4.2.3.7.2 — Immunotoxicity

Immunotoxicity studies evaluating immune function per ICH S8

Requirements by Phase

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

Content Requirements

• Immunotoxicity studies evaluating immune function
• Weight-of-evidence approach from standard toxicity studies
• Additional immunotoxicity studies if warranted (TDAR, NK cell, lymphocyte subsets)
• Assessment per ICH S8 decision tree

Expected Deliverables

• Immunotoxicity study report
• Weight-of-evidence immunotoxicity assessment

ICH Guidelines: S8

Regulatory Requirements (ICH M3R2)

• All new human pharmaceuticals should be evaluated for immunotoxicity potential using standard toxicity studies and additional immunotoxicity studies as appropriate.
• [before Phase 3] If additional immunotoxicity studies are indicated, they should be completed before exposure of a large patient population (e.g., Phase III).

Regulatory Requirements (ICH S8)

• [Nonclinical Development] Evaluation of potential adverse effects of human pharmaceuticals on the immune system should be incorporated into standard drug development.
• [Nonclinical Development] All new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity.
• [Nonclinical Development] Whether additional immunotoxicity studies are appropriate should be determined by a weight of evidence review of factor(s) in section 2.1.
• [Nonclinical Development] Data from Standard Toxicity Studies (STS) should be evaluated for signs of immunotoxic potential.
• [Nonclinical Development] The assessment of immunotoxicity should include: statistical and biological significance of the changes; severity of the effects; dose/exposure relationship; safety factor above the expected clinical dose; treatment duration; number of species and endpoints affected; changes that may occur secondarily to other factors; possible cellular targets and/or mechanism of action; doses which produce these changes in relation to doses which produce other toxicities; and reversibility of effect(s).
• [Nonclinical Development] If the pharmacological properties of a test compound indicate it has the potential to affect immune function, additional immunotoxicity testing should be considered.
• [Nonclinical Development] Compounds structurally similar to compounds with known immunosuppressive properties should also be considered for additional immunotoxicity testing.
• [Nonclinical Development] If the compound and/or its metabolites are retained at high concentrations in cells of the immune system, additional immunotoxicity testing should be considered.
• [Nonclinical Development] A weight of evidence review should be performed on information from all the factors outlined above to determine whether a cause for concern exists.
• [Nonclinical Development] A finding of sufficient magnitude in a single area should trigger additional immunotoxicity studies.
• [Nonclinical Development] If additional immunotoxicity studies are not performed, the sponsor should provide justification.
• [Nonclinical Development] If a cause for concern is identified, additional immunotoxicity studies should be performed to verify the immunotoxic potential of the compound.
• [Nonclinical Development] It is recommended that an immune function study be conducted, such as a T-cell dependent antibody response (TDAR).
• [Nonclinical Development] Where a specific target is not identified, an immune function study such as the TDAR is recommended.
• [Nonclinical Development] The species, strain, dose, duration, and route of administration used in additional immunotoxicity studies should be consistent, where possible, with the standard toxicity study in which an adverse immune effect was observed.

Source: ICH S8