To provide guidelines for investigators participating in research involving an investigational medical device and those applying for approval for the use of a Humanitarian Use Device (HUD).
Federal regulations provide specific guidance on investigational devices of various categories. When reviewing and approving a device study, the IRB requires sufficient information from the investigator to ensure that s/he is complying with these regulations.
This policy reflects:
- Code of Federal Regulations, Title 21, Part 812: Investigational Device Exemptions (21 CFR 812)
- Code of Federal Regulations, Title 21, Part 814: Premarket Approval of Medical Devices (21 CFR 814)
- FDA Guidance on IDE Policies and Procedures, v. 1/20/98
- FDA Guidance: Frequently Asked Questions about Medical Devices, v. January 2006
- FDA Draft Guidance: The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications, v. 12/27/11
- FDA Guidance on Humanitarian Device Exemption (HDE) Regulation: Questions and Answers, v.7/8/10
- FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, v. 4/25/06
- FDA Guidance on In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions, v 6/25/10
- FDA Guidance: Exception from Informed Consent Requirements for Emergency Research, FDA, v. March 2011.
Device – Any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized.
- Class I – a device for which the controls authorized in the Food, Drug and Cosmetic Act are sufficient to provide reasonable assurance of the safety and effectiveness of the device. It is not purported or represented to be for a use in supporting or sustaining human life, or for a use, which is of substantial importance in preventing impairment of human health, and does not present a potential unreasonable risk of illness or injury
- Class II – a device which cannot be classified as a class I device because the general controls by themselves are insufficient to provide reasonable assurance of the safety and effectiveness of the device, and for which there is sufficient information to establish special controls to provide such assurance.
- Class III – the most stringent regulatory category for medical devices. Class III devices are usually those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury.
FDA – U.S. Food and Drug Administration.
Humanitarian Use Device (HUD) – A new device, which receives FDA approval for individuals with rare conditions affecting <4000 patients in the U.S. each year.
Humanitarian Device Exemption (HDE) – In order to use the HUD, the device manufacturer must receive an HDE from the FDA.
HDE Holder – The device company or investigator to whom the FDA’s HDE was granted.
Investigational Device – A medical device that is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device.
Investigational Device Exemption (IDE) – If a device is considered to be significant risk, the sponsor must receive an IDE from the FDA in order to proceed with clinical studies.
In Vitro Diagnostic (IVD) Device – In Vitro Diagnostics (IVDs) are reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, to cure, mitigate, treat, or prevent disease. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.
Non-Significant Risk (NSR) Device – A device that does not meet the definition for a significant risk device.
Pre-Market Approval (PMA) – The process of scientific and regulatory review to ensure the safety and effectiveness of Class III devices. The PMA requirements are found in 21 CFR Part 814.
Significant Risk (SR) Device – A device that presents a potential for serious risk to the health, safety, or welfare of the subject.
510(k) Device – A device that has been granted “substantial equivalence” to an existing marketed device under section 510(k) of the Food, Drug, and Cosmetic Act.
The following guidelines outline an investigator’s requirements and obligations to the IRB preparatory to the use of an investigational device, 510(k) device, or Humanitarian Use Device.
I. INVESTIGATIONAL DEVICE EXEMPTIONS
A. General Information
Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit premarket notification to the FDA. The FDA reviews these notifications to determine if the new device is “substantially equivalent” to a device that was marketed prior to the passage of the Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990. If so, the device may be marketed immediately.
Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the IDE regulations [21 CFR part 812] and require premarket approval before marketing. Studies that propose to evaluate a significant risk device must be conducted under an Investigational Device Exemption (IDE) granted by the FDA. The determination that an IDE is necessary is generally made by the study sponsor. Non-significant risk devices may be studied without the need for an IDE, however Institutional Review Board (IRB) oversight is still required.
Investigational devices are regulated according to their risk classification. Depending upon its risk category, the use of an investigational device will require different standards.
Classifications and Controls used for Various Devices
IDE, PMA – 21CFR812
Class I, II
“abbreviated” IDE requirements – 21CFR812.2(b)
Class I, II, III
510(k) determination by FDA – Food, Drug & Cosmetic Act, Section 510(k); 21 CFR Part 807, Subpart E.
HDE – 21CFR814, Subpart H
B. IRB Submission Guidelines
The Cottage Health System (CHS) IRB will conduct its review and base its approval in compliance with published guidance from the FDA concerning the evaluation of experimental medical devices.
Non-significant risk devices. Investigators wishing to open studies using non-significant risk devices are required to provide as much of the following additional information as possible with their Office of Research applications:
- A thorough justification of why the sponsor thinks it is a NSR device;
- Information from prior investigations;
- Written letters from other IRBs, if available, showing that they determined it was a NSR device;
- Any applicable FDA correspondence regarding classification of the device..
Whenever the CHS IRB reviews an application for a study involving a medical device for which the Investigator has not obtained an IDE, the IRB will carefully evaluate the claim that the device is a non-significant risk device. It will review the application including the description of the device, reports of prior investigations, the proposed investigational plan, and the patient selection criteria and monitoring procedures. In addition, the IRB will evaluate the potential harms that may arise in the context of the actual use of the device, taking account of the risks associated with any surgical procedures that need to be performed.
The CHS IRB will use the above information in order to help make its decision regarding NSR status. However, despite receiving all of the above information, the IRB may still consider the device to be significant risk. If so, a statement will be made to the investigator in writing. The IRB’s statement will be forwarded to the device manufacturer by the investigator. It is then the responsibility of the device manufacturer to notify the FDA of the IRB’s decision and to complete the requirements needed for a SR device.
Significant risk devices. Significant risk devices are categorized as class III devices. These devices are usually those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Due to the level of risk associated with these devices, they require an approved IDE and a premarket approval (PMA) application. The IRB Application cover page asks for the investigational device category and the IDE number. Investigators participating in sponsored trials, will receive this information from the device manufacturer. This information must be included on all applications. Because the standards for SR devices are the most stringent, the IRB accepts the SR classification by the sponsor when accompanied by the IDE number. However, any FDA documentation should be provided to the IRB either with the original application or as it becomes available from the sponsor.
IRB fees. The usual IRB application fee for new and continuing studies is required for device studies, unless circumstances qualify for a fee waiver.
II. 510(k) DEVICES
A. General Information
A premarket notification [510(k)] is a marketing application submitted to the FDA to demonstrate that a medical device is as safe and as effective, or substantially equivalent to, a legally marketed device that was or is currently on the U.S. market and that does not require premarket approval. The premarket notification requirement for new devices and devices that are significant modifications of already marketed devices is set forth in section 510(k) of the Food, Drug and Cosmetic Act. Therefore, devices determined by the FDA to be “substantially equivalent” are often referred to as “510(k) devices.” Most devices are cleared for commercial distribution in the U.S. by the premarket notification [510(k)] process. The premarket notification requirements are also outlined in 21 CFR Part 807, Subpart E.
Device manufacturers file a 510(k) application with the FDA to demonstrate that a new device is substantially equivalent to another device that is legally on the market without a Pre-Market Approval (PMA). If the FDA agrees that the new device is substantially equivalent, it can be marketed immediately. Clinical data are not required in most 510(k) applications; however if the FDA feels that clinical data are necessary to demonstrate substantial equivalence, the clinical studies need to be conducted in compliance with the requirements of the IDE regulations and all applicable CHS IRB policies.
B. IRB Submission Guidelines
IRB submission of a 510(k) device is needed when the FDA requires additional data to support the 510(k) claim, or if the manufacturer wishes to either use the device or to collect data prior to the FDA’s final determination. The general IRB application guidelines apply to 510(k) submissions, however in addition to the standard application, the investigator must provide the IRB with all relevant correspondence to and from the device company and the FDA regarding the device’s 510(k) application and status. The study will be reviewed by the Full Board, and informed consent will be required, if applicable. The study may be closed after the manufacturer has received the FDA’s final determination of the device’s 510(k) designation. In order to close the study, the investigator must submit a copy of the FDA’s final determination letter.
IRB fees. An IRB fee may be required for 510(k) submissions and will be determined on a case-by-case basis.
III. IN VITRO DIAGNOSTIC DEVICES
A. General Information
IVDs that are being tested for possible future marketing are considered devices, and may also be biological products. They are test articles under Food and Drug Administration regulations and are subject to FDA regulations governing investigational devices (IDE regulations). When IVDs are used in research involving human subjects (or human samples), FDA’s regulations for the protection of human subjects (informed consent and IRB review) generally also apply.
- IDE Exempt Studies
- Studies may be exempt from FDA’s IDE regulations when the research meets all of the following criteria
- The sponsor has labeled the device properly;
- The testing is non-invasive;
- The testing does not require an invasive sampling procedure that presents significant risk;
- The testing does not by design or intention introduce energy into a participant; and
- The testing is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically-established diagnostic product or procedure.
Investigators should also be aware that IVD testing performed in the laboratory setting is subject to the requirements of the Clinical Laboratories Improvement Act (“CLIA”). If an investigator intends to share results of an IVD test with research subjects or their care providers, the IRB must be informed of this fact and the testing and reporting of results must conform to the institution’s CLIA Policy.
B. IRB Submission Guidelines
Unlike DHHS regulations, FDA regulations do not provide for exemption from IRB review when research involves existing specimens and the investigator records information without identifiers or linking codes. Nor do FDA regulations define “human subjects” with reference to the identifiability of the subject or of the subject’s private information (i.e., the donors of specimens/samples remain “human subjects” even when the specimens/samples are de-identified). Current FDA guidance indicates that IRB review is required for any IVD study involving human specimens/samples, even when the research involves no identifiers and the biological materials cannot be linked to any identifying information.
With a few narrow exceptions (emergency and some DOD research), FDA regulations do not permit waiver of consent, even when studies are minimal risk and would meet criteria for waiver of consent under DHHS regulations. Under FDA regulations, informed consent is required for IVD studies involving samples that are identifiable (i.e., are labeled with identifiers or accompanied by the patient’s identifiable clinical information), as well as for studies in which the samples are not identifiable but are coded or linked to identifiable information.
The current FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (4/25/06), however, indicates that under some circumstances, when samples taken from excess clinical or research specimens cannot be identified (e.g., all linking codes and identifiers have been removed, or the investigator has no access to the code keys or identifying information), the agency will exercise “enforcement discretion” and permit the IRB to approve the study without requiring informed consent of the sample sources.
To be eligible for approval without a requirement for informed consent, FDA indicates that IVD research must meet the following criteria:
- The research must be conducted under an IRB-approved protocol;
- The research must meet criteria for an IDE exemption (see above);
- The research must use specimens left over from clinical care, specimen repositories, or other research (i.e., the specimens may not be collected specifically for the proposed research, and no additional specimen may be collected for the purpose of research);
- Individuals caring for the patients are different from and do not share information about the patient with those conducting the investigation (we do not interpret this criterion to exclude investigators who also perform clinical services, provided that the research meets the other criteria established by FDA;
- The specimens are provided for research without identifiers (codes are permissible only if neither the investigator nor anyone associated with the study has access to the code key or can identify the person who was the source of the specimen);
- Any clinical information supplied with the specimen must not be individually identifiable.
- No test results from the research may be reported to any subject or that subject’s health care provider; and
- The supplier of the specimens must have established policies and procedures to prevent the release of identifying information.
If an IDE is required for an IVD study, informed consent must be obtained unless the study involves planned emergency research and the sponsor has successfully completed the entire regulatory review and community consultation process. See FDA Guidance: Exception from Informed Consent Requirements for Emergency Research (March, 2011).
Additionally, in order to waive consent, FDA recommends that the IRB review the policies and procedures that are in place to determine (1) that identifiers will not be released to investigators, and (2) whether there is the potential for test results to be needed for clinical patient management (e.g., FDA suggests that if the research involves a public health threat such as anthrax, it may be necessary to report positive results; therefore informed consent might be required).
IRB fees. The usual IRB application fee for new and continuing studies is required for IVD studies, unless circumstances qualify for a fee waiver.
IV. HUMANITARIAN USE DEVICES
A. General Information
In certain situations, novel technological devices may be designed with specialty functions in which a very small percentage of the population may benefit. In such instances, the FDA believes it to be inappropriate to pursue the standard IDE guidelines. Instead, a similar approach is used, in which the sponsor seeks HUD approval using a Humanitarian Device Exemption.
According to the regulations, the device must be used for less than 4,000 people per year, or be used less than a total of 4,000 times in any given year. In other words, if a few people need the device numerous times, then the sum of the number of devices used must remain under 4,000. If the number of uses exceeds 4,000, it would serve as the basis for the FDA disapproving an extension request at the time of HDE expiration.
One of the criteria that must be satisfied in order for a device to receive HUD marketing approval is that no comparable device (other than another HUD approved under this regulation) is available to treat or diagnose the disease or condition. Once a device with the same intended use as the HUD is approved through the premarket approval (PMA) or premarket notification [510(k)] process, an HDE cannot be granted for the HUD device.
Device Costs. If the amount to be charged is $250 or more, the FDA requires an HDE applicant to obtain a report by an independent certified public accountant, or in lieu of such a report, an attestation by a responsible individual of the manufacturing organization, verifying that the amount to be charged does not exceed the costs of research, development, fabrication, and distribution. If the amount to be charged is $250 or less, FDA will waive this requirement. FDA will, however, allow an HDE applicant to receive incidental profits that exceed the applicant’s good faith estimates of costs.
B. IRB Submission Guidelines
An HUD may be administered only if such use has been approved by the IRB located at the facility.
The HDE holder is responsible for ensuring that a HUD approved under 21 CFR 814.124 is administered only in facilities having an IRB and that use of the device at the institution was approved by the IRB. The HDE holder is responsible for ensuring that the HUD is not administered to or implanted in a patient prior to obtaining IRB approval at that institution.
The IRB has established an HUD-specific application which includes requirements for the investigator to provide the IRB with all relevant correspondence between the device company and the FDA regarding the device’s HDE application and HUD status. An operational review will be conducted to determine the feasibility of using the HUD at CHS. Due to its limited application, it can be assumed that the device would not be frequently needed. As previously mentioned, the cost of the HUD may not exceed $250 unless a report is received from an independent CPA or an attestation from the manufacturing organization is provided; this guarantee must be in writing and specified in the budget or other contractual agreement, as applicable. If operationally approved, the application will be eligible for IRB review. The IRB is responsible for initial and continuing review of the HUD, requiring Full Board review at the onset and expedited review thereafter.
The Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 301 et. Seq.) and the regulations do not require informed consent because an HDE provides for marketing approval and does not constitute research or an investigation which would normally require informed consent. However, there is nothing in the Act or regulations that preempts a State or institution from requiring such consent. If however, the HUD is the subject of a clinical investigation (i.e., safety and effectiveness data will be collected to support a premarket approval application or publication in a scientific journal), informed consent is required. Similarly, a HIPAA Authorization form is not necessary for HUDs unless clinical investigation requirements for consenting apply.
If the IRB withdraws its approval of the use of a HUD, the HDE holder shall notify the FDA in writing within 5 working days after being notified of the withdrawal of approval.
The IRB has the discretion of approving the device per the criteria approved by the FDA; for only specific groups of patients meeting certain criteria; or only when the device is used as part of a treatment protocol. The IRB may also specify limitations on the use of the device based upon any criteria it determines to be appropriate. Under certain circumstances the HUD may be used outside of the applications approved by the IRB. Such circumstances include emergency use or off-label use situations. If a physician believes the HUD for which s/he is seeking approval may result in the occasional requirement for off-label use, s/he is asked to include this request in the IRB application. The IRB will determine the appropriateness of the off-label request and notify the physician of its decision in writing.
Misuse of HUDs has taken place at facilities due to the misconception that, since the HUD was an FDA-approved device, its use could be expanded to other applications as seen fit by the investigator. Such misuse at a CHS facility shall result in an investigation and possible actions against the investigator, including reporting of the event to the CHS Institutional Official and disapproval of further privileges to use the HUD.
IRB fees. The IRB fee is waived for HUD applications.
V. Emergency Use Guidelines
Guidelines for the emergency use of test articles, applies to devices, as it does to investigational drugs. Procedures governing the emergency use of an investigational device are covered in two separate documents: the IDE regulation (21 CFR 812) and FDA’s Guidance for the Emergency Use of Unapproved Medical Devices.
In an emergency situation, if a physician determines that IRB approval cannot be obtained in time to prevent serious harm or death to a patient, an investigational device may be administered without prior approval by the IRB, if the physician fulfills the requirements of the CHS IRB Emergency Use Policy (#8012.08) and submits the emergency use application to the IRB within 5 days of the use of the device.
COTTAGE HEALTH SYSTEM POLICY
|ORIGINAL POLICY EFFECTIVE DATE:
||4/06, 1/08, 1/09