March 17, 2014

by Alexander Gaffney, RAC

Regulatory Explainer: Making Sense of Humanitarian Use Devices

A new draft guidance document issued Monday by the US Food and Drug Administration (FDA) aims to answer some of the common questions surrounding its 2013 guidance document on humanitarian device exemptions (HDEs).

What's an HDE, and Why is it Needed?

In the US, there are two common pathways for medical products intended for very small populations to reach the market. For pharmaceuticals, this pathway is known as orphan drug designation, and is intended for medicines intended to treat diseases affecting fewer than 200,000 people in the US.

For medical devices, this pathway is known as the humanitarian device exemption (HDE), and is intended for products meant to treat diseases affecting fewer than 4,000 patients each year. Devices seeking approval via this pathway are first given designation by FDA as a humanitarian use device (HUD), similar to how orphan drug products are first given orphan drug designation.

The pathway is unique in that it does not require testing to prove that the HUD is effective for its intended purpose. Rather, FDA only requires that a company provide data to show that it is safe-"will not expose patients to an unreasonable or significant risk of illness or injury"-for its intended population. In addition, the devices still need to illustrate a "probable benefit to health."

More information on its statutory definition is available at 21 CFR 814.3(m).

Why Have Reduced Testing Requirements?

The testing of products requires patients to consent to being involved throughout the clinical trials process. While companies regularly have a difficult time finding patients to enroll in clinical trials, it becomes exponentially more difficult to find enough patients to enroll a trial if there are fewer than 4,000 of them in the entire country, as is the case with HDE products.

Because the pool of potential patients is so small, it becomes phenomenally difficult to run clinical trials on HUD devices.

Why is Testing so Difficult?

Consider the following three difficulties:

A company needs to first find the patients it wishes to treat. Assuming a population of exactly 4,000 patients, this averages out to approximately one patient per 948 square miles in the US, or 80 per US state.
Once (or if) found, the company then needs to convince a patient to enroll in the clinical trial. At this point, it is unknown if the device will benefit the patient or even if it is safe for use in humans.
Some patients may already be treated to their satisfaction by another device or medical product, and not wish to enroll.

To be fair, these challenges are faced by most every device manufacturer. In addition, the program hasn't been without its critics, both in the medical research community and the mainstream press.

So It's Essentially an Incentive Program?

Exactly. To regulators and legislators, making sure that research and development incentives are in line to create treatments for extremely small populations has made the pathway worth the potential risk.

"A device manufacturer's research and development costs could exceed its market returns for diseases or conditions affecting small patient populations," FDA explains on its website. "FDA, therefore, developed and published this regulation to provide an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations."

To date, more than 50 HDEs have been approved by FDA since 1996, when the HDE pathway was established under the terms of the Safe Medical Devices Act of 1990.

How Does a Company Obtain a HUD Designation?

In January 2013, FDA finalized a 2011 draft guidance on HUD designations, in which it explains the basics of the HUD application process.

In order to obtain HUD designation, applicants must specifically state their intent to seek a HUD designation, describe the rare disease their device intends to treat, demonstrate the medical plausibility of the disease as a medically important subset, and provide proof of the incidence of the disease in the US (and that it is fewer than 4,000 persons).

How Important is the Population Estimate in the Application, and How is it Calculated?

The population estimate is particularly important, as a population of more than 4,000 will automatically disqualify the device from being able to obtain a HUD designation and thus the ability to obtain approval using an HDE application.

There are two distinctions that FDA said it wanted manufacturers to understand clearly: prevalence and incidence. The former refers to the total number of patients with a given disease at a given point in time, and is sometimes referred to as point prevalence. The latter term refers to the number of new patients, and is sometimes referred to as annual incidence.

FDA's HUD designation is based upon incidence, not prevalence.

What Does FDA Mean by Medical Plausibility?

By this, FDA means that the disease is real, and that it affects fewer than 4,000 patients.

Assume for a moment that a company was seeking approved for a subset treatment category of diabetes patients between the ages of 25 and 28 who were male, had red hair and brown eyes. While this subset might well contain fewer than 4,000 patients, the company would be hard-pressed to prove that the subset was "medically plausible"-that is, that the subset was any different than the main group of patients.

In addition, the device must be specifically intended to treat the smaller population, and not larger ones. As FDA explains in its guidance, "A medically plausible subset must be based on some feature of the device (i.e., mode of action, adverse event profile, etc.) that actually precludes its use in the treatment of patients outside the smaller subset of individuals."

"There should be justification as to why the device could not be used to treat or diagnose all remaining persons with the disease or condition," FDA adds.

I-A Sponsor-Applied for a HUD Designation. Now What?

As per FDA's new HDE: Questions and Answers guidance, sponsors who have applied for a HUD designation must first receive a favorable response from the Office of Orphan Products Development (OOPD).

Once a favorable response is received, the sponsor may file their HDE with FDA.

What's in an HDE Application?

At its most basic, a HDE is a Premarket Application (PMA), which is used by most high-risk (Class III) medical devices.

Applications must contain four primary pieces of information:

a copy or reference to the approved HUD designation letter
an explanation of why the HUD would otherwise be unavailable but for the HDE being granted, as well as the benefits and risks of existing devices
an explanation of the benefits and risks of the proposed HUD device, as well as an explanation of the disease and how the device will treat it
the amount to be charged for the device, as well as (if it's more than $250) a statement indicating that the cost of the device does not "exceed the costs of the device's research, development, fabrication and distribution." Sponsors can also apply to profit off the devices if the device is intended to treat pediatric patients or if the device occurs in such low numbers that its development would be impractical or impossible.

What if Other Devices are Already on the Market for this Indication?

FDA will only consider HDE applications if there "is no comparable device available to treat or diagnose the disease or condition," unless the comparable device is also approved under an HDE or is still in a testing phase under an investigational device exemption (IDE).

"Comparable device" does not necessarily mean "identical" to FDA, it said in the guidance. If the indications for use, technological characteristics and patient population are all the same, it may consider it "comparable."

In such cases, FDA says it will refuse to file the application.

Are HDEs Approved?

Yes, HDEs are approved for marketing, not "cleared" for marketing like 510(k)s. As such, they must meet all quality system regulations (QSRs) under 21 CFR 820.

So How Long Does it Take to Obtain HDE Approval from FDA?

FDA tries to approve HDEs within 75 days from the date of receipt, and generally notifies applicants within 30 days regarding the completeness of a submitted application.

Are HDE Applications Subject to User Fees?

No, they are exempt under the terms of the Medical Device User Fee Amendments (MDUFA) of 2012.

What are the Pediatric Requirements for HDE Devices?

In January 2014, FDA finalized its guidance on pediatric information required from sponsors of medical devices, including HDE sponsors.

FDA defines pediatric populations as including neonates (0-28 days), infants (<2 years), children (2-12 years of age) and adolescents under 21 years of age.

The Food and Drug Administration Safety and Innovation Act (FDASIA)-Section 515A if you're interested-calls for two pieces of information from each device applicant:

a description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose, or cure
the number of affected pediatric patients

Under the law, companies will need to include any descriptions of any pediatric populations that suffer from the disease that the device is intended to treat, diagnose, or cure. The caveat is that such information must be "readily available"-an addition intended to prevent companies from needing to extensively seek out non-obvious patients. A guidance document on the meaning of "readily available" is still forthcoming.

What Happens if I don't Make This Pediatric Information Available?

Pretty simple, actually: No pediatric information, no approval.

"If the applicant does not submit the information required by section 515A(a) of the FD&C Act, FDA may not approve the application until the applicant provides the required information," FDA explained in its 2014 guidance.

If FDA finds that an application is missing the pediatric section during the course of its normal review, it says it will contact the applicant and ask it to amend the application to include the required information.

If FDA does not detect this omission until the end of the review, it said it would send sponsors an "approvable letter" placing final approval on hold until section 515A data is submitted to the agency for review.

OK, my HDE got Approved by FDA. Now What?

All HUD devices (with the exception of emergency use devices) must be used under the supervision of an institutional review board (IRB).

"The IRB must have members or consultants with the appropriate experience and expertise to perform a complete and adequate review of the use of a HUD at that institution (21 CFR 56.107(a))," FDA writes in its guidance.

However, an IRB may defer its oversight to "another similarly constituted IRB that has agreed to oversee the use of the HUD," FDA added. The names and addresses of IRBs overseeing use of the devices must be made available to FDA upon request.

Sponsors must also report all adverse events experienced by HUD users to both FDA and the IRB.

Can my HUD Designation be Revoked?

Yes it can, though not automatically. FDA says that if it becomes aware that the population on which the HDE was approved has grown beyond 4,000 patients, it may revoke the HDE under 21 CFR 814.102(c) after considering factors like the feasibility of conducting a pivotal clinical investigation to demonstrate safety and effectiveness as well as the public health need for the device.

What If I Have Other Questions About HDEs or HUDs?

Check out FDA's two guidance documents on the subject:

FDA's webpage on HDEs is also worth a read if you have additional questions.

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