Heading In the Right Direction

April 23, 2025 by Clare Whitewoods

Navigating potential pitfalls in the CGT development process

This is part two of a three-part series summarizing our whitepaper, Set Your Cell and Gene Therapy Program Up for Success from Day One

In our previous post, Understanding the Risk, we explored the magnitude of potential risks from not planning ahead to clinical and commercial stages during early-phase cell and gene therapy development. In this post, we’ll look at the pitfalls to be navigated successfully to minimize that risk.

The development of CGTs involves several stages, from preclinical research through clinical trials to marketing authorization (MA) and post-marketing surveillance. Each stage presents unique challenges that developers must anticipate and address to achieve successful commercialization of their therapies.

Discovery and preclinical
The preclinical stage aims to provide a proof of concept of the product mechanism of action, pharmacological and toxicological effects, and potential efficacy. While using research-grade materials is sufficient at this stage, it is crucial to integrate considerations for cGMP, scalability, and quality to avoid future delays. Planning for reproducibility issues, scale-up failures, and regulatory hurdles ensures smoother progress through subsequent phases.

A key regulatory milestone for the preclinical stage is submitting a clinical trial application (CTA). To prepare for CTA submission, developers must choose appropriate materials and set up robust processes from the start of the preclinical stage. Partnering with an experienced CDMO at this stage allows developers to focus on what they know best—scientific discovery—while receiving support for cGMP compliance, high-quality material choice, scalability, and regulatory approval. Leveraging specialized knowledge and experience helps avoid common pitfalls, increasing the likelihood of CTA approval and successful product development.

Clinical trials: Phase I/II and Phase III
To evaluate the safety and efficacy of CGTs in the target population, phase I/II requires clinical-grade materials and either large-scale manufacture for larger population sizes or smaller trials for rare diseases. Flexibility in the manufacturing scale of clinical-grade materials is essential to adjust to the trial size.

Potential pitfalls for Phase I/II include:

• Comparability studies
  Any changes to materials or processes during this phase will necessitate comparability studies to ensure consistency and compliance with regulatory standards.

• Clinical-grade material necessity
  It is important to understand whether clinical-grade material is required for this stage. In some cases, cGMP material may not be needed for Phase I if there is a level of separation between the material used in clinical trials and the end product.

However, as CGT regulatory guidelines continue to evolve, future-proofing early clinical work with cGMP materials or those easily adaptable to cGMP standards may represent a more effective approach. Seeking guidance from regulatory bodies early is essential to understand what is required for a specific program.

In Phase III, large-scale clinical trials aim to confirm the safety and efficacy of CGTs in a broader patient population. Therefore, the requirements and potential pitfalls in this phase are largely similar to those in Phase I/II, but the scale and complexity are significantly increased. Importantly, cGMP materials become a regulatory requirement starting in Phase II and remain mandatory throughout Phase III.

Phase IV: Post-marketing surveillance
Post-marketing surveillance, or Phase IV, is crucial for monitoring the safety and efficacy of CGTs in real-world settings. During this phase, CGTs are administered to larger patient populations, requiring additional scale-up of manufacturing processes. Maintaining clinical-grade manufacture throughout this phase remains critical to preserving product quality and consistency.

A potential pitfall in Phase IV is not considering the reimbursement models, which often require cost reductions for long-term commercial success, especially in Europe. This economic pressure highlights the need for efficient manufacturing processes that maintain quality at lower costs. In the US, similar pressures come from insurance cost constraints, making cost-effective production and scalability crucial.

By focusing on reducing manufacturing costs and optimizing scale-up, developers can better align with reimbursement models, ultimately achieving cost reductions and providing broader access to CGT therapies.

In our final post, we’ll discuss how partnering with a CDMO can add value to your development process, especially in regard to CMC requirements.

Learn More About Setting Your Program Up for Success. Download Our Whitepaper Today

• Read Part 1 of this series, Understanding the Risk
• Have questions on this topic? Contact Us
• Have an idea for a topic? Let us know!

Subscribe to our blog