The FDA also introduced the Gene Therapies Global (CoGenT Global) Pilot, the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot, and the Rare Disease Endpoint Advancement (RDEA) mechanism for rare diseases; it also discussed the provision of platform technology applications, a clearer definition of accelerated approval for gene therapies (GT), exploration of simultaneous submissions and product reviews with other regulatory agencies, and a communication pilot for rare diseases. This article provides a brief summary and outlook of the training session.

Mission of the Center for Biologics Evaluation and Research (CBER)

The mission of the Center for Biologics Evaluation and Research (CBER) is to ensure the safety, purity, potency, and effectiveness of biological products, including vaccines, allergens, blood and blood products, cells, tissues, and gene therapies, used for the prevention, diagnosis, and treatment of human diseases, emergencies, or injuries. Through CBER's mission, the center also seeks to protect the public from emerging infectious diseases and bioterrorism threats.

In 2023, the FDA established the Super Office of Therapeutic Products (OTP), replacing the previous Office of Tissues and Advanced Therapies (OTAT). It employs a tiered classification management model based on risk levels and categories to ensure the safety and efficacy of cell products while streamlining the review process and improving efficiency. The U.S. has formed a three-tier regulatory framework consisting of laws, regulations, and guidelines to provide comprehensive guidance for the review and approval of cell therapy products. OTP’s offices include: Gene Therapy CMC Office, Cell Therapy and Human Tissue CMC Office, Plasma Protein CMC Office, Clinical Evaluation Office, Pharmacology/Toxicology Office, Review Office Management, and Regulatory Review. The OTP-regulated products are as follows:

• Gene Therapy: Ex vivo genetically modified cells, non-viral vectors (e.g., plasmids), replication-deficient viral vectors (e.g., adenovirus, adeno-associated virus, lentivirus), replication-competent viral vectors (e.g., measles virus, adenovirus, vaccinia virus), microbial vectors (e.g., Listeria, Salmonella).
• Stem Cells and Stem Cell-Derived Products: Hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood, embryonic stem cells, induced pluripotent stem cells (iPSCs).
• Terminally Differentiated Cell Therapies: Islet cells, chondrocytes, myocytes, keratinocytes, hepatocytes.
• Therapeutic Vaccines and Other Antigen-Specific Active Immunotherapies: Cancer vaccines and immunotherapies (e.g., dendritic cells, lymphocyte-based therapies, cancer cell-based therapies, peptides, proteins); non-infectious disease therapeutic vaccines (e.g., peptides, proteins, small molecules).
• Blood and Plasma-Derived Products: Purified and recombinant proteins for hematology (e.g., coagulation factors).
• Xenotransplantation
• Human Tissues
• Certain Devices

The FDA also briefly introduced the history of gene therapy product development and how applicants can communicate with OTP regarding meeting times/types. Additionally, the FDA highlighted that gene therapy is distinct from other medical products, typically involving:

• New technologies to manufacture products
• Invasive procedures for treatment
• Potential long-term effects
• Risks of DNA mutations or rejection by the body

Development of Cell and Gene Therapy Products

1. CMC (Chemistry, Manufacturing, and Controls) Considerations

• Production: Product complexity; early stage: product characterization, mechanism of action (MOA), cell kinetics, and vector biodistribution; later stage: quality and potency; significant pharmaceutical changes may require demonstrating product comparability.
• Extended Biological Activity and Long-Term Follow-Up: Required for product delivery procedures; compatibility of product and device.
• Immunogenicity Monitoring: Off-target effects, including tumorigenicity and insertional mutations.

2. Preclinical Development Considerations

• Animal Models: Scientific justification for model selection, and non-clinical data such as histopathology, which help infer clinical dosage levels.
• Product Kinetics Profile: Cell fate or vector biodistribution.
• Administration Route: Administer as close as possible to clinical settings; time and rate of administration, product activity in the local microenvironment.
• Standard Toxicology Evaluation: Mortality, laboratory observations, weight, gross and tissue pathology, and other endpoints recommended by current guidance documents and ICH guidelines.
• Study Design: Randomized allocation, appropriate controls, blinding, sufficient study duration, and evaluation of product durability.

3. Early-Stage Clinical Development Regulatory Considerations

• Dosing: Preclinical data to guide/support dose (potential toxicity), scientific basis for dose escalation/de-escalation, full description of safety characteristics of feasible doses, delivery devices or routes.
• Safety: Dose-limiting toxicity, follow-up time tailored to specific products, phase-based plans, stopping criteria for individual subjects and entire studies, monitoring immunogenicity, assessing viral vector shedding, and evaluating product durability and long-term effects

4. Regulatory Considerations in the Later Stages of Clinical Development

• Efficacy:
  • Approval of drugs and biologics must be based on substantial evidence of efficacy and safety.
  • Current data shows that the benefits of the product outweigh its risks both at the time of approval and throughout its lifecycle.
  • Certain product developments may be feasible for common diseases, but not for rare diseases. For example:
    • Single-arm studies support regulatory decisions
    • Large magnitude of benefit
    • Well-designed natural history studies may support rapid progression, severe, and rare diseases
  • Any related companion diagnostics or co-developed devices may be provided alongside the product.
  • For serious diseases with unmet medical needs, accelerated programs and other incentives are available.

Accelerated pathways include: Fast Track, Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), Accelerated Approval, and Priority Review. For details, see the video or slides.

The FDA has approved 22 gene therapy products, most of which are for rare diseases. OTP currently oversees over 2,600 active research products. Collaboration and flexibility are crucial in the development of cell and gene therapy products. The FDA has stated that CBER's 2024 priority is the development of products for rare diseases, and reiterated that hundreds of rare genetic and acquired diseases that affect thousands of people annually could be addressed through new gene therapies (GT). Addressing molecular defects may reduce some more common diseases to very rare diseases.

The FDA also envisions future actions by CBER regarding rare disease development, which include:

• Advancing manufacturing technologies for cell and gene therapy (GT) through research
• Application of platform technology provision
• Clearly defining the use of accelerated approval for GT
• Exploring simultaneous submissions and product reviews with other regulatory agencies
• Communication pilot for rare diseases

The FDA provided further explanation about the Global Gene Therapies Cooperation (CoGenT Global) Pilot:

• Initial participation by ICH permanent regulatory members
• Partners can participate in internal regulatory meetings, including those with sponsors
• Regulatory reviews are shared and discussed with partners
• All meetings and information sharing are conducted under strict confidentiality agreements
• The goal is to improve the efficiency of the regulatory process, reducing time and costs for both agencies and sponsors

The FDA particularly emphasized that the goal of the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot is to accelerate the development of products to address unmet medical needs in rare disease treatments.

Selected projects:

• Grace Science LLC: Codon-optimized full-length version of human NGLY1 (GS-100) using recombinant adeno-associated virus (AAV9) vector
• Myrtelle, Inc: Codon-optimized human ASPA cDNA in self-complementary DNA AAV vector (rAAV-Olig001-ASPA)
• Moderna TX: Lipid nanoparticle-encapsulated mRNA encoding human MUT protein (mRNA-3705)
• Neurogene, Inc: Recombinant AAV vector MECP2 gene therapy

The FDA emphasized that RDEA (Rare Disease Endpoint Advancement) provides a mechanism for sponsors to collaborate with the FDA throughout the development of efficacy endpoints, to advance rare disease drug development. Successful applicants may request up to four meetings with the FDA to discuss the development of new endpoints. After completing four RDEA meetings, sponsors may request additional feedback from the FDA through other formal meeting mechanisms, such as B, C, C alternative endpoints, or D class meetings.

In conclusion, gene therapy is a treatment method that uses genetic engineering technology to introduce normal or therapeutic genes into the patient's body to correct or compensate for diseases caused by genetic defects or abnormalities, thus achieving therapeutic effects. The principle is to address the mechanisms of disease by repairing, replacing, or regulating gene expression, offering potential treatments for various difficult-to-treat diseases, especially genetic diseases and some cancers.

Extended Summary

Types of Gene Therapy

• Ex vivo gene therapy: The patient's cells are genetically modified outside the body and then reintroduced into the patient. For example, using lentiviral vectors to introduce normal genes into the patient's hematopoietic stem cells, which are cultured and genetically modified outside the body, and then transplanted back into the patient to treat certain genetic blood disorders.
• In vivo gene therapy: Therapeutic genes are directly introduced into the patient’s body, where they are expressed in specific cells to exert their therapeutic effects. For example, therapeutic genes are injected directly into the patient's eye using an adeno-associated virus (AAV) vector to treat certain genetic eye diseases.

Expanding Applications of Gene Therapy

• Genetic Diseases: Gene therapy offers potential cures for many genetic diseases, such as sickle cell anemia, cystic fibrosis, and Duchenne muscular dystrophy. By correcting defective genes, gene therapy can fundamentally improve the patient's condition, enhancing their quality of life and life expectancy.
• Cancer Treatment: Gene therapy shows vast potential in cancer treatment. On one hand, gene editing techniques can enhance the patient's immune cells' ability to recognize and kill cancer cells, such as CAR-T cell therapy; on the other hand, viral vectors can deliver anti-cancer genes to cancer cells, causing them to express the gene, directly killing cancer cells or inhibiting their proliferation.
• Cardiovascular Diseases: Gene therapy can be used to treat certain cardiovascular diseases, such as myocardial infarction and heart failure. By introducing genes related to angiogenesis, it promotes the formation of new blood vessels in the damaged heart muscle, improving blood supply to the heart and reducing cardiac damage.
• Neurological Diseases: For neurological disorders like Parkinson's disease and Alzheimer's disease, gene therapy holds promise in repairing genetic defects in nerve cells or regulating metabolic pathways in nerve cells, which may slow disease progression and improve the patient's neurological function.

Challenges of Gene Therapy

• Safety Issues: One of the major challenges faced by gene therapy is safety. Viral vectors may trigger immune responses, insertional mutations, and other adverse events. Non-viral vectors have lower gene transfer efficiency and may pose biocompatibility issues. Moreover, off-target effects from gene editing techniques could lead to unintended mutations in non-target genes, bringing potential risks.
• Effectiveness Issues: Although gene therapy has shown preliminary therapeutic effects in some diseases, its long-term stability and effectiveness still need to be improved. Some patients may experience poor treatment results or disease relapse, requiring continuous optimization of the treatment plan and vector systems.
• Ethical and Social Issues: Gene therapy involves altering human genes, which raises numerous ethical and social controversies. For example, germline gene editing may have unpredictable impacts on the human gene pool, leading to ethical dilemmas such as "designer babies." The high cost of gene therapy may also result in unequal distribution of healthcare resources, exacerbating social inequality.

Outlook

• Technological Advances: With ongoing improvements in gene editing technologies, the development of new gene vectors, and the maturation of gene expression regulation techniques, the safety and efficacy of gene therapy are expected to significantly improve. For instance, more precise gene editing tools can be developed to reduce off-target effects, and safer, more efficient gene vectors can be created to improve gene transfer efficiency and targeting.
• Clinical Application Expansion: In the future, gene therapy is expected to make breakthroughs in more disease areas, offering hope to more patients. As gene therapy technology continues to evolve and clinical applications accumulate, treatment plans will become more personalized and precise, allowing for the development of optimal treatment strategies based on patients' specific conditions and genetic profiles.
• Policy Support and Regulatory Improvement: Governments and relevant organizations worldwide will increase support for gene therapy research, implementing more scientific and reasonable policies and regulatory measures to promote the healthy development of gene therapy technologies. This will help standardize the clinical application of gene therapy, protect patient safety and rights, and drive the sustainable development of the gene therapy industry.