4.2.1.3 — Safety Pharmacology

Core battery studies: cardiovascular (hERG + in vivo), CNS (Irwin/FOB), respiratory function

Requirements by Phase

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

Content Requirements

• Summary and evaluation of safety pharmacology studies
• Core battery: cardiovascular/hERG, CNS (Irwin/FOB), respiratory
• Secondary PD studies contributing to safety evaluation considered alongside
• Follow-up or supplemental studies as warranted by findings

Expected Deliverables

• hERG assay study report (GLP)
• In vivo cardiovascular telemetry report (GLP)
• CNS safety study report (Irwin/FOB, GLP)
• Respiratory function study report (GLP)
• Summary table of safety pharmacology findings

ICH Guidelines: S7A, S7B

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.

Regulatory Requirements (ICH S7A)

• [Non-clinical] Safety pharmacology studies investigate potential undesirable pharmacodynamic effects on physiological functions in relation to exposure in the therapeutic range and above.
• [Pre-FIH] The core battery (CNS, cardiovascular, respiratory) must be investigated prior to first administration in humans.
• [Pre-FIH] Follow-up or supplemental studies identified as appropriate, based on a cause for concern, should also be conducted prior to first administration in humans.
• [Non-clinical] Safety pharmacology studies should be designed to define the dose-response relationship and time course of the adverse effect observed. Doses should include and exceed the primary pharmacodynamic or therapeutic range.
• [Non-clinical] Parent compound and its major human metabolite(s) that achieve systemic exposure in humans should be evaluated.
• [Non-clinical] The safety pharmacology core battery should ordinarily be conducted in compliance with GLP.
• [Non-clinical] Follow-up and supplemental studies should be conducted in compliance with GLP to the greatest extent feasible.
• [Non-clinical] Safety pharmacology studies may not be needed for locally applied agents where pharmacology is well characterized and systemic exposure is low.
• [Non-clinical] Safety pharmacology studies may not be needed for cytotoxic agents for end-stage cancer patients, unless they have novel mechanisms of action.
• [Non-clinical] For biotechnology-derived products with highly specific receptor targeting, safety pharmacology endpoints can often be evaluated as part of toxicology/pharmacodynamic studies, reducing or eliminating separate studies.

Regulatory Requirements (ICH S9)

• [Pre-clinical] An assessment of the pharmaceutical's effect on vital organ functions (including cardiovascular, respiratory and central nervous systems) should be available before the initiation of clinical studies.
• [Nonclinical] In cases where specific concerns have been identified that could put patients at significant additional risks in clinical trials, appropriate safety pharmacology studies described in ICH S7A and/or S7B should be considered.

Note: P1: core battery (CV/hERG, CNS, respiratory)

Source: ICH S7A; ICH S7B