Patient-Reported Outcome Measures: Development, Implementation and Evaluation in Clinical Trials

What You Need to Know? 👇

What are the key requirements for using PRO instruments to support medical device labeling claims?

PRO instruments must demonstrate content validity through patient input, have documented measurement properties (reliability, construct validity, ability to detect change), and be appropriate for the target population and clinical trial design.

How does the FDA evaluate the conceptual framework of a PRO instrument?

The FDA reviews the explicit diagram showing relationships between items, domains, and concepts measured, ensuring alignment with clinical trial objectives and that patient input was used to confirm the framework throughout development.

What documentation should be provided for PRO instrument content validity?

Sponsors must provide evidence of patient interviews, focus groups, cognitive interviewing transcripts, item generation processes, literature reviews, and demonstration that saturation was reached in understanding patient perspectives.

How should missing data be handled in PRO-based clinical trials?

The protocol and statistical analysis plan should prespecify rules for handling missing items within domains and missing entire measurements, including sensitivity analyses with different imputation methods to assess robustness.

What are the specific considerations for electronic PRO instruments in clinical trials?

Electronic PRO systems must comply with 21 CFR Part 11, maintain audit trails, ensure investigator control over source data, provide data backup, and allow FDA inspection access while maintaining data integrity.

How should responder definitions be established for PRO endpoints?

Responder definitions should be determined empirically using anchor-based methods that explore associations between PRO scores and easier-to-interpret measures, confirmed in early trials before use in confirmatory studies.

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What You Need to Do 👇

Recommended Actions

1. Establish and document content validity through qualitative research with target population
2. Develop comprehensive documentation of instrument development process including:
   • Conceptual framework
   • Item generation and reduction process
   • Cognitive interviewing results
   • Measurement properties testing
3. Create detailed protocol specifications for:
   • Administration procedures
   • Training requirements
   • Data collection methods
   • Quality control procedures
4. Implement appropriate electronic systems with:
   • Security controls
   • Audit trails
   • Data backup procedures
   • Access controls
5. Develop statistical analysis plan addressing:
   • Missing data handling
   • Multiplicity adjustments
   • Interpretation methods
6. Establish procedures for:
   • Translation/cultural adaptation
   • Missing data prevention
   • Adverse event reporting
   • Data quality control
7. Create comprehensive user manual documenting all procedures and requirements
8. Plan for adequate demonstration of measurement properties including reliability and ability to detect change

Key Considerations

Clinical testing

• PRO endpoints must be stated as specific clinical trial objectives
• Clinical trial duration must be adequate to support PRO objectives
• Frequency and timing of PRO assessments must be appropriate
• Plans for handling missing data must be included
• Procedures for PRO endpoint assessment before/after patient withdrawal needed
• Adequate blinding procedures required

Human Factors

• Patient understanding must be confirmed through cognitive interviewing
• Respondent burden should be evaluated and minimized
• Training materials and procedures must be well-documented
• Administration procedures must be standardized

Software

• Electronic PRO systems must have appropriate security controls
• Data integrity must be maintained during network attacks/updates
• Audit trails required for all data changes
• Backup systems needed to prevent data loss

Cybersecurity

• System and security controls must be established
• Plans needed for ensuring data integrity during network attacks
• Secure data transmission procedures required
• Access controls must be implemented

Labelling

• Claims must be supported by evidence from well-defined and reliable PRO instruments
• Labeling claims must be consistent with instrument’s documented measurement capability
• Multiple endpoints require multiplicity adjustment in analysis

Safety

• Adverse events detected with PRO instruments must be included in trial reports
• Safety information must be transmitted timely to clinical investigators
• PRO instruments can measure important safety concerns if they represent symptoms best captured from patient perspective

Other considerations

• Content validity must be established before other measurement properties
• Reliability and ability to detect change must be demonstrated
• Cultural/language adaptations require evidence of comparable measurement properties
• Missing data handling procedures must be pre-specified

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Relevant Guidances 🔗

• Electronic Records and Electronic Signatures - Scope and Application
• Human Factors Information Needed in Medical Device Marketing Submissions (Draft)
• Applying Human Factors Engineering and Usability Engineering to Medical Devices
• Content of Premarket Submissions for Device Software Functions
• Cybersecurity in Medical Devices: Design, Implementation, and Premarket Submissions
• Patient-Reported Outcome Instruments in Medical Device Evaluation

Related references and norms 📂

• 21 CFR part 11: Electronic Records; Electronic Signatures
• 21 CFR 312.50, 312.58, 312.62, and 312.68: Record keeping requirements for clinical investigators and sponsors
• 21 CFR 812.140 and 812.145: Medical device record keeping requirements

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Original guidance

• Patient-Reported Outcome Measures: Development, Implementation and Evaluation in Clinical Trials
• HTML / PDF
• Issue date: 2009-12-09
• Last changed date: 2020-05-15
• Status: FINAL
• Official FDA topics: Medical Devices, Good Clinical Practice (GCP), Drugs, Biologics, Clinical - Medical
• ReguVirta ID: 331a47b4e359a6ab7a2d81fccb965ed2