By: Kevin Denny, MBA, DABT, Executive Technical Director, Laboratory Testing Division, WuXi AppTec
Preclinical Safety in an Era of Scientific and Regulatory Evolution
In the past, regulatory agencies were seen as slow-moving constants required for drug development. With a broad purview, regulators typically followed a fixed playbook, and regulatory change could be slow. Sponsors built around that assumption. If a nonclinical development program was grounded in accepted toxicology principles, supported by well-executed GLP studies, and aligned with the intended clinical strategy, the IND-enabling path was often reasonably predictable. Unexpected challenges could still arise, but they were often specific and manageable diversions on an otherwise predictable path.
That environment is changing. Today, the regulatory landscape is being shaped by the rapid pace of scientific advancement, the emergence of increasingly complex therapeutic modalities, and the ongoing refinement of regulatory expectations. With the increasing complexities of current IND programs, it is critical to work with regulatory agencies to seek input early in the process.
These shifts are particularly relevant in preclinical development, where expectations for model selection, translational relevance, and the overall weight of evidence continue to evolve. Complexity is further amplified in global programs, where regional differences in regulatory perspectives introduce additional planning challenges. In this context, flexibility becomes an essential component of preclinical strategy. Programs designed with adaptable study planning, integrated scientific expertise, and operational readiness are better poised to respond to changing expectations while maintaining data quality, development continuity, and regulatory credibility.
What is Driving Shifts in the Regulatory Landscape?
Regulatory changes are not temporary or isolated. They reflect shifts in science driven by the emergence of novel modalities such as mRNA-based therapies, cell and gene therapies, and antibody-drug conjugates, increasing scrutiny of benefit-risk trade-offs, and the growing role of new approach methodologies (NAMs). In a global development environment, regional differences compound complexity, creating a landscape that continues to diverge alongside the science required to support these programs.
On a broader level, this evolution reflects a well-founded effort to strengthen the relationship between preclinical evidence and anticipated human outcomes. However, many development programs are still built as if requirements remain relatively fixed, with predefined study packages, endpoints, and data requirements. In practice, that assumption is becoming less reliable. As development programs advance and new questions emerge, preclinical strategies increasingly require a capacity for adaptability in order to remain on track toward IND readiness.
Why Preclinical Programs are Especially Exposed
IND-enabling programs occupy a particularly sensitive position because they form the foundation for further development, while establishing the evidence base that informs downstream clinical strategy. Toxicology findings directly influence clinical study design, safety monitoring plans, dose-escalation strategy, and the broader benefit-risk framework presented to regulators and other stakeholders.
As regulatory expectations evolve, changes introduced late in development can have significant consequences. Additional studies or revised justifications may be required to address unexpected findings or questions that may or may not have been anticipated at the outset, often resulting in delays, increased complexity, and higher costs. For that reason, overly rigid toxicology strategies can introduce avoidable regulatory, financial, and operational risk. Programs involving novel science or less established precedents are especially susceptible to uncertainty. The objective, therefore, is not to eliminate every potential surprise, but to build a preclinical strategy that is prepared to respond to them.
What Flexibility Looks Like in Preclinical Testing
Flexibility in preclinical testing should be the standard. Each program should reflect a deliberate, scientifically grounded approach to study planning that creates room for adaptation within clearly defined parameters. By emphasizing a few key tactics, a flexible preclinical strategy enables sponsors to respond to evolving program needs without compromising scientific standards.
Modular study design
A flexible program is often built on a modular framework designed to support tiered testing, scenario planning that considers differences in agency expectations, and the ability to expand or refine studies based on data as it is acquired. In practice, this means anticipating the questions most likely to emerge based on the modality, mechanism of action, indication, and intended clinical use, then selecting assays and approaches to data collection that can generate decision-relevant evidence, even if the development program needs to be modified midstream.
This approach becomes particularly important when the clinical strategy is still evolving. Changes in route of administration, duration of dosing, patient population, or dose regimen can alter nonclinical data expectations. A modular study design helps sponsors accommodate those changes more efficiently while preserving the overall coherence of the safety package.
Evidence-based strategies
Flexibility is also reflected in how the nonclinical program is constructed. Hybrid evidence strategies integrate in vivo, in vitro, and computational data to support a more comprehensive and mechanistically informed assessment. When applied appropriately, this type of data triangulation can strengthen scientific justification, improve translational relevance, and support more focused decision-making.
At the same time, sponsors should remain realistic about the pace of regulatory acceptance for emerging tools and methods. Regulatory agencies may take a measured approach in areas where validation standards are still developing or where broader scientific consensus has not yet been established.
Early and ongoing regulatory engagement
For flexibility to be productive rather than disruptive, early and thoughtful regulatory engagement is essential. US regulatory agencies’ formal meeting pathways help structure that engagement.
- Type A meetings address urgent issues that can stall a program
- Type B meetings align on key development milestones (including pre-IND)
- Type C meetings provide a mechanism to obtain feedback on other targeted questions
Used strategically, these interactions can clarify expectations before sponsors commit to a nonclinical package. While they may not resolve every uncertainty, they often provide valuable insight into regulatory priorities, likely areas of concern, and the degree of justification that may be needed for a particular strategy.
That same approach is equally important when questions arise later in development. A regulatory hold or significant agency request can extend timelines and require additional studies. In those situations, sponsors can benefit from having a flexible, submission-ready data package. The ability to respond with scientific consistency and operational readiness is a key component of a truly flexible program.
Global alignment planning
Finally, preclinical testing must be flexible enough to adapt and respond to multi-jurisdictional requirements in a global context. Planning studies that can support submissions across regions, anticipate differences in regulatory expectations, and minimize duplicative work wherever possible are critical for drug development today.
In practice, global alignment often depends on operational details that can easily be overlooked early in development. Differences in regulatory expectations for when studies are conducted, reporting conventions, and archiving requirements can have meaningful impacts on timelines if identified too late. Incorporating those considerations upfront can reduce avoidable delays and strengthen the overall efficiency of the development program.
Building Adaptive Infrastructure as a Strategic Advantage
Adaptability is most successful when it is considered essential for any drug development program. The foundational work and planning required to achieve a flexible and effective program takes a willingness to invest time and expertise up front. It is a priority that must be built into the broader development organization and into that of any partners involved in the development process as well. In practice, that means aligning an integrated strategy that spans toxicology, CMC, clinical, and regulatory functions early so the nonclinical strategy remains connected to clinical objectives and manufacturing realities.
Organizations with broad technical capabilities and a global regulatory perspective are often better positioned to support this type of adaptive planning. When implemented effectively, this approach can reduce avoidable delays, limit study repetition, and strengthen regulatory confidence.
A Final Word
Regulatory science will continue to evolve as new modalities emerge and development paradigms shift. In that environment, sponsors that build adaptability into preclinical development will be better positioned to advance innovative therapies efficiently and responsibly.
Scientific rigor and flexibility are essential for maintaining any drug development program priorities. They function together to support high-quality data, sound decision-making, and patient safety in a quickly evolving world of scientific advancement. Flexibility is about designing programs that can accommodate change without compromising the evidence needed to support first-in-human development.
About the Author
Kevin Denny, MBA, DABT, is an Executive Technical Director at WuXi AppTec’s Laboratory Testing Division and a board-certified toxicologist. He leads nonclinical and regulatory strategy for IND-enabling programs through late-stage submissions, with deep experience in GLP toxicology, global regulatory pathways, and cross-functional program leadership.