In the evolving cell and gene therapy sector, regulatory frameworks strive to keep pace with rapid advancements in development and manufacturing technologies and treatment approaches. The current guidelines, especially for viral vector production, remain a patchwork of broader biopharmaceutical regulations, necessitating a nuanced interpretation by manufacturers, who must adapt their quality systems to ensure safety and efficacy. Regulatory maturity in this sector mirrors the lengthy journey of monoclonal antibodies, which required decades of collaborative efforts between industry stakeholders and regulators to establish. The FDA has been proactive in issuing high-level guidance that balances the need for direction and manufacturing flexibility, while harmonization efforts continue internationally. As the industry progresses, it is crucial that emerging regulations foster innovation without sacrificing patient safety and that they are clear and adaptable enough to meet the diverse needs of therapies in development. For cell and gene therapy developers aiming to advance their novel therapies while navigating this regulatory complexity, a manufacturing partner who is well versed in the existing regulations — and has a strong understanding of the sensibility of regulators to anticipate expectations where details have not yet been defined — can be critical to success.
Navigating the Frontier of Biomedical Innovation: The Cell and Gene Therapy Explosion
The cell and gene therapy sector represents the forefront of biomedical innovation –– a burgeoning field that promises to revolutionize the way we treat disease. Over the past five years, the landscape has undergone clear shifts as regulatory bodies adapt to the rapid pace of scientific advancement. Despite these strides, the field remains in its formative stages, marked by a pressing need to fully understand the in vivo activity of these novel therapies and their therapeutic consequences.
With each therapeutic candidate progressing through pivotal first-in-human trials and onward toward Biologics License Application (BLA) filings, the intricacies of regulation grow more pronounced. This expansion is reflected in the guidelines that the U.S. Food and Drug Administration (FDA) has issued, driven by the growing numbers of cell and gene therapies seeking approval and the industry’s need to prepare for regulatory scrutiny. The trend suggests a future rich with regulatory refinement as the discipline flourishes.
The FDA has predominantly concentrated on the clinical trial spectrum in their guidance, with the manufacture of viral vectors receiving less direct attention. This lack of targeted guidance is felt acutely as the diversity of vectors, especially those subjected to complex engineering, expand in advanced therapeutic trials. Leveraging existing frameworks for finished products provides some direction, but the absence of explicit standards means that safety assurance falls heavily on manufacturers. This is a complex endeavor for contract development and manufacturing organizations (CDMOs), who must navigate a mosaic of client expectations and a variety of interpretations of the insufficiently detailed existing regulations.
While the roadmap for adeno-associated viral (AAV) vector production has been relatively well established, a unified guidance detailing explicit requirements for all types of vectors — including retroviral (RV) and lentiviral (LV) vectors — is essential. Standardizing expectations would not only clarify the regulatory pathway but could also expedite the journey of these cutting-edge therapies from conception to clinical reality.
Challenges with Evolving Tech
The continual introduction of improved technologies for the manufacture and analysis of cell and gene therapies is a double-edged sword that further complicates regulatory compliance. While new technologies promise enhanced efficacy and precision, they also introduce a complex layer to regulatory adherence. CDMOs like Genezen typically seek newer technologies and to be at the forefront of technology innovation. However, that commitment presents unique challenges, particularly when transitioning programs that were initiated using older technologies and methodologies. When these programs are transferred in, the ensuing data differences must be addressed by conducting bridging studies to clearly demonstrate the comparability of the product produced using both the old and newer technologies. Such diligence is crucial in demonstrating to regulatory agencies that, despite the evolution of technology, the core therapeutic value remains consistent and reliable.
Regulatory Differences for Raw Material and Drug Substance Vectors
Whether a viral vector is used for in vivo gene therapies or to modify cells ex vivo has thus far been the fundamental determinant of the level of regulation guidance that has been issued. AAV vectors are largely used for in vivo therapies and thus are considered drug substances formulated into drug products. RV and LV vectors, meanwhile, have largely been used for ex vivo cell modification, and as such are considered critical starting materials / drug substances.
It is natural that products being administered directly to patients require more regulatory scrutiny. The same is true in conventional biologic and small molecule manufacturing. Critical raw materials must meet minimum requirements, drug substances receive additional scrutiny, and drug products are the most heavily regulated, as they are directly administered to patients. Cells modified ex vivo with LV or RV vectors in the manufacturing plant undergo various clarification and purification processes, at the end of which most concerns associated with the vectors have been resolved.
The Replication Competence Issue
A crucial regulatory mandate for RV vectors used in cell and gene therapies is ensuring that they are devoid of their natural replication ability. Engineered vectors must be demonstrably replication-incompetent to preclude any risk of proliferation within the body. This stringent requirement has tempered the widespread adoption of RV vectors in gene-modified cell therapy production. Genezen has scientists with extensive experience developing and performing the required assays for detecting the presence of replication-competent viruses and is thus well positioned to guide clients through the complexities of employing RV vectors, ensuring regulatory compliance, and advancing therapeutic innovation.
Reaching Full Regulatory Maturity Will Take Time
Regulatory maturity is only reached once a deep understanding of both manufacturing processes and clinical behavior and performance is realized. For monoclonal antibodies (mAbs), it took the industry about three decades to reach that point. A similar timeline can be expected for cell and gene therapies and the associated regulatory landscape.
As the industry makes advances in product designs and manufacturing and formulation technologies, it takes time for regulators to learn how these changes will affect the behavior of the new therapies and to determine what regulations should be put in place. In addition, regulatory authorities remain very cautious because these treatments involve patient cells and genes, which is quite different from a small molecule drug that adjusts blood pressure. Fully understanding how these treatments affect different individuals is going to take longer than would be required for simpler therapies.
It is also worth noting that progress in the cell and gene therapy field from the perspectives of both product development and regulatory science was impacted by the COVID-19 pandemic. Access to needed materials was limited for developers, while regulators shifted much of their focus to evaluating novel vaccines and therapeutics against the SARS-CoV-2 virus. With the pandemic behind us, the shift toward cell and gene therapies that had begun before its emergence is picking up pace, and the focus of regulatory authorities is shifting as well.
The Imperative of Robust Quality Systems
To assure the safety and quality of cell and gene therapy products, it is essential for any manufacturer, whether a biopharmaceutical company or CDMO, to implement robust quality systems. Ensuring the safety and efficacy of these therapies requires systems that can meet not only current regulatory and client needs but also anticipate future standards, and CDMOs do so with a view to supporting the full range of possible clients, from emerging pharma and biotech firms to large, international biopharmaceutical companies, for the manufacture of critical raw materials, drug substances, and drug products.
Genezen’s approach has been to ensure that our quality systems meet the expectations from clients and foresee as much as is possible the future expectations of regulatory authorities. As such, our quality system initially supported clinical manufacture of RV and LV vectors. It has successfully been extended to AAV vectors as well through the additional visual inspection and other final drug product–specific capabilities. As our clients progress towards market approval, our comprehensive and adaptable quality systems stand ready to support their commercial manufacturing ambitions. Moreover, for startups primarily versed in R&D, we offer invaluable guidance on Good Manufacturing Practice (cGMP) standards, fostering a culture of excellence and compliance.
Recent FDA Guidances
Even if a CDMO is focused on process development and manufacturing and does not support clinical trial design, implementation, or management, it is still important for regulatory experts to understand regulatory guidance regarding clinical studies. To act as true partners for their clients, particularly younger biopharma companies new to the regulatory approval process, CDMOs that provide preclinical and clinical manufacturing services must be knowledgeable about regulatory expectations for the materials used in those studies.
While the limited guidance covering the manufacture of viral vectors has been around for a while (Recommendations for Microbial Vectors used for Gene Therapy (September 2016); Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products (August 2015); Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products (March 2015); and Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013)), the FDA has been actively issuing new guidances pertaining to clinical trials.
These newer guidances include Human Gene Therapy for Rare Diseases (January 2020), Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations (September 2021), Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial (November 2022), Human Gene Therapy for Neurodegenerative Diseases (October 2022), and Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products (January 2024).
Some of these guidances, such as the one focused on neurodegenerative diseases, open pathways for cell and gene therapy developers and provide them confidence in their ability to prove clinical performance to regulators, which will likely trigger the development of more treatments for these types of diseases.
The guidance on CAR-T cell therapy is equally important. It is now finalized, removing many of the previous uncertainties faced by developers. It also includes some specific requirements for the viral vectors used to produce CAR-T cell therapies, which are beneficial for manufacturers as well. That a guidance for these therapies has been issued reflects the fact that these treatments are better established than most others in the wider cell and gene therapy field.
The most recent draft guidance on Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products, which was issued in July 2023, does impact viral vector manufacturers. Specifically, this document outlines the types of data needed to demonstrate comparability when making a process change. It is particularly important for CDMOs such as Genezen, where cutting-edge technology platforms often introduce enhancements beyond the original processes of our clients. Clarification of what data are needed to justify such manufacturing changes is therefore highly relevant.
Genezen prides itself on being thoroughly informed of the latest regulatory updates. Our commitment to regulatory compliance is more than procedural—it’s about partnership. We align closely with our clients’ ambitions to pioneer cell and gene therapies, dedicating ourselves to the collective goal of advancing treatments that hold the promise to transform patient care and outcomes.
More Regulatory Actions Anticipated
The key to successful pharmaceutical industry regulation is to provide appropriate guidance with appropriate regulatory requirements. It is difficult for manufacturers if sufficient guidance is lacking, as that often means deciphering which aspects of all other existing regulations may be potentially applicable — a massive undertaking. It is equally challenging if too much guidance and requirements must be followed, as that prevents flexibility and innovation, which are both essential to the effective performance of CDMO services. The middle ground is best.
In the case of viral vectors, there's a pressing need for more precise guidelines that clarify which existing regulations apply and what the FDA and other regulatory authorities intend in the context of viral vector manufacturing, a task that is currently as challenging as it is critical, requiring seasoned expertise for accurate interpretation. While the EU has taken a stricter stance in its most recent Annex, efforts toward regulatory harmonization are ongoing, including a mutual recognition program that promises more alignment in the future. After all, the fundamental goal for all is to make sure patients are safe.
As the sector grows and cell and gene therapies advance through clinical trials, we expect more comprehensive guidance to emerge. There is also the possibility that the FDA, following the EU's lead, may revise longstanding underlying regulations to better fit modern advancements. To navigate these changes, continuous dialogue and collaboration within the industry and with regulatory bodies are paramount. Together, we can forge a regulatory environment that safeguards patient health while fostering the development of transformative therapies.
