Design Considerations for Medical Device Pivotal Clinical Studies
This guidance provides recommendations for designing pivotal clinical studies intended to support pre-market submissions for medical devices. It focuses on two broad categories of devices: therapeutic/aesthetic devices and diagnostic devices. The guidance aims to help sponsors and investigators design studies that can demonstrate reasonable assurance of safety and effectiveness for device approval. While primarily focused on PMAs, the principles can also apply to 510(k) and de novo submissions with clinical data.
What You Need to Know? 👇
What are the key differences between clinical outcome studies and diagnostic clinical performance studies for medical devices?
Clinical outcome studies assign subjects to interventions and measure clinical endpoints to determine safety and effectiveness. Diagnostic clinical performance studies characterize how well a diagnostic device’s output agrees with a clinical reference standard, without using results for subject management.
When is randomization not feasible in medical device clinical studies and what alternatives exist?
Randomization may be impossible due to device design constraints, ethical concerns when investigators lack clinical equipoise, or when intervention assignment cannot be blinded. Alternatives include historical controls, objective performance criteria, or performance goals with appropriate bias mitigation strategies.
What constitutes valid scientific evidence for medical device approval under FDA regulations?
Valid scientific evidence includes well-controlled investigations, partially controlled studies, objective trials without matched controls, well-documented case histories by qualified experts, and reports of significant human experience. Isolated case reports and unsubstantiated opinions are not considered valid.
How does the least burdensome principle apply to medical device clinical study design?
The least burdensome principle requires using the most appropriate investment of time, effort, and resources while maintaining statutory pre-market review standards. It encourages considering alternatives to randomized studies when potential bias can be minimized through other means.
What are the main sources of bias in diagnostic clinical performance studies and how can they be mitigated?
Key biases include selection bias, spectrum bias, verification bias, disease progression bias, and reading order bias. Mitigation strategies include representative subject selection, blinding evaluators, applying reference standards consistently, and using appropriate washout periods between assessments.
What role do exploratory studies play in pivotal study design for medical devices?
Exploratory studies (first-in-human, feasibility) allow iterative device improvement, advance understanding of device function and safety, finalize device design, and determine appropriate endpoints. They help ensure the investigational device is standardized before pivotal trials begin.
What You Need to Do 👇
Recommended Actions
- Develop robust exploratory/feasibility studies before pivotal study
- Create detailed protocol including:
- Scientific rationale
- Study population definition
- Endpoints
- Statistical analysis plan
- Data management plan
- Consider pre-submission meeting with FDA to discuss study design
- Implement appropriate bias minimization strategies:
- Randomization when possible
- Blinding when possible
- Appropriate controls
- Multi-center design
- Ensure study population reflects intended use population
- Develop monitoring plan to maintain data quality
- Pre-specify handling of protocol deviations and missing data
- Document human factors considerations and training requirements
- Plan for appropriate safety monitoring
- Consider need for independent monitoring committee
Key Considerations
Clinical testing
- Studies must provide reasonable assurance of safety and effectiveness for the intended use
- Study design should minimize bias and control variability
- Pivotal studies should be preceded by exploratory/feasibility studies
- Study population should reflect intended use population demographics
- Multi-center studies preferred over single-center for pivotal studies
- Randomization and blinding recommended when possible
- Appropriate controls should be selected (active, placebo, no intervention, etc.)
Human Factors
- User skill level and training requirements must be considered
- Learning curve should be evaluated and documented
- Human factors can impact device safety and effectiveness
- Clear documentation of device-user interface needed
Safety
- Safety and effectiveness must be evaluated together
- Risk-benefit assessment required
- Safety endpoints should be pre-specified
- Adverse events must be monitored and reported
Other considerations
- Data management plan recommended
- Statistical analysis plan should be pre-specified
- Protocol deviations should be minimized and documented
- Missing data should be minimized through study design
- Changes to pivotal study should be minimized
- Independent monitoring recommended for some studies
Relevant Guidances 🔗
- Applying Human Factors Engineering and Usability Engineering to Medical Devices
- Content and Decision-Making Process for 510k Submissions: Determining Substantial Equivalence
- De Novo Classification Process for Novel Medical Devices Without Predicates
- Benefit-Risk Determinations for Medical Device Premarket Review
- Statistical Guidance for Reporting Diagnostic Test Results with Qualitative Outcomes
Related references and norms 📂
- ISO 14155:2011: Clinical investigation of medical devices for human subjects - Good clinical practice
Original guidance
- Design Considerations for Medical Device Pivotal Clinical Studies
- HTML / PDF
- Issue date: 2013-11-07
- Last changed date: 2023-08-10
- Status: FINAL
- Official FDA topics: Medical Devices, Good Clinical Practice (GCP), Premarket, Biologics, Investigational Device Exemption (IDE)
- ReguVirta ID: 676ed951eefcaca3cf592d9314fee671