Humanitarian Device Exemption (HDE): Complete Guide to FDA Rare Disease Device Pathway

The HDE Pathway: Making Rare Disease Devices Possible

Developing medical devices for rare diseases presents a fundamental economic challenge: the patient population is too small to justify the investment required for a traditional PMA, yet these patients desperately need treatment. The FDA's Humanitarian Device Exemption (HDE) pathway exists to solve this problem.

An HDE provides a regulatory pathway for Class III medical devices intended to benefit patients with diseases or conditions affecting fewer than 8,000 individuals in the United States per year. Unlike a PMA, which requires "reasonable assurance of safety and effectiveness," an HDE requires only "reasonable assurance of safety and probable benefit." This lower evidentiary standard reflects the reality that traditional clinical trials are often impractical for ultra-rare conditions.

The pathway was created by the Safe Medical Devices Act of 1990 and has been amended multiple times — by the FDA Amendments Act of 2007 (FDAAA), the 21st Century Cures Act of 2016, and the FDA Reauthorization Act of 2017 (FDARA). In January 2025, the FDA issued updates to include the HDE modular review process. As of October 2025, a draft guidance described QMS information expected in HDE submissions under the new Quality Management System Regulation (QMSR), effective February 2, 2026.

This guide covers the entire HDE lifecycle: eligibility determination, HUD designation, HDE application preparation, the review process, post-approval requirements, and the practical considerations that determine whether an HDE is the right pathway for your device.

Key Definitions

The Two-Step HDE Process

Step 1: Obtain HUD Designation from OOPD

Before submitting an HDE application, the sponsor must first obtain designation of the device as a Humanitarian Use Device (HUD) from the FDA's Office of Orphan Products Development (OOPD).

HUD Designation Application Requirements:

• A statement that the device is a medical device as defined in section 201(h) of the FD&C Act
• A description of the disease or condition the device is intended to treat or diagnose
• Documentation that the disease or condition affects fewer than 8,000 individuals in the US per year
• The proposed indication for use
• A justification for why the device qualifies as an HUD

OOPD Review Timeline: OOPD has 45 days to determine whether the product meets the statutory standards for HUD designation.

Key Eligibility Criteria for HUD Designation:

1. The device must be a medical device as defined in section 201(h) of the FD&C Act
2. The device must be intended to benefit patients in the treatment or diagnosis of a disease or condition
3. The disease or condition must affect or be manifested in not more than 8,000 individuals in the US per year

If OOPD grants the HUD designation, the sponsor receives an HUD designation letter and may proceed to Step 2.

Step 2: Submit the HDE Application to CDRH or CBER

After HUD designation is granted, the sponsor submits the HDE application to the appropriate FDA center. For most devices, this is CDRH; for devices regulated as biologics, it is CBER.

Eligibility for HDE Application:

1. The device has received HUD designation from OOPD
2. No legally marketed device exists for the same disease or condition that has been granted marketing authorization under:
   • Premarket notification (510(k))
   • Premarket approval (PMA)
   • De Novo classification

If a legally marketed device already exists for the same indication, the HDE pathway is not available.

HDE Application Contents

Required Elements

The HDE application contains many elements similar to a PMA but with reduced clinical data requirements. Key sections include:

The Probable Benefit Standard

The critical difference between an HDE and a PMA is the effectiveness standard. A PMA requires "reasonable assurance of effectiveness" — typically demonstrated through well-controlled clinical investigations. An HDE requires only "probable benefit," which means:

• The evidence must demonstrate that the device is likely to provide a clinically meaningful benefit to patients
• The standard considers the rarity of the condition and the practical limitations on clinical study design
• Data from small case series, historical controls, or even well-documented bench testing may be sufficient
• The FDA considers whether the probable benefit outweighs the risks, given the absence of alternative treatments

The September 2019 HDE guidance document explains the criteria FDA considers when evaluating "probable benefit" as part of the decision-making process.

HDE Modular Review

In January 2025, the FDA updated its guidance to include the HDE modular review process. Similar to PMA modular review, this allows sponsors to submit sections of the HDE application incrementally for review, rather than as a single complete package. Benefits include:

• Earlier FDA feedback on individual sections
• Reduced time to final decision
• Opportunity to address deficiencies section by section
• Better resource planning for both sponsor and FDA

QMSR Implications for HDE Submissions

In October 2025, the FDA issued a draft guidance describing the QMS information expected in PMA and HDE submissions under the new Quality Management System Regulation (QMSR). Beginning February 2, 2026:

• HDE submissions will be evaluated against the QMSR, which incorporates ISO 13485:2016 by reference
• FDA recommends additional elements including ISO 13485-mapped QMS information
• Pre-approval inspections will assess QMSR compliance
• Failure to meet QMSR requirements can result in denial of the marketing application

Manufacturers should begin cross-functional gap analyses and align procedures, documentation, and inspection readiness ahead of QMSR implementation.

Recent HDE Approvals: Real-World Examples

These examples illustrate the breadth of devices that qualify: implantable structural devices, liquid embolics for neurovascular conditions, and companion diagnostics for gene therapy.

Profit Restrictions and Pediatric Exemptions

General Profit Prohibition

Under section 520(m)(6) of the FD&C Act, devices approved under an HDE may not be sold for profit, with specific exceptions. The profit restriction exists because the reduced evidentiary standard means the device's effectiveness has not been fully demonstrated.

Exceptions to the Profit Prohibition

A device approved under an HDE may be sold for profit if it is intended for the treatment or diagnosis of a disease or condition that either:

1. Pediatric patients (younger than 22 years of age) — The 21st Century Cures Act expanded this exception
2. A disease or condition that does not occur in pediatric patients — or that occurs in such small numbers that developing a pediatric version is impractical

The HDE holder must request and receive FDA authorization to sell the device for profit. The FDA evaluates whether charging a profit is reasonable and consistent with the purpose of the HDE program.

IRB Oversight and Clinical Use Requirements

Institutional Review Board (IRB) Approval

An HUD may only be used at facilities that have established an IRB to supervise clinical testing of devices. Before an HUD is used:

1. The facility's IRB must approve the use of the device
2. The approval must verify that the proposed use is consistent with the FDA-approved labeling
3. The device's labeling must state that it is an HUD and that its effectiveness has not been demonstrated

The initial IRB review of an HUD is completed by the convened IRB (not expedited review).

Emergency Use Provisions

If a physician needs to use an HUD in an emergency situation before IRB approval can be obtained:

• The patient must have a life-threatening or serious disease requiring immediate treatment
• No generally acceptable alternative treatment must exist
• The physician must report the emergency use to the IRB within 5 working days
• The HDE holder must be notified

Case-by-Case vs. Standing IRB Approval

• Standing approval: The IRB approves the use of the HUD for all patients meeting the approved indications at the facility. This is the preferred approach for established devices.
• Case-by-case approval: The IRB reviews each individual use of the device. This may be required for certain devices or by certain IRBs.

Post-Approval Requirements

Annual Reporting

HDE holders must submit annual reports to the FDA that include:

• Number of devices distributed
• Summary of any complaints or adverse events
• Medical device reports (MDRs) filed under 21 CFR Part 803
• Status of any required post-approval studies
• Any changes in device labeling, manufacturing, or indications

Post-Approval Studies (PAS)

The FDA may require a post-approval study as a condition of HDE approval. Common reasons include:

• Understanding long-term device performance (especially for implantable devices)
• Further evaluating device or component performance in a larger population
• Evaluating the learning curve or training requirements
• Collecting additional safety data

The FDA and the applicant agree on the PAS protocol or outline prior to HDE approval.

HDE Supplements

Changes to an approved HDE device require an HDE supplement, similar to PMA supplements:

Mandatory Reporting

• Medical Device Reports (MDRs): Report deaths and serious injuries under 21 CFR Part 803
• Recalls and corrections: Report under 21 CFR Part 806
• Annual reports: Periodic submission of device distribution and safety data

HDE vs. Other FDA Pathways: Comparison

Critical difference: There is no user fee for HDE applications. The FY 2026 PMA fee is $579,272 (standard) — the HDE pathway eliminates this cost entirely. This is a significant incentive for devices targeting rare conditions.

Step-by-Step HDE Submission Guide

Phase 1: Eligibility Assessment

1. Confirm the device is a medical device under section 201(h)
2. Estimate the affected US patient population (must be ≤8,000/year)
3. Search the FDA database for legally marketed devices for the same indication
4. If a legally marketed device exists, the HDE pathway is not available
5. Evaluate whether the device can demonstrate probable benefit

Phase 2: HUD Designation Application

1. Prepare the HUD designation request for OOPD
2. Include disease/condition description and population justification
3. Include proposed indication for use
4. Submit to OOPD
5. OOPD review (45 days)
6. If granted, receive HUD designation letter

Phase 3: HDE Application Preparation

1. Compile device description and manufacturing information
2. Conduct and compile non-clinical testing (bench, animal)
3. Design and conduct clinical investigation (if applicable)
4. Prepare labeling with required HUD statement
5. Draft Summary of Safety and Probable Benefit (SSPB)
6. Consider modular review if appropriate
7. Align QMS documentation with QMSR requirements (effective February 2026)

Phase 4: HDE Submission and Review

1. Submit HDE application to CDRH (or CBER for combination products)
2. FDA conducts acceptance review
3. FDA conducts substantive review
4. Advisory committee meeting (may be required)
5. FDA decision: approval or denial

Phase 5: Post-Approval

1. Establish IRB relationships at target facilities
2. Begin commercial distribution (if profit authorization granted)
3. Submit annual reports
4. Complete post-approval studies (if required)
5. Submit HDE supplements for any changes
6. Report adverse events and recalls per MDR and 806 requirements

Practical Considerations

When HDE Is the Right Choice

• The device treats a condition affecting fewer than 8,000 US patients per year
• Clinical trials with traditional statistical power are impractical
• No alternative device with marketing authorization exists for the same indication
• The device is Class III (or could be classified as Class III)
• The sponsor has sufficient evidence to demonstrate safety and probable benefit

When HDE Is NOT the Right Choice

• The condition affects more than 8,000 patients per year
• A legally marketed device already exists for the same condition
• The device qualifies for 510(k) clearance (Class II with predicate)
• The device could pursue De Novo classification with a reasonable evidence base
• The sponsor wants unrestricted ability to sell for profit and the condition occurs in adults

Common Pitfalls

1. Overestimating the patient population: If OOPD determines the condition affects more than 8,000 individuals/year, the HUD designation will be denied. Accurate epidemiological data is essential.

2. Overlooking existing marketed devices: The HDE pathway is unavailable if any device has been cleared or approved for the same condition. Conduct a thorough search before pursuing HDE.

3. Insufficient safety data: While the effectiveness standard is lower, the safety standard is not. The device must still demonstrate reasonable assurance of safety.

4. Ignoring IRB requirements: Failure to establish IRB relationships before marketing can delay adoption. Begin IRB outreach during the application process.

5. Non-compliance with post-approval obligations: Annual reports, MDR filings, and post-approval study milestones are mandatory. Non-compliance can result in withdrawal of HDE approval.

FAQ

What is the difference between an HUD and an HDE?

An HUD (Humanitarian Use Device) is the designation of the device itself — it confirms the device is intended for a rare condition. An HDE (Humanitarian Device Exemption) is the marketing application submitted to obtain FDA approval to sell the HUD. You need both: first get HUD designation, then submit the HDE application.

How many patients qualify as "rare" for the HDE pathway?

The disease or condition must affect or be manifested in not more than 8,000 individuals in the United States per year. This is different from the Orphan Drug Act definition of a rare disease (fewer than 200,000 people in the US total).

Is there a user fee for the HDE application?

No. HDE applications are exempt from user fees. This is in contrast to the FY 2026 PMA fee of $579,272 or the De Novo fee of $173,782.

Can I sell an HDE-approved device for profit?

Generally no, with exceptions. The device may be sold for profit if it treats a pediatric population (under 22 years) or a condition that does not occur in pediatric patients. The HDE holder must request and receive FDA authorization.

What is the "probable benefit" standard?

Probable benefit is a lower evidentiary standard than "reasonable assurance of effectiveness." It means the device is likely to provide a clinically meaningful benefit, considering the rarity of the condition and the practical limitations on conducting traditional clinical trials.

Does the HDE pathway require clinical trials?

Not necessarily in the traditional sense. Clinical data is typically required, but the standard accepts smaller studies, case series, historical controls, or even well-documented non-clinical evidence when clinical studies are impractical.

What happens if another device gets approved for the same condition?

If a device receives marketing authorization (510(k), PMA, or De Novo) for the same condition after your HDE is approved, your HDE remains valid. However, the HDE pathway would not be available for new devices targeting that condition.

How does QMSR affect HDE submissions?

Starting February 2, 2026, HDE submissions will be evaluated against the QMSR, which incorporates ISO 13485:2016. The October 2025 draft guidance recommends including ISO 13485-mapped QMS information. Pre-approval inspections will assess QMSR compliance.

What is the HDE modular review process?

Modular review allows sponsors to submit sections of the HDE application incrementally for FDA review, rather than as a complete package. This enables earlier feedback and can reduce total review time. The FDA updated its guidance to include HDE modular review in January 2025.

Where can I find a list of approved HDE devices?

The FDA maintains a public database of CDRH Humanitarian Device Exemptions at the FDA HDE database, listing all approved devices with HDE numbers, company names, device descriptions, and approval dates.

Can digital health devices qualify for HDE?

Yes. Digital health products (SaMD) that meet the definition of a medical device and target rare conditions affecting ≤8,000 individuals/year in the US can qualify. The Digital Medicine Society (DiMe) has published an HDE preparation guide specifically for digital health products.