E9(R1) Addendum: Estimands & Sensitivity Analysis in Medical Device Trials
The ICH E9(R1) Addendum introduced a critical refinement to clinical trial design: the estimand framework. For medical device trials, this structured approach helps sponsors define exactly what treatment effect they aim to estimate, while explicitly addressing how intercurrent events such as device malfunctions, patient withdrawals, or treatment crossovers impact trial conclusions.
This clarity is essential in regulatory submissions. FDA reviewers expect to see a well-defined strategy for handling missing data, device failures, and long-term attrition. Equally important, sensitivity analyses must demonstrate that trial results remain consistent under reasonable alternative assumptions. Without this planning, sponsors risk unexpected FDA questions late in the review process, delaying approval timelines.
FDA Expectations and Best Practices
In medical device submissions—whether IDE, PMA, or 510(k)—FDA reviewers typically expect:
Justified sample size assumptions, including how intercurrent events might affect statistical power
Pre-specified subgroup analyses, ensuring clinically meaningful populations are evaluated
Clear documentation of missing data handling, with transparent methods for addressing device failures or patient discontinuations
Alignment across the clinical protocol, SAP, and final analysis report, ensuring consistency and traceability
Meeting these expectations requires early and deliberate planning. Misalignment between study objectives, estimands, and statistical methods can trigger FDA feedback that necessitates redesign—or worse, additional trials.
Early engagement with regulatory biostatisticians helps avoid these pitfalls. A fully traceable documentation trail supports FDA inspections and audits, while independent statistical review at key milestones strengthens regulatory defensibility.
BSC® has supported hundreds of device sponsors in meeting these expectations, including direct engagement with the FDA through Q-submissions, pre-submission meetings, and advisory panel hearings.
Looking Ahead: Advanced Statistical Methods for Device Trials
Medical device development is rapidly evolving, with sponsors adopting advanced statistical approaches to meet both clinical and regulatory needs.
Bayesian adaptive designs allow sponsors to update trial parameters as data accumulates, improving efficiency while maintaining FDA compliance.
Real-world evidence (RWE) is increasingly integrated into device submissions, requiring careful propensity score matching and hybrid study designs.
Longitudinal modeling is essential for digital health and connected devices, where continuous data streams require advanced statistical approaches to capture evolving patient outcomes.
When implemented correctly—with a clear regulatory strategy—these methods can accelerate development timelines without increasing regulatory risk.
How BSC® Helps Sponsors Succeed
With over 35 years of exclusive focus on regulatory biostatistics, BSC® combines deep statistical expertise with hands-on FDA experience. We have successfully supported IDE, PMA, and 510(k) submissions for complex devices—including orthopedic, spinal, cardiovascular, and diagnostic technologies.
BSC® provides:
Advanced expertise in Bayesian adaptive designs, complex endpoints, and longitudinal modeling
Strategic planning of estimands and sensitivity analyses to anticipate FDA questions
Direct support for FDA interactions, including Q-subs, pre-sub meetings, and panel hearings
Comprehensive alignment of clinical protocols, SAPs, and final reports to meet regulatory expectations
By involving BSC® early in the development process, sponsors minimize the risk of FDA queries, avoid costly delays, and ensure that their clinical evidence package withstands regulatory scrutiny.
Ready to Strengthen Your FDA Strategy?
BSC® helps device sponsors define clear estimands, plan sensitivity analyses, and design FDA-compliant trials that withstand rigorous review.
Contact BSC® today to discuss how we can support your next medical device submission.
References
European Medicines Agency. (2020). ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (EMA/CHMP/ICH/436221/2017) https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-addendum-estimands-and-sensitivity-analysis-clinical-trials-guideline-statistical-principles-clinical-trials-step-5_en.pdf
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (1998). ICH harmonised tripartite guideline: Statistical principles for clinical trials E9. U.S. Food and Drug Administration.