Navigating the Regulatory Landscape for CGTs: Success through Early, Informed Delivery System Choices 

Cell and gene therapies (CGTs) are redefining what is possible in modern medicine, but they are also redefining how we approach delivery system selection. Across the pharmaceutical industry, CGT development teams are finding themselves at a frustrating intersection. The science backing the therapy is advanced, the regulatory team is ready to engage, and the clinical development timeline is set. Yet one detail delays progress: the delivery system. 

The fact is, most delivery systems on the market today were never originally intended for CGTs and available regulatory guidance is layered, nuanced, and often hard to effectively implement without deep experience. So, while teams may be able to effectively source a delivery system, there remains a structural challenge preventing effectively selecting the delivery system for their novel CGT. As a result, teams face hard questions with no obvious right answer: 

• What’s the “right” device for Phase 1? 
• Can we leverage cleared devices? Are we able to modify them slightly? 
• Are we inadvertently backing ourselves into a corner for the commercial product? 

These are not just technical dilemmas. They are strategic ones. And the answers can have long-term consequences on cost, risk, and program viability. 

At Suttons Creek, we support combination product teams untangling these exact challenges every day. In this article, we unpack what is changing in the CGT-device space, how delivery system decisions impact your entire development program, and what to prioritize at every phase to achieve regulatory and commercial success. 

 

Devices are now a Frontline Concern in CGT Development 

While drug-device combination products have long been part of the pharmaceutical landscape, devices present unique challenges when combined with a CGT. CGTs are often administered through sensitive routes (e.g., intrathecal, intraocular, intralesional) and their active ingredients, often living cells or gene constructs, are extremely sensitivity to the delivery system’s materials of construction, fluid pathways, particulate matter, transportation, handling, and other mechanical and fluid shear forces. Further, sterility and endotoxin hazards are also amplified. Because most commercial delivery systems were not designed for CGTs, teams must employ selection rigor so that the combination product does not fall short when faced with the complex stability, sterility, and material compatibility requirements of these next-gen combination products. 

Complicating matters, CGT therapeutic areas are moving into areas historically dominated by medical devices and surgical procedures. Consequently, this has pushed the clinical risk boundaries CGT teams must consider into areas which pharmaceutical development hasn’t traditionally navigated. For example, a traditional biologic might be injected subcutaneously with a syringe, a CGT might require a surgically assisted endoscopic delivery through a custom catheter for placement in a precise anatomical site. 

This shift changes the nature of device selection. You are not choosing a container or accessory. You are choosing a clinical enabler and, in many cases, a regulatory gatekeeper. 

 

Why CGT Teams Are Struggling—and Where the Risk Lies 

We see recurring pain points across the CGT development teams we assist: 

• Delayed device decisions: Teams may wait until Phase 2 or later to address commercial delivery needs, only to realize that their early assumptions do not scale to the commercial program. 

• Overuse of “off-the-shelf” devices: Early-phase studies may leverage widely available components without fully assessing compatibility, leading to unexpected failures or data gaps in regulatory submissions. 

• Fragmented internal ownership: Device strategy has a hand in clinical operations, CMC, regulatory, and quality. This sprawling impact means no one may outright own device strategy holistically. 

• Lack of integration with risk management and design controls: Even teams that include the device constituent in INDs often fail to build out the design history file (DHF) or establish essential drug delivery outputs (EDDOs) early enough to support a robust BLA. 

These missteps do not usually manifest as single-point failures. Instead, they slowly erode program momentum: CGTs commercial launch date is shifted to accommodate additional testing and data collection, unplanned bridging activities, fragmented program direction, and strained team efficiency. Cumulatively, partnerships are strained and team chemistry fractures as regulators ask for more data than anticipated. 

 

How the Regulatory Landscape Has Shifted—and What It Means for You 

Regulators have signaled, clearly and repeatedly, that successful therapeutic delivery is a critical component of safe and effective CGT development. Over the last decade, FDA has released multiple guidance documents that, when read together, inform device-related expectations which should be addressed in both investigational and commercial submissions. Key takeaways include: 

• You must demonstrate compatibility between your delivery system and the CGT product. Mechanical, chemical, and specific considerations for biological characteristics, including biological activity and route of administration, are key to forming this foundational data set. 

• Devices should be as close to the final commercial version as possible in preclinical and early clinical studies, particularly if those studies will support pivotal marketing claims, to reduce unplanned data requests from regulators. 

• You must have documented justification supported by robust evidence for each change made to the delivery system during asset development (e.g., between Phase 1 and BLA submission), so that individual and the totality of changes made do not introduce new risks or invalidate earlier data collected. 

• A combination product DHF clearly linking user needs, design inputs, design outputs, verification and validation testing, and risk management activities forms the basis of the safety and efficacy of the delivery system used for the CGP’s intended use. A drug-agnostic dossier is not a winning formula. 

• The CGT may be approved with limited long-term data. Consequently, extensive post-marketing surveillance and/or Post-Market Requirements / Post-Market Commitments (PMR/PMC) may be required to monitor and evidence enduring safety and efficacy. 

• Since CGTs often target rare diseases, recruiting enough patients for clinical trials is challenging. Small clinical study and commercial populations could hinder gathering delivery system useability and long-term surveillance data. 

In other words, CGT-device compatibility is not something that can be “retrofitted” at the end of the development program. It needs to be woven into your program plan from the start. 

 

What to Prioritize in Device Selection 

Choosing the right delivery system is not purely a procurement decision; it is a clinical, regulatory, and strategic imperative. Key questions to ask: 

• Is the device already cleared or approved? 

• Is it being used within its cleared/approved indications for use? 

• How does the delivery system interact with the CGT (e.g., physically, chemically, and functionally)? 

• Are there limitations from the delivery system’s general use you need to address? 

• What testing or risk mitigations are required to bridge compatibility gaps? 

Remember, while leveraging a legally marketed device should derisk a program, it does not eliminate the need to demonstrate compatibility, especially when dealing with sensitive materials, exotic routes, or unique dose forms. 

 

Essential Drug Delivery Outputs and the Five Rights of Medication Use 

The concept of EDDOs is especially critical in CGTs. Consider: 

• Precision: Does the delivery route or dosing regimen demand custom controls and methods to verify and validate combination product system design? Are there limits to delivery which must be designed into or labeled onto the product? Are individual dose containers specifically formulated for an individual patient? 

• Sensitivity: Does the drug substance require tight controls to ensure product viability following delivery? Is the CGT impacted by shear forces, surface materials, dead volume, or head-space gas? 

• Stability: Can your product survive multi-component prep, load, and flush process? Are there well-defined methods to verify and validate the product throughout the stability program? 

• Scalability: Does the projected CGT manufacturing method require specialized facilities, logistics, process steps, primary containers, and/or personnel? 

Design inputs should be informed by the biologic product intended for delivery and your risk management plan must reflect both investigational and commercial use cases. 

 

What Phase-Appropriate Decision Making Really Looks Like 

A fully developed commercial combination product is not necessary to meet regulatory expectations in a Phase 1 clinical study, however; the FDA does expect logical, risk-based, progression over the development program supported by your internal documentation. Regardless of eventual commercial status, FDA generally views these investigational situations as ‘combination products’ when reviewing a clinical submission. Here is how we recommend approaching combination-product device strategy and design controls across clinical phases, including CGTs: 

Phase 1: Prove the Concept, Minimize the Variables 

In Phase 1, the goal is proof of concept for the therapy, not the device. Leverage commercially available, cleared or approved, devices wherever possible. However, be realistic about their limitations and clearly justify these limitations and use-case variances in the supporting DHF documentation. Capture enough information through basic compatibility testing and risk assessment to avoid surprises in later stages and demonstrate system safety, which is the priority for regulators at this point in development. Establish phase-appropriate design controls and track key decisions to set the program’s foundation. 

Phase 2: Prepare for Commercialization 

In Phase 2, the focus shifts and begins to include key characteristics of the delivery system. Start defining EDDOs: the key characteristics of the delivery system that enable safe and effective CGT delivery. Consider: 

• How is the delivery of the intended dose defined? 

• How is the dose’s target site controlled? 

• What product preparation steps must the user take to safely and effectively deliver the dose? 

• How is delivery initiated by the user? 

• How is delivery progression observed by the user? What tasks must the user undertake to continue delivery? 

• How does the user know the dose has completed? Are there tasks that must be completed at dose completion? 

During this phase, the team should begin to formalize design inputs and define how critical dose-delivery elements are considered within the development program so they can be validated directly or incorporated into the bridging program and whether updates to the development program are appropriate. 

When developing a clinical program, consider that for many genetically-targeted therapies, Phase 2 may be combined with either Phase 1 or 3 (or, skipped entirely). In the event of clinical phase consolidation, these considerations should be accounted for in in the total clinical effort. Additionally, this year FDA has noted their desire to further accelerate development of genetically-targeted medicines, further heightening the need to develop a robust device strategy early in development. 

Phase 3: Execute Commercial Delivery Strategy 

By Phase 3, delivery system design should be locked, validation test plans defined, and partnerships solidified for any components not developed in-house, including fully integrated risk management and quality agreements. Risk-based, and phase-appropriate, variances to full marketing development should be limited and clearly justified with formal plans to build a complete, market-ready, DHF. For example, labeling and clinical study documentation risk-controls should be limited. 

 

A Practical Example: Delivering ILX-01 

Consider ILX-01, a CGT therapy involving genetically modified induced pluripotent stem cells (iPSCs) delivered into the small intestine. This product required: 

• On-site thawing and reconstitution, 

• Loading into a catheter to be placed within an endoscope for local delivery 

• Specific handling to preserve viability and sterility. 

The team developed a phase-appropriate, flexible, plan to balance the program cost, product quality, and development timeline. 

For Phase 1, the team identified a legally marketed catheter that could be cost-effective to meet the preliminary study needs. The clinical sponsor would still need to assess whether the CGT could tolerate being pushed through the catheter, what impact this delivery process had on viability, and what the essential delivery features were. 

By Phase 2 and 3, it became clear that a custom device was needed. The team engaged a CDMO to develop the system to meet 21 CFR Part 4 compliant design control requirements, integrate risk management to holistically address system risks, and develop a DHF to support the BLA submission. 

This example illustrates the importance of lean and flexible early development, with an eye on future development plans. The Phase 1 decisions didn’t lock the team into a corner, and the verification and validation data they began capturing early ultimately enabled a smooth transition to commercialization. 

 

Final Thoughts: Success Comes from Planning, Not Perfection 

Cell and gene therapies hold tremendous promise, rewriting the rules of drug development and developing highly targeted therapies. However, their success hinges not just on science, but on the systems that enable their delivery. The therapy must be delivered to the right patient, at the right time, and in the right way in order to act as desired. Devices, while sometimes treated as secondary, are the interface between your product and the patient. Regulatory, clinical, and commercial success all depend on getting the delivery system right. 

If you are struggling to translate regulatory guidance into actionable plans, or you are unsure whether your device strategy will hold up under BLA scrutiny, you are not alone. We have walked this path with many teams in a variety of therapeutic areas for different drug modalities, and the earlier the conversation starts, the more flexibility you retain. 

At Suttons Creek, we are not here to sell cookie-cutter solutions. We are here to help you think it through, step by step and phase by phase, with the right expertise at the right time. With bespoke guidance, you can de-risk decisions early, build toward launch efficiently, and avoid last-minute surprises. 

AUTHOR

Max Lerman, PhD, Associate Technical Director, Suttons Creek – With over three years at the FDA as a member of the infusion devices team, Max has deep experience in developing and setting review practices for infusion, life-critical drug delivery, and electroporation systems and was also a member of AAMI ID and IP infusion pump committees. Prior to the FDA, Max spent over two years at Medtronic developing and maintaining electrocautery platforms. This industry experience and insider knowledge can be critical support to Suttons Creek clients and their combination product development and regulatory approval success.