Changes to Investigational Device Exemption (IDE) Protocols and When FDA Approval is Required

What You Need to Know? 👇

What types of device changes can be implemented during a clinical trial without prior FDA approval?

Developmental changes to the device or manufacturing process that don’t constitute significant design changes or alter basic principles of operation, and are made in response to information gathered during the investigation, can be implemented with 5-day notice.

How quickly must sponsors notify FDA when making protocol changes under the 5-day notice provision?

Sponsors must submit a Notice of IDE Change to FDA within 5 working days after implementing the change. The change is considered implemented when investigators are notified or when modified devices are distributed to investigators.

What constitutes “credible information” for supporting device modifications in clinical trials?

Credible information includes data from design controls (§820.30), preclinical/animal testing, peer-reviewed literature, or reliable clinical information. For protocol changes, it includes investigator recommendations, trial data, IRB approval, or DSMB concurrence supporting the modification.

Can sample size be reduced during a clinical trial without prior FDA approval?

No, reducing sample size typically requires prior FDA approval as it normally leads to loss of statistical power and affects the scientific soundness of the investigational plan, which doesn’t meet the 5-day notice criteria.

What protocol changes require prior FDA approval versus 5-day notice?

Changes affecting data validity, risk-benefit relationship, scientific soundness, or subject safety require prior approval. Changes like increasing follow-up frequency, adding safety observations, or modifying secondary endpoints may qualify for 5-day notice if they don’t affect these factors.

How does FDA respond to 5-day notice submissions and what are the consequences of incorrect determinations?

FDA typically doesn’t respond to 5-day notices unless clarification is needed. However, FDA reserves the right to question sponsor determinations and may require prior approval if the change could jeopardize patient safety or study validity.

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What You Need to Do 👇

Recommended Actions

1. Establish process to assess if changes require prior approval, 5-day notice, or annual reporting
2. Document risk analysis and credible information supporting changes
3. Complete all testing before implementing changes under 5-day notice
4. Submit changes within required timeframes (5 days or annual)
5. Maintain documentation of changes and supporting rationale
6. Notify/obtain IRB approval as needed
7. Consider impact on data poolability and validity
8. Consult FDA if uncertain about change category
9. Review agreements/determinations before implementing changes
10. Keep participating IRBs informed of all changes

Key Considerations

Clinical testing

• Protocol changes affecting data validity, risk/benefit relationship, scientific soundness, or subject safety require prior FDA approval
• Minor protocol changes not affecting these aspects can be implemented with 5-day notice
• Changes to sample size or number of investigational sites require prior approval

Non-clinical testing

• Preclinical/animal testing data can serve as credible information to support device changes
• Testing must be completed before implementing changes under 5-day notice

Labelling

• Minor labeling changes clarifying instructions or increasing safety can be reported in annual reports
• Adding contraindications, warnings, precautions may require protocol changes and prior approval

Safety

• Changes enhancing safety without significant design changes can be implemented with 5-day notice
• Changes affecting subject safety require prior approval

Other considerations

• Manufacturing changes not constituting significant design changes can use 5-day notice
• Changes to basic principles of operation require prior approval
• Minor changes to study purpose, risk analysis, monitoring procedures can be reported annually

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Relevant Guidances 🔗

• Design Controls for Medical Device Manufacturers
• Early Feasibility Medical Device Clinical Studies Including First in Human (FIH) Studies
• IDE Clinical Investigation Decision Process and Requirements
• Continuing Review of Clinical Investigations by Institutional Review Boards (IRBs)

Related references and norms 📂

• 21 CFR 812: Investigational Device Exemptions
• 21 CFR 820.30: Design Controls

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Original guidance

• Changes to Investigational Device Exemption (IDE) Protocols and When FDA Approval is Required
• HTML / PDF
• Issue date: 2001-05-28
• Last changed date: 2023-08-10
• Status: FINAL
• Official FDA topics: Medical Devices, Investigational Device Exemption (IDE), Premarket
• ReguVirta ID: d449cfdc001b39cf85d4d1a5db61980f