Humanitarian Device Exemption (HDE):

Post-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

• Understand the regulatory responsibilities for an 

approved Humanitarian Device Exemption (HDE)

• Describe the post-approval reporting requirements 

• Understand the purpose of the annual incidence 

reassessment

2 
Learning Objectives

• Understand the different types of HDE Supplements

• Understand the role of the Pediatric Advisory 

Committee and Institutional Review Boards (IRBs) 

with HDEs

3 
HDE Post-approval Requirements

• Post-Approval Requirements specific to HDEs

– HDE Supplements (21 CFR 814.108) 

– IRB Approval (21 CFR 814.124) 

– HDE Periodic Reports (21 CFR 814.126) 

• General Requirements for all Medical Devices

– Medical Device Reporting (21 CFR 803.50 and 803.52) 

– Recalls (21 CFR 806.10) 

4 
Responsibilities of HDE Holders and 

Institutional Review Boards (IRBs)

5 
HDE Holder Responsibilities

• Ensure that the Humanitarian Use Device (HUD) 

is used only in facilities with functioning IRBs

6 
HDE Holder Responsibilities

• Maintain records:

– names and addresses to which the HUD was shipped

– correspondence with Institutional Review Boards (IRBs)

– other information requested by FDA or the reviewing IRB

7 21 CFR 814.126(b)(2) 
IRB Responsibilities

• IRB Requirements 

− must have policies for approval and continuing review of 

HUD

− may require informed consent prior to use

• IRB Approval of an HUD at an institution 

− blanket approval for particular HUD or

− case-by-case basis

8 
Emergency Use of an HUD

• Physician may use HUD if unable to obtain IRB approval 

prior to use: 

− if patient is at risk of serious harm or death

− must submit report to IRB chair within 5 days

• notification of use of device

• identification of patient

• date of use

• reason for use

21 CFR 814.124(a) 9 
Emergency Use of an HUD

• FDA recommends that physician

– obtain informed consent from patient

– check with the IRB for any applicable policies

– maintain patient protection measures

– submit follow-up report to HDE holder

10
Research of an HUD

• Use of Device on-label

– for the indications approved under the HDE

– exempt from the Investigational Device Exemption regulation (21 CFR Part 812) 

– comply with the requirements for IRB review/approval (21 CFR Part 56) 

– comply protection of human subjects (21 CFR Part 50)

• Use of Device off-label

– for an indications other than what was approved under the HDE

– comply with the IDE regulation (21 CFR Part 812)

– comply with the requirements for IRB approval (21 CFR Part 56)

– comply protection of human subjects (21 CFR Part 50)

11
HDE Reports

• Termination/Withdrawal of IRB Approval

• Periodic Reports

• Post-Approval Study Reports

– if mandated to conduct a post-approval study

12
Termination/Withdrawal of

IRB Approval

• If IRB withdraws approval of HUD:

– the holder of the HDE must notify the FDA

– within 5 working days

13

21 CFR 814.124 (b) 
FDA Withdraw of an Approved HDE

• after HDE is approved

• another device with same indication may become legally 

marketed

– premarket approval (PMA), premarket notification (510(k)), de novo

• HUD no longer meets requirements of 520(m)(2)(B)

• FDA may withdraw the HDE

14
HDE Periodic Reports

• Device Accountability

– number of devices shipped or sold since HDE approval in the calendar year

– account for multiple devices used in same patient (and vice versa)

• Clinical Experience

– known safety information

– medical device reports (MDR)

– data from post-approval studies

– information that may impact labeling

• Supplemental Device Changes 15
HDE Periodic Reports

Updated information on HUD/HDE Status

• HDE justification

- 21 CFR 814.104(b)(2)

• Probable benefit outweighs risk

- 21 CFR 814.104(b)(3)

• Annual Incidence Reassessment

- 21 CFR 814.126 16
Annual Incidence Reassessment (AIR)

• Updated patient population estimate (PPE) to current 

U.S. population to ensure that the HUD continues to 

qualify through the HUD/HDE pathway

• If the PPE exceeds 8000 as a result of the AIR, the HDE 

may become ineligible for HUD/HDE pathway 

– Options: withdraw HDE, convert to treatment IDE, or identify 

population through new HUD or orphan subset

17
HDE Periodic Reports: Device Cost

If cost of the device exceeds $250, HDE holder must 

report:

− assessment completed by an independent Certified Professional 

Accountant (CPA) or a “responsible individual” of the company

− verifying that the amount charged does not exceed the costs of 

research, development, fabrication, and distribution

18
Additional Reports

• Medical Device Reporting (MDR) (21 CFR 803) 

• Recall Notification (21 CFR 806.10)

• Post-approval Study Reports

19
HUD Manufacturer Must Report

• HUD-related deaths, serious injuries, or malfunctions

• Within 30 calendar days

• Based on information which they may receive or otherwise become 

aware of, from any source,

• Which reasonably suggests that the HUD:

– May have caused or contributed to a death or serious injury; or

– Malfunctioned and the malfunction of the device would be likely to cause or 

contribute to a death or serious injury if the malfunction were to recur. 

20
HDE Supplements in the

Code of Federal Regulations

Addressed under:

• 21 CFR 814.108 

– “Supplemental applications” under Subpart H (HUDs)

• 21 CFR 814.39

– “PMA Supplements” under Subpart B (PMAs)

21
Types of HDE Supplements

• 75-Day Supplement

• 30-Day Notice

• Special HDE Supplement: Changes Being 

Effected

22
75-Day Supplements

• Device modifications/Design changes 

• Labeling changes

• Manufacturing/Sterilization Site changes

• Post-Approval Study (PAS) Protocol 

changes

• Requests for annual distribution number 

(ADN) and profit eligibility

 modification to ADN

23

Examples

• Change in 

materials

• Hardware/software 

modification 

• Extended shelf life
30-Day Notice

• Modifications to 

manufacturing process

• FDA may convert to 75-Day PMA Supplement

– if submission does not qualify for 30-Day Notice

24

Examples

• Convert a process from manul to 

automated

• Obtain new manufacturing equipment

• Use an alternate supplier
Special HDE Supplement:

Changes Being Effected

 Changes that enhance the safety of device

• Labeling

– newly acquired safety-related information not previously 

submitted to the FDA, and

– add/strengthen a contraindication, warning, precaution, or 

information about an adverse reaction. 

• Manufacturing Process Change 

– generally those that add a step to the quality control or 

manufacturing processes to enhance safety, but does not

impact effectiveness 25
Special HDE Supplement:

Changes Being Effected

• Can be implemented prior to 

 FDA approval

• 30-Day review

Guidance: 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 

75-Day Humanitarian Device Exemption (HDE) Supplements for Manufacturing 

Method or Process Changes

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

ucm080192.htm

26

Examples

• Improved instructions for use

• New quality assurance step
HDE Supplements

• Requests for new/expanded indications for use 

(IFU) outside of existing HUD designation

– cannot be submitted as an HDE supplement

– require a new HUD designation

27
Pediatric Advisory Committee (PAC)

• Conducts periodic annual review of approved HUDs labeled 

for pediatric patients that are allowed to make profit

• Ensures that HDE remains appropriate (Section 520(m)(2)) for 

the pediatric population for which is it approved

– Section 520(m)(8) of Food, Drug and Cosmetic Act

• FDA’s Office of Pediatric Therapeutics (OPT), Office of the 

Commissioner (OC) coordinates review

28
PAC Review

• Information presented to PAC includes: 

– MDRs received since approval and relevant safety information

– summary of any post-approval studies

– summary of relevant peer-reviewed literature published since approval

• Review Questions

– does probable benefit/risk profile of the device for the pediatric 

population continue to support the HDE for which the exemption was 

granted 

More Information about the PAC:

www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/default.htm

29
Summary

• A sponsor has a number of regulatory responsibilities after an 

HDE is approved and for updating FDA on changes to the 

device

• After approval of an HDE, there are post-approval reporting 

requirements 

• Annual incidence reassessment is an annual estimate of the 

target population with the disease or condition 

30
Summary

• Modifications that affect the safety and probable benefit of 

the device require the FDA’s review and approval of an HDE 

Supplement 

• Organizations such as the Pediatric Advisory Committee and 

Institutional Review Boards have specific roles for HDEapproved devices

31
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

32
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

33
Providing Industry Education

1. CDRH Learn – Multi-Media Industry Education

 over 80 modules - videos, audio recordings, power point presentations, software-based 

“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

34