Preclinical IND-enabling studies establish safety and dosing parameters that allow clinical trials to proceed. Developmental and Reproductive Toxicology studies (DART) can be an important component of that preclinical program, providing early safety data that clarifies potential reproductive risks and informs trial design and monitoring considerations. When done well, insights from DART studies have the potential to expand patient enrollment and align clinical planning with safety monitoring, ultimately streamlining the IND path.

A New Regulatory Landscape for DART

DART studies are a critical component of understanding a new drug’s impact on fertility and embryo-fetal development. This can be informative for clinicians designing the subsequent required clinical studies.  They also define contraception and pregnancy-testing requirements, guide trial eligibility and monitoring to de-risk IND submissions, and provide regulators with a more complete and scientifically defensible safety profile.

However, DART study design has entered a period of transformation. Updated guidance from the International Council on Harmonization (ICH), particularly S5(R3) and S6(R1),¹ encourages more flexible, scientifically justified approaches to preclinical safety testing, including reproductive and developmental toxicology safety testing. These approaches empower sponsors to integrate multiple data sources—mechanistic, pharmacologic, and in vitro—into a cohesive risk assessment, reducing dependence on legacy animal testing.

Regulators in both the U.S. and Europe are reinforcing this shift through initiatives such as the Drug Development Tools (DDT) qualification program,² which provides a pathway to validate alternative methodologies. The aim is clear: increase scientific rigor while reducing unnecessary animal use.

This evolution is especially important for sponsors pursuing accelerated regulatory pathways, such as Fast Track, Breakthrough Therapy, or Priority Review, where compressed timelines demand efficiency at every stage. Advancements in targeted drug discovery, new delivery technologies, and clinical trial designs have enabled the rapid development of novel therapeutics. Still, traditional sequential toxicology programs don’t fit these accelerated pathways, and DART studies are no less critical for clinical development.

Best Practices for IND Acceleration Through DART

At first glance, including DART can seem like an inherent extension of the drug approval process. However, thoughtful design and early regulatory alignment can identify safety risks sooner, refine species and dose choices, and prevent additional delays, thereby improving the process’s efficiency and sharpening predictions. With a few strategic decisions, the process of drug development can leverage DART study timing to enhance IND scheduling.

1. Engage Regulators Early

Early dialogue is one of the most effective ways to accelerate IND submissions. Pre-IND meetings allow sponsors to align with regulators on key design elements, including dosing regimens and study endpoints. For complex molecules such as biologics or antibody-drug conjugates (ADCs), these discussions can clarify the appropriateness of in vitro assays or other alternatives when traditional testing models lack relevance.

Equally important is ensuring consistency in Chemistry, Manufacturing, and Controls (CMC) across preclinical batches. Manufacturing variability can affect toxicology outcomes, making early alignment between CMC and toxicology teams critical to avoid regulatory delays.

2. Adopt a Weight-of-Evidence (WoE) Framework

A well-executed WoE strategy integrates diverse data sources to create a comprehensive and scientifically defensible picture of reproductive safety. Mechanistic data, pharmacokinetic/pharmacodynamic (PK/PD) modeling, and human genetic information can all contribute to a more predictive understanding of potential risks, providing an improved regulatory framework to accelerate drug development.

By leveraging this existing data to paint as complete a picture as possible within preclinical phases, sponsors can often narrow the scope of animal testing, reducing the number of studies needed while maintaining scientific credibility. For example, if the mechanism of action (MOA) is well characterized and the reproductive risk is predictable, regulators may accept a scientifically justified, streamlined package or defer specific studies, rather than requiring full confirmatory testing in all cases.

3. Parallelize Where Appropriate

Traditionally, DART studies are conducted sequentially, completing one before initiating the next phase of development. But for accelerated programs, this model may not be the best path. Conducting certain DART studies in tandem with early clinical trials can dramatically shorten development timelines. For instance, developers can initiate reproductive toxicology studies with early human trials, expediting regulatory review while maintaining high safety standards. Today, regulators are increasingly open to such approaches when justified by risk-benefit considerations.

4. Leverage Emerging Tools and Technologies

Technological innovation is reshaping what’s possible in reproductive toxicology. Emerging in vitro models now allow early screening for placental transfer and developmental toxicity. Others can mimic key reproductive processes, providing mechanistic insights that were previously unavailable. Meanwhile, advanced decision support technology is also gaining traction. By analyzing large datasets from historical studies, machine learning algorithms can identify structure-activity relationships and predict reproductive risks earlier in development.

While these technologies aren’t yet replacements for in vivo studies, their role as complementary data streams is expanding. Used judiciously, they can help refine study design, focus resources, and improve the predictive power of DART assessments.

Pitfalls and Watchouts

Even the most thoughtfully designed DART program can run into problems. Complex molecules, evolving regulations, resource constraints, and competing timelines introduce risks that can derail even well-planned IND submissions. Recognizing where programs commonly stumble and addressing those pitfalls early can help sponsors maintain momentum and credibility. Here are some key challenges of DART that are particularly common:

• CMC inconsistency: Manufacturing changes between preclinical and clinical lots can lead to inconsistent toxicology data. Ensure tight change control is in place when manufacturing process changes occur and consider conducting bridging studies when needed. 
• Overreliance on new tools: In vitro or automated methods enhance insight but rarely replace in vivo evidence in regulatory submissions. Ensure that advanced technologies and tools are a complement, rather than a replacement for traditional methods. Regulators expect both new technologies and standard toxicology data to evaluate safety. 
• Patient-specific risk balance: One size doesn’t fit all and can lead to wasted resources. Tailor study timing to the disease severity and document the rationale for study design decisions in pre-IND phases. 

Ultimately, strategic foresight, scientific justification, and proactive communication with regulators remain the cornerstones of successful DART planning.

A Final Word

Developmental and Reproductive Toxicology has long been viewed as a compliance checkpoint. But for sponsors who approach it strategically, DART becomes a powerful tool that can streamline IND submissions, strengthen regulatory confidence, and conserve valuable time and resources. A modern DART program is where science meets speed. Done well, it safeguards patients, satisfies regulators, and accelerates breakthroughs to market. In the race to bring safe, effective therapies to patients faster, DART doesn’t have to be a bottleneck. It can be a differentiator.

References

1. International Council for Harmonization. (n.d.). Safety guidelines. Retrieved October 30, 2025, from https://www.ich.org/page/safety-guidelines
2. U.S. Food and Drug Administration. (2025, July 21). Drug development tool (DDT) qualification programs. https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tool-ddt-qualification-programs

Kevin Denny, DABT (1994–2024), is Executive Director of Toxicology at WuXi AppTec. He is a board-certified nonclinical toxicologist with more than 40 years in pharmaceutical drug development. A recognized expert in Developmental & Reproductive Toxicology (DART), regulatory strategy, and quality, he designs IND-enabling programs that balance rigor and speed. Kevin has led cross-functional teams in pharma, biotech, and CRO settings; directed pharmacology, ADME, and GLP toxicology studies; and guided multiple programs to successful IND, NDA, and BLA submissions. His therapeutic focus spans CNS, neurology, neurodegeneration, and pain. He has established and managed GLP laboratories in the U.S. and France, overseen extensive study outsourcing, and built high-trust collaborations with CROs and investigators.