Humanitarian Use Device Guidance

Purpose and Applicability

This webpage describes the policies and procedures about medical devices that have been classified by the Food and Drug Administration (FDA) as humanitarian use devices (HUDs). The IRB requirements for HUDs differ depending on whether the use is for clinical or research purposes and whether the clinical use is an emergency or non-emergency situation.

Multi-site and collaborative research. In some circumstances, HSD may agree to rely on another IRB for the review of a HUD application. The information in this guidance is specific to situations when UW is conducting the review. For information about situations when the UW IRB will rely on an external IRB for review of a HUD application, contact hsdrely@uw.edu ^[10].

Regulations and Policy

IRB review. The FDA regulations require standard IRB review when clinicians use a HUD. When the HUD is being used for clinical care, this includes the requirement to obtain prospective IRB approval and ongoing review (except in emergency situations) per the FDA clinical investigations regulations, even though the clinical use of a HUD is not considered to be research (21 CFR 56; SOP IRB Review ^[12]). When the HUD is being used for research (i.e., if safety and effectiveness data are being collected), prospective IRB approval and ongoing review per the FDA clinical investigation regulations is required.

Continuing review. The FDA regulations allow continuing review of the use of HUDs to be conducted by the expedited review process if deemed appropriate by the IRB and the HUD is being used solely for clinical purposes.

Consent. If the FDA has issued a HDE ^[13], that means that the device is approved by the FDA for marketing and the use of the HUD does not constitute research. Therefore, the FDA and its HDE regulations do not require informed consent as defined by the FDA’s research regulations (21 CFR 50). However, it is HSD policy to require documented consent from patients prior to the clinical use of a HUD, whenever possible. Research use of a HUD requires that subjects provide a standard research consent.

PROCEDURES – Clinical Use of a HUD

IRB review requirement

• Clinical emergency use (on-label or off-label)
  • If the HUD has already been approved by the UW IRB (review this list ^[14]), no interaction with HSD or the UW IRB is required.
  • If the HUD has not been approved by the UW IRB, follow the instructions in APPLICATION Notification of Emergency Use, Device ^[15]

• Clinical non-emergency use (on-label or off-label)
  • If the HUD has already been approved by the UW IRB (review this list ^[14]), no interaction with HSD or the UW IRB is required.
    If repeated off-label uses are expected and they were not described in the application reviewed by the IRB, it is best practice to modify the existing application for general off-label use. This does not require approval from the FDA.
  • If the HUD has not been approved by the UW IRB, submit a standard IRB application in the Zipline system ^[16].

 

Initial IRB review for non-emergency clinical use of a HUD (21 CFR 814.124)

• Convened IRB review. The FDA requires the initial review and approval to be conducted by the full convened IRB.

• What is reviewed. It is HSD policy to require the physician to provide the following materials for the IRB to review.
  • The standard APPLICATION IRB Protocol ^[17] form should be completed as applicable for the clinical care situations. This should include a description of: (1) how the physician proposes to use the clinical device; (2) any screening procedures; (3) the HUD procedure; (4) any patient follow-up visits, tests, or procedures; and (5) which physicians may use the device.
  • SUPPLEMENT Devices ^[18]
  • Consent form that will be used with patients
  • HDE approval document from the FDA
  • Product labeling information
  • Patient information sheet/packet (if there is one)
  • Photo or drawing of the device and any description information

• Criteria for approval. The FDA recommends that an IRB apply the review criteria described at 21 CFR 56.111 and elsewhere in the FDA regulations part 56 “as much as possible”. Review Appendix A ^[9] for the UW IRB’s interpretation of this recommendation.

• What is approved. The IRB is not required to review and approve each individual use of a HUD but rather, the IRB may approve the use of the device as it sees fit as long as the approval period is no longer than one year. For example, the FDA states that the IRB may specify limitations on the use of the device based on:
  • Measures of disease progression
  • Prior use and failure of any alternative treatments
  • Reporting to the IRB, the IRB Chair, or other appropriate IRB member
  • The outcome of follow-up precautions and evaluations
  • Any other criteria it determines are appropriate

• Financial charges to the patient. The FDA allows the patient to be charged for the HUD within certain constraints. The FDA monitors the HDE holder on this issue. The IRB does not review charges nor request justification for them. HUDs cannot be used until UW Medicine has notified its Medicare Contractor of the intended use. This is necessary in order to obtain reimbursement for the use (and sometimes for the entire inpatient admission that was required in order to use the HUD). It is the physician’s responsibility to contact the UW Medicine Compliance or billing office for this purpose.

• IRB approval period. Identification of the IRB approval period follows the same considerations and requirements as an IRB review of greater than minimal risk research. That is, the period may not exceed one year. If the risk of the device warrants it, the IRB may approve a shorter approval period, or it may approve the HUD for a specific number of patients and require a summary report before approving the use in additional patients (as long as the review occurs within one year of the initial approval).

• Number of patients. It is the responsibility of the HDE holder, not the IRB, to monitor how many HUD devices are distributed each year in the U.S. Over-enrollment of the number of HUDs used clinically at the UW is not defined by HSD as noncompliance.

Consent requirement

• Clinicians are expected to obtain written documentation of the clinical consent, from the patient or the patient’s legally authorized representative, whenever possible. This includes any extra steps that may be required with parents of children, patients with cognitive impairments, patients with limited English proficiency, and patients with low educational attainment. If it is not possible to obtain consent documentation, the clinician should follow standard UW Medicine policies for how to provide necessary clinical care in the absence of documentation of patient consent.

• The clinical consent form should include the elements listed below (the required elements for research consent are not required for a clinical HUD consent).
  • An explanation that the HUD is designed to diagnose or treat the disease or condition described in the HDE labeling
  • No comparable device is available to treat the disease or condition
  • A description of the use of the HUD
  • All known risks or discomforts
  • An explanation of the postulated mechanism of action of the HUD in relation to the disease or condition
  • A sentence indicating that although the device is authorized by federal law, the effectiveness of the device for this use has not been demonstrated

• The physician should obtain the HUD consent by providing the materials listed below to the patient.
  • Any patient information packet prepared by the HDE holder. Most HDE holders develop patient information packets that generally contain a discussion of the potential risks and benefits of the HUD and any procedures associated with its use.
  • A consent form containing the information listed above.

Device risk determination

Because the clinical use of a HUD is not research, the IRB is not required to determine whether the device is “significant risk” or non-significant risk”.

HIPAA authorization

Because the clinical use of a HUD is not research, the UW research HIPAA authorization form is not required and should not be used. The UW IRB expects that appropriate HIPAA notifications and clinical authorizations will have already been obtained through the standard UW Medicine process used with all patients.

Radiation safety

Because the clinical use of a HUD is not research, any use of procedures involving radiation exposure that is necessary in connection with the HUD does not require review and approval of the UW Radiation Safety Committee.

UW Medicine requirement

HUDs cannot be used until UW Medicine has notified its Medicare Contractor of the intended use. This is necessary in order to obtain reimbursement for the use (and sometimes for the entire inpatient admission that was required in order to use the HUD). It is the physician’s responsibility to contact the UW Medicine Compliance or billing office for this purpose.

Protected or vulnerable population determinations

Because the clinical use of a HUD is not research, the IRB is not required to make any regulatory determinations regarding the inclusion of protected or vulnerable populations.

Compensation for injury language

The clinical use of a HUD is not covered by the UW compensation for injury program.

Continuing review

Continuing review must follow the procedures and requirements described by the FDA in its clinical investigation regulations (21 CFR 56), even though the use of a HUD is not considered to be research (SOP IRB Review ^[12]).

• Level of review. It is HSD policy that the IRB should decide as part of its initial review whether subsequent continuing review may be conducted by the expedited review process (WORKSHEET Expedited Review ^[19]) with the requirement that at least one reviewer must have appropriate expertise.
  • The FDA HDE guidance states that expedited review is appropriate (but not required) because the initial review is performed by the full IRB, a HUD marketed under a HDE is a legally marketed device, and the clinical use of the HUD does not constitute research.
  • The IRB may decide that subsequent continuing reviews of a HUD may occur by the expedited review process only if the HUD is being used solely for clinical purposes.

• HUD annual report submission. The physician should submit the annual report at the same time as the status report as a Report of New Information (RNI) ^[20] submission.

Modifications

It is HSD policy to require a modification to the IRB application for broadening the clinical purpose for which an approved HUD is used at UW Medicine, if physicians expect to use an approved HUD beyond the purpose(s) described in the initial IRB application. This does not require FDA approval.

Reporting of adverse events

• Adverse event reporting. FDA regulations require the HUD user (i.e., the physician) and the HDE holder to provide adverse event reports to the FDA and to the IRB. This is typically accomplished via the Medical Device Reporting (MDR) system (FDA guidance ^[21]).
• Additional HDE holder reporting requirements. The manufacturer must submit reports to FDA and the IRB whenever a HUD may have caused or contributed to a death or serious injury* or has malfunctioned and would be likely to cause or contribute to death or serious injury if the malfunction were to recur [21 CFR 814.126(a)].
• The physician must use the RNI process to provide adverse event reports to the IRB (Report Events and New Information ^[20]). When the HUD is for clinical use, no regulatory determination by the HSD Regulatory Affairs team (i.e., noncompliance or unanticipated problem assessment) is required. Rather, the IRB should review the RNI in the context of “new risk information” and determine whether the criteria for approval for the clinical use of the HUD at UW (Appendix A ^[9]) are still met. The IRB may require the physician to update the consent form with new risk information or require them to modify procedures in order to continue using the device at UW.
  • *Serious injury means 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.

Reporting by the IRB

It is HSD policy to copy the HDE holder on any communication in which the UW physician is informed that the IRB approval has been suspended or terminated.

Procedures – Research Use of a HUD

IRB review requirement

The research use of a HUD device (e.g., research designed to gather safety and effectiveness data about the HUD) must be reviewed and approved by an IRB following standard procedures and FDA regulations. This is true even if the HUD has already been approved by the UW IRB for clinical use.

Requirements for on-label research use of a HUD.

For example, a researcher wishes to collect safety and effectiveness data on the FDA-approved use of the HUD.

• An Investigational Device Exemption (IDE) application to the FDA is not required
• Standard prospective IRB review and approval must be obtained
• Standard research consent must be obtained from subjects
• Standard pediatric safeguards, as required by the FDA for any research involving children, must be applied

Requirements for off-label research use of a HUD

For example, a researcher wishes to use the HUD for a purpose or population not approved under the HDE, and to collect safety and effectiveness data on that new use.

• An Investigational Device Exemption (IDE, not HDE) approval must be obtained from the FDA
• Standard prospective IRB review and approval must be obtained, like for any research study, applying all relevant FDA regulations (e.g., device risk determination)
• Standard research consent must be obtained from subjects
• Standard pediatric safeguards, as required by the FDA for any research involving children, must be applied

Definitions

Humanitarian use device (HUD). A HUD is a device that is intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 8,000 individuals in the United States per year. HUDs can be used (i.e., marketed) without having been shown to meet the standard effectiveness criteria applied to other devices. Clinical use of a HUD is not considered to be research, but the FDA nonetheless requires IRB review prior to use.

Humanitarian device exemption (HDE). The term “HDE” refers both to a type of application submitted to the FDA and also to the FDA’s approval of the application. A HDE application to the FDA is not required to provide research data demonstrating that the device is effective. However, it must contain sufficient information for the FDA to determine that: (1) the probable health benefit outweighs the risk of injuries or illness; (2) the device will not expose patients to unreasonable or significant risk; and (3) there is no comparable device available to treat or diagnose the disease or condition. An approved HDE authorizes marketing of a HUD.

HDE holder. The person who obtains the approval of a humanitarian device exemption (HDE) from the FDA. Once the HDE is approved, the HDE holder is responsible for ensuring that the HUD is used only under the review and oversight of an IRB.

Related Materials

APPLICATION IRB Protocol ^[17]
APPLICATION Notification of Emergency Use, Device ^[15]
GLOSSARY Humanitarian Device Exemption ^[13]
SOP IRB Review ^[12]
SUPPLEMENT Devices ^[18]
WEBPAGE Apply for Review ^[16]
WEBPAGE UW IRB Approved Clinical Use HUDs ^[14]
WEBPAGE Report Events and New Information ^[20]
WORKSHEET Expedited Review ^[19]

Regulatory References

• 21 CFR 814 Subpart H
• 21 CFR 50
• 21 CFR 56
• FDA Guidance – Humanitarian Device Exemption (HDE) Program: Guidance for Industry and Food and Drug Administration Staff. September 6, 2019 ^[22]
• FDA – Medical Device Reporting (MDR): How to Report Medical Device Problems ^[21]

Version Information

Open the accordion below for version changes to this guidance.

Keywords: FDA; HUD

Appendix A – IRB Criteria for Approval for Clinical Use of a HUD

The IRB must be satisfied that the HUD is being used for clinical care only and not for research purposes.

Risks to patients are minimized [21 CFR 56.111(a)(1)]:

• by using procedures which do not unnecessarily expose subjects to risk
• whenever appropriate, by using procedures already being performed on the patients for diagnostic or treatment purposes.

Risks to patients are reasonable in relation to anticipated benefits. [21 CFR 56.111(a)(2)]

• The IRB takes into consideration whether the HUD is being used off-label.
• As part of its review of the HDE application, the FDA must determine that the device will not expose patients to an unreasonable or significant risk of illness or injury, and the probable benefit to health from the device outweighs the risks. The IRB is cognizant that this determination applies only to use of the device within its approved indications.
• The IRB is also cognizant of when the FDA has indicated that the HUD is unsafe for pediatric populations (as indicated in the labeling).

The clinical care plan makes adequate provisions for monitoring the safety of patients. [21 CFR 56.111(a)(6)]

There are adequate provisions to protect the privacy of patients and to maintain the confidentiality of the data. [21 CFR 56.111(a)(7)]

• The UW IRB assumes that all components of the HIPAA regulations that are relevant to clinical care will be appropriately implemented, following the standard procedures of UW Medicine.
• The UW IRB believes that the clinical care components of HIPAA apply to any records and reports that clinicians are expected to provide about patient outcomes with the HUD to the holder of the HDE and the FDA.

The criteria the IRB uses to assess the consent form and process are:

• sufficient information is provided
• patients or their representatives will be given sufficient opportunity to consider whether or not to receive/use the HUD
• information regarding the HUD will be communicated in language understandable to the patient