Welcome to today’s 

FDA/CDRH Webinar

Thank you for your patience while additional time is provided for 

participants to join the call. 

Please connect to the audio portion of the webinar now:

U.S. Callers Dial: 800-369-3163

International Callers Dial: 1-773-756-4627

Passcode: 3000516

Conference Number: PWXW9442225
Humanitarian Device Exemption 

(HDE) Program - Final Guidance

Stephanie Shedd, RAC

Biomedical Engineer

Division of Submission Support

Office of Regulatory Programs 

Office of Product Evaluation and Quality

Center for Devices and Radiological Health

October 21, 2019
3

• Definitions/Objectives

• Background of HDE program

• Scope of Guidance

• HDE Application Content, Review, and Timelines

• Post Approval Requirements

• Special Considerations for HDEs

• Summary/Significant Changes in HDE Guidance

• Resources 

• Questions

Agenda
4

• Humanitarian Use Device (HUD): A medical device intended to 

benefit patients in the treatment or diagnosis of diseases or conditions 

that affect or are manifested in not more than 8,000 individuals in the 

United States per year.

• Humanitarian Device Exemption (HDE): A marketing application for 

a HUD, exempt from effectiveness requirements and subject to 

certain profit and use restrictions.

• Institutional Review Board (IRB): A committee that oversees the 

use of HUDs at medical facilities, per FDA regulations governing 

IRBs. 

• Appropriate Local Committee (ALC): A standing committee that 

has expertise and experience in reviewing and making treatment 

decisions for clinical care. 

Definitions
5

Objectives

• Provide an overview of the scope of the HDE program described 

in the FDA’s Guidance Document Humanitarian Device 

Exemption (HDE) Program : Guidance for Industry and Food 

and Drug Administration Staff issued September 6, 2019

• Review significant changes made in the final guidance 

document

– Final guidance supersedes Guidance for HDE holders, 

Institutional Review Boards (IRBs), Clinical Investigators, 

and Food and Drug Administration Staff, Humanitarian 

Device Exemptions (HDE) Regulation: Questions and 

Answers, issued July 8, 2010.
6

Evolution of the HDE Program

1990

• Safe Medical Devices Act 

• Exemption from requirement to demonstrate reasonable assurance of 

effectiveness (Sections 514 and 515 of the FD&C Act)

1997

• Food and Drug Administration Modernization Act (FDAMA)

• Allowed use of HUDs under HDEs without prior IRB approval in certain 

emergency situations

2007

• Food and Drug Administration Amendments Act (FDAAA)

• Allowed HUDs indicated for use in pediatric patients, or a pediatric 

subpopulation, to be sold for profit

2012

• Food and Drug Administration Safety and Innovation Act (FDASIA) 

• Further expanded the eligibility of devices able to make a profit
7

• 21st Century Cures Act (“Cures Act”) - effective 12/13/2016

– Modified the HUD threshold to “not more than 8,000 individuals in the United 

States per year”

– Revised requirement for approval of the use of HUDs at medical facilities

– HDE Commitment: Publish draft guidance within 18 months to define the 

criteria for establishing ‘‘probable benefit’’ – published 6/30/2018

– Current guidance represents finalization of this draft guidance and responses 

to public comments.

21st Century Cures Act
8

• Operational aspects of HDE Program

• Principal criteria that the FDA uses to determine 

probable benefit

• FDA’s assessment of whether probable benefit 

outweighs the risk of injury or illness from its use

• Post-Approval requirements for HDEs

• Special Considerations for HDEs

• Decision tools for FDA staff when reviewing HDE

applications 

Scope of Guidance Document
9

• HUD Designation should be submitted to and approved by Office of Orphan 

Products prior to HDE submission

– Guidance Document Humanitarian Use Device (HUD) Designations -

Guidance for Industry and Food and Drug Administration Staff, revised 

September 5, 2019

• HDE Filing review: Application should be organized and administratively 

complete (21 CFR 814.104(b))

– Appendix A of the guidance

– Applicant should provide a justification for any alternative approach

– Filing decision made within 30 days from the date the HDE was 

received. 

HDE Application Content
10

• Reviewer may use discretion to use interactive review to obtain missing 

information during filing review or substantive review

• Device description: 

– all components and accessories and their mode of action

– design drawings and specifications 

– materials 

• Indications for Use

– consistent with HUD designated disease or condition

HDE Application Content cont’d
11

• Valid Scientific Evidence to demonstrate safety and probable benefit of the 

device

– may include bench, animal, and/or clinical

• principles of the “3Rs”: reduce, refine, and replace animal use in testing 

when feasible

– guidance encourages collection and submission of patient preference 

information

• Explanation of why probable benefit outweighs risk

• Manufacturing Information – in accordance with Quality System Regulation (21 

CFR 820)

• Labeling 

– physician 

– patient, if applicable

HDE Application Content cont’d
12

Elements unique to HDE filing include: 

• HUD designation

– Copy of or reference to FDA’s HUD designation letter

• Amount to be charged for device

– If more than $250, a report must be provided verifying that the amount charged 

does not exceed the costs of research, development, fabrication, and distribution. 

– Should still include if eligible for profit-making

• Comparable devices

– Statement that no other comparable device, other than a HUD approved under HDE 

or for use under an approved clinical investigation, is available to treat or diagnose 

the disease or condition

HDE Filing
13

• Substantive review of HDE Application must demonstrate:

– the device will not expose patients to an unreasonable or significant risk of 

illness or injury AND

– the probable benefit to health from use of the device outweighs the risk of 

injury or illness from its use, taking into account the probable risks and 

benefits of currently available devices or alternative forms of treatment

HDE Review - Safety
14

• When there is evidence for FDA to reasonably conclude that patients are likely 

to benefit from the use of the device, in terms of:

– Type of benefit(s)

– Magnitude of benefit(s);

– Probability of the patient experiencing one or more benefit(s); 

– Duration of effect(s);

– Patient perspectives; and/or

– Care-partner (e.g., parent or aide) perspectives.

HDE Review – Probable Benefit
15

• Reviewer’s determination of “probable benefit” under an HDE:

– Accepts greater uncertainty, as a reasonable assurance of effectiveness is 

not required 

– Considers intended use of the device, including target patient population and 

size of population

• Ex: the smaller the patient population, the greater the uncertainty FDA 

would expect

– Takes into account currently available alternative treatments or diagnostics

– Takes into account patient perspectives on risk, uncertainty, and probable 

benefit

Guidance: Consideration of Uncertainty in Making Benefit-Risk Determinations, https://www.fda.gov/media/115672/download

HDE Review – Probable Benefit cont’d
16

• FDA actions made within 75 days of receipt: 

– Approval order;

– Approvable letter;

– Major deficiency letter;

– Not approvable letter; and

– Denial order

• Major amendments will extend review time up to 75 days

• Voluntary withdrawal

– Failure to respond within 75 days, unless extension is requested

– Extensions granted up to 360 days

Timeline of HDE Actions
17

• An IRB must provide oversight at facilities where HUDs are used

• Statutory language allows either an IRB or “an appropriate local committee” to 

approve the use of a HUD to treat or diagnose patients at a facility.

• “Appropriate local committee” may include a standing committee at the 

facility that includes physicians with experience in the treatment of rare 

diseases or conditions

• Approval for individual HUD use not required; a generalized approval may 

be granted for the facility. 

• Emergency use does not require prior approval

Post Approval Requirements - IRB
18

• Has expertise and experience in reviewing and making treatment decisions for 

clinical care, particularly in applying innovative medical device technologies to 

clinical care. 

• Includes physicians with experience in the treatment of rare diseases or 

conditions

• Examples may include:

– Peer Review Committee

– Credentialing Committee

– Quality Care Committee

Appropriate Local Committee (ALC)
19

• For initial review, FDA recommends review of:

– A copy of the HDE approval order

– A description of the device

– The product labeling

– The patient information packet that may accompany the HUD

– A sample consent form for the use of the HUD in clinical care, if required by 

the IRB or ALC or by facility policy

– A summary of how the physician proposes to use the device, including a 

description of any screening procedures, the HUD procedure, and any 

patient follow-up visits, tests or procedures 

IRB / ALC Review of HUD use
20

• All adverse events, whether expected or not, must be reported 

and evaluated in accordance with Medical Device Reporting 

requirements in 21 CFR part 803. 

– Device manufacturers and user facilities submit to FDA and 

IRB/ALC

– Adverse events for HUDs that are approved and labeled for 

pediatric patients or in a pediatric subpopulation, and exempt 

from the profit prohibition, will be reviewed periodically by 

FDA’s Pediatric Advisory Committee (PAC)

Post Approval Requirements- Adverse Events
21

• HDE supplements – 21 CFR 814.108

– Supplements may follow review guidelines for PMAs, with some changes to 

review timelines. 

– A request for new indications should be accompanied by a new HUD 

designation

• Periodic Reports - 21 CFR 814.126

– Updated information to demonstrate that the HUD designation is still valid

– Updated explanation of why the device would otherwise not be available

Post approval- additional FDA submissions
22

• May be required as a Condition of Approval in order to: 

– Understand long-term performance

– Evaluate learning curve or training issues

• Full protocol/protocol outline, including relevant timepoints, is agreed upon prior 

to HDE approval 

– If only a protocol outline is agreed upon, a full protocol is developed following 

approval, in a protocol supplement to the HDE

• Recommendations included in the guidance document Procedures for Handling 

Post-Approval Studies Imposed by PMA Order

Post Approval Study
23

• HUDs under an HDE cannot be sold for an amount that exceeds the costs 

of research and development, fabrication, and distribution of the device 

(i.e., for profit) unless: 

– Intended and labeled only for pediatric patients or in a pediatric 

subpopulation, 

– Disease does not occur in any pediatric populations or pediatric subgroups

– Disease or condition occurs in pediatric patients in such numbers that 

the development of the device for such patients is impossible, highly 

impracticable, or unsafe.

• Applicant should provide adequate supporting documentation in the HDE

Special HDE Considerations - Profit
24

• If eligible, a HUD can be sold for a profit up until the number of devices sold 

exceeds the annual distribution number (ADN). 

• The applicant should provide the number of devices per year reasonably 

needed for each individual in the HDE application/supplement and provide 

adequate documentation to support such number. 

• The ADN will be equal to or greater than 8,000, depending on how many 

devices per year are reasonably needed to treat diagnose, or cure an individual

• Once the ADN has been exceeded, then the sales of the HUD for the remainder 

of the year are subject to the general prohibition on profit 

– unless FDA approves an ADN modification request in an HDE supplement 

Special HDE Considerations - ADN
25

• Informed consent not required from patient treated or diagnosed with an HDEapproved HUD 

– IRB or ALC may choose to require additional information be provided to 

patients

– Written documents provided to patients should include much of the 

information provided in the HDE patient labeling

• Labeling must: 

– Be truthful and non-misleading

– Include the statement “Humanitarian Device. Authorized by Federal law for 

use in the [treatment or diagnosis] of [specify disease or condition]. The 

effectiveness of this device for this use has not been demonstrated” as 

required in 21 CFR 814.104.

Special HDE Considerations –

Information to Patients
26

• Patients who are 21 years of age or younger (i.e., up to, but not including, the 

22nd birthday) at the time of the diagnosis or treatment (Section 520(m) of the 

FD&C Act)

• HUDs labeled for use in pediatric patients or in a pediatric subpopulation may 

be eligible to be sold for profit

• HDE applications for devices intended for use in both pediatric and adult 

populations include: 

– data supporting the use in both pediatric and adult populations or,

– an appropriate rationale specifically addressing how the data provided for 

one population (e.g., adults) are sufficient to support approval of an HDE 

application with indications for use in both populations.

Special HDE Considerations - Pediatrics
27

• Approved HUDs are required to be reviewed annually by the FDA Pediatric 

Advisory Committee (PAC)

– Ensures that the HDE remains appropriate for the pediatric populations for 

which it was approved. 

– Conducts periodic review of adverse events for these devices when they are 

exempt from the profit prohibition

For more information on the PAC, see https://www.fda.gov/advisory-committees/committees-and-meeting-materials/pediatric-advisorycommittee

Special HDE Considerations - Pediatrics
28

• Incorporated filing checklist into guidance (Appendix A)

– Checklist helps to ensure that the application contains the necessary 

information to conduct a substantive review. 

– Elements in the checklist stem from either statutory or regulatory 

requirements 

– Format and content are consistent with the analogous checklists for other 

types of premarket submissions. 

– Concerns identified by the Agency regarding results and outcomes of 

nonclinical and clinical studies should be addressed in the substantive review 

and should not preclude a filing decision.

HDE Reviewer Tools – Filing Checklist
29

• Considerations for the Probable Benefit-Risk Assessment & Probable Benefit-Risk 

Assessment Summary (Appendices B & C) 

– Worksheets provide flexibility and use of scientific judgment in assessing the totality 

of the evidence to determine if a specific device meets the standard for HDE 

approval. 

– Allow FDA to take into account considerations relevant to HDE applications (e.g., a 

relatively small patient population) under a framework that is consistent across 

device marketing submission types 

– Prompt reviewers to consider specific criteria for 

• Probable benefit

• Risk

• Sources of uncertainty

HDE Reviewer Tools – Assessment of Probable 

Benefit and Risk
30

• Per the Cures Act, a HUD is defined as a device for use in a patient population 

that does not exceed 8,000 patients per year. 

• Criteria provided for:

– Determining probable benefit

– Assessing whether the probable benefit outweighs the risk of use

• Allows for use of “appropriate local committees” in addition to IRBs to approve 

HUD use at facilities

• Provides reviewer tools to ensure consistency, as well as flexibility, in reviewer 

decision-making. 

Summary
31

• Humanitarian Device Exemption (HDE) Program : Guidance for Industry and Food and Drug 

Administration Staff 

• Humanitarian Use Device (HUD) Designations - Guidance for Industry and Food and Drug 

Administration Staff 

• Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement DecisionMaking Process

• 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day Humanitarian Device 

Exemption (HDE) Supplements for Manufacturing Method or Process Changes

• Procedures for Handling Post-Approval Studies Imposed by PMA Order

• Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval 

and De Novo Classifications

• Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket 

Approvals, De Novo Classifications, and Humanitarian Device Exemptions 

• Patient Preference Information – Voluntary Submission, Review in Premarket Approval Applications, 

Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision 

Summaries and Device Labeling 

• eCopy Program for Medical Device Submissions

Resources
32

Questions?

Division of Industry and Consumer Education: DICE@fda.hhs.gov

Office of Regulatory Programs, Division 1: Division of Submission 

Support: CDRHPremarketProgramOperations@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording will be available at:

http://www.fda.gov/training/cdrhlearn

Under Heading: How to Study and Market Your Device; Sub-Heading: 

HUD/HDE

Please complete a short survey about your FDA CDRH webinar 

experience. The survey can be found at www.fda.gov/CDRHWebinar

immediately following the conclusion of the live webinar.