Overview of Non-Exempt, Significant Risk Medical Device Clinical Studies

September 21, 2016 - Lael Pickett; and Liz Scheurer, Principal Clinical Research Scientist, Neurocritical Care

The white paper “Overview of U.S. Medical Device Clinical Trials” provided a brief overview of U.S. clinical studies regulations, types of clinical studies and how to determine if an Investigational Device Exemption (IDE) is required (Figure 1).

This paper will focus on Non-Exempt clinical studies that present a significant risk to study subjects and require that an IDE be filed and approved by U.S. Food and Drug Administration (FDA) and an Institutional Review Board (IRB) prior to initiating the study.1

figure 1 us fda clinical study regulations by study type

FDA regulations in 21 CFR § 812.3(m) define what a “significant risk” investigational device is:

  1. Intended as an implant and presents a potential for serious risk to the health, safety or welfare of a subject. Note: “implant” is defined in 21 CFR § 812.3(d) as a device that is placed into a surgically or naturally formed cavity of the human body for a period of 30 days or more. FDA may determine that devices placed in subjects for shorter time periods meet the definition of implant.
  2. Purported or represented to be for use in supporting or sustaining human life and presents a potential for serious risk to the health, safety or welfare of a subject. Note: life support or life sustaining devices are described in 21 CFR § 860.3(e) as devices that are essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.
  3. Used for substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise presenting impairment of human health and presents a potential for serious risk to the health, safety or welfare of a subject.
  4. Otherwise presents a potential for serious risk to the health, safety or welfare of a subject.

Interestingly, FDA does not define “serious risk” in its 21 CFR Part 812 Investigational Device Regulations, even though it is critical to determining whether or not a device meets the definition of significant risk device. However, a definition of “risk to health” is described in 21 CFR § 806.2(k) as “a reasonable probability that use of, or exposure to, the product will cause serious adverse health consequences or death; or that use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences, or an outcome where the probability of serious adverse health consequences is remote.”

FDA has published an Information Sheet “Guidance For IRBs, Clinical Investigators, and Sponsors – Significant Risk and Nonsignificant Risk Medical Device Studies,” that provides examples of Non-Exempt, significant risk studies that could be subject to abbreviated study requirements. Examples include: surgical laser, bronchial tubes, cardiac mapping and ablation catheters, extracorporeal circulation systems, hydrocephalus shunts, hemodialyzers and bone growth stimulators. See the FDA Information Sheet for additional examples.

If there are questions as to whether a study is Non-Exempt and presents a significant risk to study subjects, a Sponsor may consult FDA in accordance with its “Procedures for Handling Inquiries Regarding the Need for an Investigational Device Exemptions Application for Research Involving Medical Devices – October 26, 2001 (#D01-01).”

Significant risk devices require that an IDE application be filed with and approved by FDA prior to initiating a clinical evaluation. Additionally, the clinical site’s IRB must review and approve the study prior to initiation.

IDE Application

FDA regulations 2 , and guidance 4

(1) The name and address of the sponsor.

(2) A complete report of prior investigations of the device and an accurate summary of those sections of the investigational plan or, in lieu of the summary, the complete plan. The report of prior investigations shall include reports of all prior clinical, animal and laboratory testing of the device and shall be comprehensive and adequate to justify the proposed investigation. The report also shall include:

  • A bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device, copies of all published and unpublished adverse information, and, if requested by an IRB or FDA, copies of other significant publications.
  • A summary of all other unpublished information (whether adverse or supportive) in the possession of, or reasonably obtainable by, the sponsor that is relevant to an evaluation of the safety or effectiveness of the device.
  • If information on non-clinical laboratory studies is provided, a statement that all such studies have been conducted in compliance with applicable requirements in the good laboratory practice regulations in 21 CFR Part 58 should be included, or if the study was not conducted in compliance with these regulations, a brief statement of the reason for the noncompliance should be included. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study.

(3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device.

(4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement.

(5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement.

(6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB.

(7) The name and address of any institution at which a part of the investigation may be conducted that has not been identified in accordance with paragraph 6 above.

(8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device.

(9) A claim for categorical exclusion under 21 CFR §25.30 or §25.34 or an environmental assessment under §25.40.

(10) Copies of all labeling for the device.

(11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent.

(12) Any other relevant information FDA requests for review of the application.

FDA IDE Review

FDA has thirty calendar days to review an IDE application. FDA may approve, approve with conditions or disapprove an IDE application. It is not uncommon for FDA to conditionally approve or disapprove an IDE application and provide the sponsor with a list of questions that must be satisfied to obtain full IDE approval. Most US IRBs will not review significant risk studies until FDA IDE approval has been obtained. FDA approval of an IDE application may be granted in a staged manner i.e., a cap on initial enrollments with a required stop and submission of a safety report. This approval method is not unusual in first-in-human studies and ensures that the agency is adhering to the mission of protecting the study subjects.

IRB Review

Sponsors should check with each clinical site’s IRB as to what is required for submission and approval. Obviously the clinical study protocol, informed consent form and FDA letter of IDE approval is required. Additionally sponsors must provide IRBs with copies of any other documents that will be provided to study subjects such as questionnaires, as well as copies of any materials that may be used to recruit potential study participants (e.g. newspaper ads, flyers, etc.). It is not unusual for IRBs to slightly modify the informed consent form to comply with center specific language and any recruitment materials to ensure that potential subjects are aware of all study risks and that their privacy is protected.

Sponsor IDE Responsibilities

  • Sponsors are responsible for selecting qualified investigators and providing them with the information that they need to conduct the investigation properly. They must also ensure proper monitoring of the investigation and IRB review and approval, submit an IDE application to FDA for significant risk device studies, and inform the IRB and FDA promptly of any significant new information about the investigation. 5
  • A sponsor cannot begin an investigation or any part of an investigation until an IRB and FDA have both approved the application or supplemental application. 6
  • A sponsor is responsible for selecting investigators qualified by training and experience to investigate the device. 7
  • A sponsor must select monitors qualified by training and experience to monitor the investigational study in accordance with the IDE and other applicable FDA regulations. 7
  • A sponsor can ship investigational devices only to qualified investigators participating in the investigation. 7
  • A sponsor must obtain a signed agreement from each participating investigator that includes: 7
    • The investigator’s curriculum vitae
    • A statement of the investigator’s relevant experience, including the dates, location, extent, and type of experience
    • An explanation of the circumstances that led to termination of a study if the investigator was involved in an investigation or other research that was terminated
    • A statement of the investigator’s commitment to:
      • Conduct the investigation in accordance with the agreement, the investigational plan, the IDE and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB or FDA
      • Supervise all testing of the device involving human subjects
      • Ensure that the requirements for obtaining informed consent are met.
    • Accurate financial disclosure information to allow the sponsor to submit a complete and accurate certification or disclosure statement as required under 21 CFR 54, Financial disclosure by clinical investigators. The sponsor shall also obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for one year following completion of the study.
  • A sponsor must supply all investigators participating in the investigation with copies of the investigational plan and a report of prior investigations of the device. 8
  • A sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, the IDE requirements, any other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA must promptly either secure compliance, or discontinue shipments of the device to the investigator and terminate the investigator’s participation in the investigation. A sponsor must also require that the investigator dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a subject. 9
  • Sponsors must immediately conduct an evaluation of any unanticipated adverse device effect. A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to subjects must terminate all investigations or parts of the investigations presenting that risk as soon as possible. Termination must occur no later than 5 working days after the sponsor makes this determination and no later than 15 working days after the sponsor first received notice of the effect.
  • A sponsor may not resume a terminated investigation without IRB and FDA approval. For a nonsignificant risk device investigation, a sponsor may not resume a terminated investigation without IRB approval. If the nonsignificant risk study was terminated for unanticipated adverse device effects, the sponsor must also obtain FDA approval.
  • The sponsor must maintain accurate and complete records relating to the investigation. 10  These records include:
    • All correspondence including required reports
    • Records of shipment of the device
    • Records of disposition of the device
    • Signed investigator agreements including financial disclosure information
    • Records concerning complaints and adverse device effects whether anticipated or not
    • Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigation or a particular investigatin
  • The sponsor must provide the following reports in a timely manner to FDA, the IRBs, and/or the investigators: 11
    • Unanticipated Adverse Device Effects
    • Withdrawal of IRB Approval
    • Withdrawal of FDA Approval
    • Current List of Investigators
    • Progress Reports (usually on the anniversary date of IDE conditional or full approval)
    • Recalls and Device Disposition
    • Final Report
    • Informed Consent Form
    • Significant Risk Device Determination
    • Other Reports
  • An investigational device or its immediate package must bear a label with the following information: 12
    • Name and place of business of the manufacturer, packer, or distributor
    • Quantity of contents, if appropriate
    • The statement, “CAUTION ­­ Investigational device. Limited by Federal (or United States) law to investigational use.”

The label must also describe all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions.

The labeling of an investigational device must not contain any false or misleading statements nor imply that the device is safe or effective for the purposes being investigated.

The sponsor should provide detailed information on device labeling in the investigational protocol. This information may vary depending on the device and the nature of the study. Product labeling should be sufficient to ensure stability of the test article for the duration of the study (storage requirements, calibration procedures), bear sufficient directions for proper administration, and detail procedures to follow in the event of patient injury.

A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator cannot: 13

  • Promote or test market an investigational device, until after FDA has approved the device for commercial distribution.
  • Commercialize an investigational device by charging the subjects or investigators a higher price than that necessary to recover costs of manufacture, research, development, and handling.
  • Unduly prolong an investigation. If data developed by the investigation indicate that premarket approval (PMA) cannot be justified, the sponsor must promptly terminate the investigation.
  • Represent that an investigational device is safe or effective.

However, the sponsor may advertise for research subjects to solicit their participation in a study. Appropriate advertising methods include but are not necessarily limited to: newspaper, radio, TV, bulletin boards, posters and flyers that are intended for prospective subjects.

Advertisements should be reviewed and approved by the IRB to assure that they are not unduly coercive and do not promise a certainty of cure beyond what is outlined in the consent and the protocol. No claims should be made, either explicitly or implicitly, that the device is safe or effective for the purposes under investigation, or that the test article is known to be equivalent or superior to any other device.

FDA considers direct advertising for study subjects to be the start of the informed consent and subject selection process.

While FDA requirements for significant risk clinical investigations are extensive, they are necessary to ensure study subject safety and welfare.

At Minnetronix, our extensive development experience, commitment to patient safety, and flexible manufacturing environment provide ideal partnership opportunities for limited clinical builds. We equip our customers with Minnetronix developed product design and/or manufacturing information to ensure successful clinical study applications.


[1] 21 CFR § 812.422

[2] 21 CFR § 812.20 Application

[3] 21 CFR § 812.27 Report of prior investigations

[4] https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm162453.htm

[5] 21 CFR § 812.40 General responsibilities of sponsors

[6] 21 CFR § 812.42 FDA and IRB approval

[7] 21 CFR § 812.43 Selecting investigators and monitors

[8] 21 CFR § 812.45 Informing investigators

[9] 21 CFR § 812.46 Monitoring

[10] 21 CFR § 812.140 Sponsor records

[11] 21 CFR §812.150 Sponsor records

[12] 21 CFR §812.5 Labeling

[13] 21 CFR §812.7 Promotion of investigational devices