2.4 — Nonclinical Overview

Nonclinical overview: integrated assessment of pharmacology, PK, and toxicology (~30 pages for NDA)

Requirements by Phase

IND Phase 1: minimal IND Phase 2: minimal IND Phase 3: minimal NDA: required

Content Requirements

• Nonclinical testing strategy and rationale
• Pharmacology overview (primary, secondary, safety pharmacology)
• Pharmacokinetics overview (absorption, distribution, metabolism, excretion)
• Toxicology overview (single-dose, repeat-dose, genotoxicity, carcinogenicity, reproductive/developmental toxicity)
• Integrated overview and conclusions
• GLP compliance status for each study
• Impurity qualification assessment (for new chemical entities)
• Literature references

Expected Deliverables

• Nonclinical overview document (~30 pages)

Page guidance: ~30 pages

ICH Guidelines: ICH M4S

Regulatory Requirements (ICH M3R2)

• Nonclinical safety studies should be adequate to characterize potential adverse effects that might occur under the conditions of the clinical trial to be supported.
• Clinical trials should be extended based on the demonstration of adequate safety in previous clinical trial(s) and additional nonclinical safety information.
• Serious adverse clinical or nonclinical findings should be evaluated to determine the appropriateness and design of additional nonclinical and/or clinical studies.
• In toxicity studies, effects should be characterized using doses up to the MTD, or other limiting doses (exposure multiples, saturation, MFD).
• Limit doses for acute, subchronic, and chronic toxicity studies should be 1000 mg/kg/day for rodents and non-rodents, unless specific conditions apply.
• Doses providing a 50-fold margin of exposure (AUC) to clinical systemic exposure are generally acceptable as the maximum dose for acute and repeated-dose toxicity studies.
• [Phase 3] For Phase III clinical trials (US), dose-limiting toxicity should generally be identified in at least one species using the 50-fold margin of exposure as the limit dose.
• If genotoxicity endpoints are incorporated into a general toxicity study, the maximum dose should be MFD, MTD, or 1000 mg/kg/day limit dose.
• [before Phase 1] The core battery of safety pharmacology studies (cardiovascular, central nervous, respiratory systems) should generally be conducted before human exposure, in accordance with ICH S7A and S7B.
• [before Phase 1] In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data in repeated-dose toxicity study species should be evaluated before initiating human clinical trials.
• [before Phase 3] Further PK information (absorption, distribution, metabolism, excretion) and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before Phase III).
• Nonclinical characterization of a human metabolite(s) is warranted only when observed at exposures >10% of total drug-related exposure and significantly greater levels in humans than maximum exposure in toxicity studies.
• [before Phase 3] Metabolite characterization studies should be conducted to support Phase III clinical trials.
• Acute toxicity information can be obtained from dose-escalation or short-duration dose-ranging studies defining MTD in general toxicity test species.
• Acute toxicity data can be obtained from non-GLP studies if clinical administration is supported by appropriate GLP repeated-dose toxicity studies.

Note: NDA: full ~30 pages

Source: ICH M4S