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THE HUMAN RESEARCH PROTECTION PROGRAM

THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

INVESTIGATIONAL DEVICES


Brief Overview: Investigational Devices

In addition to the guidance below, please also review the IDE Decision Worksheet and on the UCSF HUB.


The Food and Drug Administration (FDA) regulates research involving medical devices as well as all aspects of device manufacturing, marketing, and distribution [Code of Federal Regulations Title 21, parts 800-1299].
For most studies involving devices, an investigator or sponsor must obtain an Investigational Device Exemption (IDE) from the FDA.
The responsible branch of the FDA is the Center for Devices and Radiological Health (CDRH).
A device is considered investigational if either condition applies:
  the device is not approved for marketing in the United States or

the device is approved for marketing but is being clinically evaluated for a new indication.
All device studies involving human subjects must be submitted to the Committee of Human Research (CHR) for review and approval before the investigation can begin.

When is an Investigational Device Exemption (IDE) Required?


Testing an Unapproved Significant Risk Device: An investigational device exemption (IDE) from the FDA is required to do a clinical study of an unapproved device that poses a significant risk to subjects. The majority of IDE studies are conducted to collect safety and effectiveness data used to support Premarket Approval (PMA) applications submitted to the FDA.

Testing a Legally Marketed Device for a New Indication: IDE regulations apply to significant risk studies testing an FDA-approved device for a new indication.

IMPORTANT NOTE: An IDE is not required for off-label use of an FDA-approved device used by a physician in the practice of medicine.

Example: Significant risk (SR) studies involve implantable devices such as cardiac pacemakers, orthopedic implants, and stents. SR studies can also involve products not introduced into the body, such as computer software used for prenatal risk evaluation. Each of these studies would require an IDE.

For more informatin please see HRPP Guidance on Significant and non-significant Risk Devices.

Example: A legally marketed coronary stent would be considered an investigational device and would require an IDE if used as part of a study to collect safety and effectiveness data for treating conditions involving other vascular sites.

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When is an Investigational Device Exemption (IDE) Not Required?


Testing A non-significant Risk (NSR) Device: An IDE is not needed for research use of some non-significant risk devices or devices that are substantially equivalent to currently marketed devices.
  CHR review and approval are required for all NSR studies.
  The FDA authorizes institutional review boards to conduct a risk assessment of all proposed non-significant risk studies.
 

Study approval is dependent on the investigator supplying the CHR with sufficient information, generally provided by the study sponsor, regarding the device and its intended use.

IMPORTANT NOTE: Although FDA approval is not required, the agency can assume study jurisdiction at any time deemed necessary.

Example: Nonsignficant risk devices include daily wear contact lenses and associated care products; conventional gastroenterology and urology endoscopes; externally worn monitors for insulin reactions; general catheters (biliary, urological); and, nonimplantable electrical incontinence devices.

For more information please see HRPP Guidance on Significant and non-significant Risk Devices.

    Practice of Medicine: A physician can use a legally marketed device without CHR approval for any condition or disease within a “legitimate healthcare practitioner-patient relationship”. However, the results of an off-label use of a medical device cannot be presented as research.
    Specific IDE-Exempt Studies: Federal regulations describe the following IDE-exempt studies.
    Please review the HRPP information sheet, Exemptions from IDE Requirements for a complete list of all types of investigations which are exempt from FDA IDE requirements, according to 21 CFR 812.2.
    The more common IDE-exempt investigations submitted to the CHR meet the following criteria:
    Investigations conducted with legally marketed devices used according to labeling.
    Studies using in vitro diagnostics labeled for “research purpose only” as per regulations [21 CFR 809.10(c)] and if the testing:
     
is noninvasive;
      does not require invasive sampling procedure that presents significant risk;
      does not introduce energy into a subject; and
     
is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure;
   
Additional guidance on studies using in vitro diagnostics is available.

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CHR Application Requirements

The general CHR application process is described on the "Applying and Reporting to the CHR" section of our website.

If your study involves a device, check the appropriate box in the "Drugs and Devices" section of the CHR Application. Also supply the CHR with the key information listed below.

For Significant Risk Studies include all of the following that are available:


An IDE number – the CHR will not issue final approval until the IDE number is reported to and verified by the CHR. Verification can be accomplished by providing a copy of the sponsor's protocol with the IND number listed, or by submitting correspondence from the sponsor or FDA indicating the IND number for the study. However, the CHR will review the research before the IDE application is submitted to the FDA.
 
Investigator’s Brochure
  Directions for use, typically provided by the manufacturer
Device labeling consistent with federal regulations [21 CFR 812.5].
 
Clinical protocol [also known as “sponsor protocol” or “multicenter protocol”]. By any name, this document should describe the methodology to be used and offer an analysis that the study is scientifically sound.
  An explanation of the device cost as determined by the reimbursement category provided by FDA with each approved IDE. This information is needed for the consent form (see below).
Clearance from the Radiation Safety Committee for radiation-emitting devices.
For Non-Significant Risk Studies include all of the following that are available:


In the CHR 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 CHR with adequate justification that the device, and/or its proposed use, does not pose a significant risk to subjects.
 
Include any detailed 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.
 
Device labeling consistent with federal regulations [21 CFR 812.5].
  Clinical protocol [also known as “sponsor protocol” or “multicenter protocol”]. By any name, this document should describe the methodology to be used and offer an analysis 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 reimbursement category overview provided by the FDA.

IMPORTANT NOTE: If the CHR determines that the proposed non-significant risk study is actually a significant risk study, the sponsor must submit to the FDA a report of the CHR findings within 5 working days after learning of the CHR’s determination [21 CFR 812.150(9)].

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Consent Forms

All medical device studies involving human subjects require informed consent. The CHR provides template forms for informed consent with the required elements. Investigators should include the following key points within the sections noted below:

Purpose and Background Section


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.
 
Should 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 Section


Must state that the FDA may review research and subjects’ 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.

Example: The informed consent for a clinical trial testing a new cardiac pacemaker must list legally marketed pacemakers as well as other investigational pacemakers that would be alternatives to the present study.

Cost


Provide specific information regarding the participation in the device study. If applicable,
   
state if the sponsor is supplying the device at no charge.
    state whether the subject or their insurance carrier will be billed for the device,
    state that the cost may not be covered by insurance because the therapy is experimental,
 
provide a discussion of the cost of implanting and, if anticipated as part of the study, the cost of explanting the device.
  Describe how the subject can obtain more detailed information about the possible financial risks, if needed.

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Adverse Event Reporting

Adverse events associated with research participation must be reported expeditiously to both the Committee on Human Research (CHR) and to the FDA.


Investigator’s Responsibilities: All investigators have an obligation to report certain adverse events directly to the IRB.
  Please review the CHR Guidelines on Adverse Event Reporting for a detailed description of the CHR reporting requirements.
 
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 need to report all adverse events to the sponsor and the sponsor will submit appropriate reports to the FDA.
Investigator-Sponsor Responsibilties: Investigators who hold an IDE have responsibilities for reporting adverse events associated with the investigational device. In addition to reporting to the CHR, an investigator-sponsor must directly report the following adverse event information to the FDA:
  Unanticipated adverse events investigated under a sponsor’s monitoring requirements [21 CFR 812.46(b)], must be reported to FDA within 10 working days after the sponsor receives notice of the effect.

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Types of IDE Applications



Commercial IDE: An IDE application submitted by a sponsor seeking FDA clearance to market a medical device.
Investigator-Initiated IDE: By submitting an IDE application to the FDA and conducting the clinical investigation, a physician takes on the responsibilities of both “sponsor” and “investigator.”
Emergency Use IDE: This is an exception to investigational device regulations permitting the one-time treatment of one patient per institution without prior FDA approval.
 
There are strict reporting requirements and every effort must be made to obtain prior authorization from the CHR.
  The emergency use of an investigational device must meet all of the following criteria:
   
the patient has a life-threatening or severely debilitating condition, and
    there are no other available treatments, and
    there is not sufficient time for prior IRB review and approval.
      IMPORTANT NOTE: Research may not be conducted under an emergency use IDE and subsequent use(s) of the investigational device require prior CHR review and approval. For more information, please review the CHR Emergency Use Guidelines.

Additional IDE Mechanisms Allowing Expanded Access: There are several regulatory mechanisms that allow expanded access to investigational medical devices while clinical studies and/or FDA review are on-going. Because FDA is primarily concerned with protecting public safety, the number of patients who can be treated under these special access mechanisms is limited and generally determined by the existence of sufficient safety and efficacy data. A brief discussion of each mechanism follows.

 
Compassionate Use IDE: Under an existing IDE, the FDA may allow treatment of a small number of seriously ill patients who have no acceptable alternatives. The FDA requires the sponsor/investigator to supply a supplement to an existing IDE justifying the compassionate use.

IMPORTANT NOTE: Compassionate use requires FDA review and approval and concurrence of a CHR Chair before treatment can be initiated. The study involving the existing IDE must already be approved by the CHR.

 

Treatment IDE: If FDA has reviewed sufficient safety and efficacy data obtained under an existing IDE, wider access to an unapproved device may be granted to desperately ill patients under Treatment IDE regulations.

IMPORTANT NOTE: Prior FDA and CHR review and approval are required.

 

Continued Access: After the completion of a controlled clinical trial, a Supplement to an existing IDE can be submitted and the FDA may allow continued access to the device provided there are no safety concerns. The Continued Access Policy allows access to promising devices while the marketing application is being prepared by the sponsor or reviewed by the FDA.

IMPORTANT NOTE: Prior FDA and CHR review and approval are required.

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Timing the IDE Submission

Pre-IDE Process: The FDA encourages applicants to communicate with the reviewing division of the Office of Device Evaluation (ODE) prior to the submission of the original IDE application. More information about the Pre-IDE Process is available.

The IDE Submission: The IDE submission to the FDA and the CHR application should be initiated at the same time. The FDA has 30 days to review the IDE application. Likewise, the CHR makes every effort to review an application within a 30-day window, but a longer review period is often necessary. An investigator cannot initiate a clinical study until the FDA and CHR have granted approval.

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Responsibilities of Investigators and Sponsors

While conducting significant risk and non-significant risk device studies, investigators and sponsors have specific responsibilities. The obligations span a broad range, including FDA and IRB approvals, informed consent, study monitoring, and multiple reporting requirements. Links to detailed information pertinent to each role are provided below:

Significant Risk Studies Sponsor Responsibilities
Investigator Responsibilities
Non-Significant Risk Studies Sponsor Responsibilities
Investigator Responsibilities

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Control of Investigational Devices – Investigator Responsibilities

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 CHR-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 investigation 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:
    The type and quantity of the device, the dates of its receipt, and the batch number or code mark.
    The names of all persons who received, used, or disposed of each device.
    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 disposition of the unused supplies as directed by the sponsor.

Sample Investigational Device Accountability Log

Special Medical Device Regulations

Humanitarian Device Exemption (HDE)

An HDE is a type of Premarket Application described under the Safe Medical Devices Act (SMDA) of 1990 and allows 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 fewer than 4,000 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 CHR review prior to use. The CHR requires a standard application and use of a consent form similar to research consent.
    The CHR has posted a sample consent form for Humanitarian Use Devices.
Drug-Device Combination Products: If an investigator is interested in evaluating a combination product, the following links may be useful:

The Office of Combination Products (OCP) was created in 2002 to facilitate the review process for combination products by coordinating interactions between reviewing branches.

As an aide to sponsors, the OCP provides applicable guidance documents for combination products.

Some recent combination product approvals include:
    drug-eluting coronary stents;
    spinal fusion putty; and,
   
an influenza vaccine administered via an intranasal delivery device.
  A complete listing of recently approved combination products is available.

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Import/Export of Investigational Devices

A complete overview of medical device import/export regulations is provided by the CDRH. Clinical investigators should be aware that 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.

Definitions and Quick Links


Significant and Non-Significant Risk Devices: See HRPP Guidance on Significant and Non-Significant Devices.

Types of Marketing Applications
  Premarket Notification [510(k)] applies to Class I, Class II, and some Class III devices.
   
A sponsor must demonstrate “substantial equivalence,” meaning that the new device is as safe and effective as the predicate device(s).
    New guidelines describing streamlined 510(k) options are available.
    Clinical studies using 510(k) devices may be subject to IDE regulations. Prior FDA and CHR approval are required.
  Premarket Approval (PMA) has more stringent requirements for high risk Class III devices. In most cases an investigational device exemption (IDE) is required to clinically evaluate devices subject to PMA regulations.
  Humanitarian Device Exemption (HDE) is part of the FDA Modernization Act aimed at encouraging device development for conditions with fewer than 4,000 patients.

Product Development Program (PDP) is part of the “reengineering” of the PMA process underway and aims to facilitate bringing Class III devices to market faster. Interested parties are encouraged to contact FDA:

PDP Reengineering Team
Center for Devices and Radiological Health (HFZ-150)
9200 Corporate Blvd
Rockville MD 20850


Device Classification: The level of regulatory controls placed on a medical device is determined by the risk classification. Most research reviewed by the CHR involves 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 Premarket Notification 510(k) regulations.

Guidance for devices that emit radiation.

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Resources

RKS • Regulatory Knowledge and Support Service

  The Regulatory Knowledge and Support Service, part of the UCSF Clinical and Translational Science Institute, is available to help researchers understand and meet the many regulatory and compliance requirements in the pre-award and post-award process. The RKS Program includes the Diagnostics and Therapeutics Regulatory Consulting Service (DTRCS), which is available to provide advice and guidance to investigators planning submissions to the U.S. Food and Drug Administration.
FDA Offices and Resources
  Center for Devices and Radiological Health
 
Guidance for IRBs and Clinical Investigators
  Device Advice Index
 
The Office of Combination Products (OCP)
Applicable FDA Regulations
 
21 CFR 11: Electronic Records; Electronic Signatures
 
21 CFR 54: Financial Disclosure by Clinical Investigators
 
21 CFR 812: Investigational Device Exemptions
 
21 CFR 814: Premarket Approval of Medical Devices
 
21 CFR 820: Quality System Regulation
 
21 CFR 860: Medical Device Classification Procedures