Written by Nathan Manley, Ph.D., Senior Principal, Head of Nonclinical, Dark Horse Consulting Group, Inc.
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Introduction
Construction of an efficient, pressure-tested, 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 and is a frequent service Dark Horse Consulting (DHC) provides to clients. In this white paper, we illustrate the why, when, and how of roadmap construction. We begin by describing the value-add of a well-designed roadmap, both in terms of gaining investor interest and deployment of secured funds. We then consider the optimal timing for a roadmap buildout as it relates to preclinical development activities and fundraising efforts. Finally, we deconstruct the ‘how’ behind roadmaps, by providing an overview of the DHC approach to generating a robust development plan that holistically considers a program’s current state and key milestones, calibrated against industry best practices and regulatory expectations.
Graphical Abstract – Construction of preclinical development roadmap defines critical path CMC and nonclinical activities, identifies the optimal timing of regulatory engagements, and informs key business operations strategy such as timing of fundraising efforts, vendor contracting, and hiring. The example roadmap presents a ‘reverse engineered’ timeline for a CGT product with target IND submission date of Q2 in Year 3.
Why build a roadmap?
One of the most common questions posed to preclinical CGT companies by potential stakeholders is ‘how much is it going to cost and how long is it going to take?’ In this context, the target milestone (i.e., ‘it’) has evolved with the maturing CGT industry. Not long ago, investors were signing on to novel CGT programs boasting preclinical proof-of-concept (PoC) efficacy data in a domain of unmet medical need. Although early PoC data still can land initial seed funding, the more common inflection point for major investment is now that of safety and initial PoC efficacy in patients, which can be used to 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 outcome (for example, we have yet to see a major impact of CAR-T therapies in the solid tumor space despite a multitude of preclinical efficacy data1). Consequently, a clear and data-driven understanding of development activities, the associated costs, and expected timeline to clinic have become critical talking points for potential stakeholders.
A well-constructed roadmap also ensures that utilization of internal capabilities versus external services strikes the right balance between cost and time. For example, outsourcing process development and manufacturing activities typically accelerate timelines, which will save on overall operational costs due to the shorter timeline, but also drive 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 cost savings long-term. A key objective of the development roadmap is to identify which activities are needed when, and whether they will reflect a continuous or occasional need in the future. This kind of information is instrumental in answering the question of insourcing vs. outsourcing and in guiding the type and timing of strategic hires. When considering whether a given company need should be outsourced or addressed through hiring is whether the required skill is readily available as an external service (e.g., regulatory support, quality management, manufacturing operations, supply chain) or if it represents a highly specialized skill that should be brought in-house to enhance the company’s competitive advantage.
An increasing trend within biotech is the virtual start-up: an executive team comprised of key thought leaders operating on a lean initial budget and relying heavily on a combination of external consultants and contract labs. Success with this nimble approach requires a robust roadmap with accurate costing, a realistic view of program risks, and identification of potential acceleration opportunities. At DHC, we draw from the collective experience our team has obtained from prior roles within academia, biotech, and regulatory agencies, and the lessons learned from serving over 500 clients in the CGT space to tailor development solutions within the program’s specific design space.
Finally, the roadmap should inform the timing of fundraising activities based on the identification of key value inflection points and the resources needed to get to each one. Early preclinical activities (e.g., in vitro candidate screening studies, small pilot PoC studies) 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 contract manufacturer (or building out an internal process development team), and running large-scale or long-term in vivo studies, tend to come with a much higher price tag. 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 successfully reaching the next development milestone.
When is the right time?
Having covered the major reasons to build a roadmap, let’s now consider the optimal timing. 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 (i.e., manufacturing process/scale, product testing plan) and nonclinical (i.e., model selection, efficacy/safety endpoints).
2. Insource or outsource? While some of these decisions may come later, it is 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 above, outsourcing versus insourcing strategy will impact the timing of high-cost activities (e.g., building/launching 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 simultaneously 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.
Another way to consider the same question is to ask it from the other direction: when is it too late to build a roadmap? The short answer? It’s never too late. If you have a clear understanding of your current state and your target destination, mapping out the activities and resources needed to get there ensures efficient progression and anticipation of potential challenges. As discussed further in the next section, the roadmap also can help identify opportunities for acceleration, their associated risk, and compensatory de-risking through regulatory engagement.
How to build a roadmap to success
Constructing an effective and actionable roadmap begins with a clear understanding of the program’s current and target future state. As described in the prior section, this process begins with a general understanding of the core design elements and mechanistic approach that will enable the product’s intended clinical use, which may be captured in a draft TPP. (Note: it doesn’t hurt to also have preclinical PoC data indicating the candidate therapeutic can perform as advertised.) The current state identifies where we are in the product’s development life cycle. For example, has a therapeutic candidate been nominated such that we are ready to initiate formal product development? The roadmap should account for any additional studies needed to de-risk a development candidate and/or if multiple candidates will initially be advanced towards a later go/no-go decision point. Comparing the current state against the desired future state then enables us to fill in the space between.
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 desired 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 needed to reach a clinically-suitable manufacturing process and set of control strategies. For example, when evaluating a current state process, we look at the degree of manual or open manipulations and how much industrialization will be needed to reach clinical readiness, while also considering forward-compatibility to pivotal/commercial readiness. Raw materials used in the current process are evaluated to identify those that may need to be replaced with a higher quality material and/or qualified for use via additional testing. Finally, we map out the control strategies that will be needed, both in terms of production location/environment and what testing should be implemented to ensure batch-to-batch safety, activity, and quality. The resulting CMC program considers what is necessary to be suitable for FIH and forward compatible with a future commercial state, facilitated by DHC’s up to date view of the landscape of CGT and supporting markets (e.g., reagents/equipment suppliers), as well as direct insight into evolving regulatory mindsets.
In parallel, we consider the nonclinical development path for each product based on its unique biology, potential safety concerns, and intended clinical use. This begins by identifying which model systems are appropriate to characterize product safety and activity. Are the chosen models well-established or will some degree of model development or characterization be required? If the latter, initial model development will need to be completed prior to kicking off more definitive efficacy and safety studies. As nonclinical studies progress, a key objective of the roadmap is to ensure that CMC activities will produce stage appropriate test article, ultimately yielding clinically representative material ahead of pivotal safety studies. In addition, a frequent request of DHC is to provide guidance on the minimum viable nonclinical data package that could be accepted by regulators to further streamline development activities, particularly in light of the FDA’s recently released Roadmap to Reducing Animal Testing in Preclinical Safety Studies2. Similar to how we advise on CMC strategy, DHC leverages continuous regulatory engagement to understand current regulatory expectations and to pressure test streamlined data packages that challenge nonclinical conventions.
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 potential timeline acceleration or cost saving opportunities—and the relative risk (business or regulatory) that may come with shortcuts. Roadmap estimates always should be vetted against empirical data (e.g., vendor quotes, operational costs, etc.) and should provide sufficient granularity to inform timing of key supportive activities such as fundraising, hiring, and third party contracting.
Finally, the roadmap should lay out the program’s regulatory strategy. The optimal timing of regulatory engagement should be defined and depends mainly on two factors: 1) when you need regulatory buy-in on key program decisions and 2) when you will have sufficient information or 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. Mapping a program’s current state to a future target milestone should strike the appropriate balance between internal and external resourcing, align with industry benchmarks, and include strategically timed regulatory engagements that de-risk perceived challenges and proposed shortcuts. 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.
References
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