Validation

Validation against published Phase 3 trial results.

Evinexus emulated the treatment and control arms of CheckMate-057 and TAILOR, then compared the digital twin estimates with the published trial estimates and confidence intervals. Informed by the FDA-collaborative ENCORE research approach, Evinexus assesses whether each estimate lands inside the trial's confidence interval (estimate agreement) and preserves the direction of the treatment effect (direction agreement). Across both case studies below, both criteria were met on every comparison — while removing years of follow-up.

Concordance

Published trial and digital twin estimates.

Each row is one arm's estimate. The reference trial's own 95% CI is shaded behind every row, so an estimate landing inside that band reads as agreement rather than leaving the reader to compare two intervals by eye.

Case 1 · Methodology study

CheckMate-057 reproduced with an Evinexus digital twin control, 194 days sooner to the primary analysis.

Overall survival · advanced non-squamous NSCLC

Reproduced hazard ratio

0.73

vs trial 0.73 · all three methods within CI

Study duration shortened

194d

up to 6.4 months sooner to primary OS analysis

Methods at full regulatory + estimate agreement

3 / 3

Three prespecified borrowing approaches

All three twin estimates reproduce the trial's hazard ratio of 0.73 and fall inside its 95% confidence interval.

Case 1 · Methodology study — reference trial vs. Evinexus digital twin

Reference RCT

CheckMate-057 (original RCT)0.73 (0.59–0.89)

Evinexus digital twin

Method 10.73 (0.59–0.90)
Method 20.73 (0.59–0.89)
Method 30.73 (0.60–0.91)

RWD study

Method 10.73 (0.59–0.92)
Method 20.74 (0.61–0.91)
Method 30.72 (0.59–0.88)
0.501.00

Hazard ratio (95% CI), nivolumab vs control

Reference RCTEvinexus twinRWD studyTrial estimateTrial 95% CI

Case 1 · Methodology study. Reference trial and Evinexus digital twin estimates, hazard ratio with 95% confidence interval, by arm.

Reference RCT, CheckMate-057 (original RCT). Hazard ratio 0.73 (0.59–0.89).

Evinexus digital twin, Method 1. Hazard ratio 0.73 (0.59–0.90).

Evinexus digital twin, Method 2. Hazard ratio 0.73 (0.59–0.89).

Evinexus digital twin, Method 3. Hazard ratio 0.73 (0.60–0.91).

RWD study, Method 1. Hazard ratio 0.73 (0.59–0.92).

RWD study, Method 2. Hazard ratio 0.74 (0.61–0.91).

RWD study, Method 3. Hazard ratio 0.72 (0.59–0.88).

Case 2 · RAS WT metastatic colorectal cancer

Cetuximab + FOLFOX-4 vs FOLFOX-4 alone

TAILOR · Progression-free survival (PFS)

Methods reproduced

3 / 3

Three prespecified borrowing approaches

Days saved

967d

Method 1

Hybrid cohort

473 patients

193 randomized + 280 control, of which 80 digital twins

Every method's 95% CI overlaps the trial reference.

Case 2 · RAS WT metastatic colorectal cancer — reference trial vs. Evinexus digital twin

Reference RCT

TAILOR (original RCT)0.69 (0.54–0.89)

Evinexus digital twin

Method 10.74 (0.58–0.94)
Method 20.73 (0.56–0.92)
Method 30.73 (0.57–0.94)
0.501.00

Hazard ratio (95% CI), cetuximab vs control

Reference RCTEvinexus twinTrial estimateTrial 95% CI

Case 2 · RAS WT metastatic colorectal cancer. Reference trial and Evinexus digital twin estimates, hazard ratio with 95% confidence interval, by arm.

Reference RCT, TAILOR (original RCT). Hazard ratio 0.69 (0.54–0.89).

Evinexus digital twin, Method 1. Hazard ratio 0.74 (0.58–0.94).

Evinexus digital twin, Method 2. Hazard ratio 0.73 (0.56–0.92).

Evinexus digital twin, Method 3. Hazard ratio 0.73 (0.57–0.94).

Twin estimates are propensity-weighted. Full results at SABCS 2026 and ASH 2026; prospective and regulatory validation warranted.

Regulatory context

Regulatory and study-design context.

  • FDA

    Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products (draft guidance, 2023).

  • FDA ENCORE

    An FDA-collaborative research project developing methods to calibrate real-world evidence against randomized trials. Not an FDA qualification or acceptance framework.

  • ICH E10

    Choice of Control Group and Related Issues in Clinical Trials.

Where it degrades

Limitations

These results are retrospective emulations of completed trials. Prospective and regulatory validation is required before applying the approach to an active development program.

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