Investigational Devices

The FDA defines a medical device as: 

An instrument, apparatus, tool, machine, plan, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

• intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in a human, or

• intended to affect the structure or any function of the body of a human, and which does not achieve its primary intended purposes through chemical action within or on the body of a human, and which is not dependent upon being metabolized for the achievement of its primary intended purposes, and 

• recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them.

• A clinical investigation of a device means research involving one or more participants to determine the safety or effectiveness of a device, either directly or indirectly.
  • Direct evaluations of safety or effectiveness (per study aims or outcome measures). For Example:
    • “To assess the performance of the Heartin device in detecting atrial fibrillation and evaluate patient outcomes”
    • “To assess the accuracy and reliability of the XYZ continuous glucose monitor compared to venous blood glucose measurements in adult patients with diabetes”
• Indirect evaluations of safety or effectiveness (main question to answer: does the study provide data on a device’s safety or effectiveness?)
  • Is the main study intervention directly related to the medical device?
  • Is the medical device essential to achieving a study condition?
  • Do the study outcome measures depend on the device use?
  • Other factors: the device is significant risk; the device is not FDA-approved

• If a medical device is only being used as a measurement tool, with no safety or effectiveness being assessed directly or indirectly, IDE regulations do not apply.
• Companion In Vitro Diagnostic Devices (Precision Therapy): studies using an investigational IVD to guide therapeutic management of participants (e.g., detect a specific mutation) in a therapeutic product trial qualify as a clinical investigation of a medical device even if study aims do not include determining safety and effectiveness of the IVD (seen as an indirect evaluation).

An IDE is required when conducting a clinical investigation of a medical device that is not deemed “IDE exempt or Not a Significant Risk device (NSR).” IDEs are required when the clinical investigation of the medical device is a significant risk (SR).

 Under 21 CFR 812.3(m), an SR device means an investigational device that:

• Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a participant;

• Is purported or represented to be for use supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a participant;

• Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health, and presents a potential for serious risk to the health, safety, or welfare of a participant; or

• Otherwise presents a potential for serious risk to the health, safety, or welfare of a participant.

If the device meets IDE exempt criteria or meets the definition of Not Significant Risk (NSR), an IDE is not required.

An NSR device study is one that does not meet the definition for an SR device study. 

FDA regulations require sponsors to make the initial risk determination of whether the device is significant risk or not significant risk. The sponsor’s determination may be presented to the IRB. The FDA is also available to help the sponsor, clinical investigator, and IRB in making the risk determination.

Unless the FDA has already made a risk determination for the study, the IRB must review the sponsor's SR or NSR determination for every investigational medical device study reviewed and modify the determination if the IRB disagrees with the sponsor. If the FDA has already made the SR or NSR determination for the study, the agency's determination is final.

The FDA recognizes certain categories of device research that do not require IDE approval and are not subject to FDA device regulations (21 CFR 812), even though the device is being used in a clinical investigation. These categories, or IDE exemptions, are described in the UCSF Worksheet: Devices.

The more common IDE-exempt investigations submitted to the IRB meet the following criteria:

• Investigations conducted with legally marketed devices used according to labeling. “Legally marketed” means that the device has undergone one of the pathways that the FDA requires for a device to be legally placed on the market in the US. This includes Device Registration and Listing with the FDA, 510(K) Clearance, Pre-Market Approval, and De Novo Approval 
  • Note: Legally marketed devices should not be confused with commercially available devices. Just because the device can be purchased commercially (over the counter) does not mean it meets the FDA definition of legally marketed. 
• Studies using in vitro diagnostics labeled for “research purpose only” per regulations [21 CFR 809.10(c)], and if the testing:
  • is noninvasive;
  • does not require an invasive sampling procedure that presents a significant risk;
  • does not introduce energy into a participant; and
  • is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure.

Additional FDA guidance on studies using in vitro diagnostics is available. 

All studies involving human subjects that meet the definition of research require IRB review. Additionally, studies requiring an IDE will need FDA approval before IRB approval can be granted.

The sponsor/sponsor-investigator is responsible for determining whether their planned use of an investigational device is IDE-exempt or qualifies for an abbreviated IDE. The IRB or HRPP analysts may request additional information if it is unclear whether the criteria for an IDE exemption or abbreviated IDE are met. Additionally, the IRB, HRPP analysts, or researchers may consult with the FDA.  FDA opinion is the ultimate authority regarding device classification.

Studies that involve an IDE-exempt use of a device can be reviewed via the expedited process (i.e., does not require a convened IRB committee review) if the study also qualifies for expedited review.

If the sponsor/sponsor-investigator determines that the study qualifies for an abbreviated IDE, the study will need review by the convened IRB (full board) initially. If the IRB concurs with the sponsor/sponsor-investigator’s determination that the device is a nonsignificant risk, the study may be reviewed via the expedited process for future reviews, if the entire study qualifies for expedited review. If the IRB disagrees with the sponsor’s nonsignificant risk determination, the sponsor/sponsor-investigator must either ask the FDA for a risk determination or apply to the FDA for an IDE.

Studies requiring an IDE require review by the convened IRB (full board).

Chart source:: https://www.cc.nih.gov/orcs/ide/exemption-criteria-study-risk-determination#collapseone

• A device should be listed if the use of the device is required by the study design. For example:
• Studies comparing different standard of care procedures where participants will be randomized to receive a particular procedure.
• Studies of an investigational device.
• Studies that qualify for an IDE exemption or abbreviated IDE, or require an IDE.

Note: Indirect devices may need to be listed

The FDA will need to be consulted if:

• The sponsor/sponsor-investigator makes a non-significant risk (abbreviated IDE) determination or an IDE Exempt determination, and the IRB disagrees.

• The sponsor/sponsor-investigator wishes to have a device determination directly from the FDA.

• The IRB requires consultation by the FDA. Note: documentation of the consultation will be required.

• IRB Application: 
  • Indicate that the study involves a device in the "Initial Screening Questions" section. 
  • Check the appropriate box in the "Drugs and Devices" section of the IRB Application.
• An IDE number: If the sponsor’s protocol does not list the IDE number, you must submit documentation from the sponsor or FDA identifying the IDE number for this study. The IRB will not issue final approval until the IDE number is reported to and verified by the IRB. However, the IRB may review the research before the IDE application is submitted to the FDA.
• Investigator’s Brochure
• Directions for use, typically provided by the manufacturer and device labeling  consistent with federal regulations [21 CFR 812.5]
• Scientific/sponsor's protocol: This document should describe the methodology to be used and demonstrate that the study is scientifically sound.
• An explanation of the device cost, which is determined by the reimbursement category provided by FDA with each approved IDE. This information is needed for the consent form.
• Clearance from the Radiation Safety Committee for radiation-emitting devices.

• IRB Application: 
  • Indicate that the study involves a device in the "Initial Screening Questions" section. 
  • Check the appropriate box in the "Drugs and Devices" section of the IRB Application
  • Check “Yes” when asked if a Non-Significant Risk (NSR) determination is being requested for the investigational device. Then complete the "Non-Significant Risk Determination for an Investigational Device" section to provide the IRB with adequate justification for why the use of the device in this study poses non-significant risk.
• Detailed device information from the sponsor, such as a description of the device and how it is used.
• Diagrams and/or in situ photographs of the device are very useful (attach as "Other Study Documents").
• Directions for use, typically provided by the sponsor or manufacturer and device labeling consistent with federal regulations [21 CFR 812.5].
• Scientific/sponsor's protocol: This document should describe the methodology to be used and demonstrate that the study is scientifically sound.
• An explanation of the device cost: Non-significant risk devices are placed in Category B and are most likely eligible for reimbursement. See the FDA’s reimbursement category overview.

All medical device studies involving human participants require informed consent. Include the following key points within the consent form template sections noted below:

Purpose and background

• Must include a clear statement that the device is investigational and has not been approved by the FDA for clinical use or, if applicable, that the device has been approved for specific clinical indications but not for the use being studied.
• Must include a brief lay description of the device and what it is designed to do.
• Must not describe the issuance of an IDE as an approval or endorsement by the FDA.

Confidentiality

• Must state that the FDA may review research and participant medical records to verify study data.

Alternatives

• Must include a list of the various alternatives to participation in the study. This should name the standard therapies available with approved devices, as well as other experimental treatments with investigational devices.

Cost

• Please use the cost language provided on the consent form template that best matches your study design. 

Adverse events associated with research participation must be reported expeditiously to both the IRB and to the FDA (21 CFR 812.150).

Investigator’s responsibilities

• All investigators have an obligation to report certain adverse events directly to the IRB.
• Under IDE regulations, there are additional and separate federal requirements for reporting adverse events to the FDA. When the study sponsor holds the IDE, investigators must report all adverse events to the sponsor, which will then submit appropriate reports to the FDA.

• Investigators who hold an IDE have responsibilities for reporting adverse events associated with the investigational device.
• In addition to reporting to the IRB, an investigator-sponsor must report unanticipated adverse events discovered by a sponsor’s monitoring requirements directly to the FDA within 10 working days after the sponsor receives notice of the effect. See FDA regulations.

An IDE application submitted by a sponsor seeking FDA clearance to market a medical device.

By submitting an IDE application to the FDA and conducting the clinical investigation, a physician takes on the responsibilities of both “sponsor” and “investigator.”

A Humanitarian Device Exemption (HDE) allows the FDA to grant an exemption from the effectiveness provisions of the Premarket Approval (PMA) regulations. Devices approved under an HDE are referred to as Humanitarian Use Devices (HUD). The provisions for obtaining an HDE are:

• the device is designed to treat or diagnose a disease or condition that affects no more than 8,000 individuals per year in the U.S.;
• the device is not available otherwise, and there is no comparable device available to treat or diagnose the disease or condition; and
• the device will not expose patients to unreasonable or significant risk, and the benefits to health from the use outweigh the risks.

Treatment under an HDE is not considered research, but the FDA requires IRB review prior to use. The IRB requires a standard application and use of a consent form similar to research consent. The initial review for this application must be done by the full committee; however, the annual continuing reviews can be done through expedited procedures.

The IRB has posted a sample consent form for Humanitarian Use Devices. However, you may also adapt the sample consent supplied by the study sponsor.

Applicants are encouraged to request feedback from the FDA regarding potential or planned IDE applications or other premarket submissions. For more information, review the UCSF HUB's Pre-IDE Process page and FDA's Pre-Submission Program guidance document.

The completed IDE application should be approved by the FDA before the IRB Application is submitted, as the FDA may require significant revisions to the study protocol before issuing the IDE. The FDA has 30 days to review the completed IDE application. If there is no response from the FDA by the 30-day deadline, the submission is considered approved, and an IRB protocol can be submitted. An investigator cannot initiate a clinical study until both the FDA and IRB have granted approval.

While conducting significant risk and non-significant risk device studies, investigators and sponsors have many specific responsibilities. The obligations span a broad range, including FDA and IRB approvals, informed consent, study monitoring, and multiple reporting requirements.

Investigators conducting studies in which an investigational device will be used must ensure adequate control of the device. Adequate control and handling of investigational devices include all of the following:

• The investigator must ensure that the investigational device is used only in accordance with the IRB-approved protocol, the signed agreement, the investigational plan, and applicable FDA regulations.
• The investigator must administer the investigational device only to participants under the investigator’s direct personal supervision or under the supervision of a sub-investigator directly responsible to the investigator.
• The investigator must not supply the investigational device to any person not authorized to receive it.
• The investigator must maintain the following accurate, complete, and current records relating to the investigator’s participation in an investigation.
  • Records of receipt, use or disposition of a device that relate to a) The type and quantity of the device, the dates of its receipt, and the batch number or code mark; b) the names of all persons who received, used, or disposed of each device; c) why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.
• If the investigation is terminated, suspended, discontinued, or completed, the investigator must return any unused supplies of the investigational device to the study sponsor or otherwise provide for the disposition of the unused supplies as directed by the sponsor.

Here is a sample Investigational Device Accountability Log you can use.

A complete overview of medical device import/export regulations is provided by the Center for Devices and Radiological Health (CDRH). Clinical investigators should be aware that the FDA does not recognize regulatory approvals from other countries; therefore, an imported medical device must meet all FDA requirements. The IDE sponsor must be located in the United States. Anyone who intends to import an investigational device takes on the responsibilities of a sponsor.

The level of regulatory controls placed on a medical device is determined by the risk classification. Most of the clinical studies at UCSF requiring IDEs from the FDA are significant risk, Class III devices. The FDA provides an overview of the risk-based classification scheme. To help determine device classification, regulatory controls, and exemptions, the Center for Devices and Radiological Health (CDRH) maintains:

• A searchable classification database containing information about all approved Class I, Class II, and Class III devices.
• A device listing categorized by medical specialty.
• A Listing of Class I and Class II devices deemed exempt from Pre-market Notification (510(k) regulations.
• Guidance for devices that emit radiation.