# Stage 1 — Context of Use & ASME V&V40 Risk Assessment

**Model:** ASMD / Xenpozyme (olipudase alfa) QSP v2.0
**Pipeline:** IQANOVA AI-QSP Master Pipeline v2.0
**Date:** 2 May 2026
**Authors:** Igor Goryanin · IQANOVA Ltd / University of Edinburgh

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## 1a. Context of Use (COU) statement

| Field | Specification |
|---|---|
| **Decision to be supported** | (i) Adult-to-paediatric dose-bridging for olipudase alfa enzyme replacement therapy (ERT). (ii) Long-term efficacy projection beyond 2-year clinical follow-up. (iii) Identification of patient sub-populations at risk of sub-optimal response (anti-drug-antibody-positive; severe baseline pulmonary involvement). |
| **Application stage** | Post-marketing. Xenpozyme is approved by FDA, EMA, MHRA and PMDA for non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) types A/B and B. Model also intended to support label-extension dossiers and academic-investigator second-generation ERT comparison work. |
| **Target population** | Adult and paediatric (≥1 year) patients with non-CNS ASMD on weight-based 3 mg/kg fortnightly intravenous regimen following the SmPC dose-escalation schedule. |
| **Primary endpoints** | DLCO percent predicted (lung function); spleen volume (multiples of normal, MN); liver volume (MN); plasma lyso-sphingomyelin (LysoSM); plasma ceramide. |
| **Secondary endpoints** | Platelet count (% change from baseline); paediatric height Z-score (catch-up growth); ADA titre and ADA-modified clearance. |
| **Model influence (LMH)** | **Medium** — model output informs label/regulatory bridging discussions, dose-justification narratives, and outcome simulations beyond the trial follow-up window. The model is not used as a stand-alone replacement for clinical evidence. |

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## 1b. ASME V&V40-2018 risk assessment

| Risk dimension | Rating | Justification |
|---|---|---|
| **Model influence on decision** | **Medium** | Model is one input alongside published Phase II/III ASCEND, ASCEND-Peds, and 2-year OLE data; it is not the sole evidence basis for any decision. |
| **Decision consequence** | **High** | Decisions concerning paediatric dose adequacy and ADA-positive sub-population management have direct clinical-care and label implications in a vulnerable rare-disease cohort. |
| **Overall credibility risk** | **High** | Per ASME V&V40 §6.4 risk matrix (Medium influence × High consequence → High overall risk). Triggers full credibility activities including code verification, calculation verification, model-form uncertainty assessment, and applicability/relevance assessment. |

### Required minimum credibility activities

| Activity | Required level | Stage in pipeline |
|---|---|---|
| Code verification (numerical correctness) | Demonstrated | Stage 6 (libSBML zero-error gate; ODE solver tolerance verification) |
| Calculation verification (mesh/time-step convergence) | Demonstrated | Stage 6 (rtol=1e-6 / atol=1e-8 with halving check) |
| Validation — quantity comparison | Demonstrated | Stage 5 / Stage 6 internal calibration (RMSE per endpoint) |
| Validation — applicability | Demonstrated | Stage 6 external validation (Week-104 holdout; paediatric bridge) |
| Sensitivity analysis | Demonstrated | Stage 7 (LHS N=3000, Spearman) |
| Identifiability | Demonstrated | Stage 8 (FIM + profile likelihood) |
| Uncertainty quantification | Demonstrated | Stage 9 (Bayesian meta-analysis posterior) |
| Model-form uncertainty | Discussed | Manuscript Limitations section |

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## 1c. Applicable regulatory frameworks

| Framework | Section / clause | Pipeline stage |
|---|---|---|
| FDA Model-Informed Drug Development (MIDD) Pilot Program | Phase II/III dose justification; paediatric extrapolation guidance (FDA 2019) | All stages — model-informed evidence package |
| EMA Reflection paper on extrapolation in paediatric medicines (EMA/189724/2018) | §3 (model qualification); §5 (paediatric bridging) | Stage 6 paediatric bridge validation |
| EMA Qualification of Novel Methodologies for Drug Development | Article 57 procedure | Stage 12 regulatory report |
| ASME V&V40-2018 Standard | §6 risk; §7 credibility activities | Stages 1, 6, 12 |
| ICH M15 (draft 2024) — General Principles for MIDD | §4 documentation; §5 evaluation; §6 reporting | Stage 12 regulatory report |
| ICH E11A — Pediatric Extrapolation | §5 modelling and simulation in paediatric programmes | Stage 6 paediatric validation |
| GCP / GMP | Clinical data provenance (only published trial data used) | Stage 4 data provenance |

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## 1d. Credibility activities checklist (gate to subsequent stages)

| # | Gate | Stage | Status at Stage 1 close |
|---|---|---|---|
| G1 | SBML L3V2 model passes libSBML structural validation with zero errors and zero unit warnings | 2 | OPEN |
| G2 | Every datapoint provenanced (source, type, year, reliability A/B/C) | 4 | OPEN |
| G3 | Every fitted parameter has bounds and a literature anchor or explicit FITTED label | 5 | OPEN |
| G4 | All calibration RMSE meet pre-specified per-endpoint benchmarks | 5 | OPEN |
| G5 | GSA includes all parameters at ±30%; identifies dominant drivers per endpoint | 7 | OPEN |
| G6 | All parameters classified (Well/Moderate/Weak); actions stated for Weak | 8 | OPEN |
| G7 | Bayesian meta-analysis achieves R̂ < 1.01 and ESS > 400 | 9 | OPEN |
| G8 | Combination/dose decisions cross-referenced against GSA-dominant parameters | 10 | OPEN |
| G9 | All figures 300 DPI; consistent style; informative captions | 11 | OPEN |
| G10 | All 14 R-phases populated; all DOCX validate; PDFs generated | 12 | OPEN |

**Status at end of Stage 1: All preconditions defined; gate to Stage 2 OPEN.**
