Guide to IND-Enabling Studies: Prep for Clinical Trials

Before investigational drugs can be tested in humans, sponsors must obtain clearance from the U.S. Food and Drug Administration (FDA) through an Investigational New Drug (IND) application. This submission must include results from a series of nonclinical assessments, collectively known as IND-enabling studies, designed to demonstrate that it is reasonably safe to proceed to first-in-human (FIH) trials.

These foundational studies help drug developers:

• Identify potential safety concerns early
• Define safe starting doses and dosing ranges
• Establish parameters for clinical monitoring

By guiding dose selection and ensuring a strong safety profile, IND-enabling studies are critical for risk mitigation in early development and setting the foundation for regulatory success.

What are IND-Enabling Studies?

IND-enabling studies encompass a range of in vitro and in vivo experiments that characterize a drug's pharmacologic and toxicologic properties. Together, these data support the scientific rationale for human exposure and ensure that the first clinical study is appropriately designed and justified.

Key Components of an IND-Enabling Program

The scope of IND-enabling studies depends on several factors, including the drug class, route of administration, duration of intended treatment, and target patient population. However, most programs include the following core elements:

Overview of Key Focus Areas:

• Pharmacology and safety pharmacology — evaluation of the drug's intended mechanism of action as well as potential off-target effects on vital organ systems.
• Pharmacokinetics (PK) — understanding how the drug is absorbed, distributed, metabolized, and excreted (ADME).
• Toxicology — defining safe exposure limits, identifying potential adverse effects, and assessing reversibility of toxicity.

Pharmacology

Safety pharmacology studies evaluate a compound's effects on critical physiological systems (typically cardiovascular, respiratory, and central nervous systems) in relevant animal models. Primary pharmacodynamic studies also assess how the drug exerts its therapeutic effect, its dose-response relationship, and potential off-target activity.

Pharmacokinetics

Pharmacokinetics (PK) studies characterize the drug's exposure profile in animal species used for toxicity testing. These may include in vitro metabolism and plasma protein binding assessments as well as in vivo exposure and distribution studies. Together, these data inform the prediction of human pharmacokinetics and support the selection of safe, scientifically justified starting doses for Phase 1 trials.

More advanced PK work, such as radiolabeled mass balance studies, drug-drug interaction (DDI) evaluations, and metabolite profiling, is often completed later in development but may be initiated earlier depending on the molecule's complexity.

Toxicology

Toxicology studies form the cornerstone of IND-enabling packages. Sponsors generally conduct both acute (single-dose) and repeated-dose toxicity studies in two species (one rodent, one non-rodent) via clinically relevant administration routes. These studies help establish the no-observed-adverse-effect level (NOAEL) and maximum tolerated dose (MTD)—key parameters for dose selection in humans.

Genotoxicity evaluations, including assays for gene mutation and chromosomal damage, are typically required before first-in-human dosing and must be completed prior to Phase 2 trials. Additional studies—such as reproductive, immunotoxicity, and abuse liability testing—may be conducted as appropriate to the therapeutic indication and mechanism of action.

Moving Beyond IND Submission

IND-enabling studies support initial clinical entry, but continued nonclinical development may be needed. Many programs require long-term toxicity and carcinogenicity studies before late-phase or marketing applications. As programs progress, ongoing integration of nonclinical and clinical findings is essential for refining risk assessments and ensuring patient safety throughout development.

IND-Enabling Studies & Orphan Designation

IND-enabling studies are the catalyst of a successful drug development program. They validate safety for human exposure, guide early clinical design, and build the confidence regulators need to authorize in-human testing.

For sponsors pursuing orphan drug designation or preparing regulatory submissions across FDA and EMA pathways, a clear IND-enabling strategy is essential to staying on schedule and minimizing costly setbacks.

Only Orphans Cote supports sponsors developing rare-disease therapies in achieving market authorization with the greatest economic benefit. Since the IND is one of the most critical milestones in drug development, OOC helps turn strong science into practical, successful regulatory outcomes.

Contact us to discuss how our team can support your orphan designation strategy in parallel with IND preparation.