top of page

Subscribe to Our Newsletter

Thanks for submitting!

Gene Therapy for Rare Diseases: Navigating Data Integrity and Development Challenges

Gain valuable insights into the critical considerations for developing gene therapy products aimed at treating rare diseases.

The landscape of modern medicine is continuously evolving, driven by remarkable advances in the field of gene therapy. These cutting-edge treatments hold the promise of transforming the lives of patients afflicted by rare diseases, offering hope where there was once despair.

However, the development of gene therapy products for rare diseases presents unique challenges and complexities. In this comprehensive guide, we explore the critical role of data integrity in maintaining trust and credibility throughout the development process.

The Challenge of Rare Diseases

The National Institutes of Health (NIH) reports that nearly 7,000 rare diseases affect more than 25 million Americans. Approximately 80% of these rare diseases are caused by a single-gene defect, and approximately half of all rare diseases impact children. Since most rare diseases lack approved therapies, there is a significant unmet need for effective treatments.

Many rare diseases are serious or life-threatening conditions, underscoring the urgency of developing innovative therapies.

Developing safe and effective products to treat rare diseases, however, is a complex endeavor. Challenges abound, ranging from the difficulty of finding and recruiting patients with rare diseases for clinical trials to the highly diverse clinical manifestations and unpredictable disease progression rates among affected individuals.

These challenges are equally applicable to the development of gene therapy (GT) products, where unique considerations come into play. Yet, despite these formidable obstacles, research and development in the field of GT for rare diseases continue to surge at a rapid pace.

Data Integrity and Rare Disease Research

While the general chemistry, manufacturing, and controls (CMC) considerations for product manufacturing, testing, and release of GT products for rare diseases mirror those for other GT products, there are unique aspects to consider.

These include limited population sizes, fewer manufacturing lots, and challenges in establishing critical quality attributes (CQAs).

In traditional product development, CQAs are rigorously evaluated at each phase of clinical development.

Data from multiple drug product lots are correlated to clinical outcomes, providing a robust basis for decision-making. However, with smaller study populations, it may be challenging to conduct enough manufacturing runs to establish the necessary critical process parameters (CPP) to ensure CQAs.

Furthermore, GT products may exhibit CQAs with higher variability than traditional drugs or well-characterized biologics, adding to the uncertainty surrounding these attributes. Despite these challenges, demonstrating process control and ensuring a consistent product with well-defined CQAs are essential for licensure and regulatory compliance.

Early Focus on Data Integrity

Given the unique challenges of developing GT products for rare diseases, it becomes even more critical for sponsors to establish a well-controlled manufacturing process and suitable analytical assays as early as possible in the development journey. Ideally, this should occur before the administration of the GT product to the first subject.

In cases where changes to the manufacturing process are necessary, a comparability assessment may be required. To ensure product consistency and compliance with regulatory requirements, sponsors must prioritize characterizing the product's CQAs and implementing manufacturing CPPs before initiating clinical studies.

Innovative strategies for understanding CQAs may involve leveraging prior knowledge from similar products, utilizing product characterization data from nonclinical studies, assessing CPPs during engineering runs, or manufacturing multiple small lots instead of a single large lot. This approach can provide a more comprehensive view of product variability and quality attributes.

Collaboration and Communication

Sponsors developing GT products for rare diseases are encouraged to engage in early and ongoing communication with regulatory agencies, such as the Office of Tissues and Advanced Therapies (OTAT) within the Center for Biologics Evaluation and Research (CBER). These discussions should occur before investigational new drug application (IND) submission and during product development.

Key considerations for such communication include:

  • Product-Related Variations: Rare diseases may present unique challenges in terms of product-related variations, such as impurities in viral vectors or variability in genetically-modified cell therapies. Sponsors should establish assays to characterize these variants to ensure program success.

  • Potency Assays: Potency assays are crucial for assessing product function, consistency, and stability. They also provide evidence of comparability after manufacturing process changes. It's essential to evaluate multiple product characteristics before initiating clinical studies and qualify a potency test for suitability.

  • Challenges in Manufacturing: Limited availability of starting materials, a lack of reference materials, or limited process understanding can pose manufacturing challenges. Sponsors are encouraged to consider implementing manufacturing changes for commercial-scale production and demonstrating product comparability early in development.

Preclinical Considerations

Before moving into clinical trials, a robust preclinical program is essential for characterizing the benefit/risk profile of the investigational GT product for the intended patient population.

The objectives of a preclinical program for a GT product include identifying a biologically active dose range, establishing feasibility and safety of the clinical route of administration, supporting patient eligibility criteria, and identifying potential toxicities.

In cases where pediatric first-in-human clinical trials are contemplated, the preclinical program should also include studies demonstrating a prospect of direct benefit, especially when clinical evidence from adult subjects with the same disease is lacking.

Key elements of a preclinical program for an investigational GT product include in vitro and in vivo proof-of-concept studies, biodistribution assessments, and comprehensive toxicology studies that align with the planned clinical trial parameters. Additional nonclinical studies may be necessary to address factors such as developmental and reproductive toxicity or changes in the manufacturing process.


Developing gene therapy products for rare diseases is a complex and challenging undertaking, but it offers hope to patients facing devastating conditions with no available treatments. Data integrity, from the earliest stages of development through clinical trials, is paramount in ensuring the success of these therapies.

By addressing the unique considerations of rare diseases, engaging in transparent communication with regulatory agencies, and implementing robust preclinical programs, sponsors can navigate the complex landscape of GT products for rare diseases effectively.

As the field continues to evolve, the commitment to data integrity will remain central to preserving trust, advancing scientific knowledge, and delivering life-changing therapies to those who need them most.

Contact BioBoston Consulting today or visit our website to learn more about how we can support your organization.

4 views0 comments
bottom of page