Regulatory Toolbox

Sponsors are responsible for maintaining their IDE submission throughout the 'life' of their IDE. There are several different types of submissions used to notify the FDA of changes and to request approval for modifications to the current investigation. To learn more about IDE sponsor and investigator responsibilities, please view the FDA's website on IDE Responsibilities.

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Supplement: A written submission from the sponsor while an IDE is under review or has been approved regarding requested changes to the protocol or the device. Supplements are intended to seek FDA's approval for something new or different.

Report: A written submission from the sponsor after an IDE has been approved regarding study progress and unanticipated events. Reports are intended to provide notification or updates for FDA's routine monitoring of a clinical investigation.

Amendment: A written response from the sponsor in response to the FDA's request for more information regarding a previous submission.

All IDE submissions should be sent to the contact identified by the FDA in your initial acknowledgement letter.

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The FDA tracks requests for a new protocol, changes to the approved protocol, or changes to the device, such as device design or manufacturing change, as supplements. List of submissions tracked as Supplements include:

• Change in correspondent, manufacturer, or sponsor
• Request for approval of changes in design or manufacturing
• Request for approval of a change in informed consent or protocol
• 5-day notices- Notification that changes not requiring prior FDA approval have been made
• Request for compassionate use, or live case demonstration
• Proposed changes to the approved protocol
• Request for approval of expansion of the study (increase subject enrollment and/or add study sites)
• Request an extension of time to respond to an FDA letter
• Request for waiver
• Institutional Review Board (IRB) certification
• Request for Centers for Medicare and Medicaid Services (CMS) recategorization
• Notification that the study has been suspended or resumed
• Acknowledgement and response to clinical hold
• Request for approval to terminate the study without final report
• Request for approval of a new study or protocol

Timeline Requirements for Supplements

Changes requiring prior approval: most of the time, changes that are made in the Investigational Plan, need to be pre-approved by FDA. Examples of these changes are:

• Changes in the Investigational Plan or Protocol
  • Affecting the validity of data/information,
  • Patient risk to benefit relationship,
  • Scientific soundness of investigational plan,
  • Right, safety or welfare of subjects.
• Developmental Changes in the device, including manufacturing changes, that present a significant change in design or basic principle of operation

Changes requiring 5-day notice: these changes do not require prior approval, but notice must be provided to FDA within 5 working days of making the change:

• Changes Effected for Emergency Use are considered to be changes in the investigational plan to protect the life or well-being of the subject in the case of emergency.
• Non-significant changes in design or manufacturing
• Certain changes to the clinical protocol – for changes that do not fit the criteria for prior approval such as:
  • Modification to inclusion/exclusion criteria to better define the target patient population
  • Increasing the frequency at which data or information is gathered
  • Inclusion of additional patient observations or measurements
  • Modifying secondary endpoints

Changes submitted with the annual Progress Report: Other minor changes can be submitted in the annual progress report including minor changes in the following areas: the purpose of the study, risk analysis, monitoring procedures, labeling, informed consent materials, and IRB information.

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For IDE reports, the FDA will respond to the sponsor within 30 days if the FDA has questions or requests for additional information; otherwise the FDA may close the submission without issuing a formal response. If a report is deficient, the sponsor response to the deficiencies identified in the FDA's communication is designated as an amendment to that report.

• Unanticipated Adverse Device Effects: Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device if that effect, problem or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (21 CFR 812.3(s)). Report to the FDA within 10 working days.
• Withdrawal from IRB approval: Report to the FDA within 5 working days.
• Deviation from the investigational plan: The investigator must notify the sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Report to the FDA within five working days.

  If it is not an emergency, prior approval from the sponsor is required for changes in or deviations from the investigational plan. If the change or deviation may affect the scientific soundness of the investigational plan or the rights, safety or welfare of the subject, the sponsor is required to obtain prior IRB approval and also to obtain FDA approval for a significant risk device investigation by submitting an IDE supplement.

• Failure to Obtain Informed Consent: Report to the FDA within five working days.
• Current Investigators list: Report every six months.
• Annual Progress Report: Submit at least yearly. See below for more information.
• Interim Progress Report: Submit if requested by FDA.
• Recall and Device Disposition: Report to FDA within 30 working days after the request is made for an investigator to return, repair, or dispose of any unit of the device.

All IDE submissions should be sent to the person identified by the FDA in your initial notification letter.

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Amendments are any response to FDA's request for more information. The FDA tracks any IDE submission sent as a response to deficiencies communicated in an FDA disapproval, approval with conditions, or deficient report letter as an IDE Amendment to that submission. For example, if you receive an “approval with conditions” letter after you submit your original IDE, your response intended to address deficiencies in that letter will be logged in as an Amendment. Amendments may be submitted to supplements and reports, as well as to the Original IDE.

Submissions tracked as Amendments:

• Response to Disapproval
• Response to Approval with Conditions
• Response to Refuse to Accept
• Response to Report Deficient
• Voluntary Withdrawal by Sponsor

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Progress reports are yearly written submissions from the sponsor while the IDE is in effect regarding the study progress. Progress reports are intended to provide updated information for the FDA's routine monitoring of the clinical investigation. If the FDA deems that the investigation merits closer monitoring, it can require that reporting occur more frequently (e.g., via interim reports).

All IDE submissions should be sent to the person identified by the FDA in your initial notification letter. Although there is not a standard format for progress reports, specific topics need to be addressed so the FDA can evaluate the clinical investigation effectively. An outline of a typical report is provided:

• FDA Form 3514: The use of this form is optional. If you choose not to use the form, ensure that the relevant information is contained in the cover letter:
  • Statement that this is an original IDE submission
  • Device name and intended use
  • Sponsor's contact information
    • Name, address, telephone number, fax number, email address
  • Manufacturer information
    • Name, address, contact person, telephone number, fax
• General Information: Please state your:
  • IDE number o Device name and indication(s) for use
  • Sponsor's name address, phone numbers, and fax
  • Sponsor's email address
  • Contact person
• Study Progress: Data from the beginning of the study should be reported, but data collected since previous report should be identified.
  • Brief Summary of the Study Progress
  • Number of Investigators/Investigational Sites (Include a list of investigators.)
  • Number of Subject Enrolled o Number of Devices Shipped
  • Brief Summary of the Results
  • Summary of Anticipated and Unanticipated Adverse Effects
  • Deviations from the Investigational Plan (Describe all the deviations from the investigational plan since the last progress report.)
• Risk Analysis: A thorough risk analysis and risk mitigation strategies are critical for the FDA's decision to allow a study to continue. The risk analysis from the initial application can be updated with any relevant changes, including a summary of new adverse information since the last progress report that may affect the risk analysis. This includes preclinical data, animal studies, foreign data, clinical studies, etc. Reprints of any articles published from data collection from this study should also be attached. Present a new risk analysis, if necessary, based on any new information and study progress.
• Other Changes: A summary of any changes in the manufacturing process and quality control, including changes that have not been submitted as a supplemental application should be included. Summarize all changes in the investigational plan that were not required to be submitted in a supplemental application.
• Future Plans: Progress towards product approval, including a projected date for PMA or 510(k) submission. If there are any plans to change the investigation, e.g., to expand the study size or indications, to discontinue portions of the investigation or to change manufacturing practices, state in this section. (NOTE: Actual proposals for these changes should be made in a separate supplemental application since they may require prior approval.)

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