Investigational In Vitro Diagnostic Devices Used in Therapeutic Product Clinical Trials (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This is a draft guidance. Not for implementation.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 trials?

Investigational IVDs used in therapeutic product trials are subject to the IDE regulation (21 CFR Part 812) regardless of their source or manufacturer. Requirements depend on risk classification: significant risk devices need FDA-approved IDE applications, non-significant risk devices require IRB approval and abbreviated IDE compliance, while exempt devices must meet specific criteria under 21 CFR 812.2(c).

How do I determine if an IVD is considered investigational in a clinical trial?

An IVD is investigational if it’s the object of an investigation to determine safety or effectiveness. This includes novel IVDs, legally marketed IVDs used for different intended uses, or significantly modified IVDs. For example, a HER2 test approved for breast cancer becomes investigational when used for lung cancer patients in clinical trials.

What factors determine whether an investigational IVD poses significant risk?

Key factors include: whether erroneous results could lead to serious harm, if subjects would forego effective treatments, exposure to safety risks from investigational therapeutics, the strength of biomarker-therapeutic product relationships, and whether invasive sampling beyond standard care is required. The potential for serious risk, not likelihood, is the determining factor.

What information must sponsors provide to IRBs regarding investigational IVDs?

Sponsors must identify each investigational IVD, assess its risk classification (SR, NSR, or exempt), provide rationale for the assessment, describe how IVD results will guide subject management, and explain associated risks. This information is required even if IRB forms don’t specifically request it, ensuring proper risk evaluation and informed consent.

Can a therapeutic product trial proceed without an approved IDE for investigational IVDs?

No, if the trial involves significant risk investigational IVDs, an FDA-approved IDE is required before beginning, regardless of IND status. Non-significant risk IVDs require IRB approval and abbreviated IDE compliance. Exempt IVDs must meet specific criteria but still require IRB approval and informed consent compliance.

How should sponsors manage both IDE and IND requirements for the same study?

IDE submissions should cite corresponding IND numbers for cross-referencing. Sponsors can use letters of authorization or master files to share confidential information between applications. Both regulations apply independently - IND exemption doesn’t exempt from IDE requirements. Clinical holds can be placed by either therapeutic or device review centers.

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What You Need to Do 👇

Recommended Actions

1. Determine if IVD is investigational by assessing if it’s a novel IVD, used for different intended use, or significantly modified
2. Assess risk level (Significant Risk, Non-Significant Risk, or Exempt) based on:
   • Clinical consequences of erroneous results
   • Impact on subject treatment decisions
   • Risks of specimen collection
   • Therapeutic product risks
3. For Significant Risk devices:
   • Submit IDE application to FDA
   • Obtain FDA approval before starting investigation
   • Ensure IRB approval
4. For Non-Significant Risk devices:
   • Obtain IRB approval
   • Comply with abbreviated IDE requirements
   • Monitor for changes that could affect risk level
5. For IDE applications:
   • Include complete device description
   • Provide analytical validation data
   • Document software validation
   • Include risk analysis and benefit/risk assessment
   • Define cut-off values and intended use
6. Ensure proper labeling and informed consent documentation
7. Consider Q-submission meetings with FDA for guidance on study design and requirements
8. Maintain ongoing surveillance of risk level throughout the investigation
9. Ensure compliance with CLIA requirements if applicable
10. Consider cross-referencing between IDE and IND through letters of authorization or master files when appropriate

Key Considerations

Clinical testing

• Clinical protocols must contain description of laboratory tests used to monitor drug effects and minimize risk
• Clinical investigation design must be well-designed and sufficiently powered
• Ongoing surveillance during clinical investigation is recommended to monitor IVD risk

Non-clinical testing

• Preclinical information must justify subject exposure to investigational IVD
• Complete report of prior investigations including clinical, animal and lab testing required for IDE application

Software

• Software validation level information critical for evaluating appropriate IVD use
• Complex multivariate algorithmic software may require extensive data submission
• All necessary instruments and software must be listed and described

Labelling

• Must be labeled according to 21 CFR 809.10(c)
• For investigational use, must bear statement “For Investigational Use Only. The performance characteristics of this product have not been established”
• Informed consent documents must clearly explain investigational nature and risks

Safety

• Risk analysis including investigation justification required
• Benefit/risk assessment must demonstrate benefits outweigh risks
• Analytical performance around cut-off values critical for subject safety
• Risks of invasive sampling procedures must be considered

Other considerations

• Sample type, acquisition and processing descriptions required
• Intended use must be clearly defined including analyte detection, specimen type, conditions
• Cut-off values must be established and justified
• Analytical validity including precision, reproducibility, sensitivity, specificity must be demonstrated

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Relevant Guidances 🔗

• Vocal Fold Medialization Devices - Testing and Documentation Requirements
• Early Feasibility Medical Device Clinical Studies Including First in Human (FIH) Studies
• Changes to Investigational Device Exemption (IDE) Protocols and When FDA Approval is Required
• Clinical Study Design for Surgical Ablation Devices Used in Treatment of Atrial Fibrillation Under Direct Visualization
• Clinical Investigation of Medical Devices for Treatment of Urinary Incontinence
• Clinical Data Presentation for Orthopedic Implant Device Submissions
• Clinical Trial Considerations for Neurological Devices Intended to Slow, Stop, or Reverse Disease Progression
• Clinical Study Design Recommendations for Devices to Treat Opioid Use Disorder
• Clinical Decision Support Software Functions: Device vs Non-Device Classification
• Clinical Investigation Requirements for Prostate Tissue Ablation Systems

Related references and norms 📂

• 21 CFR Part 50: Protection of Human Subjects
• 21 CFR Part 56: Institutional Review Boards
• 21 CFR Part 812: Investigational Device Exemptions
• 21 CFR 809.10: Labeling for in vitro diagnostic products
• 42 CFR Part 493: Laboratory Requirements

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Original guidance

• Investigational In Vitro Diagnostic Devices Used in Therapeutic Product Clinical Trials
• HTML / PDF
• Issue date: 2017-12-18
• Last changed date: 2020-03-02
• Status: DRAFT
• Official FDA topics: Medical Devices, Good Clinical Practice (GCP), Investigational New Drug Application (INDA), Laboratory Tests, Drugs, Labeling, IVDs (In Vitro Diagnostic Devices), Biologics, Investigational Device Exemption (IDE)
• ReguVirta ID: 2e5180856cffbe65582befab97106f84