In Vitro Companion Diagnostic Device and Therapeutic Product Co-Development (DRAFT)

This is a draft guidance. Not for implementation.

What You Need to Know? 👇

What are the key regulatory requirements for investigational IVDs used in therapeutic product clinical trials?

The requirements depend on risk assessment. Significant risk IVDs require FDA-approved IDE applications before use. Non-significant risk IVDs follow abbreviated requirements under 21 CFR 812.2(b). Exempt IVDs under 21 CFR 812.2(c)(3) have minimal requirements but still need proper analytical validation.

How should sponsors coordinate review timelines for contemporaneous marketing authorization?

Use modular PMA submissions for IVDs, submit manufacturing modules early for timely inspections, establish letters of authorization between sponsors, and consider priority review eligibility. Plan for BIMO inspections and ensure both products meet their respective review timelines through early coordination.

What analytical validation is required before using an investigational IVD in pivotal therapeutic trials?

Complete analytical validation demonstrating reliable performance around clinical decision points is essential. This includes precision, accuracy, limits of detection/quantitation, specificity studies, and preanalytical validation. The IVD should be fully specified with fixed protocols before pivotal trial initiation.

When are bridging studies necessary between clinical trial assays and candidate companion diagnostics?

Bridging studies are required when the candidate IVD companion diagnostic differs from the clinical trial assay used in pivotal studies. High analytical concordance must be demonstrated using original trial samples, including both test-positive and test-negative specimens to avoid bias.

What clinical trial designs best support both therapeutic product approval and IVD companion diagnostic validation?

Biomarker-stratified designs enrolling both test-positive and test-negative subjects provide the most information, allowing assessment of predictive versus prognostic value. Selection designs with only marker-positive subjects support selection claims but cannot establish predictive utility.

How should sponsors handle specimen collection and banking for codevelopment programs?

Collect specimens from all subjects tested for trial participation, not just enrolled subjects. Bank both original specimens and processed materials. Ensure proper annotation including disease characteristics, sample handling details, and storage conditions. Plan for international sample export restrictions.

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What You Need to Do 👇

Recommended Actions

1. Determine early if IVD companion diagnostic is needed for therapeutic product development
2. Assess risk level of investigational IVD use and determine applicable IDE requirements
3. Develop analytically validated test before pivotal clinical trials
4. Design clinical trials to support both therapeutic product and IVD companion diagnostic claims
5. Establish specimen collection and banking plan
6. Consider modular PMA approach for IVD submission
7. Coordinate review timelines between FDA centers
8. Submit appropriate letters of authorization between sponsors
9. Plan for manufacturing and BIMO inspections
10. Ensure consistent labeling between products
11. Establish post-marketing plans for both products
12. Maintain ongoing communication between therapeutic product and IVD sponsors throughout development

Key Considerations

Clinical testing

• Clinical evidence to support IVD companion diagnostic use should be generated in major efficacy trials of therapeutic product
• Trial designs must support both therapeutic product and IVD companion diagnostic claims
• Consider prospective-retrospective approaches when appropriate
• Ensure adequate representation of markers in study population
• Establish appropriate cutoffs for IVD companion diagnostics

Non-clinical testing

• Analytical validation studies should be completed before using test in pivotal clinical trials
• Evaluate critical analytical performance characteristics of early prototype tests
• Consider specimen handling and storage requirements
• Plan for adequate specimen collection and banking

Labeling

• Labeling of therapeutic product and IVD companion diagnostic must be consistent
• IVD labeling should specify analytes referenced in therapeutic product labeling
• Claims should be supported by evidence from clinical trials
• Consider predictive, selection and monitoring claims based on trial design

Safety

• Assess risk level of investigational IVD use in clinical trials
• Consider IDE requirements based on risk assessment
• Address safety monitoring in clinical trials
• Report adverse events appropriately for both products

Other considerations

• Plan for contemporaneous marketing authorizations
• Consider modular PMA approach for IVD submissions
• Coordinate review timelines between centers
• Address manufacturing and BIMO inspection requirements
• Establish appropriate letters of authorization between sponsors

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Relevant Guidances 🔗

• In Vitro Companion Diagnostic Devices: Development, Review Process, and Labeling Requirements
• Research Use Only and Investigational Use Only In Vitro Diagnostic Products - Labeling and Distribution Requirements
• Marketing and Distribution Requirements for Analyte Specific Reagents (ASRs)
• Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices

Related references and norms 📂

• 21 CFR Part 812: Investigational Device Exemptions
• 21 CFR Part 820: Quality System Regulation
• 21 CFR Part 803: Medical Device Reporting
• 21 CFR Part 809: In Vitro Diagnostic Products for Human Use

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Original guidance

• In Vitro Companion Diagnostic Device and Therapeutic Product Co-Development
• HTML / PDF
• Issue date: 2016-07-15
• Last changed date: 2019-05-14
• Status: DRAFT
• Official FDA topics: Medical Devices, Laboratory Tests, Premarket Approval (PMA), Drugs, 510(k), Premarket, IVDs (In Vitro Diagnostic Devices), Biologics
• ReguVirta ID: 905f09f2b9c8cfc838543e61bfa3f716