Regulatory Perspectives For CGT Development: Continued Need For Standards And Perseverance

By Jiwen Zhang, Ph.D., SVP, Regulatory Affairs and Quality Assurance at Renovacor, Inc.

Disclaimer: The views, thoughts, and opinions expressed in this article belong solely to the author, and shall not be attributable to the author's employer, organization, any committee of which the author is a member, or any other group or individual.

A year ago, when I wrote the article for Cell & Gene titled, “COVID-19 and Beyond: Perspectives from a Regulatory Affairs Professional,” we were in the thick of the COVID-19 pandemic but were hoping that vaccines and antiviral treatments would give us a fresh start in 2021. A year later, the rapid spread of new variants and surge of cases has made me feel utterly frustrated and unsettled, wondering, “when is this pandemic going to end so we can truly go back to normal and accelerate drug development?” Then in December, the ISO Technical Specification document on cell manufacturing equipment was published (ISO - ISO/TS 23565:2021 - Biotechnology — Bioprocessing — General requirements and considerations for equipment systems used in the manufacturing of cells for therapeutic use), it made me pause and reflect.

The publication of this standard document has been 10 years in the making (New SCB Coordinated Standards Published — Standards Coordinating Body). Back in 2011, there was no such standard. There wasn’t even clarity on how exactly cell processing equipment should be regulated. Regulations for cell and gene therapies were fragmented globally. Some countries required cell processing equipment and materials registered and approved as medical devices, posing significant challenges to adopting innovative tools into the cell therapy manufacturing workflow. At an FDA conference in early 2011, I asked colleagues from the Office of Tissues and Advanced Therapies (OTAT, or OCTGT back then), “how is equipment regulated?” In response, an OTAT colleague clarified by stating that if cell therapy products are regulated as drugs and the equipment is used in processing these drug products, such equipment is not a medical device but just manufacturing equipment. Manufacturing equipment does not need to be regulated as a medical device to ensure its safety or perform as intended. Standards can achieve that goal. In that same year, OTAT and the Alliance for Regenerative Medicine (ARM) started collaborating to identify and develop standards for cell and gene product development. Working together with an exceptionally passionate group of colleagues in the cell and gene space, I began a journey to advocate for suitable regulations for advanced therapies and developing standards for manufacturing tools, such as equipment and ancillary materials for cell and gene therapy products. With tremendous support from the National Institute of Standards and Technology (NIST), FDA, and in collaboration with experts from Japan, the UK, and other countries, the International Standards Organization Biotechnology Technical Committee (ISO/TC 276) was established in 2014 with initial standard project proposals including cell manufacturing equipment and ancillary materials. The formation of the Standards Coordinating Body (SCB) in 2016 and funding from the FDA in 2017 under the 21^st Century Cures Act further boosted the advancement of standards development. In 2018, the three-part Technical Specification (TS) documents on ancillary materials were published (ISO - ISO/DIS 20399 - Biotechnology — Ancillary materials present during the production of cellular therapeutic products and gene therapy products). Three years later, the TS document for cell manufacturing equipment had also arrived.

When equipment and ancillary material projects were first proposed at ISO/TC 276 in 2014, it was healthily debated if the cell and gene space was ready for such standards, or if standards would stifle innovation. Fast forward to 2021, the lack of standards was specifically called out numerous times at the FDA’s Toxicity Risks of Adeno-associated Virus (AAV) Vectors for Gene Therapy Advisory Committee in September 2021. The AdCom meeting was valuable to the AAV gene therapy field for providing a comprehensive review of AAV toxicities to monitor and manage. Though the meeting was focused on toxicities and clinical management, the FDA did raise questions to the expert panel regarding quality issues of AAV products. The FDA raised specific concerns over AAV product impurity, such as co-packaged non-vector from manufacturing process, and empty capsids. The FDA asked the expert panel if there should be upper thresholds on the total vector dose and empty capsids. Unfortunately, due to lack of measurement standards, limited knowledge and experiences, the expert panel did not believe the field was ready to set such limits.

The Need for Standards in Implementation

The need for standards not only lies in the identification and development of standards, but also in implementation. In November 2021, the FDA released the draft guidance titled, “Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products.” The draft guidance document provided considerations when using registry data for regulatory decision making. For gene therapy products targeting rare genetic diseases, these considerations can be quite challenging: patient numbers are significantly small, natural history data are scarce, pathological conditions progress rapidly. It is difficult to identify patients to enroll into a registry in the first place, making it more difficult to construct a robust data set with accuracy, completeness, provenance, and traceability. However, scientific integrity and patients’ welfare demands that the clinical data be reliable for regulatory decision making. Data quality should not be comprised because of feasibility challenges. It is imperative that all stakeholders, including researchers, patients, and regulators work together to identify pragmatic solutions to meet these data requirement standards.

Standards development has come a long way, and it has been an essential part of the journey in advancement of the cell and gene therapy field. In the last decade, there have been ups and downs and stagnation. However, with passion and perseverance, cell and gene colleagues have made remarkable progresses. ISO/TC 276 alone has published 39 document standards since its inception in 2014. Other organizations have also published numerous valuable standards. The SCB prepared a report on the standards landscape in 2017,  most recently updated in Fall 2020 (The Regenerative Medicine Standards Landscape (squarespace.com)). SCB is also working with experts on an impressive list of standards projects (Project Working Groups — Standards Coordinating Body).

Working together is key to tackle the issues and challenges associated with innovative science and technologies, such as cell and gene therapies. The 2021 September FDA AdCom meeting was a great example of recent accomplishments made in the field, where they characterized AAV associated toxicities collectively so that all the sponsors can leverage the understanding and approach with their respective product development.

Clearly, there are still a lot of unknowns and uncertainties when it comes to AAV associated toxicities. What is the optimal monitoring and management strategy for liver and neural toxicities? Can AAV field leverage the experiences in the CAR-T space on managing cytokine release syndrome (CRS) to design how to monitor and manage thrombotic microangiopathy (TMA)?  How can we improve full AAV capsid content during production to reduce toxicity risks? As frustrating as the pandemic has been, the cell and gene therapy field is working tirelessly to forge ahead in effort to answer these questions, address challenges, and realize the promises of the cell and gene therapy products and deliver the transformative medicines to patients.