4.2.3.5.2 — Embryo-Fetal Development

Embryo-fetal development study (Segment II) in 2 species (rodent + rabbit) evaluating teratogenic potential

Requirements by Phase

IND Phase 2: conditional IND Phase 3: required NDA: required

Content Requirements

• EFD studies in 2 species (rat + rabbit)
• Brief methodology and important findings
• Teratogenic potential assessment
• Maternal toxicity and embryo-fetal findings
• GLP required, 2 species

Expected Deliverables

• Rat EFD study report (GLP)
• Rabbit EFD study report (GLP)
• Summary table of embryo-fetal findings by species

ICH Guidelines: S5(R3)

Regulatory Requirements (ICH M3R2)

• [Phase 3] For monoclonal antibodies with low embryo-fetal exposure, developmental toxicity studies can be conducted during Phase III, with reports submitted with marketing application.
• [before Phase 3] In the US, embryo-fetal development assessment can be deferred until before Phase III for WOCBP with pregnancy precautions.
• Combination studies are not recommended if individual agents show embryo-fetal risk, as human developmental hazard is already identified.
• [marketing] If individual agents have been tested in embryo-fetal studies but combination embryo-fetal studies are warranted, the combination study(ies) should be available to support the marketing application.
• Preliminary embryo-fetal studies should be conducted under high-quality scientific standards and GLP conditions.

Regulatory Requirements (ICH S9)

• [Marketing application] Embryofetal toxicity studies of anticancer pharmaceuticals should be available when the marketing application is submitted.
• [Nonclinical] For small molecules, embryofetal toxicology studies are typically conducted in two species as described by ICH S5(R2).

Note: P2: required if women of childbearing potential enrolled

Source: ICH S5(R3)