4.2.1.1 — Primary Pharmacodynamics

In vitro and in vivo studies evaluating primary pharmacodynamic effects of the drug on its intended target

Requirements by Phase

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

Content Requirements

• Summary and evaluation of primary PD studies
• Relate pharmacology to selectivity, safety, and potency of drugs in the class
• In vitro and in vivo studies on intended target
• Dose-response relationships for primary pharmacological effect

Expected Deliverables

• Study report per ICH E3 format
• Summary table of primary PD study results

ICH Guidelines: M3(R2), S7A

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 S1A)

• [Pre-marketing approval] For different salts, acids, or bases of the same therapeutic moiety, where prior carcinogenicity studies are available, evidence should be provided that there are no significant changes in pharmacokinetics, pharmacodynamics, or toxicity.

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.
• [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] 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)

• [Phase I] The start dose should be scientifically justified using all available nonclinical data (e.g., pharmacokinetics, pharmacodynamics, toxicity), and its selection based on various approaches (see Note 2).

Source: ICH M3(R2); ICH S7A