Executive Brief
Zetyra Executive Brief
Validated Statistical Calculators for Efficient Clinical Trial Design
The Clinical Trial Efficiency Problem
FDA Published Major Guidance (January 12, 2026)
FDA released draft guidance extending Bayesian methodology to drugs and biologics.
“Bayesian methodologies help address two of the biggest problems of drug development: high costs and long timelines.”
— FDA Commissioner Marty Makary
This brief shows exactly how—with quantified ROI.
Trials Are Too Expensive and Too Slow
Phase III clinical trials cost $50-100 million and require 4-6 years to complete. Yet most trials use conservative statistical designs that systematically inflate costs:
| Inefficiency | Impact | Cost to Industry |
|---|---|---|
| Ignoring baseline covariates | 15-35% sample size inflation | $7-35M per Phase III trial |
| No interim monitoring | Continuing futile/successful trials to completion | 6-18 months unnecessary enrollment |
| Binary go/no-go decisions | Investing $50-100M in Phase III programs destined to fail | 50-60% Phase III failure rate |
Example
A standard Phase III trial enrolling 500 patients at $50K/patient = $25M. With efficient design, this could be 400 patients = $20M, saving $5M without reducing statistical power.
Why Efficient Designs Aren't Used
Despite decades of statistical research, most trials don't leverage modern methodologies because:
Software is expensive
$5,000-$15,000 annual licenses
IT barriers
Desktop installation requires IT department
Limited scope
Separate tools for each methodology, no integration
Opaque validation
Commercial vendors publish no accuracy data
Poor documentation
Minimal regulatory guidance for FDA/EMA submissions
Result: Only a small fraction of trials use covariate adjustment, group sequential designs, or Bayesian methods—even though FDA/EMA explicitly encourage these approaches.
The Opportunity
Three proven statistical methodologies can substantially reduce trial costs and duration:
CUPED (Covariate Adjustment): Leverage baseline measurements to reduce sample size 15-35%
Group Sequential Design: Monitor interim data with pre-specified stopping rules, reduce expected sample size 20-40%
Bayesian Predictive Power: Quantify probability of Phase III success given Phase II data, reduce false-go decisions
FDA guidance explicitly supports all three methods. The barrier isn't regulatory—it's accessible, validated, affordable software.
The Zetyra Solution
Zetyra is a web-based platform offering validated statistical calculators for efficient trial design. Unlike commercial alternatives, Zetyra provides:
1. CUPED
Covariate-Adjusted Power Analysis
- What it does: Calculates sample size reduction from baseline-outcome correlations
- Typical savings: 15-35% fewer patients
- Use case: Any trial with continuous or time-to-event endpoint
- FDA support: May 2023 guidance explicitly encourages covariate adjustment
2. Group Sequential
Interim Analysis Boundaries
- What it does: Calculates stopping boundaries with rigorous Type I error control
- Typical savings: 15-30% expected sample reduction
- Use case: Phase II/III trials with DSMB oversight
- FDA support: Nov 2019 guidance calls these “simplest adaptive designs”
3. Bayesian
Predictive Power Analysis
- What it does: Computes probability of trial success given interim data
- Typical benefit: Quantitative go/no-go vs binary p-values
- Use case: Phase II decisions, rare disease trials
- FDA support: January 12, 2026 draft guidance extends to drugs/biologics
Validation Excellence: 51 Tests, 100% Pass Rate
Zetyra's accuracy is publicly validated against gold-standard benchmarks:
| Calculator | Tests | Benchmark | Max Deviation | Result |
|---|---|---|---|---|
| Group Sequential | 30 | gsDesign R package | 0.0046 z-score | 10x better than criterion |
| CUPED | 12 | Analytical formula | Exact match | Zero numerical error |
| Bayesian | 9 | Conjugate priors | Exact match | Zero numerical error |
All validation code is public: github.com/evidenceinthewild/zetyra-validation
This transparency is unique. Commercial vendors (East, PASS, ADDPLAN) publish no validation data.
Key Differentiators vs. Commercial Software
| Feature | Zetyra | East | PASS | ADDPLAN | nQuery |
|---|---|---|---|---|---|
| All 3 methodologies | — | — | — | — | |
| Public validation | — | — | — | — | |
| Web-based (no IT) | — | — | — | — | |
| Annual cost | $1,188 | $15,000 | $8,000 | $12,000 | $6,000 |
Bottom line: Zetyra is the only platform integrating CUPED + Group Sequential + Bayesian with publicly validated accuracy, at a fraction of commercial pricing.
Business Impact — Quantified Case Studies
30% Sample Size Reduction with CUPED
Scenario: HER2+ metastatic breast cancer, single-arm Phase II evaluating objective response rate (ORR)
Standard Design
240 patients
14 months • $12.0M
CUPED-Adjusted
168 patients
10.4 months • $8.4M
Methodology: Baseline tumor burden correlates ρ=0.55 with response. CUPED variance reduction formula: VRF = 1-ρ² = 0.70, yielding 30% sample size reduction.
Savings: $3.6M (30%) + Phase III start 3.6 months earlier + $150-300M additional revenue from market entry acceleration
Early Stopping Saves $18M
Scenario: PCSK9 inhibitor for major adverse cardiovascular events (MACE) in secondary prevention
| Design Type | Max Events | Patients | Duration | Cost |
|---|---|---|---|---|
| Fixed Sample | 430 | 2,400 | 48 months | $76.8M |
| Group Sequential | 442 | 2,450 | 36 months | $58.7M |
Methodology: 4-look O'Brien-Fleming design with non-binding futility. Trial stopped at Interim Analysis 2 (Month 36, 220 events) when observed HR=0.68 exceeded efficacy boundary (Z=2.89 > 2.754).
$18.1M
Cost savings (24%)
12 months
Duration reduction
$2.4B NPV
Earlier approval gain
Bayesian Decision Framework
Scenario: Duchenne muscular dystrophy (DMD) gene therapy, 6-minute walk distance endpoint
Traditional Approach
p = 0.08
“Not significant” → No-go (potentially wrong)
Bayesian Approach
P(benefit) = 78%
Go with quantified confidence
Value: Quantitative risk assessment enables informed decisions vs. binary thresholds. Especially valuable in rare diseases where classical power calculations are unrealistic.
Result: FDA Breakthrough Therapy Designation, Accelerated Approval granted, patient access 18 months earlier
NSCLC Immunotherapy: Phase II → Phase III Development
| Program Element | Traditional | Zetyra-Optimized | Savings |
|---|---|---|---|
| Phase II | 80 patients, 12 mo, $4.0M | 53 patients, 8 mo, $2.4M | $1.6M (40%) |
| Phase III | 500 patients, 54 mo, $100M | 425 expected, 42 mo, $87.5M | $12.5M (13%) |
| Total Program | 66 months, $104M | 50 months, $89.9M | $14.1M (14%) |
| BLA Submission | Month 72 | Month 56 | 16 months earlier |
Revenue impact: $2B peak annual sales, 16-month earlier launch
→ $2.67B additional revenue → $2.1B NPV
11,750×
ROI per program
($14.1M savings / $1.2K subscription)
Why Zetyra?
1. Transparency Creates Trust
- Public validation suite on GitHub
- 51 automated tests, 100% pass rate
- Maximum deviation 0.0046 z-score (10× better than tolerance)
- Anyone can reproduce our accuracy claims
Commercial competitors publish zero validation data.
2. Integration Saves Time
- Single login, consistent interface across all 3 calculators
- Shared parameter sets—design once, refine efficiently
- No juggling between East, PASS, and custom R code
Typical pharma toolchain: $21-23K/year
Zetyra: $1,188/year (95% cost reduction)
3. Regulatory-Ready Documentation
- FDA/EMA guidance citations embedded in calculator outputs
- Pre-written protocol language for covariate adjustment, interim analyses, Bayesian methods
- Reduces time spent cross-referencing guidance documents
4. Zero IT Friction
- Web-based: works on any device, no installation
- Instant updates: new features deploy without IT tickets
- Time to first calculation: 1 hour vs. 2-8 weeks
Small biotechs benefit most: No IT department required, no upfront capital, immediate access.
5. Public API for Programmatic Access
- • RESTful endpoints (Appendix A in technical white paper)
- • R/Python workflows supported today
- • Used by validation test suite—proven in production
Regulatory Support is Strong
FDA explicitly encourages efficient designs:
CUPED: May 2023 guidance calls covariate adjustment “low-hanging fruit” for improving efficiency
Group Sequential: November 2019 guidance describes these as “simplest and most established” adaptive designs
Bayesian: January 12, 2026 draft guidance - FDA Commissioner Marty Makary: “Bayesian methodologies help address two of the biggest problems of drug development: high costs and long timelines”
The regulatory environment is favorable. Zetyra makes compliance straightforward.
Getting Started
Who Uses Zetyra?
- Biostatisticians designing Phase II/III trials
- Clinical development teams evaluating design options
- CROs providing statistical consulting services
- Academic medical centers running investigator-initiated trials
Pricing
Evidence Pro
$99/month ($1,188/year)
Full CUPED, GSD, Bayesian calculators
Evidence Collective
$349/month ($4,188/year)
Team features for 5 biostatisticians
Enterprise
Custom pricing (coming soon)
FDA compliance features
Free trial available. No credit card required.
Next Steps
The future of clinical trial design is transparent, validated, accessible, and efficient.
Every day trials continue with inflated sample sizes costs millions and delays patient access to new therapies. Zetyra provides validated tools to design more efficient trials today—no regulatory barriers, no IT complexity, no PhD in statistics required (though your biostatistician will love the methodology).