4.2.3.1 — Single-Dose Toxicity

Acute toxicity studies in 2 species (rodent and non-rodent) to determine lethal dose and target organ toxicity

Requirements by Phase

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

Content Requirements

• Data summarized very briefly by species, by route
• Table format helpful: species, route, dose, mortality, clinical signs
• Studies ordered by species, route, duration (shortest first)
• NOAEL, MTD, cause of death for each study
• 2 species required (rodent + non-rodent)

Expected Deliverables

• Study report per ICH E3 format (GLP)
• NOAEL summary table
• MTD determination table

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)

• 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.
• Lethality should not be an intended endpoint in studies assessing acute toxicity.
• [Phase 1] For microdose trials, acute toxicity or single-dose studies can be primary support, and high dose selection should be appropriate for the intended clinical dose and route, performed in GLP compliance.
• [before Phase 3] Information on acute toxicity should be available to support Phase III to predict human overdose consequences.
• [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.
• [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 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.

Regulatory Requirements (ICH S5R3)

• [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.

Note: 2 species required

Source: ICH M3(R2) Section 4