4.2.3.2 — Repeat-Dose Toxicity

Repeat-dose toxicity studies with duration matching or exceeding planned clinical exposure. ICH M3(R2) Table 1 defines minimum durations.

Requirements by Phase

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

Content Requirements

• Studies summarized by species, route, duration
• Brief methodology description
• Highlight important findings: target organ toxicity, dose-response, NOAEL, adverse effect levels
• Supportive toxicokinetics included
• Non-pivotal studies in less detail
• Duration per ICH M3(R2) Table 1

Expected Deliverables

• Study report per ICH E3 format (GLP)
• NOAEL/LOAEL summary table
• Toxicokinetic data tables
• Target organ toxicity summary

ICH Guidelines: M3(R2)

Regulatory Requirements (FDA SAFE STARTING DOSE)

• [Preclinical] The NOAEL should be the highest dose level that does not produce a significant increase in adverse effects in comparison to the control group, considering biologically significant effects.
• [Preclinical] For most systemically administered therapeutics, HED conversion should be based on normalization of doses to body surface area (b=0.67, i.e., (Wanimal/Whuman)^0.33).
• [Preclinical] Unless evidence is provided to the contrary, HED calculations should be based on b = 0.67 (standard conversions based on mg/m² relationships).
• [Before Phase 1] The default safety factor for MRSD calculation is 10.
• [Preclinical] If the HED is based on an alternative index of effect, such as the pharmacologically active dose (PAD), this exception should be prominently stipulated.
• [Before Phase 1] If the pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the clinical starting dose.

Regulatory Requirements (ICH M3R2)

• 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.
• [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.
• Acute toxicity data can be obtained from non-GLP studies if clinical administration is supported by appropriate GLP repeated-dose toxicity studies.
• The duration of animal repeated-dose toxicity studies in two mammalian species (one non-rodent) should be equal to or exceed the duration of human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies (Table 1).
• [Phase 1] Repeated-dose toxicity studies in two species (one non-rodent) for a minimum of 2 weeks generally support clinical trials up to 2 weeks.
• Clinical trials of longer duration should be supported by repeated-dose toxicity studies of at least equivalent duration.
• [before Phase 1] The NOAEL from nonclinical safety studies in the most appropriate animal species provides important information for clinical starting dose estimation.
• [Phase 1] Approach 4 for multiple dose trials requires 2-week repeated-dose toxicity studies in rodents and non-rodents, with dose selection based on exposure multiples of anticipated AUC at maximum clinical dose.
• [Phase 1] Approach 5 requires a 2-week toxicity study in a rodent and a confirmatory non-rodent study to investigate if rodent NOAEL is non-toxic in non-rodent.
• [Phase 1] If toxic effects are observed in the non-rodent at rodent NOAEL exposure (Approach 5), clinical administration should be deferred until further nonclinical studies in that species are conducted.
• Women not of childbearing potential can be included in clinical trials without reproduction toxicity studies if relevant repeated-dose toxicity studies (including female reproductive organ evaluation) have been conducted.
• [Phase 1, Phase 2] WOCBP can be included in repeated-dose Phase I and II trials before female fertility study if female reproductive organs are evaluated in repeated-dose toxicity studies.
• [before Phase 1] Repeated-dose toxicity studies of appropriate duration in adult animals, the core safety pharmacology package, and the standard battery of genotoxicity tests should be available before initiation of trials in pediatric populations.

Regulatory Requirements (ICH S5R3)

• [All] High dose in definitive studies should be based on toxicity, saturation of systemic exposure, exposure margin, maximum feasible dose (MFD), or limit dose (1 g/kg/day).
• [All] Lower dose levels should establish a NOAEL, consider exposure, pharmacology, and toxicity, and generally provide a low multiple (1 to 5-fold) of human exposure at MRHD.
• [All] Increased concern when NOAEL occurs at exposures < 10-fold human MRHD exposure; effects > 25-fold human MRHD exposure are usually of minor concern.

Regulatory Requirements (ICH S9)

• [Pre-Phase III] Results from repeat dose studies of 3 months' duration following the intended clinical schedule should be provided prior to initiating Phase III studies.

Note: P1: 14-28 days. P2: 3-6 months. P3: 6-9 months. NDA: chronic

Source: ICH M3(R2) Table 1