SOP #40 Research Studies Involving Investigational Medical Devices

Owner: Vice President of Academic Affairs
Author: CSS IRB
Contact: irb@css.edu
Policy Number: 40
Effective Date: 10/8/2021

Policy

It is the policy of the CSS IRB that all human research studies involving medical devices must be reviewed and conducted in compliance with Investigational Device Exemption (IDE) requirements (21 CFR 812) unless determined to be exempt via 21 CFR n812.2(c).

Purpose

The purpose of this policy is to ensure compliance with all Food and Drug Administration (FDA) investigational device regulations by defining investigator and institutional responsibilities and by establishing procedures for the proper review, control, storage, use and handling of these devices.

Definitions

Medical Device means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

  • Recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them;
  • Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or;
  • Intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.

Test Article Test article means any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulations.

Investigational Devices are medical devices which are the object of clinical research to determine their safety or effectiveness. Studies undertaken to develop safety and effectiveness data for medical devices involving human subjects must be conducted according to the requirements of the Investigational Device Exemption (IDE) regulations (21 CFR 812). Investigational devices are classified as either significant risk or non-significant risk devices.

Significant Risk (SR) Device is one that presents a potential for serious risk to the health, safety, or welfare of the subject. Such a device is intended as an implant; is to be used in supporting or sustaining human life; or is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health. Examples of significant risk devices are catheters (other than urological), ventilators, CPR devices, TMJ prostheses, stents, lithotripters, sutures and absorbable bandages/materials, ECT devices, extended wear contact lenses, pacemakers, contraceptive devices, most laser systems, and most hemodialysis systems.  Investigations involving significant risk devices must meet the full IDE requirements including the submission of an IDE application to the FDA. Prior IRB approval is required.

Non-Significant Risk (NSR) Device is one that does not present a potential for serious risk to the health, safety, or welfare of the subject. Examples of non-significant risk devices are: most daily wear contact lenses, lens solutions, heel cups, antibacterial surgical garments, incontinence devices, oral training splints, and ultrasonic tooth cleaners.  Unless otherwise notified by FDA, an investigation of a non-significant risk device is considered to have an approved IDE if the sponsor fulfills the abbreviated requirements of the IDE regulations.

Major Differences Between SR and NSR Studies are in the IDE approval process and in the sponsor’s record keeping and reporting requirements, as outlined below.

  1. Significant Risk (SR) Device Studies
    1. SR device studies must follow all the IDE regulations at 21 CFR 812.
    2. SR device studies must have an IDE application approved by FDA before they may proceed.
  2. Nonsignificant Risk (NSR) Device Studies
    1. NSR device studies must follow the abbreviated requirements at 21 CFR 812.2(b).
    2. These abbreviated requirements address labeling, IRB approval, informed consent, monitoring, records, reports, and prohibition against promotion. However, there is no need to make progress reports or final reports to the FDA.
    3. NSR device studies do not have to have an IDE application approved by FDA.
    4. Sponsors and IRBs do not have to report the IRB approval of an NSR device study to FDA. This means that an IRB may approve an NSR device study and an investigator may conduct the study without FDA knowing about it.
    5. An IRB’s NSR determination is important because the IRB serves as the FDA’s surrogate for review, approval, and continuing review of the NSR device studies. An NSR device study may start at the institution as soon as the IRB reviews and approves the study and without prior approval by FDA.

Investigation, as it pertains to devices, means a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device.

Sponsor means a person who initiates, but who does not actually conduct, the investigation, that is, the investigational device is administered, dispensed, or used under the immediate direction of another individual.

Investigational Device Exemption (IDE) is issued by the FDA to allow the use of investigational devices in human subjects. The IDE permits use of the device in a clinical investigation to evaluate the safety and/or efficacy of the investigational medical device. An IDE may be held either by a commercial sponsor or by a physician-investigator.  Clinical studies of SR investigational devices must comply with FDA’s investigational device exemption (IDE) regulations and be conducted only with IRB approval.  If an investigational device is a “non-significant risk device”, an investigator does not need to submit an IDE; the IDE will be “considered approved” under FDA regulations.  Such devices do not have to comply with FDA premarket approval and performance standards prior to use in research studies. Such studies of devices “considered approved” by the FDA must still be submitted to the IRB for approval prior to use in human subject research.

Custom Devices are similar to approved devices but custom-made, based on the individual needs of a patient as determined by a medical professional.  To be considered a custom device, the device must meet all of the following criteria:

  1. It necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement in order to comply with the order of an individual physician or dentist;
  2. The device is not generally available to, or generally used by, other physicians or dentists;
  3. It is not generally available in finished form for purchase or for dispensing upon prescription;
  4. It is not offered for commercial distribution through labeling or advertising; and
  5. It is intended for use by an individual patient named in the order form of a physician ordentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice (such as a particular operating tool).

FDA regulations do not require IRB review and approval for custom device use.

Transitional Devices are devices that were regulated as drugs prior to the May 28, 1976, the date the Medical Device Amendments were signed into law (the amendments gave FDA authority to regulate medical devices). Any device that was approved by the New Drug Application process is now governed by the PMA regulations. The original NDA approval number is maintained.

Premarket Notification, or 510(k), is submitted to FDA before a manufacturer proposes to market a medical device.  FDA regulations allow a manufacturer/sponsor to claim that a new device is substantially equivalent to models that the FDA has already approved for marketing.  Such devices are granted a 510(k) designation.  The manufacturer/sponsor must apply to the FDA for this designation, and the FDA will provide a letter in response indicating whether or not it is granted. IRB approval is still required before an investigator may conduct research using a device with a 510(k) designation. If FDA agrees the new device is substantially equivalent to a legally marketed device for which premarket approval is not required, the manufacturer may market it immediately. FDA does not require clinical data in most 510(k)s.  However, if clinical data are necessary to demonstrate substantial equivalence, the clinical study must comply with the IDE, IRB, and human subject protection (informed consent and additional safeguards for children in research) regulations.

Premarket Approval (PMA) is an application that is the most stringent type of device marketing application for medical devices.  FDA approves a PMA if it determines that the application contains sufficient valid scientific evidence to provide reasonable assurance that the device is safe and effective for its intended use(s).

Humanitarian Use Device is a device that is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or is manifested in fewer than 4,000 individuals in the United States per year.  The Office of Orphan Products Development (OOPD) determines if a device meets specific requirements, including scientific rationale and population prevalence, for designation as a HUD.

Humanitarian Device Exemption (HDE) is an application that is similar to a PMA, but because a HUD is exempt from the effectiveness requirements of a PMA, an HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose.  However, the HDE must contain sufficient information for FDA to determine that the probable benefit to health outweighs the risk of injury or illness, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.

Under the statute, once the HDE is approved, the HDE holder is responsible for ensuring that the approved HUD is only administered at institutions that have an IRB constituted and acting pursuant to 21 CFR 56, including conducting continuing review of the use of the HUD.  In addition, an HUD should be administered only if such use has been approved by the Institutional Review Board or by a similarly constituted IRB that has agreed to oversee such use and to which the local IRB has deferred in a letter to the HDE holder.   An HDE holder may wish to ensure that this happens by not shipping the HUD to the facility until it has received confirmation of IRB approval.  NOTE:  HUDs should not be used until AFTER the HDE applicant obtains approval of the HDE from FDA and the IRB approves its use.  IRBs should ensure that HDE approval has been granted before approving the device for use at their institution.

Unanticipated Adverse Device Effects UADEs is defined by the FDA as 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. It also means any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.  UADEs must be promptly reported to the IRB.  (See, CSS IRB SOP #24 Unanticipated Problems and Adverse Event Reporting / Including Report Form.)

IRB Exempt Determinations

There are five device exemption categories that may be applied to clinical research studies. It is important to understand that these exemptions apply only so long as study investigators remain qualified to conduct the research.  If the IRB grants an exemption, it means that the study does not require an Investigational Device Exemption (IDE). It does not mean that the study is “exempt” from IRB review per 45 CFR 46.101(b). As part of the initial IRB application process, the PI should indicate which of the following five exemption categories applies to the proposed study:

  1. Devices, other than transitional devices, in commercial distribution prior to May 28, 1976 when used or investigated in accordance with labeling in effect at that time;
  2. Devices, other than transitional devices, introduced into commercial distribution on or after May 28, 1976, that the FDA determines to be substantially equivalent to a device in commercial distribution prior to May 28, 1976, and which is used or investigated in accordance with approved labeling;
  3. A diagnostic device (including in vitro diagnostic products in compliance with 21 CFR 809.10(c) if the testing:
    1. Is non-invasive
    2. Does not require an invasive sampling procedure that presents significant risk
    3. Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
  4. Devices undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put the subject at risk, or
  5. Custom devices, as defined by 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.

The IRB will consider the information provided by the PI, sponsor, or FDA which indicates that the device meets one of the categories above. If the IRB agrees that the study is exempt from IDE requirements, the IRB does not need to make a SR/NSR determination and will evaluate the study in accordance with 21 CFR 50, 21 CFR 56, 45 CFR 46 and all applicable IRB policies and procedures. However, if unsure, the IRB may request that the PI consult with the FDA to verify that the study is exempt from IDE requirements. (See page eight (8) for FDA contact information.)

Responsibilities of the Investigator

The investigator holds additional responsibilities when conducting a clinical trial evaluating

FDA-regulated drugs, devices, and other articles. These responsibilities include, but are not limited to, the following:

  1. The investigator is responsible for indicating on the IRB application that the proposed research is FDA-regulated and for providing relevant information regarding the test article.
  2. The investigator is responsible for ensuring that a clinical investigation is conducted according to the signed investigator statement for clinical investigations of drugs (including biological products) or agreement for clinical investigations of medical devices, the investigational plan and other applicable regulations, and any requirements imposed by the FDA or IRB.
  3. The investigator is responsible for personally conducting or supervising the investigation. When study-related tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. The investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the clinical study.
  4. The investigator must maintain a list of the appropriately qualified persons to whom significant trial-related duties have been delegated. This list should also describe the delegated tasks, identify the training that individuals have received that qualifies them to perform delegated tasks (e.g., it can refer to an individual’s CV on file and/or training conducted by the investigator or sponsor), and identify the dates of involvement in the study. An investigator should maintain separate lists for each study conducted by the investigator.
  5. The investigator is responsible for protecting the rights, safety, and welfare of subjects under their care during a clinical trial. This responsibility includes:
    1. Informing subjects that the test articles are being used for investigational purposes and ensuring that the requirements relating to obtaining informed consent are met;
    2. Providing or arranging for reasonable medical care for study subjects for medical problems arising during participation in the trial that are, or could be, related to the study intervention;
    3. Providing reasonable access to needed medical care, either by the investigator or by another identified, qualified individual (e.g., when the investigator is unavailable, or when specialized care is needed);
    4. Adhering to the protocol so that study subjects are not exposed to unreasonable risks;
    5. As appropriate, informing the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and the subject agrees to the primary physician being informed.
  6. The investigator is responsible for reading and understanding the information in the investigator brochure or device risk information, including the potential risks and side effects of the drug or device.
  7. The investigator is responsible for maintaining adequate and accurate records in accordance with FDA regulations and to making those records available for inspection by the FDA. These records include, but are not limited to: correspondence with other investigators, the IRB, the sponsor, monitors, or the FDA; drug and device accountability records; case histories; consent forms; and documentation that consent was obtained prior to any participation in the study. Records must be obtained for a minimum of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such. For clinical investigations of medical devices, required records must be maintained for a period of 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol. Other regulations, such as HIPAA, organizational policies, or contractual agreements with sponsors may necessitate retention for a longer period of time.
  8. The investigator is responsible for controlling test articles according to FDA regulations and the Controlled Substances Act, if applicable.
  9. For research reviewed by the CSS IRB, the investigator proposing the clinical investigation will be required to provide a plan – to be evaluated by the IRB - that includes storage, security, and dispensing of the test article.
    1. The investigator is responsible for investigational drug accountability that includes storage, security, dispensing, administration, return, disposition, and records of accountability. Such details will be provided in the IRB submission and reviewed by the IRB for acceptability.
    2. The investigator may delegate in writing, as part of the IRB submission, the responsibility detailed in ‘a’ above to the Pharmacy Service.
    3. Investigational drugs and devices must be labeled in accordance with federal and state standards.
    4. All devices received for a study must be stored in a locked environment under secure control with limited access. When applicable, proper instructions on the use of the device must be provided to the subjects. A log must be kept regarding the receipt, use, and/or dispensing of the device, and the disposition of remaining devices at the conclusion of the investigation.
  10. The investigator shall furnish all reports required by the sponsor of the research including adverse events (See, CSS IRB SOP #24 Reporting an Unanticipated Problem Involving Risks to Subjects  or Others/Adverse Event and Report Form.), progress reports, safety reports, final reports, and financial disclosure reports.
  11. The investigator will permit inspection of research records by the sponsor, sponsor representatives, CSS IRB, the FDA, accrediting bodies, and any other agencies or individuals entitled to inspect such records under regulation, organizational policy, or contractual agreement.

Responsibilities of the IRB

Device Studies. For studies involving an investigational device, the sponsor is responsible for determining whether submission of an IDE application to FDA is required before a study may proceed. The IDE regulations (21 CFR 812) describe three types of device studies: significant risk (SR), nonsignificant risk (NSR), and exempt studies.  SR device studies must have an IDE application approved by FDA and have IRB approval before they proceed, and they must follow all of the IDE requirements. NSR device studies must follow the abbreviated IDE requirements at 21 CFR 812.2(b), including informed consent and IRB review, and do not require submission of an IDE application to FDA.

Studies involving an investigational medical device determined to represent a SR may not proceed without submission of an Investigational Device Exemption (IDE) application to the FDA and subsequent receipt of confirmation of the FDA decision on the application. The term “exemption” in this case means exempt from laws prohibiting unapproved products to move in interstate commerce. It does not mean that the study is “exempt” from IRB review.  The IDE allows the investigational medical device to be used in a clinical study to collect safety and efficacy data required to support a marketing application. An IDE may be held either by a commercial sponsor/institution or by a sponsor-investigator.

For studies involving SR devices where the CSS PI is not the sponsor, the PI must provide the IRB at the time of his/her initial IRB submission with the IDE number and one of the following three documents to validate the IDE:

  1. Written communication from the sponsor.
  2. Written communication from the FDA (required for investigator-held IDE).
  3. Sponsor protocol imprinted with IDE number.

The sponsor is responsible for making the initial risk determination, SR or NSR, and presenting it to the IRB. If the sponsor has determined that a device study is NSR, the IRB must review the sponsor’s determination. The IRB must review the sponsor’s significant risk (SR) or non-significant risk (NSR) determination for every investigational medical device study and modify the determination if the IRB disagrees with the sponsor. If the IRB disagrees with the sponsor’s NSR assessment and decides the study is SR, the IRB must inform the clinical investigator and, where appropriate, the sponsor.

To make a SR/NSR determination, the IRB will review information such as the sponsor’s risk designation and justification, description of the device, reports of prior investigations, study protocol, and subject selection criteria at a convened meeting. If the PI requests an NSR determination, he/she will be required to provide additional information via the initial application questions regarding why the investigational device does not meet the definition of a SR device (see Definitions above).

The IRB should not confuse their responsibility to make an SR/NSR determination for a device study with the concept of “minimal risk.” “Minimal Risk” is a term used in the IRB regulations in part to identify certain studies that IRBs may approve through an expedited review procedure. For a device study to be eligible for expedited review, it must be an NSR study AND present no more than minimal risk to the subject. (See, 21 CFR 56.110)

The IRB must make the SR/NSR determination before conducting its review of the study under Part 56. The judgment about whether a study poses a significant risk or nonsignificant risk is based on the significance of the potential harm that may result from participation in the study, including the use of the device.  The IRB’s decision to approve a study for implementation is based on the study’s risk-benefit assessment.

If the IRB determines that a study involves an NSR device, the IRB may then approve the  study using standard approval criteria (See, CSS IRB SOP #12 Criteria For IRB Approval Of Research and Checklist.) Once the study receives IRB approval the PI must still follow the abbreviated IDE requirements including labeling, informed consent, monitoring, records, reports, and prohibition on promotion. Abbreviated IDE requirements under FDA Investigational Device Exemptions, §812.2 (b):

  • Labeling - The device must be labeled in accordance with the labeling provisions of the IDE regulations (§812.5) and must bear the statement "CAUTION - Investigational Device. Limited by Federal (or United States) law to investigational use";
  • IRB Approval – The sponsor must obtain and maintain Investigational Review Board (IRB) approval throughout the investigation as a nonsignificant risk device study;
  • Informed Consent – The sponsor must assure that investigators obtain and document informed consent from each subject according to 21 CFR 50, Protection of Human Subjects, unless documentation is waived by an IRB in accordance with §56.109(c);
  • Monitoring - All investigations must be properly monitored to protect the human subjects and assure compliance with approved protocols (§812.46). Guidance on monitoring investigations can be found in Guideline for the Monitoring of Clinical Investigations at (https://www.fda.gov/media/116754/download).
  • Records and Reports - Sponsors are required to maintain specific records and make certain reports as required by the IDE regulations.
  • Investigator Records and Reports – The sponsor must assure that participating investigators maintain records and make reports as required (see Responsibilities of Investigators); and
  • Prohibitions –Commercialization, promotion, test marketing, misrepresentation of an investigational device, and prolongation of the study are prohibited (§812.7). Investigators are only required to submit study progress and final reports to the IRB.

The IRB’s risk determination for the device must be recorded in the minutes of the convened meeting and in written correspondence (e.g., study approval letter) with the PI. If the IRB disagrees with the sponsor’s NSR assessment and decides that the study is SR, the IRB will document this determination, and where appropriate, inform the sponsor. The IRB may also vote to allow continuing review to be conducted using the expedited review procedure if the research poses no more than minimal risk to subjects and no additional risks have been identified.

The FDA is available to assist sponsors, investigators, and IRBs in making these determinations. Sponsors, clinical investigators, and IRBs who need assistance in making a risk determination for a medical device may contact:

IDE Staff

Office of Device Evaluation

Center for Devices and Radiological Health

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

(Tel) 301-796-5640

Based on the information provided, FDA will determine if a device study is SR, NSR, or exempt from the IDE requirements found in 21 CFR Part 812. If FDA makes the SR, NSR, or exempt determination for a study, the agency's determination is final.

Resources

Allina Health HRPP/IRB SOPs https://www.allinahealth.org/-/media/allina-health/files/for-medical-professionals/research/allina-resea rch-administration-home/hrpp-irb-sop-manual.pdf?la=en&hash=50A1A5F7B07CC65A86FB9F9B3471800 3

Wright State University Humanitarian Use Device Policy

https://www.wright.edu/sites/www.wright.edu/files/page/attachments/P23_HUD%20Policy_Approved_ V1_06082018.pdf

Wright State University Research Involving Medical Devices

https://www.wright.edu/sites/www.wright.edu/files/page/attachments/P21_Device%20Policy_Approve d_V3_06082018.pdf

University of Vermont  Investigational Devices

https://www.uvm.edu/rpo/irb-policies-and-procedures#devices_II

Rutgers Investigational Drugs and Devices https://orra.rutgers.edu/investigational-drugs-and-devices

Johns Hopkins

https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-approval-process

FDA IDE Approval Process https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-approval-process#:~:tex t=An%20IDE%20application%20is%20considered,approved%20with%20conditions%2C%20or%20disappr oved.

FDA  Guidance for IRBs, Clinical Investigators, and Sponsors IRB Responsibilities for Reviewing the

Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed (2013)   https://www.fda.gov/media/85294/download

FDA Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors  Frequently Asked Questions About Medical Devices (2006) https://www.fda.gov/media/75381/download

FDA Investigational Device Exemptions (IDE) https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-approval-process

Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors Significant Risk and

Nonsignificant Risk Medical Device Studies     https://www.fda.gov/media/75459/download

This is a new policy per the 2018 Common Rule Requirements.

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