For almost a decade, the FDA guidance on humanitarian use devices (HUDs) dated July 8, 2010 has been the go-to document for industry, FDA staff, clinicians/users, and IRBs to understand how to apply the regulations at 21 CFR 814.100, which govern the approval, use, and review of HUDs. Since then, amendments to the HUD program have been made by a variety of federal actions, and FDA produced draft guidance documents to accommodate the changing regulatory and industry landscape. However none were final until September 6, 2019, when the FDA produced Humanitarian Device Exemption (HDE) Program: Guidance for Industry and Food and Drug Administration Staff, which supersedes the July 8, 2010, version.

The new 2019 guidance encompasses both the cumulative amendments made to the program in the interim and a few new ones, including:

  1. Allows for use of HUDs in emergency situations without IRB approval.
  2. Allows HUDs indicated for use in pediatric patients or in pediatric subpopulations to be sold for profit, with certain restrictions.
  3. Increased the maximum number of patients affected by the disease or condition that a HUD is designed to treat or diagnose from 4,000 to 8,000 individuals annually.
  4. Removed the requirement that reviewing IRBs be local.
  5. Allows for the use of an “appropriate local committee” (ALC) in place of an IRB for local review.

At First Glance

An initial scan of the guidance reveals it to be fundamentally different in format from its predecessor: instead of an informal 30-page Q&A, the current guidance uses formal numbered sections and extends to 57 pages. The added content favors industry and FDA staff rather than IRBs and user facilities; that said, it does serve IRBs well in addressing the changes imposed by the 21st Century Cures Act specific to the new role for “appropriate local committees.” More about that later.

The new guidance especially assists industry by providing specific instructions on how to prepare the HDE application and a clear explanation of how the FDA determines probable benefit. Extensive instructions are provided regarding required submission elements, along with a detailed description of FDA review actions for the HDE application. The new guidance also includes thorough, helpful forms and worksheets designed for the FDA staff. Taken together, these updates provide great transparency into the HDE application and approval process.

A separate guidance document entitled Guidance for Industry and Food and Drug Administration Staff: Humanitarian Use Device (HUD) Designations describes clearly how the Office of Orphan Products Development determines that a device qualifies as an HUD. For example, it explains how the 8,000 threshold use is confirmed, how the assertion of a rare disease or condition is verified, and what kind of documentation is required for these determinations.

A Shifting IRB Role?

The original mandate found at 814.124 requiring review and oversight of the HUD by a duly constituted IRB is not negated by the guidance. However, it provides a shared or delegated model of review route by allowing an “appropriate local committee” (ALC) to assume or share these responsibilities. This may benefit organizations, such as small community health centers, that would like to employ HUDs but don’t have a local IRB to directly approve use. Since the regulations require that certain uses (emergency or off label-use) must be reported to the IRB, the need for an IRB to provide oversight is not negated—but it may be provided by a central IRB which in turn can delegate oversight of HUD use to the ALC.

The ALC is defined as a standing committee at the facility that has expertise and experience in reviewing and making treatment decisions for clinical care, and it should include physicians with experience in the treatment of rare diseases or conditions. It also recommends that the ALC include a senior level executive medical staff or faculty member. “Appropriate” is further defined as being free of any conflicts of interest. According to the guidance, a peer review committee, credentialing committee, or Quality Care Committee may fit the bill. Like an IRB, the ALC should have written policies and procedures relating to review and approval of HUDs and should have the relevant expertise represented. A webinar hosted by CDRH on October 21, 2019, fielded questions regarding the relationship between the IRB and ALC, making it clear that the IRB oversight mandated by 814.124 remains in place and admitting that further clarification is needed regarding the relationship of the IRB and ALC.

The nature of review, either by IRB or ALC, is unchanged. The materials to be reviewed, the focus of the review, and the criteria for approval remain the same. The regulatory basis for approval is also unchanged. Unfortunately, the appendix in the previous guidance, which provided a decision tree for IRB review, is gone. Initial review must occur at a convened meeting, and while an IRB may conduct initial review, it can defer continuing review to the ALC. It is clear that review by this committee requires the same familiarity with regulations that was previously the IRB’s sole concern.

Subtle but significant changes are also contained in section VII (C) “Information To Patients.” After reiterating the fact that the regulations do not require informed consent in the use of HUDs, the guidance refers to the selective use of a “written document” rather than a written “informed consent” to provide information to patients. The content of this document is as previously described in 2010, including a list of required elements. Additionally, whereas the 2010 guidance stated that the “patient should always receive” any published information documents from the HDE holder, the current guidance is not so direct; it leaves their use up to the discretion of the IRB or ALC.

Safety Reporting

As directed under the 2010 guidance, adverse events are reported in keeping with the medical device reporting requirements found at 21 CFR 803. Device manufacturers and user facilities must submit these reports to the FDA and IRB/ALC. Annual reports from the HDE holder may be submitted to the ALC or IRB at their request. Guidance for emergency use and off-label use remain very similar.

What’s Behind the Changes?

Without access to the regulators’ minds and thinking, one can only speculate on what prompted these changes. Historically, IRBs have struggled to understand the distinction between HUDs and investigational device exemptions (IDEs) and their respective oversight. Both this latest document and the 2010 guidance emphasize that the primary difference is that HUDs are approved devices, while IDEs are investigational. Nevertheless, HUDs are often treated more like IDEs, resulting in the IRB asking the clinician using the HUD for details applicable to research, such as: who is the PI, where is the protocol, and to whom will you report SAEs/UAP?  In the use of HUDs outside of research, none of these apply. Allowing the ALC mechanism for review and oversight may serve to emphasize this distinction between HUDs and IDEs. Of course, the investigational use of HUDs remains under the sole purview of IRBs.

What Do I Do Now?

In summary, the new guidance looks different from the previous guidance, but the content is very similar. With the exception of the increase in uses to 8,000 and the provision to use ALCs, other changes appear minor; the source regulation remains in place and holds sway. There will no doubt be many requests for clarification from the FDA on the role of ALCs and their relationship to IRBs.

For all stakeholders in the HUD process, the first order of business is to update your regulatory guidance files with the new guidance. (You will find that if you do an online search for the previous 2010 guidance, it will not appear.) IRBs may want to retain the decision tree for review of HUDs found in the 2010 guidance, as it does not appear in—and is not contradicted by—the new guidance. HDE manufacturers will find the worksheets in the new guidance very helpful even though they are designed for FDA staff/reviewers.

Next, update your SOPs to reflect the new guidance. If your institution plans to take advantage of the new ALC mechanism, a new SOP will be required to govern their activity, and it would be wise to include a clear description of roles and division of duties between the IRB and ALC. Any change in policy should be reflected in related internal forms, and finally, training should be scheduled to update all stakeholders.

The recording, transcript, and slides for the aforementioned CDRH webinar on the new guidance are accessible online. This presentation is a great place to start for those charged with managing HUDs in any setting.

Need more information on medical devices? Advarra has you covered. We have experience with all categories of device studies, including implantable and portable devices, diagnostic tools, mobile medical devices, human factors testing, and HUD/HDE studies. Check out our blog Reporting to the IRB: Unanticipated Device Effects (UADEs) in Medical Device Studies or contact us for specialized support.

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