Preclinical roadmap to first-in-human

Construction of an efficient development roadmap is an essential tool for preclinical cell and gene therapy (CGT) companies looking to obtain stakeholder buy-in and advance to first-in-human (FIH) clinical studies.

A well-designed development roadmap can be a powerful strategic asset — shaping investor confidence and guiding capital deployment. Yet questions persist around the optimal timing for roadmap buildout and how it should evolve alongside preclinical development activities and fundraising efforts.

Why build a roadmap?

One of the most common questions posed to preclinical CGT companies by potential stakeholders is ‘how much will it cost and how long will it take?’ In this context, the target milestone has evolved with the maturing CGT industry. Not long ago, investors were willing to back novel CGT programs on the strength of preclinical proof-ofconcept (PoC) efficacy data in areas of unmet medical need. While early PoC data can still secure seed funding, the more common inflection point for major investment is now demonstration of safety and initial PoC efficacy in patients which helps substantiate and refine the program’s path to commercialization.

Investor caution is understandable as expectations have been tempered by examples where promising preclinical data failed to translate to meaningful patient outcomes. Consequently, a clear and data-driven understanding of development activities, associated costs, and expected timeline to clinic have become critical talking points for potential stakeholders.

A well-constructed roadmap balances the use of internal capabilities versus external services to optimize cost and time. For example, outsourcing process development and manufacturing activities typically accelerates timelines, which saves operational costs but also drives larger costs for the outsourced activities than could be achieved internally. In contrast, building internal capabilities may come with larger upfront costs and a longer initial timeline that ultimately leads to long-term cost savings. A key objective of the development roadmap is to identify which activities are needed when, and whether they represent continuous or intermittent needs.

Finally, the roadmap should inform the timing of fundraising activities by identifying key value inflection points and the resources required to reach each one. Early preclinical activities can be completed on a relatively lean budget, potentially covered by initial seed funding or non-dilutive grants. Later preclinical activities, such as signing on with a CMO or running large-scale in vivo studies, tend to come with higher price tags. Having a quarterly breakdown of upcoming big-ticket items is critical for determining the proper cadence of fundraising efforts and ensuring sufficient cash runway(s) for reaching the next milestone.

When is the right time?

Although roadmap construction generally should take place early in development, there are prerequisites to ensure that the resulting plan is detailed enough to be actionable.

1. Have you defined your overall therapeutic approach? Drafting an initial draft target product profile (TPP) is a great way to define key program elements, such as product design features, the proposed therapeutic mechanism, and target clinical indication. Having a reasonable sense of these core program elements is important for mapping the path to clinic, as they inform the overall strategy for CMC and nonclinical work.

2. Insource or outsource? While some of these decisions may come later, it’s important to have a general sense of what development activities are likely to be kept internal vs. which are to be farmed out, as this informs both internal hiring strategy and the type(s) of external service providers that will be needed. As noted, outsourcing versus insourcing strategy will impact the timing of high-cost activities (e.g., building a new facility, signing a large vendor contract) and the overall development timeline.

3. What are we building toward and is there an absolute deadline? The ultimate end goal of any CGT product should be to eradicate unmet medical need or overcome current standard of care limitations, while also achieving unparalleled market success. Such aspirations notwithstanding, initial construction of the roadmap should have more defined and attainable milestones, such as ‘IND submission’ or ‘clinical PoC/safety data.’ In many cases, the maximum allowable time to the relevant milestone is known, enabling one to back-fill activities and understand the extent to which there may be buffer in the timeline.

Once the above prerequisites are met, there is no time like the present to begin the roadmap construction process. Getting started early means that all subsequent activities can be properly mapped against one another, the available budget, and the defined end goal.

How to build a roadmap to success

Constructing an effective, actionable roadmap begins with a clear understanding of the program’s current state and target future state. This process starts with defining the core design elements and mechanistic approach supporting the product’s intended clinical use, often captured in a draft TPP. The current state reflects the program’s position in the development life cycle — for example, whether a therapeutic candidate has been nominated and formal development can begin. The roadmap should also account for additional studies needed to de-risk the candidate and for scenarios in which multiple candidates advance toward a later go/no-go decision point.

At DHC, we typically use a risk-based, gap analysis approach to determine must-have and nice-to-have activities that will move a program towards its future
state. Gaps are identified based on current industry best practices for the specific therapeutic approach and indication (typically including nice-to-haves), and the relevant regulatory expectations for the specific CGT modality (generally defining must-haves). Using a risk-based approach, activities are evaluated for their potential to impact the program’s overall probability of technical and regulatory success (PTRS) and timeline, thereby providing a framework for workstream prioritization.

In the context of CMC, the roadmap defines the steps required to achieve a clinically suitable manufacturing process and control strategy. When evaluating a current-state process, we assess the extent of manual or open manipulations, the level of industrialization needed for clinical readiness, and forward compatibility with pivotal and commercial manufacturing. We also define the necessary control strategies, including production environment considerations and testing to ensure batch-to-batch safety, activity, and quality. The resulting CMC program supports FIH readiness while remaining compatible with future commercial requirements.

In parallel, we define the nonclinical development path for each product based on its biology, safety profile, and intended clinical use. This begins with selecting appropriate model systems to characterize safety and activity, including determining whether models are established or require further development. Where model development is needed, it must be completed before initiating definitive efficacy and safety studies. As nonclinical studies advance, a key roadmap objective is to ensure alignment with CMC activities so that stage-appropriate, clinically representative test articles are available ahead of pivotal safety studies.

Once key CMC and nonclinical activities are defined, expected costs and durations are calculated. We typically recommend starting with a conservative view of time and cost (i.e., what you may want to tell the board), while also identifying opportunities for timeline acceleration or cost savings, and the relative business or regulatory risks. Roadmap estimates should be vetted against empirical data (e.g., vendor quotes, operational costs) and should provide sufficient granularity to inform the timing of supportive activities such as fundraising or hiring.

Finally, the roadmap should lay out the program’s regulatory strategy. The optimal timing of regulatory engagement should be driven two factors: when regulatory buy-in on key program decisions is needed and when you will have sufficient data to support the questions you want to ask. When timed correctly, regulatory engagements ensure that a program is sufficiently de-risked prior to writing any big checks or choosing to embark on any shortcuts.

Conclusions

For preclinical CGT companies looking to chart a cost-effective and time efficient path to clinic, construction of a development roadmap can bring essential clarity and direction. When all the pieces come together, the resulting roadmap product serves as a versatile tool that can streamline internal planning, foster external partnerships, and guide the path to success.