Human Gene Therapy for Rare Diseases

The guidance document titled "Guidance for Industry: Human Gene Therapy for Rare Diseases" offers extensive suggestions for sponsors engaged in the development of human gene therapy products targeting rare diseases in both adult and pediatric populations. It addresses a range of factors, encompassing chemistry, manufacturing, and controls (CMC), preclinical investigations, clinical trials, expedited programs, and interactions with the FDA. The guidance underscores the distinctive hurdles and factors pertinent to rare diseases, such as the constrained size of study populations, varied clinical presentations, and the assessment of bioactivity results.

Rare disease:

A rare disease is defined as a condition that impacts fewer than 200,000 individuals in the United States. There exist approximately 7,000 such rare diseases. It's estimated that between 25 million to 30 million Americans are affected by these conditions. The etiology of many rare diseases remains unknown, though they frequently stem from genetic or chromosomal alterations. Diagnosing and treating rare diseases is often more challenging compared to more prevalent ailments. They are also referred to as rare disorders.

?CMC considerations:

Considerations for chemistry, manufacturing, and controls (CMC) in developing gene therapy (GT) products for rare diseases mirror those for other GT products, but with challenges due to limited population size and fewer lots manufactured. Sponsors must establish a well-controlled manufacturing process and analytical assays early to assess critical quality attributes (CQAs) like potency and purity. When altering manufacturing, a comparability assessment may be necessary. Unique feasibility, safety, and interpretability challenges for rare diseases or GT products should be addressed in clinical development programs, especially with limited study populations.

1. Product-related variations, such as impurities in viral vectors and variability in genetically modified therapies, can significantly impact the interpretation of clinical data in rare disease studies. Establishing assays to characterize these variations is crucial for program success.
2. Potency assays are essential for evaluating product functionality, consistency, and stability, especially after manufacturing process changes. It's recommended to evaluate multiple product characteristics before clinical studies to better understand product function. Qualifying a potency test measuring relevant biological activity before trials for marketing approval is strongly advised.
3. Developing and validating manufacturing processes, performing comparability studies, and creating suitable assays for Critical Quality Attributes (CQAs) can be challenging with limited starting materials or process understanding. Sponsors should consider implementing manufacturing changes for commercial-scale production and demonstrating product comparability before starting clinical trials for marketing approval. If comparability cannot be demonstrated, additional clinical data may be necessary.

Preclinical Considerations:

Key considerations in the preclinical program for a gene therapy product targeting rare diseases encompass:

?1. Determining a biologically active dose range.

2. Advising on initial clinical dose, escalation schedule, and dosing regimen.

3. Validating feasibility and ensuring safety.

4. Assessing safety and feasibility of the gene therapy delivery system and procedure.

5. Evaluating immune responses to the vector and transgene product expression.

?These factors are vital in defining the benefit-to-risk profile for the target patient group and are integral to rare disease gene therapy product development.

In the development of a preclinical program for an investigational gene therapy (GT) product, the following elements are recommended,

1. Preclinical proof-of-concept (POC) studies should be conducted in vitro and in vivo to establish feasibility and support the scientific rationale for clinical trial administration. These studies guide both preclinical toxicology and early-phase clinical trial design, with animal models reflecting human response.
2. Biodistribution studies are essential to assess vector distribution, persistence, and clearance from administration site to target and non-target tissues, including biofluids where feasible. These data inform tissue transduction, transgene expression, and guide preclinical toxicology and early-phase clinical trial design.
3. Toxicology studies for the investigational GT product should mirror elements of planned clinical trials where possible, comprehensively identifying, characterizing, and quantifying potential local and systemic toxicities. Additional assessments may include safety and feasibility of GT delivery system, procedure, and immune responses against vector and transgene product.
4. Additional nonclinical studies may be necessary to address factors such as developmental and reproductive toxicity risks, and significant changes in manufacturing impacting comparability between clinical trial and licensure products.

?Clinical Considerations:

Study Population:

In selecting study populations for gene therapy (GT) product trials targeting rare diseases, evaluating existing data for risk and benefit assessment is crucial. Key considerations include:

• Conducting genetic testing for accurate diagnosis, necessitating potential companion diagnostics for trial planning.
• Managing safety risks from pre-existing antibodies to GT components, potentially excluding affected patients and developing companion diagnostics.
• Designing trials based on disease severity to account for adverse event reporting and potential benefits, especially in earlier disease stages.
• Addressing ethical concerns, especially for pediatric patients, in line with FDA regulations and ensuring proper consent procedures.
• Avoiding enrollment of healthy volunteers due to permanent unintended effects and invasive procedure risks, underscoring the need for comprehensive informed consent.

?Study Design:

In designing clinical studies for rare diseases, where patient enrollment is limited, collecting comprehensive data from each subject starting from the first-in-human study is crucial. Randomized, concurrent-controlled trials are preferred for establishing effectiveness and safety data, with early randomization encouraged. Consideration should be given to placebo controls and stratified randomization based on disease severity. Intra-subject control designs may be useful for genetically targeted indications, while single-arm trials with historical controls may be considered if randomized trials are not feasible. Efforts should be made to identify relevant biomarkers and leverage scientific information from related diseases. Concomitant medications may be allowed if their discontinuation poses risks, with stable dosages justified in the protocol.

?Dose selection:

In selecting the dose for gene therapy (GT) products,

• Utilize all available clinical data sources, including publications and similar product experiences, to inform dose selection.
• Non-human data, such as animal models and in vitro studies, may be crucial for estimating starting human doses and understanding enzyme kinetics.
• For early-phase studies addressing serious diseases with unmet needs, starting with a potentially therapeutic dose is ideal, though dose exploration may be necessary to find the optimal therapeutic dose.
• Repeat administration of the GT product may be considered if transgene expression decreases over time, but careful assessment of immunogenicity and its clinical impact is essential, particularly regarding potential enhanced immune responses.

?Safety:

To ensure safety in GT clinical trials:

• ?Tailor monitoring plans to patient and product characteristics, incorporating preclinical and human data .
• Monitor immune responses against GT components early, developing assays accordingly.
• Stagger GT product administration in first-in-human trials to mitigate risks, with dosing intervals coordinated with regulators.
• Recognize potential long-term effects, determining follow-up durations based on preclinical and disease understanding.
• Implement study stopping rules in early-phase protocols to halt trials if adverse events occur, enabling prompt adjustments for subject safety.

Efficacy Endpoints:

In selecting efficacy endpoints for clinical trials of gene therapy (GT) products for rare diseases:

• Understanding disease pathophysiology and natural history is crucial for endpoint selection, even if full mechanism understanding is not required for approval.
• Consider seeking accelerated approval based on surrogate endpoints, requiring data demonstrating their correlation with clinical benefit.
• Identify disease aspects meaningful to patients, potentially influenced by GT product activity, to inform endpoint selection.
• Longitudinal profiling of clinical measurements over time can provide valuable insights into treatment effects.
• Patient experience data are encouraged by the FDA, offering additional insights into the clinical benefit of GT products, and should be collected and submitted during product development.

Various programs exist for sponsors of gene therapies (GTs) aiming to tackle unmet medical needs in severe or life-threatening conditions. These include regenerative medicine advanced therapy designation, breakthrough therapy designation, fast track designation, accelerated approval, and priority review. Their purpose is to streamline and hasten the development and review processes for such therapies.

References:

https://www.fda.gov/media/113807/download

Additional references:

1. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry, January 2020. https://www.fda.gov/media/113760/download.
2. Preclinical Assessment of Investigational Cellular and Gene Therapy Products; Guidance for Industry, November 2013. https://www.fda.gov/media/87564/download.
3. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products; Guidance for Industry, June 2015. https://www.fda.gov/media/106369/download.