Official guidance for US drug development

The FDA guidance documents and ICH guidelines that govern nonclinical work, and where to find the current version of each

In the United States, the documents that describe how nonclinical studies should be designed are published by the Food and Drug Administration as numbered guidance documents, and most of the nonclinical ones are adopted versions of guidelines agreed through the International Council for Harmonisation.^[S1] This page lists the ones a nonclinical programme is most likely to need, with what each covers. Guidance from the European regulator is included separately, for programmes that will also be filed there.

What a guidance document is, and is not

FDA guidance documents describe the agency current thinking on a topic. They are not regulations, they do not bind the agency or the public, and an alternative approach may be used if it satisfies the applicable statutes and regulations. That is stated on the documents themselves. The practical consequence for a sponsor is that a study design departing from guidance is not automatically unacceptable, but the departure has to be justified, and the place to establish that is a meeting with the agency rather than the final report.

Nonclinical safety: the framework

M3(R2): which studies are needed, and when

The central document. It sets out which nonclinical safety studies are needed before each stage of clinical development, how the duration of repeat-dose toxicology relates to the duration of the intended trial, and what is required to support a marketing application. Issued by the agency in January 2010.^[S2]

The S series: study-specific guidance

• {'items': ['S7A, safety pharmacology, July 2001. Defines the core battery covering the central nervous, cardiovascular and respiratory systems.^[S3]', 'S7B, delayed ventricular repolarization, October 2005. The nonclinical assessment of QT interval prolongation.^[S4]', 'S2(R1), genotoxicity, June 2012. The standard assay combinations and how results are interpreted.^[S5]', 'S5(R3), reproductive and developmental toxicity, May 2021. Study designs and the circumstances for alternative approaches.^[S6]', 'S1A, S1B and S1C(R2), carcinogenicity. S1A addresses whether long-term rodent studies are needed at all; the others cover conduct and dose selection.^[S7]', 'S9, anticancer pharmaceuticals, March 2010. A different package applies to products for patients with advanced cancer.^[S8]']}

E6(R3): good clinical practice

The current good clinical practice guideline, adopted internationally on January 6, 2025 and issued by the agency as a guidance document in September 2025.^[S9] It governs clinical trials rather than nonclinical work, and is listed here because the boundary matters: the good laboratory practice regulation applies to nonclinical laboratory studies, and good clinical practice applies once humans are dosed. The two are separate systems and a laboratory compliant with one is not thereby compliant with the other.

European guidance on first-in-human trials

Issued by the European Medicines Agency and effective February 1, 2018, this addresses how nonclinical data are integrated to set the starting dose and the escalation scheme in first-in-human trials.^[S13] It is included here because programmes intended for both markets are often designed against it as well, and because its treatment of the nonclinical-to-clinical dose calculation is more detailed than the equivalent US material.

Cancer trial eligibility criteria

Final guidance issued July 2020, addressing how eligibility criteria for cancer trials handle organ function and prior or concurrent malignancies, with the aim of not narrowing enrolment unnecessarily.^[S10] This is a clinical trial design document rather than a nonclinical one, and is listed here because organ function criteria are often set with reference to nonclinical findings.

Project Optimus

An initiative of the agency oncology centre directed at dose optimization, with the aim that the dose taken into registration trials is selected from adequate dose-finding rather than from the maximum tolerated dose alone.^[S11] It has a direct nonclinical consequence: exposure-response characterization in the nonclinical package carries more weight under this approach than it did previously.

European nonclinical guidance index

The European agency index page for nonclinical development guidance, useful when a programme will be filed in Europe as well as the United States.^[S14] Where the two agencies have adopted the same ICH guideline the content is the same; the differences lie in the additional guidance each publishes on its own.

Finding the current version of a US guidance document

Guidance documents are revised, and a superseded version can remain in circulation. The agency maintains a searchable database of its guidance documents, which is the place to confirm the current version and its issue date before designing a study against it.^[S1] Search by the guideline designation, such as M3(R2) or S2(R1), rather than by topic.

How the same guideline is cited in different jurisdictions

An ICH guideline is adopted separately by each regulator, and cited differently in each. In the United States it becomes a numbered FDA guidance document with an issue date, referenced by that designation. In Japan the same guideline is implemented through a ministry notification and cited by notification number. A study report or protocol prepared for one jurisdiction will therefore cite the guideline in a form that looks unfamiliar in the other, even though the technical content is the same. This matters when reviewing documentation from a laboratory that works across regions.

An approval worth reading

Resmetirom, approved March 14, 2024

The agency announced this as the first treatment approved for adults with noncirrhotic fatty liver disease with moderate to advanced fibrosis.^[S12] It is listed here as a reference point for programmes in this area, because the approval established what the agency accepted as an endpoint in a disease where endpoints had been an open question. This site does not comment on the efficacy of any approved product; the approval and its stated indication are the facts recorded here.

About this page

This is a reference list maintained for people who commission nonclinical work in the United States. Guidance documents are revised and links change, so the issue date is given for each and the current version should be confirmed in the agency database before use.^[S1] Guidance describes the agency current thinking and is not binding. This site does not recommend any laboratory. Last reviewed: September 3, 2026.

References

1. FDA — Search for FDA Guidance Documents. https://www.fda.gov/regulatory-information/search-fda-guidance-documents (accessed 2026-09-03)
2. FDA — ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, January 2010. 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)
3. FDA — ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals, July 2001. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s7a-safety-pharmacology-studies-human-pharmaceuticals (accessed 2026-09-03)
4. 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)
5. 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)
6. FDA — ICH S5(R3) Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals, May 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s5r3-detection-reproductive-and-developmental-toxicity-human-pharmaceuticals (accessed 2026-09-03)
7. FDA — ICH S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals, March 1996（connection: S1B, July 1997、S1C(R2), September 2008）. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s1a-need-long-term-rodent-carcinogenicity-studies-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. FDA — ICH E6(R3) Good Clinical Practice (GCP), September 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r3-good-clinical-practice-gcp (accessed 2026-09-03)
10. FDA — Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies, final guidance (July 2020). https://www.fda.gov/media/123745/download (accessed 2026-09-03)
11. FDA — Project Optimus (Dose optimization initiative in oncology, Oncology Center of Excellence). https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus (accessed 2026-09-03)
12. FDA — Press release: FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease (March 14, 2024). https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease (accessed 2026-09-03)
13. EMA — Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products (Revision 1、Effective February 1, 2018). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-and-mitigate-risks-first-human-and-early-clinical-trials-investigational-medicinal-products-revision-1_en.pdf (accessed 2026-09-03)
14. EMA — Non-clinical development guidelines. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-guidelines/non-clinical-guidelines/non-clinical-development-guidelines (accessed 2026-09-03)