ADC Bioanalysis Knowledge Base

ICH_S9_oncology

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ICH S9 — Nonclinical Evaluation for Anticancer Pharmaceuticals (2009)

概述 Overview

Document: ICH S9 Guideline — Nonclinical Evaluation for Anticancer Pharmaceuticals
Agency: ICH (adopted by FDA, EMA, PMDA, HC)
Adopted: Step 4 — November 2009 (FDA effective: March 2010)
Status: Final; supplemented by ICH S9 Q&As (2018)
PDF: https://database.ich.org/sites/default/files/S9_Guideline.pdf
Q&As: https://database.ich.org/sites/default/files/S9_Q&As_Q&As.pdf

ICH S9 is the primary nonclinical framework for ADC development in oncology indications. Its central principle: for drugs treating life-threatening diseases (advanced cancer), nonclinical study requirements can be substantially abbreviated compared to non-oncology drugs. The clinical benefit of a potential cure or meaningful life extension outweighs the risk of incomplete nonclinical characterization.

核心要点 Key Points

1. Scope and ADC-Specific Application

Scope: Cancer drugs for patients with serious/life-threatening conditions where standard therapies are insufficient. Covers:

  • Cytotoxic small molecules
  • Targeted therapies
  • Biologics including ADCs (antibody component: see ICH S6(R1); payload: cytotoxic = S9 scope)

ADC duality principle: An ADC must be evaluated as a combination of S6(R1) and S9:

  • The antibody backbone → ICH S6(R1) (see separate wiki entry)
  • The released cytotoxic payload → ICH S9
  • The intact ADC as a conjugate → both apply; FDA/EMA typically require studies with the intact ADC in addition to the payload alone

2. Study Types — Required vs. Not Routinely Required

Study TypeRequired for ADC?Timing
General toxicology (repeat-dose)Yes — GLP 4-week in one relevant species (usually monkey)Before IND / FIH
Genotoxicity (standard battery)Yes — Ames test, in vitro chromosomal aberration/MN, in vivo if necessaryBefore IND; in vivo micronucleus before Phase 2
Safety pharmacology (CV, CNS, respiratory)Yes — ICH S7A/B batteryBefore FIH
Reproductive toxicity (EFD)Not required before Phase 1/2 for advanced cancer; required before NDALabeled with pregnancy warning; required before NDA/BLA for adjuvant/curative settings
Carcinogenicity (2-year rodent studies)Not requiredGenerally not required for cancer drugs
PhotocarcinogenicityCase-by-case (e.g., if payload is phototoxic)Pre-approval if relevant
Juvenile animal studiesCase-by-case for pediatric indicationsMay be required by FDA pediatric data requirements

Key S9 principle (ADC-relevant): Because ADC payloads are highly genotoxic (calicheamicin, PBDs, auristatins), the in vitro genotoxicity battery may be positive (expected, given mechanism). This does not prevent clinical development if a favorable benefit-risk exists. Document clearly and address in clinical risk communications.

3. Nonclinical Toxicology Study Design for ADCs

Species selection:

  • Must be pharmacologically relevant — expresses target antigen with adequate affinity
  • Cynomolgus monkey is most common (human antigen cross-reactivity for most oncology targets)
  • Rat: often not pharmacologically relevant unless target is rodent-cross-reactive; use as second species if toxicology driven by payload (cytotoxic mechanism; not target-specific)
  • Rodent surrogates: murine anti-mouse target ADC analogue used for in vivo efficacy; not required for IND-enabling tox unless only relevant species is rodent

GLP 4-week repeat-dose study design:

  • Dose levels: ≥3 dose levels + vehicle control
  • Top dose: typically MTD or dose-limiting dose (1.5–2× anticipated therapeutic dose on exposure basis)
  • Satellite TK groups: PK samples at each dose level (Day 1 and last dosing day minimum)
  • Recovery group: 4-week recovery at NOAEL dose
  • Endpoints: body weight, food consumption, clinical observations, clinical pathology (CBC, serum chemistry), macroscopic and microscopic pathology (≥30 tissues per SENASA)
  • Toxicokinetics: TAb, cAb, free payload at minimum

Dose frequency: Match intended clinical dosing schedule (Q3W for most ADCs); single-dose study may suffice for defining DLTs; repeat-dose required for IND-enabling

4. Toxicokinetic (TK) Requirements

TK is performed alongside toxicology studies to characterize systemic exposure at toxicity dose levels. Per ICH S9 + S3A:

  • Minimum TK design: 6–8 time points on Day 1 and last dosing day (e.g., Day 22 for Q3W study); pre-dose + 0.5, 1, 4, 8, 24, 48, 72, 168 h (adjust for antibody vs. payload PK)
  • Analytes: TAb (minimum); add cAb and free payload for full characterization
  • TK parameters: AUC₀–τ, Cmax, t½ if terminal phase available
  • Safety margin calculation: NOAEL TK AUC₀–∞ in monkey ÷ projected human therapeutic AUC (from Phase 1 PK prediction) → target ≥3–10× safety margin for oncology

5. Genotoxicity Strategy for ADC Payloads

ADC payloads are typically genotoxic by mechanism (tubulin inhibitors cause aneuploidy; DNA alkylators/intercalators cause DSBs). ICH S9 guidance:

Payload classGenotoxicity expectationS9 approach
Tubulin inhibitors (MMAE, DM1)Aneugenic (spindle poison) — positive in chromosomal aberration; Ames negativeExpected positive; document as mechanism-related; label accordingly
DNA alkylators (calicheamicin, PBDs, duocarmycin)Clastogenic and/or mutagenic — positive Ames + in vitro CAExpected positive; no de-risking possible; included in label
Topoisomerase I inhibitors (DXd, SN-38)Clasotgenic via indirect mechanism (replication fork collision)Positive in vitro CA; in vivo MN may be negative at non-toxic doses

ICH S9 principle: A positive genotoxicity result does not prevent clinical development if:

  1. The mechanism is understood (target-based; not unexpected adduct formation)
  2. Clinical benefit in a life-threatening indication outweighs genotoxic risk
  3. Appropriate patient counseling and contraception requirements are included in the label

常见问题和挑战，具体案例和解决方案

Challenge 1: No Pharmacologically Relevant Rodent Species — What Nonclinical Package Is Needed?

Problem: Target antigen (e.g., HER2, TROP-2, Nectin-4) is not expressed or not cross-reactive in rats or mice. The only relevant species is cynomolgus monkey. FDA generally requires two species for small molecule IND tox but S6(R1) allows single-species for biologics.

ICH S9 / S6(R1) answer: One pharmacologically relevant species (cynomolgus monkey) is sufficient for antibody or ADC toxicology studies. A second rodent species may be required by FDA if the rodent is relevant to the payload’s toxicological mechanism, even if not relevant to the ADC’s pharmacological target.

Solution:

  1. Conduct 4-week GLP monkey study with the intact ADC (antibody component provides target-mediated delivery; payload provides cytotoxic readout)
  2. Consult FDA at pre-IND meeting on whether an additional rodent study with free payload (unconjugated) is required to characterize the payload toxicity profile independently
  3. Reference existing payload nonclinical safety data if the same payload class (e.g., MMAE) has been extensively characterized in other approved ADCs

Case: Enfortumab vedotin (Padcev) — Nectin-4 is expressed in monkey but not rat. GLP IND tox used cynomolgus monkey as single relevant species per S6(R1); MMAE payload toxicity profile extrapolated from brentuximab vedotin (same linker-payload). FDA accepted single-species package at pre-IND.

Challenge 2: Embryo-Fetal Developmental (EFD) Toxicity — When Is It Required for Labeling?

Problem: A sponsor enrolling female cancer patients in a Phase 2 study needs to know whether EFD studies are required before starting the study.

ICH S9 answer:

  • EFD studies are not required before Phase 1 or 2 in patients with advanced cancer
  • However, the label must include a pregnancy warning based on the mechanism of action (all cytotoxic payloads are embryotoxic by mechanism)
  • EFD studies are required before NDA/BLA if the drug will be used in a less advanced setting (e.g., adjuvant, neoadjuvant, or curative intent)

Current ADC practice:

  • All approved ADCs have pregnancy warnings: “Can cause embryo-fetal harm based on mechanism of action”
  • EFD studies typically submitted with NDA/BLA or as post-marketing commitment (PMC)
  • Patients of reproductive potential: required to use contraception; male patients: advise not to father children

Challenge 3: Repeat-Dose Toxicity Study with an ADC — What NOAEL Is Clinically Relevant?

Problem: The NOAEL in a cynomolgus monkey repeat-dose study is 3 mg/kg Q3W. The intended clinical starting dose is 0.8 mg/kg Q3W. The 3.75× mg/kg margin seems adequate, but exposure-based safety margin may differ because monkey PK (clearance, DAR) differs from human.

Solution:

  1. Convert NOAEL to exposure-based safety margin using TK data: NOAEL AUC₀–τ (monkey) ÷ projected human AUC at 0.8 mg/kg
  2. Human AUC at 0.8 mg/kg projected by allometric scaling from monkey TK (CL ∝ BW^0.75 for antibody; adjust for FcRn binding difference between species)
  3. Use the exposure-based safety margin (AUC-based) as the primary determinant of starting dose, not the mg/kg-based margin

Target: ≥3–10× AUC-based safety margin between NOAEL exposure and projected human exposure at starting dose (ICH S9 flexibility for oncology)

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