Comment from Evotec

We support efforts to facilitate oncology drug development through scientifically justified approaches that reduce unnecessary animal testing while maintaining robust patient safety assessments. For consistent implementation & regulatory predictability of streamlined nonclinical strategies we respectfully offer the following recommendations. 1) We support alternative approaches to certain 3-month general toxicology studies, including a WoE risk assessment in appropriate cases. Clarification of the expected content & sufficiency criteria would help with implementation across sponsors & review divisions while preserving case-by-case flexibility. It would be helpful to clarify what types of evidence may support the conclusion that a target is “well understood” & that the totality of evidence is sufficient to replace or reduce an animal toxicology study. Potential evidence include: Target biology & expression profile Physiological function & disease-state relevance Product-specific pharmacology Pharmacokinetic & safety data Published literature Prior experience with target / product class Known animal / human toxicities 2) We support inclusion of fit-for-purpose NAMs as contributors to WoE risk assessment. The guidance does not describe how sponsors should position NAM-generated data within the overall assessment. We recommend clarifying how the principles described in draft guidance 'General Considerations for the Use of New Approach Methodologies in Drug Development' apply in the oncology-specific context. It would be valuable to clarify how sponsors should describe: Context of use Human biological relevance Technical characterization Fit-for-purpose justification Contribution of NAM data to WoE assessment We also recommend that the FDA clarify when NAMs may be considered supportive, gap-filling, confirmatory, or potentially decision-enabling within oncology WoE packages. 3) We support emphasis on pharmacologically relevant species for biologics & recognition that a WoE-based approach may be appropriate when no pharmacologically relevant species exists. We suggest providing examples of evidence that support species relevance determinations & scientifically justified single-species strategies. Evidence could include: Target binding / lack of binding Binding without functional activity Functional potency Downstream pharmacology Target expression Tissue cross-reactivity Pharmacodynamic response Translational pharmacology data Relevant alternative methods / NAMs Clarification would help sponsors demonstrate a lack of pharmacologically relevant species & when pharmacological activity may be considered sufficiently similar to support a single-species approach. 4) We support FDA’s recommendation that, for ADCs with cytotoxic payloads, a 3-month toxicology study may be conducted in rodents only when payload safety is well characterized & the payload is the primary driver of toxicity. We recommend clarifying what evidence may support conclusions that the payload is: a) “well characterized” b) the main driver of toxicity Potential evidence could include: Prior experience with the same payload Experience with approved ADCs containing the same payload Payload / linker pilot studies Linker stability data ADC & payload toxicokinetics Free payload exposure Exposure-toxicity relationship Distribution data Established class tox profile Clarification would facilitate application of the recommendation & alignment with ICH S9 & ICH S9 Q&A. 5) We support FDA’s recommendation that a WoE risk assessment be submitted when an ADC target is novel & binding does not occur in rodents. To avoid ambiguity & ensure alignment with existing ICH S9 Q&A recommendations, we recommend clarifying the expected content of this additional WoE assessment & how it should be interpreted relative to existing guidance. Potential WoE elements include: Target biology Human tissue expression Off-target/off-tumor risk assessments Human tissue cross-reactivity data In vitro functional assays Translational pharmacology data Prior scientific knowledge Fit-for-purpose NAMs Clarity would help avoid that the recommendation is interpreted as creating a default expectation for additional animal models when alternative approaches may adequately address the relevant risks. 6) We support the recommendation that sponsors discuss alternative approaches with the FDA early in development. To facilitate implementation, we suggest providing further guidance regarding: Appropriate timing for discussions Minimum briefing package Potential briefing package could include: Proposed context of use Scientific rationale for alternative approach Available pharmacology, toxicology, & pharmacokinetic data NAM validation / fit-for-purpose justification The specific regulatory decision supported by the alternative approach Further clarity would facilitate efficient sponsor-review division interactions & broader adoption of justified streamlined strategies.