Humanitarian Device Exemption (HDE): 

Overview and Pre-approval Activities

Donna Headlee, RN, BSN, CCRP

Branch Chief, Premarket Programs Branch

Division of Industry and Consumer Education

Office of Communication and Education

Center for Devices and Radiological Health

U.S. Food and Drug Administration
Learning Objectives

• Define Humanitarian Device Exemption (HDE) and 

Humanitarian Use Device (HUD)

• Describe the approval threshold: determination of 

reasonable safety and probable benefit

• Identify the contents of an HDE application

• Describe the HDE review process

2 
Learning Objectives

• Understand the different types of actions for an HDE

• Describe the contents of an HDE approval package

• Identify strategies/best practices for a successful 

HDE submission and review process

3 
Rationale for HDE Program

• Rare diseases or conditions occur in a small number of patients

• Challenges: 

– to treat or diagnose the disease or condition 

– to gather valid scientific evidence to support safety and effectiveness

• Safe Medical Devices Act of 1990

• Alternative regulatory pathway for medical devices to 

treat/diagnose rare diseases or conditions

4 
What is a Humanitarian Use Device 

(HUD)? 

• A medical device intended to benefit patients in the 

treatment or diagnosis of a disease or condition that 

affects or is manifested in not more than 8,000 

individuals in the United States per year. 

Defined by 21 CFR 814.3(n) and 

Updated by Section 3052 of 21st Century Cures Act

5 
What is a Humanitarian Device 

Exemption (HDE)?

• A marketing application for a HUD

• Exempt from the effectiveness requirements of 

Sections 514 and 515 of the FD&C Act

• Subject to certain profit and use restrictions

Section 520(m) of FD&C Act

6 
Two-Step Process 

• Step 1: Obtain designation of the device as a HUD 

from the FDA’s Office of Orphan Products 

Development (OOPD).

• Step 2: After HUD designation is granted, submit an 

HDE application to the Center for Devices and 

Radiological Health (CDRH) or Center for Biologics 

Evaluation and Research (CBER).

7 
Eligibility for HDE

1. Received HUD designation

AND

2. No legally marketed device for same disease or 

condition granted under:

– Premarket notification (510(k))

– Premarket approval (PMA)

– de novo 8 
Approval Threshold

 Reasonable 

Assurance Safety 

 And

Probable Benefit*

 *Exempt from requirement to establish

 reasonable assurance of effectiveness 9 
Basis to Approve HDE

• device use (benefit) outweighs risk of injury/illness 

(safety) 

• accounting for other available options:

• currently available devices or alternative forms of 

treatment 

• their respective benefits and risks

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Contents of HDE Application

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HDE Application - Contents

• Copy of/reference to HUD designation letter 

• Explanation of why device not otherwise available

• Statement that no comparable device is legally marketed 

(approved or cleared)

• Device description:

– all components and accessories and how they work

– design drawings and specifications

– materials

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HDE Application - Contents

• Indications for Use

– consistent with HUD designated disease or condition

• Valid Scientific Evidence

– may include bench, animal, and/or clinical

• Explanation of why probable benefit outweighs risk

13
HDE Application - Contents

• Manufacturing Information

– must comply with the Quality System Regulation (21 CFR 820) 

• Amount being charged

• Request for Profit

– if requesting exception to profit prohibition

• Labeling 

– physician 

– patient, if applicable

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Required Labeling Statements

• The device is a humanitarian use device and

• Although the device is authorized by Federal Law, 

the effectiveness of the device for the specific 

indication has not been demonstrated 

15
Clinical Evidence

• Sources:

– clinical studies subject to Investigational Device 

Exemptions (IDEs) [i.e., conducted in United States]

– outside of United States (OUS) experience

– literature analyses

– whether adverse or supportive

16
Clinical Evidence

• Evidence should include: 

– summaries, 

– conclusions, and

– results of all clinical experience or investigations 

• Generally includes information on both safety and probable 

benefit 

17
Limitations of Clinical Evidence

• Rare disease/condition:

– Limited patient population available to study

– smaller sample sizes

• Lack of available comparable device

– no active control arm

– no randomization

18
HDE Review Process

19
HDE Review Process (1/2)

HUD 

Designation

HDE 

Submission 

Filing 

Review

Substantive 

Review

Not Filed Day

30

Filed

20
HDE Review Process (2/2)

Substantive 

Review

FDA 

Action

21

Major Deficiency Letter

or 

Not Approvable Approvable Pending Deficiencies

or

Approval 

Advisory 

Committee

(if needed)
Multi-Disciplinary FDA Review Team

• Team Leader/Lead Reviewer 

• Non-Clinical 

– engineering

– sterility, stability and shelf life

– bench testing

– biocompatibility

– microbiology

– animal studies

• Clinical 

– statistical

– medical

– epidemiology

– labeling

• Compliance

– quality systems and 

manufacturing

– bioresearch monitoring

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Scientific, Regulatory, Quality System Review
Filing Review

• Purpose

– threshold determination that the application is sufficiently complete 

to permit substantive review

• FDA Action:

– FDA sends Applicant written notification of filing review

– Decision Options: Filed or Not Filed

– completed within 30 calendar days of FDA receipt of HDE

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Reasons for Not Filing

• Incomplete 

– all the information required (21 CFR 814.104(b))

– a statement of either certification or disclosure, or both 

(21 CFR Part 54)

• FDA determines that there is a comparable device 

available 

• Contains an untrue statement or omits material 

information

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Substantive Review

• Purpose

– Scientific, Regulatory and Quality Systems review

• Interactive Process between FDA and Applicant

– address deficiencies that can be addressed in an appropriate 

timeframe

– allows review to continue and meet the review milestones

– FDA Review Clock does not stop

25
Advisory Committee Meeting

• Independent panel of experts

– expert clinicians

– statisticians

– industry representative

– patient representative

26
Advisory Committee Meeting

• FDA may seek input from Advisory Committee for reasons 

such as:

– novel technology expected to have a significant impact on 

clinical practice

– study results provide significant uncertainty as to whether 

the probable benefit of the device outweigh its probable risk

– unanticipated serious safety concerns

– significant study data quality or data integrity issues 

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Advisory Committee Meeting

• Provide recommendations:

– safety and probable benefit

– benefits outweigh the risks

– conditions of approval

– labeling 

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FDA Actions

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FDA Actions

• Approval Order: 

– Device may be marketed

– identifies conditions of approval

• Approvable Pending Deficiencies Letter: 

– Device is not legally marketed

– identify clarifications/deficiencies that need to be addressed to make HDE application 

approvable

– Common reasons: unresolved labeling; unresolved post-approval study design; and/or 

FDA has not determined that the manufacturing facilities, methods and controls are in 

compliance with the Quality System Regulation

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FDA Actions

• Major Deficiency Letter: 

– device is not legally marketed

– identifies deficiencies that cannot be adequately resolved interactively

• Not Approvable Letter:

– device is not legally marketed

– identify deficiencies that need to be addressed to make the HDE application approvable

– collection of new clinical/preclinical evidence

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Approval of an HDE 

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HDE Approval Package

Once a HDE is approved, FDA makes these documents publically 

available:

• Approval Order

• Summary of Safety and Probable Benefit (SSPB)

• Labeling 

– professional labeling

– patient labeling (if applicable)

• Consumer Information 

– a short, plain-language summary of the device and its intended use

33
HDE Approval Order

• HDE Approval Order

• HDE and HUD numbers

• conditions of approval

• post-approval requirement

• specific items that may be identified on case-by-case 

basis

– Annual Distribution Number (ADN), if applicable

– specific reporting requirements

– post-approval studies

34
Conditions of Approval

• Approved labeling

• Post-approval record-keeping requirements

• HDE supplements for changes 

35
• Mandatory Reporting

– periodic (annual) 

– medical device reports (MDRs) and product recalls

• Post-approval studies

• Updates to clinicians

Conditions of Approval

36
Post-Approval Studies (PAS)

• May be required as a condition of approval

• Reasons/Examples why FDA may require a PAS:

– understand long-term performance • especially for implantable devices

– further evaluate device/component performance

– evaluate learning curve or training issues

• FDA and Applicant agree on PAS protocol/outline prior to 

HDE approval

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• FDA’s summary of the HDE Submission

• Basis for FDA’s approval of HDE

• Contains:

– device description

– pre-clinical information

– clinical information

Summary of Safety and Probable Benefit 

(SSPB)

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Limitations of HDE Approval

• IRB approval is required before the HDEapproved device is used

- approval required at site, not for each patient 

- except in emergency situations

• Check your IRB Policies

39
Limitations of HDE Approval

• Labeling

- must clearly identify device as an HUD

- must state effectiveness for that indication has not 

been demonstrated

- must identify pediatric population, if applicable

• Profit Restrictions

- HDE may not be sold for profit except in certain 

circumstances. 40
HDE Approvals

41

www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsand 

Clearances/HDEApprovals/ucm161827.htm 
HDE Database

 

42 www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/hde.cfm 
Successful Submission Strategies

• Be organized

• Be prepared

• Be responsive 

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Be Organized

• Well-organized

• Administratively- and scientifically-complete submission 

• Contain:

– comprehensive table of contents 

– detailed sections 

– all test reports 

– labeled graphs/tables

– consecutive page numbers (e.g., 1, 2, 3)

44
Be Prepared

• Have your team ready to answer questions

• Have copies of the HDE submission and any other 

submissions/interactions with FDA (e.g., Pre-Subs)

• Be ready for manufacturing and bioresearch 

monitoring inspections

45
• Provide complete and accurate contact information

– include email, phone number, and fax number

– list alternate contact

– foreign applicant should have a U.S. representative

• Be upfront and responsive

– answer FDA’s questions when you say you will

– if you don’t understand a question, call/email and ask

• Be in touch 

– discuss questions, concerns with lead reviewer

– have your subject matter experts available for consult with FDA

46

Be Responsive
Be Responsive

• Be ready to interact on labeling

– have your decision-makers available for quick 

turnaround 

• Develop post-approval study plan early

– work with the FDA team to gain agreement on postapproval study 

47
Summary

• An approved HDE authorizes the applicant to market an 

HUD.

• Basis for approval: reasonable assurance of safety and 

probable benefit.

• An HDE application consists of information describing the 

device, and valid scientific evidence to support 

reasonable safety and probable benefit.

48
Summary

• The FDA website contains useful information on the HDE 

program and approved HDEs.

• The HDE Review Process involves several key decision 

points and interactions between FDA and the applicant 

to help complete the review.

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Summary

• The HDE approval package contains the approval order 

outlining the conditions of approval, the labeling, the SSPB, 

and consumer information

• A well organized, complete application will assist the review 

process

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Resources

• Humanitarian Device Exemption (HDE): Questions and Answers - Draft Guidance for HDE 

Holders, Institutional Review Boards, Clinical Investigators, and Food and Drug 

Administration Staff

www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm389154.htm

• Guidance for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators, and 

FDA Staff - Humanitarian Device Exemption (HDE) Regulation: Questions and Answers

www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm110194.htm

• Guidance for Industry and Food and Drug Administration Staff – Humanitarian Use Device 

(HUD) Designations

www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM336515.pdf

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Resources

• Device Advice – Humanitarian Device Exemption

www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/

PremarketSubmissions/HumanitarianDeviceExemption/default.htm

• HDE Approvals

www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/ 

HDEApprovals/default.htm

• HDE Checklist for Filing Decisions

www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice

/PremarketSubmissions/HumanitarianDeviceExemption/UCM056830.pdf

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“how to” modules

 accessible on your portable devices: www.fda.gov/Training/CDRHLearn

2. Device Advice – Text-Based Education

 comprehensive regulatory information on premarket and postmarket topics:

www.fda.gov/MedicalDevices/DeviceRegulationandGuidance

3. Division of Industry and Consumer Education (DICE) 

 If you have a question - Email: DICE@fda.hhs.gov

 Phone: 1(800) 638-2041 or (301) 796-7100 (Live Agents 9am–12:30 pm; 1-4:30 pm EST)

 Web Homepage: 

www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ContactUs-- DivisionofIndustryandConsumerEducation/default.htm

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