Neurodegenerative diseases are a diverse group of disorders characterized by the progressive degeneration of the central or peripheral nervous system, and they can have various causes and clinical characteristics. This guidance document is a resource for sponsors on different aspects of product development, preclinical testing, and clinical trial design. It acknowledges the unique challenges and considerations associated with developing GT products for such complex and varied diseases. Below are the key summaries from the guidance.
CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS (CMC)
The considerations for Chemistry, Manufacturing, and Controls (CMC) when developing gene therapy (GT) products for the treatment of neurodegenerative diseases are crucial for ensuring the safety and efficacy of these advanced therapies. Here, we will elaborate on the specific CMC considerations outlined in your text:
Route of Administration and Product Volume:
Neurodegenerative diseases often require the delivery of GT products to the brain or spinal cord. The unique challenges associated with these routes of administration, such as limited access and reduced clearance, must be considered during product development. Additionally, the volume of product that can be administered safely to these sites is a critical CMC parameter.
Delivery Device Compatibility:
When a device is used to deliver the investigational product, it is essential to demonstrate the compatibility of the product with the delivery device. This includes assessing whether the device affects the product's strength, potency, or impurity levels. Compatibility studies should be conducted with the final formulated product intended for clinical use, simulating conditions planned for the clinical study.
Critical Quality Attributes (CQAs):
CQAs are characteristics of an investigational drug product that impact its safety, efficacy, and consistency. In the context of GT products for neurodegenerative diseases, CQAs include factors related to purity, identity, potency, and strength.
- Purity Assessment: This involves evaluating residual product-related impurities (e.g., incomplete viral particles, cellular subtypes) and process-related impurities (e.g., host cell proteins, host cell DNA, endotoxin). For viral vector-based products, assessing empty and wild-type viral particles, as well as replication-competent viruses, is crucial. Minimizing host cell protein and host cell DNA levels is essential to avoid unwanted immunogenic reactions.
- Identity: Establishing the identity of the drug product before initiating nonclinical studies is vital. This ensures that the product used in studies aligns with the intended investigational product.
- Potency Assays: Potency assays are critical to assessing the functional activity, consistency, and stability of the product. GT products designed for neurodegenerative diseases may have multiple modes of action, necessitating the evaluation of multiple product characteristics to establish a potency matrix. A qualified potency test that measures relevant biological activities should be in place before initiating clinical trials.
- Strength: Product strength is another important CQA. It should be carefully measured and evaluated, especially for GT vectors expected to maintain biological activity over a long period. Evaluating product strength requires a qualified assay to ensure accuracy, precision, sensitivity, and specificity.
Process Control and Manufacturing Changes:
Sponsors should demonstrate process control to ensure consistent product quality with predefined CQAs. Any manufacturing process changes should be evaluated for their impact on CQAs. A risk analysis and, if necessary, a comparability study should be conducted before implementing changes. Sufficient samples should be retained for potential retrospective analysis.
Plasmid Contamination Considerations:
For GT products based on viral vectors (e.g., adeno-associated virus (AAV)), plasmids used to generate these vectors must meet acceptable purity limits. Manufacturing controls should prevent cross-contamination of plasmids, especially in multi-product manufacturing facilities.
Early Engagement with FDA:
FDA encourages sponsors to engage with the agency early in the drug development process, such as at the pre-investigational new drug application (pre-IND) meeting. Continuous collaboration with FDA can help prevent delays related to manufacturing changes introduced at various stages of product development.
Consideration of Unintended Immune Responses:
GT products may induce unintended immune responses against host cells, potentially leading to latent infections or unwanted gene expression. It is recommended that GT products be designed to reduce such immune responses and avoid the inclusion of foreign genes that do not contribute to the product's biological function.
Product Characterization Studies:
Assays for evaluating product quality attributes should be implemented early in product development and qualified as suitable. These assays should be accurate, precise, sensitive, and specific.
Discussion with FDA:
Sponsors developing GT products for neurodegenerative diseases are strongly encouraged to engage with the FDA's Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) to discuss product-specific considerations, including design, purity, and other relevant factors.
CONSIDERATIONS FOR CLINICAL TRIALS
The development of gene therapy (GT) products for the treatment of neurodegenerative diseases requires a carefully tailored preclinical program to establish the safety and efficacy of these therapies. The key objectives of such a program include identifying biologically active dose ranges, determining initial clinical dosing levels and regimens, ensuring the safety of the proposed route of administration, defining patient eligibility criteria, and identifying potential toxicities. Here are the recommended elements for a preclinical program specific to investigational GT products for neurodegenerative diseases:
Proof-of-Concept Studies:
- Conduct preclinical in vitro and in vivo proof-of-concept (POC) studies to establish the feasibility and scientific rationale for administering the investigational GT product in clinical trials. These studies can guide the design of subsequent preclinical toxicology studies and early-phase clinical trials.
- Utilize animal models of neurodegenerative disorders that closely mimic human responses to assess disease relevance, identify risks, and identify potential biomarkers for clinical trial monitoring.
Biodistribution Studies:
- Perform biodistribution studies to assess the distribution, persistence, and clearance of the viral vector and, if applicable, the expressed transgene product. This analysis should cover target and non-target tissues, including biofluids such as blood and cerebrospinal fluid (CSF). This data will inform tissue transduction, transgene expression patterns, and guide the design of toxicology studies and early-phase clinical trials.
Toxicology Studies:
- Design toxicology studies that align with elements of the planned clinical trial, including dose range, route of administration, dosing schedule, and evaluation endpoints, to the extent feasible.
- Conduct these studies in animal models of neurodegenerative disease and, if appropriate, in healthy animals. The study design should be comprehensive enough to identify, characterize, and quantify local and systemic toxicities, their onset (acute or delayed), potential mitigation, resolution, and the dose-response relationship.
- Consider additional assessments such as clinical neurological evaluations, neuropathology, and the immune response directed against the vector and expressed transgene product.
- Analyze any abnormal findings or lesions for frequency, severity, potential causes, and clinical significance.
Consideration of Animal Models:
- Due to anatomical differences between rodents and humans, consider using animals with larger brains or spinal columns (e.g., pigs or nonhuman primates) for additional safety information and to facilitate dose extrapolation.
- Larger animals can also help evaluate surgical dosing procedures and delivery device systems intended for clinical use, with scientific justification provided for the choice of animal models.
Functional Endpoints:
- Functional endpoints, often requiring neurobehavioral testing, may be necessary to demonstrate the activity of the investigational GT product in neurodegenerative disease models.
- Ensure that personnel are adequately trained, include appropriate controls, employ masked assessment of study endpoints, and use well-defined scoring systems to minimize potential bias in these studies.
Developmental and Reproductive Toxicity:
- Evaluate the potential for developmental and reproductive toxicity based on factors such as vector construct, expressed transgene product, biodistribution data, and the target patient population.
- Consider additional pharmacology/toxicology studies if significant changes occur in the manufacturing process or product formulation that could impact comparability between clinical trial and licensure product.
- The preclinical program should provide a robust scientific basis for the investigational GT product's benefit-risk profile and guide clinical trial design. It is essential to engage with regulatory authorities and follow established guidelines to ensure the success of preclinical studies for GT products in the treatment of neurodegenerative diseases.
CONSIDERATIONS FOR CLINICAL TRIALS
The development of clinical trials for gene therapy (GT) products intended to treat neurodegenerative diseases involves several critical considerations, including study design, patient population, dose selection, safety monitoring, and endpoints. Here are the key recommendations and considerations for planning clinical trials for investigational GT products for neurodegenerative diseases:
Study Design:
- Use of Placebo-Controlled Trials: In cases where the disease course is well-characterized, highly predictable, and can be objectively measured, randomized, concurrent-controlled trials (including placebo or sham-procedure arms) are generally recommended, even for first-in-human studies.
- Add-On Design: To minimize unnecessary exposure to placebos, consider add-on designs in which a treatment known to be effective for the neurodegenerative condition is given to all trial participants, with subjects randomized to receive the investigational GT product or placebo.
- Innovative Trial Designs: Innovative trial designs, such as adaptive designs, enrichment designs, dose-controlled studies, or historical controls, may be considered when justified and when they facilitate efficient product development. Early discussions with regulatory authorities are encouraged.
Study Population:
Genetic Diagnosis: In trials involving neurodegenerative disorders due to gene mutations, genetic diagnosis is essential for identifying potential participants. Genetic mutation presence should be confirmed before enrollment.
Exclusion Based on Pre-existing Antibodies: Sponsors may consider excluding trial participants with pre-existing antibodies to elements of the GT product. A companion diagnostic may be needed for such cases.
Pediatric Considerations: For diseases affecting both adults and children, consider initiating first-in-human trials in adults to gather preliminary safety and efficacy data. Ethical considerations should guide the inclusion of pediatric subjects in later stages of development.
Dose Selection:
- Dose-Ranging Studies: Early-phase trials should include dose-ranging study designs. Substantial dose exploration throughout clinical development is encouraged to identify safe and therapeutic dose ranges.
- Initial Dose and Regimen: The choice of the initial dose and regimen should be supported by preclinical data and available clinical information. The initial dose should ideally be reasonably safe and demonstrate therapeutic potential, especially for high-risk procedures or when treating children.
- Staged Approach for Invasive Procedures: For GT products requiring invasive surgical procedures, a staged approach (starting with unilateral administration) may be used to minimize risks before proceeding to bilateral administration in the early-phase study.
- Detailed Product Delivery Procedure: Study protocols should include a detailed description of the product delivery procedure and the devices used to ensure consistency across study sites.
Safety Considerations:
- Monitoring Immune Responses: Immune responses to GT products should be closely monitored, including cellular and humoral immune responses to both the vector and the transgene-encoded protein.
- Immunosuppressant Use: Immunosuppressant treatments, such as corticosteroids, may be used before and after product administration to minimize immune responses. Justification should be based on clinical data.
Study Endpoints:
- Diverse Endpoint Exploration: Explore a wide range of endpoints in early-phase trials to assess safety, activity, and efficacy. Clinical endpoints should measure potential clinical benefit, while biomarkers and surrogate endpoints may indicate GT product activity.
- Primary Efficacy Endpoints: For marketing applications, primary efficacy endpoints should be either clinically meaningful endpoints directly measuring clinical benefit or surrogate endpoints reasonably likely to predict a clinical benefit. Use of a surrogate endpoint may be appropriate under certain circumstances, such as when the GT product targets a well-understood monogenic change.
Follow-Up Duration:
- Long-Term Follow-Up: The duration of follow-up depends on factors like vector persistence, genome integration, and transgene activity. Long-term follow-up is recommended to evaluate safety and the durability of clinical effects.
Patient Experience Data:
- Patient Experience Data Collection: Collect patient experience data during product development and submit them in the marketing application. These data can provide additional insights into the clinical benefit of the GT product.
- These considerations are crucial for designing and conducting clinical trials of investigational GT products for neurodegenerative diseases. Collaborating with regulatory authorities and early communication about trial designs can help streamline the development process and ensure the collection of robust clinical data to support product approval