De-Risking U.S. Market Entry Of Early-Stage Therapeutics

By Melissa Allensworth, principal, Tunnell Consulting

Biopharma companies developing early-stage therapeutics often find moving from preclinical through translational medicine to clinical development is an arduous journey on the path to first-in-human (FIH) clinical trials. Therefore, focused, precise strategy and planning on the road to FIH is essential and lays the foundation for IND-enabling studies promoting regulatory and commercial pathways.

Early-stage therapeutic development can falter without proper medical and scientific data coupled with complete documentation elucidating the path from preclinical to FIH. Good science does not always get to the clinic, as documentation and repeatability are paramount to the therapeutic journey. By aligning preclinical research, translational medicine, and clinical development with regulatory expectations; differentiating therapeutic assets early and on an ongoing basis; and leveraging external expertise, companies can avoid costly missteps and possibly accelerate their entry into the highly competitive U.S. market.

Start With The Regulatory Pathway Top Of Mind

One of the most effective ways to de-risk a therapeutic program is to approach preclinical development with a regulatory mindset. Instead of viewing toxicology and pharmacology studies as scientific experiments, developers should ask: What are the FDA requirements for our IND submission? What scientific data will support the safety of our therapy in humans?

While these are big questions, this approach requires an early understanding of FDA regulations and guidelines. Sponsors who engage the FDA early and proactively — often through a pre-IND meeting — gain valuable insight that can shape clinical study design and prevent delays later in development.

For example, a preclinical oncology program recently avoided months of delay by consulting the FDA early. The agency’s feedback prompted the sponsor to expand toxicology testing, a step that proved critical for IND submission preparedness. This early course correction ultimately saved the sponsor both time and development costs.

Early FDA engagement also signals regulatory maturity to investors and partners, which can be critical for securing funding or partnerships during this capital-intensive phase.

Identifying Gaps Early In Development

While promising data may suggest a therapeutic asset has potential for IND-enabling studies, gaps can often go unnoticed — whether scientific, manufacturing, medical, clinical, or regulatory, among others. In early-stage development there are a lot of moving parts that need to work in concert. This is why comprehensive gap assessments are essential. By way of example, areas to consider:

• The biological rationale for the target: Is the mechanism of action (MOA) well supported by data? Are there known or potential off-target risks? If so, are these risks properly and scientifically documented?
• Translational medicine – “bench to bedside:” It is essential to understand how your therapeutic asset can transition from research to treating patients with unmet medical needs. Clinical and regulatory outcomes, coupled with translational medicine, help increase the probability of success.
• Manufacturing and formulation readiness: Drug manufacturing requires strict adherence to cGMP, even at the early stage. This ensures a drug is safe and compliant with regulatory requirements for human use.

Gap analyses should be iterative and conducted in collaboration with scientific, medical, and regulatory expertise. By identifying gaps early, companies can take corrective actions before they evolve into regulatory concerns.

As an example, in diseases with crowded therapeutic indications, sponsors who integrate unique biomarkers or genetic testing endpoints in clinical studies can demonstrate early differentiation from competing therapies. This helps bolster regulatory discussions and investor confidence, illustrating the power of a thorough gap assessment paired with strategic study design.

Don’t Just Outsource — Strategically Partner

Clinical development is often outsourced to CROs, which is invaluable to the sponsor for providing technical expertise and know-how. However, outsourcing without well-managed strategic oversight is risky — especially in early-stage programs where misalignment can have costly consequences.

Choosing a CRO partner should be based on cost or availability but, more importantly, on the CRO’s track record with similar IND-enabling studies and FDA submissions. Ask tough and thoughtful questions: Have you supported sponsors with successful IND submissions? Do you have direct experience with the regulatory distinctions of our therapeutic area?

In parallel, regulatory consultants can offer valuable perspectives. Their guidance on study design, data interpretation, and FDA communication can make the difference between a smooth IND review or a less favorable outcome. It’s critical to establish robust coordination and clear communication between the sponsor, the CRO, and expert consultants to ensure aligned goals, timelines, and efficient execution.

Differentiate Early Or Risk Getting Lost Later

Scientific novelty is no longer enough to carry a therapeutic across the finish line. In crowded indications like oncology or rare diseases, differentiation must be clearly defined early.

That means designing studies that not only show that a therapy works but also how it compares to standard of care (SOC) or competing investigational therapies. Head-to-head studies in animal models can be powerful, particularly when paired with validated biomarkers or imaging endpoints that support MOA.

PK/PD modeling is another strategic asset. When well executed, this modeling allows developers to justify clinical dosing and scheduling, de-risk early trial design, and align expectations with regulators. Together, these strategies build a scientific narrative that distinguishes the asset and sets the stage for downstream success.

Tell A Clear And Concise Scientific Story — Fully Backed By Data

Ultimately, what the FDA (and investors) look for is a cohesive, compelling, and scientifically backed therapeutic story. That story begins long before the IND is submitted and must be fully supported by scientific data.

Sponsors should be thinking in terms of narrative coherence across pharmacology, drug safety, toxicology, CMC, and more. The rationale for target selection, the logic behind the chosen animal models, the alignment between MOA and expected clinical outcomes — all of these elements should thread together into a single narrative that supports human clinical trials.

This narrative becomes the backbone of the IND package, and it should evolve in parallel with scientific, medical, and clinical evidence. While the IND is the deliverable, the details truly matter.

Conclusion

Preclinical and translational development is more than a prerequisite to FIH clinical trials — it’s where a therapeutic asset’s future is forged. For companies targeting the U.S. market, this phase represents a critical opportunity to identify, assess, and mitigate the scientific and regulatory risks that often derail promising programs.

By taking a strategic, data-driven approach to early development — one rooted in regulatory foresight, differentiation, and scientific rigor — biopharma innovators can position their therapeutic assets for a proven regulatory pathway, stronger investor confidence, and a clearer path to commercialization.

Lastly, it is important to note there is no substitute for experience in leading novel therapies to FIH. Collaborate early and fully with experts who have trod this road before, including scientific, medical, clinical, regulatory, manufacturing, supply chain, and more. The U.S. market is demanding, but with thoughtful planning and expert guidance, companies can turn early-stage uncertainty into long-term success.

Lessons Learned: Key Takeaways For Executives

• Engage the FDA early — A pre-IND meeting can surface critical insights, prevent delays, and demonstrate regulatory maturity to investors.
• Conduct comprehensive gap assessments — Systematically review scientific, clinical, regulatory, and manufacturing elements to catch issues before they become showstoppers.
• Choose CROs and consultants strategically — Select partners with proven experience in IND-enabling studies and maintain strong oversight to avoid costly misalignment.
• Differentiate from competitors early — Use biomarkers, translational medicine, and PK/PD modeling to show how your asset stands apart in crowded indications.
• Tell a cohesive scientific story — Ensure every element of preclinical and translational work threads into a clear data-backed narrative that supports your IND submission.
• Think beyond science — Position regulatory strategy, investor confidence, and commercialization planning as integral parts of early development, not afterthoughts.

About The Author:

Melissa Allensworth is principal and leader of Tunnell Consulting’s early-stage practice. She has extensive experience in clinical development from preclinical/translational medicine to Phase 1-3 drug development and has been instrumental in facilitating virtual biotech models for early-stage clients. Her consulting services include protocol development and trial design, regulatory services (FDA, EMA, and NMPA for pre-IND/IND submission), translational medicine, pharmacovigilance/safety, clinical operations, data management, and more. Allensworth’s therapeutic experience includes hematology/oncology (blood and solid tumors) with modalities such as small molecules, cell therapies (CAR-T), gene therapies (AAV and Lenti), immuno-oncology, and precision medicine. She also has worked with leading experts in NASH/liver fibrosis and CNS therapies. Contact her at melissa.allensworth@tunnellconsulting.com.