortia on various initiatives are all making progress and contributing to the sector’s growth. Patient advocacy groups, in particular, are integral to helping with therapy development, patient care and management, and ultimately patient access to innovative treatment for unmet needs.”


In the coming years, patients who may have exhausted all of 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 2020 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 regarding the durability of treatment effect and potential risks. Therefore, there are regulatory requirements related to long-term follow-up. ”

Zhang stresses that industry professionals should continue to investigate and adopt new manufacturing and analytical technologies that will impact cell and gene therapy development and adoption. And, there is an ongoing need for continued dialogue with both individual sponsors and consortia on key topics for advancement of RWE and master protocol.