5.3.3.1 — Healthy Subject PK and Tolerability

Single- and multiple-dose PK and initial tolerability studies in healthy volunteers

Requirements by Phase

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

Content Requirements

• Reports of PK and initial tolerability in healthy subjects
• Single ascending dose (SAD) studies
• Multiple ascending dose (MAD) studies
• Full CSR per ICH E3 format

Expected Deliverables

• SAD study report (ICH E3 format)
• MAD study report (ICH E3 format)

ICH Guidelines: E3, M4E(R2)

Regulatory Requirements (ICH M3R2)

• [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).
• [before Phase 1] All relevant nonclinical data (pharmacological dose response, pharmacological/toxicological profile, pharmacokinetics) should be considered when determining the recommended starting dose in humans.

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 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).

Note: P1: protocol for planned study. P2+: completed reports

Source: ICH E3; ICH M3(R2)