A Roadmap to Phase I Challenges for Cell and Gene Therapy Products


Applied Clinical Trials

Cell and gene therapies are the latest wave of advanced technologies that will shape the face of the modern-day biopharma arena, enabling a path to pinpoint a faulty gene or cellular mechanism at the root of a specific disease.

The biopharmaceutical industry has long been shaped by an ever-changing landscape, with emerging healthcare trends and breakthrough science disrupting the status quo to offer new hope for patients with unmet medical needs. Cell and gene therapies (CT/GT products) are the latest wave of advanced technologies that will shape the face of the modern-day biopharma arena, enabling a path to pinpoint a faulty gene or cellular mechanism at the root of a specific disease. 

Despite this growing promise, the product development pathway is not without significant challenges, making a “one size fits all” approach outdated and ineffective. Sponsors are finding themselves in uncharted territories with initiating First-in-Human (FIH) studies, or Phase I studies. However, with careful regulatory preparation, it is possible to demystify the development process and turn a hazy crystal ball into a detailed roadmap for success. 

Below are some of the common clinical, preclinical, and Chemistry Manufacturing and Control (CMC) challenges sponsors need to be aware of in early development of CT/GT products. 

Timing of First-Patient-In (FPI)

Clinical trial initiation for CT/GT differs in several ways when compared to more traditional products. Apart from potential complications, due to issues with manufacturing and/or supply of the clinical trial material, there are a few procedural items that commonly lead to delays when working to achieve FPI for a CT/GT trial.

When developing a CT/GT product, be prepared for two institutional oversight reviews. These are required at each clinical trial site, prior to site activation. Some reviews occur in parallel, while others are in succession with IBC first and IRB last. 

1. Institutional Biosafety Committee (IBC) assessments may require several rounds of review spanning several weeks to months.

2. A local Institutional Review Board (IRB) review and assessment can average 3-6 months due to limited resources and expertise at a clinical trial site. A central IRB review can significantly reduce the review time. A central IRB is an IRB that is not located within the academic site or institution and therefore has resources and expertise readily available to expedite the review.

Be sure to anticipate the delays that often occur during these review processes. In addition, CT/GT trial specific items are required in the Informed Consent Form (ICF). Neglecting to include language specific to CT/GT studies can cause a significant delay in IBC/IRB reviews. Some examples include language regarding the potential for delayed adverse effects due to the body’s integration of the CT/GT product, how the body may eliminate (shed) the GT product, and a long duration of follow-up post treatment with the CT/GT product.

Preclinical Safety Evaluation 

CT/GT products are still considered relatively new due to the recent emergence of corresponding underlying technologies. As a result, a strong preclinical safety evaluation to support a Phase I study that will withstand higher bars for regulatory review is required. 

As the standard pharmacology, pharmacokinetic/ADME and toxicology evaluations used to assess the safety of traditional drugs/biologics are not applicable for the assessment of CT/GT products, the FDA takes a more flexible, science-driven approach when conducting regulatory review, due to the novelty and unique challenges of each product.

Key factors that are essential in planning the preclinical development program to support a Phase I study are: 

· For CT products: it is imperative to assess the cell fate post-administration in the preclinical setting. 

· For GT products: the preclinical safety assessment is dependent on the vector/construct and selected transgene(s) (payloads) engineered into the vector. The vector/construct characteristics and the desired biological effects of the transgene(s) will define the preclinical safety assessment.

· For CT/GT products: the selection of the appropriate animal species and/ or disease animal model is dependent on the desired biological effects of the CT/GT product

CMC Challenges 

While CMC development experience in traditional drugs/biologics can serve as a starting point, there are many unknowns in the CT/GT world that make it difficult to rely on previous models. Some common CT/GT CMC challenges that sponsors face are:

· Use of human or animal-derived raw materials. Many recombinant protein-based raw materials have secondary components that are animal derived thereby complicating the adventitious agent control strategy.

· At early stages, cell therapy manufacturing can be more art than science; processes are often manual and can only be performed by a few highly-skilled individuals. Optimizations that allow the process to be scalable, robust, and consistent can be elusive and exceedingly difficult to implement with scale

· Prohibitively short shelf life for clinical material and/or limited availability of final product. Low production yields can significantly inhibit the ability to perform comprehensive release testing prior to dosing the patient.

Outside of the box thinking is practically a necessity to close some of the CMC gaps where current guidance may not apply. Sponsors may need to take a more proactive approach when developing CT/GT products. This can include working with vendors to ensure that raw materials are compliant, and if possible, GMP or clinical grade. In addition, Sponsors should also be prepared to get creative with approaches to manufacturing and should turn to automation to solve some of the bottle-necks. 

Developing analytical assays for CT/GT products is often a major hurdle for CMC personnel. However, product-specific solutions can be designed to overcome these challenges. Continuous evaluation of the methodology is paramount; sponsors will need to remain agile and able to optimize or replace insufficient or failing methods throughout development. 

Finally, the FDA recognizes the challenges that CT/GT product sponsors are facing and is eager to work collaboratively to support the initiation of Phase I studies. Early interactions (e.g. Pre-IND Meetings) are essential to developing transparent working relationships and will pay off later down the road. 


No two CT/GT products are exactly alike, creating the need for a unique approach to product development. Sponsors, vendors, consultants, and even the Agency are still learning and adapting to address the many challenges encountered on the path to bring these complex living medicines to patients in need. In fact, it is unlikely that any one of these constituents alone has all the answers. However, with careful planning, productive collaborations, and a unified vision it is possible to blaze the trail for CT/GT product development.


Nicole (Niki) Gallo

Jason Birri

Chris Kelly

Julie Kristen Hagan






Nicole (Niki) Gallo, RAC, is Senior Consultant; Jason Birri, MS is Senior Consultant - Regulatory CMC; Chris Kelly, MS, is Senior Consultant, and Julie Kristen Hagan, MS is Senior Consultant all with the Halloran Consulting Group.

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