SOP Title Review of Research: Devices for Humanitarian Uses Purpose This document describes the National Jewish Health IRB review of Humanitarian Use Devices and Humanitarian Device Exemptions. Scope Humanitarian Use Devices (HUDs) are a class of device that is marketed under special approval by the FDA (Humanitarian Device Exemption, HDE). HUDs are given a special class of FDA approval because they have not been clearly demonstrated to be effective; rather, they have been shown to be safe and probably effective for their intended condition. With this limited approval, the FDA requires IRB review and approval before these devices can be used for clinical or research purposes. Glossary, Abbreviations and Acronyms Humanitarian Use Device (HUD): A medical device used according to its approved labeling and indication(s) in the treatment or diagnosis of a disease or condition that affects fewer than 4,000 individuals in the United States per year. Humanitarian Device Exemption (HDE): An application similar to a premarket approval (PMA) application, but is exempt from the requirement to demonstrate effectiveness. An approved HDE authorizes marketing of an HUD. Investigational Device Exemption (IDE): Permission to ship a device that is not approved (via premarket authorization, PMA) or cleared to market (via 510(k)) to conduct clinical investigations of that device. Serious injury: An injury or illness that (1) is life-threatening, (2) results in permanent impairment of a body function or permanent damage to a body structure, or (3) necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.
Procedures A. How are Humanitarian Use Devices and Humanitarian Device Exemptions used? 1. Expanded Definitions As defined in 21 CFR 814.3(n), a Humanitarian Use Device (HUD) is a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. A Humanitarian Device Exemption (HDE) is an FDA application similar to a premarket approval (PMA) application, but is exempt from the reasonable assurance of effectiveness standard. HDE approval is based, in part, on evidence that the device will not expose patients to an unreasonable or significant risk of illness or injury, and the probable benefit from use of the device outweighs the risk of injury or illness. The decision must take into account the probable risk and benefits of currently available devices and alternative forms of treatment. FDA approval of an HDE authorizes an applicant to market a HUD, subject to certain profit and use restrictions. Specifically, HUDs cannot be sold for profit, except in narrow circumstances, and they can only be used in a facility after an IRB has approved their use in the facility, except in certain emergencies. 2. There is a distinction between clinical use and research use of a HUD. a. Clinical use: A HUD used in the treatment or diagnosis of a disease or condition according to its approved labeling and indication(s) is considered clinical care. b. Research use: If a HUD is being used in a clinical investigation (i.e., collection of safety and effectiveness data), whether for its approved indication(s) or for a different indication, then this document refers to investigational use or clinical investigation of the HUD. Such investigational use is subject to the same requirements that apply to all FDA-regulated clinical studies, including 21 CFR Parts 50 (Protection of Human Subjects) and 56 (Institutional Review Boards). As long as the HUD is being studied in accordance with the approved indication(s) described in labeling, the HUD can be lawfully shipped without
an IDE. In contrast, if the HUD is being studied for a use other than its approved indication(s), the IDE regulations at 21 CFR Part 812 apply. This policy provides guidance for both clinical and research uses. B. Clinical Use of a Humanitarian Use Device The following procedure is followed when a Clinician plans to use a Humanitarian Use Device for clinical use where no comparable device is available to treat the disease or condition, and the device will be used within the current labeling and indication(s) approved for the device. 1. Clinician Responsibilities a. The Clinician contacts each facility where the device will be used before submitting to the IRB. There may be financial or logistical reasons why an institution may not allow the use of the device in its facility. b. The Clinician obtains IRB approval for use at the planned facilities. Initial Submission to the IRB for clinical use of a HUD involves the following documents with accommodations for the clinical nature of the device. As a general rule in all documents, device recipients should be referred to as patients instead of subjects. Likewise, procedures involve treatment instead of research. i. National Jewish Health Application for Treatment Use of a Drug or Device ii. Treatment protocol (if available) iii. Patient information about the HUD. Information about the HUD may be provided to patients using an information packet, brochure, or a consent form. If the IRB finds an information packet or brochure to be insufficient, the committee may request a clinical consent form. If both a consent form and another form of information are available, the patient should receive both. A HUD information packet, brochure, and/or clinical consent form should include:
an explanation that the HUD is designed to diagnose or treat the disease or condition and that no comparable device is available to treat the disease or condition; the status of the device, such as a sentence indicating that the effectiveness of this device for this use has not been demonstrated; an explanation of the postulated mechanism of action of the HUD in relation to the disease or condition; a description of any procedures associated with the use of the HUD; a description of the use of the HUD; all known risks or discomforts; and possible benefits. The IRB may require other information. iv. A description of the device, such as a Device manual and/or technical specifications v. FDA Summary of Safety and Probable Benefit document for the device vi. Copy of the HDE approval order (FDA Approval Letter for the HDE) vii. Note: No HIPAA Research Authorization is required. If a HUD is being used according to its approved labeling and indication, and not in a clinical investigation, then protected health information about a patient may be used or disclosed for treatment or diagnostic purposes without the patient s written authorization under HIPAA. Further, reporting HUD safety information to the sponsor does not require a HIPAA authorization since it falls under the permissive disclosure for FDA-related activities at 45 CFR 164.512(b)(iii). c. If there are any modifications to the HUD or the clinical use of the HUD after IRB approval, the Clinician must report these changes to the IRB promptly by following the IRB policy and procedures for amendments to protocols. d. The Clinician assumes ongoing responsibility to promptly report death or serious injury to the FDA and National Jewish Health IRB. Whenever a physician or health care provider receives or otherwise becomes aware of information from any source that reasonably suggests an HUD has or may have caused or contributed to the death or serious injury of a patient, or has malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur, the physician or health care
provider must report such findings to the FDA and the IRB as soon as possible, in keeping with the National Jewish Health IRB s policy on Unanticipated Problems Involving Risks to Subjects or Others. This reporting is in addition to, not a substitute for, FDA and/or manufacturer reporting requirements. 2. IRB Responsibilities a. Initial Review i. The initial review of an HUD is completed by the convened IRB. ii. Review Considerations: The IRB verifies that the Clinician is qualified through training and expertise to use the device. The IRB verifies that the use of the HUD, as proposed, is consistent with current labeling of the device and does not exceed the scope of the FDA approved indication(s). The IRB is cognizant that the FDA has made a determination of safety and probable benefit for use of the HUD within its approved indication(s). Therefore, while the effectiveness of the device does not have to be demonstrated, the IRB verifies that the device does not pose an unreasonable risk of illness or injury to the recipient, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Because use of a HUD does not involve research, the IRB s review does not require that the proposed use of a HUD meet the criteria for IRB approval at 21 CFR 56.111. However, the IRB still considers the review criteria at 21 CFR 56.111 and elsewhere in Part 56 as a guide. The IRB is not required to review and approve each individual use of a HUD. Rather, the IRB may use its discretion to determine how to approve use of a HUD. For example, the IRB may specify limitations on the use of the device based upon one or more measures of disease progression, prior use and failure of any alternative treatment modalities, reporting requirements to the IRB or IRB chairperson, appropriate follow-up precautions and evaluations, or any other criteria it determines to be appropriate. The HDE holder may require collection of Adverse Events for reporting purposes. Such collection is not considered safety data or part of an investigation. The IRB examines the nature of adverse
events to be collected and determines whether the AE reporting plan is appropriate. While HDE holders generally charge for the HUD that is used to treat or diagnose a patient, the IRB asks the Clinician or HDE holder to verify that HUDs will not be sold for a price that exceeds the costs of research and development, fabrication, and distribution of the device. (There are limited exceptions.) The IRB s review of a HUD does not include a Significant Risk / Non- Significant Risk determination. As noted above, use of a HUD to treat or diagnose patients is not a "clinical investigation;" the HUD as such is legally marketed for use within its HDE-approved indication(s). iii. Determination of ongoing oversight. The convened Board may make the determination at initial review that continuing review may occur using expedited process. Continuing review by expedited process is generally appropriate when initial use of the HUD is approved without any further restrictions and the continuing review period is not less than 1 year. b. Continuing Review i. The IRB may perform this review at a convened meeting or by expedited process. ii. Continuing review focuses on information that could have a bearing on human safety. During the review, the IRB considers: Adverse events or unanticipated problems involving risk to participants or others that are possibly related (more likely related than unrelated) to the use of the HUD; Any revisions to risk and benefit information available. Specifically, the IRB may ask the HDE holder for copies of the safety information submitted to FDA in the periodic reports required by 21 CFR 814.126(b)(1); and Subject complaints C. Research Use of a Humanitarian Use Device (HUD) under a Humanitarian Device Exemption (HDE) The following procedure is followed when an Investigator plans to collect safety and efficacy data about a Humanitarian Use Device within the current labeling and approved indication(s). 1. Investigator Responsibilities
a. The Investigator contacts each facility where the device will be used before submitting to the IRB. b. The Investigator follows the usual format for submitting a research protocol for full committee review. c. The Investigator follows the Institution s and IRB s policies and standard operating procedures for conduct of research. 2. IRB Responsibilities a. Initial Review i. The IRB reviews the planned investigation according the standard operating procedures for full committee review and ensures that the submission meets the criteria for IRB approval under 21 CFR Parts 50, 54, and 56. ii. Additional review considerations: The IRB verifies that the use and study of the HUD, as proposed, is consistent with current labeling of the device and does not exceed the scope of the FDA-approved indication(s). The FDA considers the study exempt from the requirement for an IDE as long as the HUD is used in accordance with its approved indication(s). The IRB s review of a HUD does not include a Significant Risk / Non- Significant Risk determination as long as the research and use remain within the HDE-approved indication(s). b. Continuing Review Continuing review is performed by the convened IRB. D. Research Use of a Humanitarian Use Device (HUD) under Humanitarian Device Exemption (HDE) and Investigational Device Exemption (IDE) Regulations The following procedure is followed when an Investigator plans to study a Humanitarian Use Device for a use other than the HDE-approved indication(s). 1. Investigator Responsibilities
a. The physician leading the project at National Jewish Health may serve as the Investigator, or serve as both Investigator and Sponsor. If serving as the Sponsor, the physician follows all FDA requirements for the Sponsor listed in 21 CFR Part 812. b. The Investigator contacts each facility where the device will be used before submitting to the IRB. c. The Investigator follows the usual format for submitting a research protocol for full committee review. As part of the submission, the Investigator also provides all required documentation about investigational use of a device. d. The Investigator follows the Institution s and IRB s standard operating procedures for conduct of research. 2. IRB Responsibilities a. Initial Review i. The IRB reviews the study according its standard operating procedure for full committee review of research involving an investigational device and ensures that the submission meets the criteria for IRB approval under 21 CFR Parts 50, 54, 56, and 812. ii. Additional research review considerations: If the HUD is a significant risk device, an FDA-approved IDE is required. However, in the event that a sponsor seeks IRB approval for research of a HUD without first obtaining an FDA-approved IDE, the IRB makes a significant risk/non-significant risk determination as described in the IRB standard operating procedure, HRP-418: Non- Significant Risk Device Determinations. If the IRB determines (or agrees with the sponsor) that the HUD qualifies as a non-significant risk device, an FDA-approved IDE is not required, but the IRB follows the abbreviated IDE regulations at 21 CFR 812.2(b). The IRB verifies that the sponsor will not charge subjects or investigators a price larger than necessary to recover the costs of manufacture, research, development, and handling. Any costs for
which a subject in a clinical investigation is responsible are, when appropriate, clearly explained in the informed consent document. b. Continuing Review Continuing review is performed by the convened IRB. References 21 CFR 803.30 21 CFR 814 FDA Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors. Frequently Asked Questions About Medical Devices, January 2006. Guidance for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators, and Food and Drug Administration Staff; Humanitarian Device Exemption (HDE) Regulations: Questions and Answers; July 8, 2010. This Guidance contains a useful Decision Tree for IRB Review of HUDs. http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidanced ocuments/ucm110194.htm FD&C Act, Section 520(m)(6): http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/overv iew/medicaldeviceuserfeeandmodernizationactmdufma/ucm109100.pdf Guidance for Industry and FDA Staff - Humanitarian Use Device (HUD) Designations, January 24, 2013: http://www.fda.gov/downloads/forindustry/developingproductsforrarediseases Conditions/DesignatingHumanitarianUseDevicesHUDS/LegislationRelatingtoHUDsH DEs/UCM336515.pdf A list of approved HDEs may be found at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hdeinformation.cfm#2.