Types of nonclinical study

Nonclinical studies fall into categories that are defined by what they measure and, in the United States, by the guidance that governs how they are designed. This article sets out those categories and the guidance each one follows, so that a study proposal can be read against the right standard. One distinction runs through all of them: exploratory work that informs a decision, and regulated work that supports a submission, are documented differently and cost differently.

Efficacy pharmacology

These studies test whether the candidate produces the intended effect in a model of the disease, and characterize the mechanism by which it does so. They are run in animal models and in cell systems, and their output supports the decision about whether to take the compound forward. They are exploratory: no guidance prescribes their design, and they are normally conducted outside the good laboratory practice regulation, which applies to nonclinical laboratory studies supporting a submission.^[S9] A result here describes the model, not the patient.

Safety pharmacology

Safety pharmacology examines effects on vital functions at and above the intended therapeutic exposure. The guidance defines a core battery covering the central nervous, cardiovascular and respiratory systems.^[S2] A separate guidance addresses the potential for delayed ventricular repolarization, measured as prolongation of the QT interval, which has its own assays because of the arrhythmia risk associated with it.^[S3] These studies contribute to the conclusion the sponsor has to reach before dosing humans: that the proposed clinical investigation is reasonably safe to conduct.^[S10]

General and repeat-dose toxicology

Repeat-dose toxicology studies identify which organs are affected, at what exposure, and whether the findings reverse when dosing stops. Their required duration is tied to the duration of the intended clinical trial, and the guidance that sets out that relationship also covers which studies are needed before each stage of clinical development.^[S1] These are the studies most often conducted under the good laboratory practice regulation, and the study report carries the study director statement of compliance.^[S9]

Pharmacokinetics

Pharmacokinetic studies measure absorption, distribution, metabolism and excretion. Their central output is exposure: how much drug reaches the circulation and the tissues, and for how long. That matters because every finding in a toxicology study is interpreted against the exposure at which it occurred, and because the exposure achieved in the animal is what the human starting dose is set relative to. Toxicokinetic measurement, meaning exposure measured within a toxicology study, is normally built into those studies rather than run separately.

Studies required for specific questions

Genotoxicity

Genotoxicity testing assesses whether a compound damages genetic material. The guidance sets out the standard combinations of in vitro and in vivo assays and how the results are interpreted, including what follows from a positive finding in one assay of the battery.^[S4] This category is absent from many general descriptions of nonclinical testing but is a standard part of the package.

Reproductive and developmental toxicology

These studies examine effects on fertility, on embryonic and fetal development, and on pre- and postnatal development. The current revision of the guidance addresses study design and also the circumstances in which alternative approaches may be used.^[S5] Timing matters here: which of these studies are needed before which clinical stage depends on the population to be enrolled, and that relationship is set out in the general guidance.^[S1]

Carcinogenicity

Long-term rodent carcinogenicity studies assess whether prolonged exposure promotes tumour formation. They are not required for every product. A dedicated guidance addresses when such studies are needed, taking into account the intended duration of treatment and other factors,^[S6] with separate guidance on how the studies are conducted and on dose selection.^[S7] These are the longest and most expensive studies in the nonclinical package, which is why the question of whether they are required is settled early rather than assumed.

Summary

Each category above answers a different question and follows a different guidance. Two practical consequences follow for a sponsor. When reading a proposal, check which guidance the study is designed against, because a study that does not follow the applicable one may not be usable for the purpose it was commissioned for. And check whether the study will be conducted under the good laboratory practice regulation, since that determines the documentation, the cost, and whether the report can support a submission.^[S9][S10]

References

1. FDA — ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, January 2010 (Revision 1). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m3r2-nonclinical-safety-studies-conduct-human-clinical-trials-and-marketing-authorization (accessed 2026-09-03)
2. FDA — ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals, April 2001. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s7a-safety-pharmacology-studies-human-pharmaceuticals (accessed 2026-09-03)
3. FDA — ICH S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals, October 2005. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s7b-nonclinical-evaluation-potential-delayed-ventricular-repolarization-qt-interval-prolongation (accessed 2026-09-03)
4. FDA — ICH S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use, June 2012. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s2r1-genotoxicity-testing-and-data-interpretation-pharmaceuticals-intended-human-use (accessed 2026-09-03)
5. FDA — ICH S5(R3) Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals, May 2021 (Revision 3). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s5r3-detection-reproductive-and-developmental-toxicity-human-pharmaceuticals (accessed 2026-09-03)
6. FDA — ICH S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals, March 1996. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s1a-need-long-term-rodent-carcinogenicity-studies-pharmaceuticals (accessed 2026-09-03)
7. FDA — ICH S1B Testing for Carcinogenicity of Pharmaceuticals, July 1997、& ICH S1C(R2) Dose Selection for Carcinogenicity Studies, September 2008 (Revision 1). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s1b-testing-carcinogenicity-pharmaceuticals (accessed 2026-09-03)
8. FDA — ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, March 2010. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s9-nonclinical-evaluation-anticancer-pharmaceuticals (accessed 2026-09-03)
9. 21 CFR Part 58 — Good Laboratory Practice for Nonclinical Laboratory Studies (§58.1 scope; §58.3 definitions). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-58 (accessed 2026-09-03)
10. 21 CFR 312.23(a)(8) — IND content and format. https://www.govinfo.gov/content/pkg/CFR-2023-title21-vol5/xml/CFR-2023-title21-vol5-sec312-23.xml (accessed 2026-09-03)