Contains Nonbinding Recommendations  
 
Humanitarian Device  Exemption 
(HDE) Program 
 
Guidance  for Industry and  
Food and Drug Administration Staff  
Document  issued on  September 6, 2019.  
The draft of this document  was issued on  June 13, 2018.  
For questions about this document  regarding CDRH-regulated devices, contact  ORP:  Office of 
Regulatory Programs/DRP1:  Division of Submission Support, Center for  Devices and  
Radiological Health, at 301-796-5640.  
For questions about this document regarding CBER-regulated devices, contact the Office of  
Communication, Outreach, and Development (OCOD)  at 1-800-835-4709 or 240-402-8010.  
This 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.  
 
An agency may not conduct or sponsor, and a  person is not required to respond to, a  collection of 
information unless it displays a currently valid OMB control number. The OMB control number   
for this infor mation collection is 0910-0661 (e xpires 09-30-2022). 
 
See additional  PRA statement in Section IX of this guidance.  
 
 
      U.S. Department of Health and Human Services 
Food and Drug Administration  
 
 
 
 
Center for Devices and Radiological Health  
Center for Biologics Evaluation and Research  
Office of Orphan Product Development   
   
    Contains Nonbinding Recommendations  
Preface  
Public  Comment 
You may submit electronic comments and suggestions at any time for Agency  consideration to  
https://www.regulations.gov .  Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers  Lane, Room 1061, (HFA-305), Rockville, MD 20852.  
Identify all comments with the docket number  FDA-2014-D-0223. Comments may not be acted 
upon by the Agency until the document is next revised or updated.  
 
Additional Copies 
 
CDRH  
Additional copies are  available from the  Internet. You may  also send an email request to CDRH-
Guidance@fda.hhs.gov  to receive a copy of the guidance. Please use the document number  
17040 and complete title of the guidance in the  request. 
CBER  
Additional copies are  available from the Center  for Biologics Evaluation and Research (CBER), 
by written request,  Office of Communication, Outreach, and Development  (OCOD), 10903 New  
Hampshire Ave., Bldg. 71, Room 3128, Silver Spring, MD 20993-0002, or  by calling 1-800-835-
4709 or 240-402-8010, by  email, ocod@fda.hhs.gov or from the  Internet at  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances.  
OOPD  
Additional copies of this guidance document are  also available from the Office of Orphan 
Products Development (OOPD), Office  of Clinical Policy and  Programs  (OCPP), Food and Drug  
Administration, 10903 New Hampshire  Ave, Silver Spring, MD 20993, or  by calling 301-796-
8660, or from the  Internet  at  https://www.fda.gov/industry/developing-products-rare-diseases-
conditions/designating-humanitarian-use-device-hud. You may  also send an e-mail request to  
orphan@fda.hhs.gov.    
ii   Contains Nonbinding Recommendations  
Table of Contents 
 
I.  Introduction .......................................................................................................................... 1  
II.  Background .......................................................................................................................... 2  
III.  Scope .................................................................................................................................... 4  
IV.  HUD Designations and  HDE Applications.......................................................................... 5  
V.  FDAs Review of HDE  Applications  .................................................................................. 5  
A.  HDE Application Required Elements and  Filing Review Principles  .................................. 8  
B.  FDA Review Actions for an HDE Application ................................................................. 11  
VI.  Assessing Probable Benefit and Risk in an HDE Application .......................................... 14  
VII.  Post-Approval Requirements ............................................................................................. 18  
A.  IRB or Appropriate  Local Committee Oversight and Approval ........................................ 18  
B.  Adverse Event Reporting ................................................................................................... 19  
C.  HDE Supplements .............................................................................................................. 20  
D.  HDE Periodic Reports........................................................................................................ 20  
E.  HUD Designation Re-Evaluation and/or HDE Withdrawal  .............................................. 22  
VIII.  Special Considerations for Devices Marketed Under an HDE .......................................... 22  
A.  Eligibility for Profit............................................................................................................ 22  
B.  The Annual Distribution Number (ADN) .......................................................................... 24  
C.  Information to Patients ....................................................................................................... 26  
D.  HDEs and Pediatric Patients  .............................................................................................. 26  
E.  Review and Approval of  the Use of HUDs in Clinical Care  ............................................. 27  
F.  Review and Approval for Clinical Testing of HUDs......................................................... 30  
G.  Emergency  Use of HUDs................................................................................................... 31  
IX.  Paperwork Reduction Act of 1995 ..................................................................................... 32  
Appendix A  Checklist for Filing Review for HDEs .................................................................. 33  
Appendix B  Considerations for the Probable  Benefit-Risk Assessment ................................... 44  
Assessment of Probable  Benefit ................................................................................................ 45  
Assessment of Risk .................................................................................................................... 47  
Assessment of Probable  Benefit-Risk  ....................................................................................... 48  
Appendix C  Probable Benefit-Risk Assessment Summary ....................................................... 53  
iii   Contains Nonbinding Recommendations  
Humanitarian Device  Exemption 
(HDE) Program 
 
Guidance  for Industry and  
Food and Drug Administration Staff 
 
This  guidance  represents  the current thinking of the  Food and Drug Administration (FDA  
or Agency)  on  this topic. It does  not  establish  any rights for any person  and is  not binding 
on  FDA or the public. You can use an alternative approach if  it  satisfies the requirements  
of the applicable statutes and regulations. To discuss an alternative approach, contact the  
FDA staff or Office responsible for this guidance as  listed on the title page.   
I.   Introduction  
FDA developed this  guidance document to provide clarity to industry  and FDA staff about the  
current review practices for the Humanitarian  Device Exemption (HDE) Program.  This  
programmatic  guidance addresses commonly asked questions about HDEs and Humanitarian 
Use Devices  (HUDs), including FDA actions on HDE applications, post-approval requirements, 
and special considerations for devices marketed under the HDE Program. This guidance  
document reflects changes in the HDE  Program resulting from  statutory  amendments made by  
the 21st  Century Cures Act (Cures  Act)1 and explains the criteria FDA  considers to determine if   
probable benefit  has been demonstrated  as part of the Agencys decision-making process  
regarding  marketing authorization  for a HUD.  This guidance document  also reflects amendments  
made to the HDE provision of the Federal Food, Drug, and Cosmetic Act  (FD&C Act) by the  
FDA Reauthorization Act of 2017 (FDARA).2   
For the purposes of this guidance, you refers to the HDE applicant or  holder, and we refers  
to FDA. FDAs  guidance documents, including this guidance, do not establish legally  
enforceable responsibilities. Instead, guidances  describe  the  Agencys current thinking on a topic  
and should be viewed only  as  recommendations, unless specific regulatory  or statutory  
requirements are  cited. The use of the word should in Agency  guidance means that something is  
suggested or recommended, but not required.  
                                                           
1  Pub. L. 114-255.  
2  Pub. L. 115-52.  
 
1   Contains Nonbinding Recommendations  
II.  Background 
HUDs are medical devices 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.3  In seeking marketing authorization under an HDE  application, the first step is  the 
preparation and submission of a HUD designation request to FDAs Office  of Orphan Products  
Development (OOPD). The HDE application, which is the primary focus of this guidance  
document, is the second step in seeking marketing  authorization for  a HUD.  
To the extent consistent with the protection of the public health and safety  and with ethical  
standards, the purpose of the HDE provision is to encourage the discovery and use of devices  
intended to benefit patients in the treatment and diagnosis of diseases or  conditions that affect  
not more than 8,000 individuals in the United States,4  FDA may  grant an HDE, which  is  an  
exemption from the effectiveness requirements of  sections 514 and 515 of the FD&C Act, if we  
find that  the device meets  all of  the following  criteria:  
1.  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 while taking into account the probable risks and benefits of 
currently available devices or alternative forms of treatment; 
2.  The device  would not be  available to a person with the disease or  condition in question
without the HDE, and no comparable device,  other than another device  approved under 
an HDE or  Investigational Device Exemption (IDE),5  is available to treat or diagnose 
such disease or  condition;   and 
3.  The device is designed to treat or diagnose  a disease or condition that affects not more 
than 8,000 individuals in the United States on an annual basis.6 
The HDE  provision was  added to the FD&C Act by the Safe Medical Devices Act of 1990  and 
included, among other things, a prohibition on profits from sale of HUDs and a requirement that  
before use  of a HUD to treat or diagnose patients at a facility, an  IRB must approve such use.7 
For purposes of this guidance, approving the use of a HUD (as opposed to approving the  
investigational use or  a clinical investigation  of a device) refers to use  of the HUD in the  
course of  routine  clinical  care to treat or diagnose patients.  Subsequent amendments to the  
FD&C Act have added  important flexibility to the HDE program while retaining the purpose of  
encouraging the discovery  of medical devices for  use in limited patient populations.  
                                                           
3  21 CFR 814.3(n).  As  subsequently explained, the current threshold is  not  more than 8,000 individuals in the  
United States. Before section 3052 of the Cures  Act took effect, the threshold was  fewer than 4,000 individuals in  
the United States.  
4  Section 520(m)(1) of the FD&C  Act.    
5  An approved IDE permits a device to be shipped lawfully  for the purposes of conducting investigations of the  
device  without complying with certain other requirements of the  FD&C  Act that  would apply to devices in 
commercial distribution.  See  section 520(g) of the FD&C  Act; 21 CFR 812.1(a).   
6  See section 520(m)(2) of the  FD&C  Act; 21 CFR 814.104(b)(1)-(3).  
7  Pub. L. 101-629, section 14.  
 
2   Contains Nonbinding Recommendations  
The Food and Drug Administration Modernization Act of 1997 (FDAMA) included a  section on 
expanding the humanitarian use of  devices,8  which among other provisions:  
   Allowed for  the use of HUDs  under  HDEs without prior  IRB approval in certain  
emergency situations  (see Section  VIII.G for more information); and  
   Provided that  FDA may suspend or withdraw  an HDE only  after providing  notice and an 
opportunity for  an informal hearing  (see Section  VII.E  for more information). 
The Food and Drug Administration Amendments Act of 2007 (FDAAA) further modified the  
HDE provision, providing that HUDs indicated for use in pediatric  patients, or in a pediatric 
subpopulation may be sold for profit, subject to certain restrictions.9 The scope of HDE-
approved devices eligible to make a  profit  was  expanded by section 613 of the Food and Drug  
Administration Safety and Innovation Act (FDASIA).10   In any  given  calendar  year, a HUD  
meeting the statutory  criteria can be sold for  a profit up until the number of devices sold exceeds  
the annual distribution number  (ADN), which is the number of devices reasonably needed to 
treat, diagnose, or  cure a  population of 8,000 individuals in the United States  (see  Section  VIII.A  
for more information).  
FDAAA also added section 515A to the FD&C Act, which requires, among other things, the  
inclusion of additional information regarding pediatric uses  in all original HDE applications, if  
such information is readily available.11  Specifically, section 515A of the FD&C Act requires that  
each new HDE  application include a description, based on readily  available information, of any  
pediatric subpopulations that suffer from the disease or condition that the device is intended to 
treat, diagnose, or  cure, and the number of affected pediatric patients.12   
The Cures Act  amended the FD&C Act to increase the maximum number of patients  affected by  
the disease or  condition that a HUD is designed to treat or diagnose to not more than 8,000 
individuals in the United States.13 Further, the Cures Act removed the requirement  that 
institutional review committees, i.e.,  IRBs, that supervise the clinical testing  of devices  or 
approve the use  of HUDs be local.14  See Sections  VIII.E and VIII.F below for more information 
regarding differences between the  use  of a HUD and clinical investigations involving HUDs. 
The Cures Act  also  required FDA to publish a guidance that defines the  criteria for  establishing  
probable benefit  as that term is used in section 520(m)(2)(C) of the FD&C Act.15  This  
                                                           
8  Pub. L. 105-115, section 203.  
9  Pub. L. 110-85, section 303.  Pediatric patients are patients  who are younger  than 22  years of age at the time of  
diagnosis or treatment. See section 520(m)(6)(E)(i) of the FD&C  Act; 21 CFR 814.3(s). 
10  Pub. L. 112-144.  Many of the statutory provisions cited throughout this guidance, including sections 515A(a)(2)  
and 520(m)(6) of the FD&C  Act,  were added by  section 302 of FDAAA  and amended by FDASIA. 
11  See Pub L. 110-85, section 302.   For further discussion of the information required for pediatric uses of  medical  
devices under section 515A,  see the guidance document, Providing  Information  About Pediatric Uses of Medical  
Devices,  (available at  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
information-about-pediatric-uses-medical-devices).  
12  See section 515A(a)(2) of the FD&C  Act.  
13  Pub. L. 114-255, section 3052.  
14  Pub. L. 114-255, section 3056.   
15  Pub. L. 114-255, section 3052(b).  
 
3   Contains Nonbinding Recommendations  
guidance includes information to define those criteria for HDE applicants, other stakeholders, 
and FDA staff. See Section III for more information about the scope of this guidance.  
FDARA further amended section 520(m)(4)(B)  of  the FD&C Act to allow either an  IRB  or an  
appropriate local committee to approve the use of a HUD to treat or diagnose patients  at a 
facility.16  We interpret this provision to provide additional flexibility for a  healthcare  facility to  
determine the individuals involved in, and processes  and procedures used by,  the committee  that 
approves the use of HUDs  at that facility  in order to meet the needs of patients. Note, however, 
that this FDARA provision did not change the requirements for  IRB oversight of a  clinical 
investigation of a  HUD. An appropriate local committee may not review and approve such a  
clinical investigation in place of  an  IRB.17 See Section VII.A. for additional information 
regarding  IRB and  appropriate local committee oversight  and approval and Section VIII.F. for 
additional information regarding investigational use of a HUD.  
III.  Scope 
This guidance provides recommendations to industry and FDA staff  about the operational  
aspects of the HDE Program and also explains the principal criteria that FDA considers  when  
determining if probable benefit(s) to health have been demonstrated  for a HUD  that is being  
reviewed through the HDE Program. Additionally, this guidance  addresses  FDAs assessment of  
whether the probable benefit(s) 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.  The decision tools in Appendices B and C are intended 
to help staff consider the probable benefit-risk  factors discussed in Section VI  when reviewing  
HDE applications. This  guidance includes sections on the following topics, among others:  
  FDA Review Actions for an HDE Application (Section  V.B); 
  Assessing Probable Benefit and Risk in an  HDE Application18  (Section  VI);  
  Post-Approval Requirements (Section VII); 
  Special Considerations for Devices Marketed Under an HDE (Section  VIII); and 
  Appendices to support the HDE Program which include:  
  Filing  Checklist (Appendix A) 
o
  Probable Benefit-Risk Assessment  Summaries (Appendices  B and C) 
o
The overarching principles in this guidance are applicable to devices that  are eligible for review  
through an HDE  application by CDRH as well as devices that are eligible for review  through  an  
HDE  application by the  Center for  Biologics Evaluation and Research (CBER). This  guidance is  
not intended to supplant or provide recommendations regarding device-specific data 
requirements, but it may  cover broader  areas not addressed in device-specific guidance 
                                                           
16  Pub. L. 115-52, section 502(b).  
17  See sections 520(g)(3) and  520(m)(4)(A) of the FD&C  Act;  21 CFR part 56; 21 CFR part 812.  
18  As required by the Cures  Act, this  guidance explains the principal criteria that FDA considers  when determining if  
probable benefit(s) to health  have been demonstrated for a HUD that is being reviewed through the HDE Program.   
 
4   Contains Nonbinding Recommendations  
documents. In addition, this guidance does not address review issues unique to combination 
products. 
IV.   HUD Designations and HDE Applications  
Before submitting an  HDE application to  CDRH or CBER, an HDE  applicant must first prepare  
and submit a HUD designation request  to OOPD  and receive a HUD designation.19 For more  
information on the preparation and submission of  a HUD designation request, refer  to 21 CFR  
814.102(a)  and the FDA  guidance Humanitarian  Use Device (HUD) Designations.20  In the  
review of  a HUD designation request, FDA  will determine whether the device  is for a rare 
disease or condition that affects or is manifested in not more than 8,000 individuals in the United 
States per  year. In the  case of a device used for diagnostic purposes, FDA will determine whether  
the documentation demonstrates that not more than 8,000 individuals per  year would be  subject  
to diagnosis  by the device in the United States.21  After receiving a HUD designation, the HDE  
applicant may submit an HDE application to the appropriate center. Each  applicant must have  its  
own HUD designation to submit an original HDE  application for a proposed indication.22  
Additionally, the HDE  applicant can utilize the HDE pathway only if no other comparable  
device (other than another device  approved under  an HDE or under an approved IDE) is  
available to treat or diagnose the disease or condition.23  
Note that if  your device is part of a combination product, an HDE may  not be the appropriate  
pathway  to market. For questions about  the availability of the HDE pathway  for combination 
products, please  contact the Office of Combination Products by email at  combination@fda.gov. 
For questions about Companion Diagnostic Devices, contact  CDRHs  Office of Health  
Technology 7/Office of  In Vitro Diagnostics and Radiological Health  at  oir-policy@fda.hhs.gov.  
V.   FDAs Review  of HDE Applications  
Approval of an HDE  application  under 21 CFR  part  814, Subpart H, is considered FDA 
approval of the device based on, among other  criteria,  evidence that 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.24  In addition, to be eligible  for HDE  application approval, FDA must determine that  
                                                           
19  21 CFR 814.102(a).    
20  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/humanitarian-use-
device-hud-designations.  
21  See 21 CFR 814.102(a)(5).    
22  See 21 CFR 814.102(a); 21 CFR 814.104(b)(1)  
23  Section 520(m)(2)(B) of the FD&C  Act; 21 CFR 814.104(b)(2).  
24  Section 520(m)(2)(C) of the  FD&C  Act; 21 CFR 814.104(b)(3).   As discussed in  more detail in Section VI, FDA  
will perform an assessment of  the probable benefits and risks of a device, considering a number of  factors, including  
the target patient population and the size of the population, as  well as available alternative treatments or diagnostics,  
as part of its determination of whether an HDE application  meets the statutory  standard for approval.  
 
5   Contains Nonbinding Recommendations  
the device would not be  available to a person with the disease or  condition in question without  
the HDE  application approval and that there is no comparable device, other than another device  
under an HDE or  IDE, available to treat or diagnose the disease or condition.25  A HUD that  
meets the HDE standard for approval is exempt from the requirement of  establishing a  
reasonable assurance of effectiveness that would otherwise be required under sections 514 and 
515 of the FD&C Act.26 FDA approval of an HDE  application authorizes an applicant to market  
a HUD in accordance  with approved labeling  and indication(s) for use, subject to certain profit  
and use restrictions set forth in section 520(m) of the FD&C Act.  
A  HUD under  an HDE  may not  serve as a predicate device for purposes of  section 513(i) of the  
FD&C Act.27  A Premarket Approval application  (PMA) could subsequently  be submitted  for the  
same device and indication(s)  approved under an HDE application if the applicant believes there 
is  sufficient evidence to  meet the evidentiary standard of  a reasonable assurance of safety and  
effectiveness; or, if  appropriate, the applicant could instead submit a  request for classification  
under  section  513(f)(2)  of the FD&C Act  (a De Novo request). If FDA approves a PMA or  
grants a De  Novo request for the HUD or another  comparable device  with the same indication, 
we may withdraw the HDE because the HUD would no longer meet the requirements of section 
520(m)(2)(B) of the FD&C Act.28 Section V.A discusses comparable devices, and Section VII.E  
discusses HUD designation re-evaluation.  
FDAs  review of HDE  applications  has  similarities  to the review of PMA  applications, with a  
few key differences. Some similarities to the PMA program include:  
   HDE amendments, supplements, and reports are  generally subject to similar  requirements   
as those for PMAs  (although timeframes differ).29  The requirements for each  of these 
types of  HDE  submissions refers back to the regulatory  requirements for  the PMA  
counterpart.  
   HUDs are subject to  the  quality system (QS) regulation under 21 CFR part 820, and HDE  
applications must include information in sufficient detail so that FDA can  make a  
knowledgeable judgment about the quality  control used in the manufacture of the 
device.30 Additional information on manufacturing information to include in an HDE  
application can be found in the FDA  guidance, Quality System Information for Certain  
Premarket Application Reviews31  If  you believe that  you cannot comply with or should 
not be subject to the QS regulation requirements, you may request an exemption or a  
                                                           
25  Section 520(m)(2)(B) of the FD&C  Act; 21 CFR 814.104(b)(2).  
26  See sections 514, 515, and 520(m) of the FD&C  Act.   
27  Under 21 CFR 807.92(a)(3),  a  legally marketed  (predicate)  device to  which a new device may be compared for a 
determination regarding substantial equivalence is a device that  was legally  marketed prior  to May 28, 1976  
(preamendments device), or a device which has been reclassified from  class III to class II or I, or a device  which has  
been found to be substantially  equivalent through the 510(k) process.   
28  21 CFR 814.118(a).  
29  See 21 CFR 814.106  (amendments); 814.108 (supplements); and 814.126 (reports).  
30  21 CFR 814.104(b)(4) and 814.20(b)(4)(v).  
31  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-system-
information-certain-premarket-application-reviews.  
 
6   Contains Nonbinding Recommendations  
variance from any device QS regulation requirement. Petitions for an exemption or  
variance must be submitted according to the procedures set forth in 21 CFR 10.30.32  
Key differences between the HDE and PMA programs include the following:  
   A HUD under  an  HDE  is  exempt from the requirement of establishing a  reasonable  
assurance of effectiveness that would otherwise be required under sections 514 and 515 
of the FD&C Act.    
   HDE  applications accepted for filing and to which the applicant does not submit a major  
amendment are reviewed in 75 days, rather than the traditional 180-day review timeframe  
for PMA  applications.33  
   HDE  applications  are not subject to user fees.  
   For a device  approved under an HDE application, medical device reports  (MDRs)  
submitted to FDA in  compliance with the requirements of 21 CFR part 803 shall also be  
submitted to the  IRB of  record.34  If an  appropriate local committee, instead of an IRB, 
approved the use of the device at  a  facility, FDA recommends that these  MDRs  be 
submitted to that committee. See Section VII  below for additional information regarding  
IRB requirements.  
   Use of HUDs  in the clinical care of patients  at a facility requires approval prior to use  by 
either an  IRB or an  appropriate local committee, with  the exception of emergency use.35  
See  Section  VII below for additional information regarding  IRB  and appropriate local  
committee  requirements.  
   An HDE holder  can only make a profit, up until the number of devices sold  within the  
calendar year  exceeds the ADN, if the device meets the eligibility criteria for the  
exemption to the profit prohibition in section 520(m)(6)(A)(i), subject to restrictions in 
section 520(m)(6) of the  FD&C Act. See Section  VIII.A below for  additional information 
regarding eligibility for profit.  
   The applicant must  include in the application a statement that no comparable device, 
other than another  HUD approved under  an  HDE or a device under  an  approved IDE, is  
available to treat or diagnose the disease or condition. The applicant must explain  in the  
HDE application why the device would not be  available for the indication in question 
without the HDE approval.36  
Applicants wishing to submit a modular HDE  for their HDE  application may use the  
procedures outlined in the FDA  guidance, Premarket Approval Application Modular Review.37  
A modular HDE, for purposes of this  guidance, is a compilation of sections or modules  
submitted at different times that together become a complete HDE application. HDE applicants  
                                                           
32  See 21 CFR 820.1(e).  
33  21 CFR 814.40 and 814.114.  
34  See 21 CFR 814.126(a).  
35  See section 520(m)(4) of the  FD&C  Act; 21 CFR 814.124(a).  
36  See section 520(m)(2)(B) of the FD&C  Act and 21 CFR 814.104(b)(2).  
37  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-approval-
application-modular-review.  
 
7   Contains Nonbinding Recommendations  
should include a copy of  or reference to FDAs HUD designation letter with each  HDE modular  
submission. Together, the modules  are expected to contain the information required for an HDE  
application. 
When submitting an HDE application, applicants  must  prepare an electronic copy of their  
submission per the FDA  guidance document, eCopy Program for Medical Device 
Submissions,38 and send the e-copy  and cover letter to the current address found on the  
following websites:  
(1)https://www.fda.gov/cdrhsubmissionaddress, for devices regulated by  CDRH; and  
(2)  https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/regulatory-
submissions-electronic-and-paper, for devices regulated by  CBER.  
A.   HDE  Application Required Elements and Filing  
Review Principles  
To use this guidance appropriately, HDE  applicants and FDA staff should review the following  
basic principles that  are in bold typeface and  followed by a description of FDAs review policies  
and procedures. These principles, and the objective criteria outlined in the Filing Checklist in 
Appendix A, inform FDAs  HDE  application filing decisions.  
FDA should determine whether the contents of the HDE  application allow the substantive  
review to proceed.  
The HDE regulations identify criteria that, if not met, may serve  as the basis for FDA  refusing to 
file an HDE  application.39  The HDE  application must contain the basic administrative and 
scientific elements listed  in 21 CFR 814.104(b), unless the applicant justifies an omission in  
accordance with 21 CFR 814.104(c). The specific  questions in the filing checklist are intended to 
help FDA  ensure that the HDE application contents are sufficiently organized and complete to 
allow  the review team  to proceed with a substantive review of the application.  
The FDAs  filing decision should not be based on a substantive review  of the data and 
information in the HDE application.  
The filing review is conducted by FDA  to ensure that the HDE application is sufficiently  
complete and to determine the basic adequacy of the technical elements of the HDE  application. 
Notably, in determining  whether an HDE application should be filed, the submitted information 
should not be evaluated to determine whether  the device will expose patients to an unreasonable 
risk of illness or injury or whether the probable benefit  to health from the use of the device  
                                                           
38  FDA has issued guidance to implement  section 1136 of FDASIA,  which added Section 745A(b) of the FD&C  Act  
(eCopy Program  for Medical Device Submissions, available at  https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/ecopy-program-medical-device-submissions).  
39  21 CFR 814.112(a).  
8   Contains Nonbinding Recommendations  
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.  
The checklist  included in Appendix A  is a tool to  help  ensure that the application contains the  
necessary information to conduct a substantive review. The elements in the checklist stem from 
either statutory or regulatory  requirements, and the format and content  are  consistent with the  
analogous checklists for other  types of  premarket submissions. FDA generally  should not refuse  
to file an HDE  application because we have reviewed the data and believe that the application is  
ultimately inadequate to meet the standard for HDE approval. Subsequently, the substantive  
review of the HDE  application will evaluate the quality of the  content and lead to a decision 
regarding whether  the  device will expose patients  to an unreasonable or significant risk of illness  
or injury  and whether the probable benefit of the  HUD  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. 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.  
FDA  should determine  whether the applicant provided a justification for any alternative  
approach. 
If the applicant believes  any  criteria in the checklist are not applicable,  the applicant should 
explain its rationale. Likewise, the applicant should provide a rationale for  any deviation from an 
applicable device-specific or cross-cutting  guidance document  and must explain any deviation 
from  FDA-recognized  consensus standard.40  FDA expects  that any item in the checklist that is  
missing from the application  will be addressed with a rationale explaining why  the item is not  
applicable and that  any deviations will be explained.  If a justification to omit certain information  
or for taking an alternative approach is provided, FDA will consider the adequacy of that  
justification or alternative approach during substantive review of the application. A given 
criterion in the checklist will be considered  Not  Present if the application  fails to include either  
the information requested or a rationale for omission.  
HDE  application  filing reviews. 
FDAs  decision to File or Not File an HDE  application  should be made in collaboration with 
the HDE review team  and  with  the appropriate supervisory oversight. FDA will notify the HDE  
applicant of the filing status within 30 calendar days from the date the HDE  application was  
received.41  Generally,  a small number of missing items from the filing checklist will not preclude  
a positive  filing decision; however, if multiple items are missing such that a substantive review  
cannot  be completed, a Not File decision will typically be made. FDA staff may use discretion  
to determine whether  missing items  are needed  for the application to be sufficiently  
administratively complete to permit substantive review  or to request  the  missing  information 
interactively during the filing or substantive review.  
                                                           
40  21 CFR 814.104(b)(4) and 21 CFR 814.20(b)(5).    
41  21 CFR 814.112(a).  
9   Contains Nonbinding Recommendations  
Additional considerations when using the filing checklist. 
Certain elements of the  HDE filing  checklist are  unique to the HDE  Program. These elements are 
discussed in additional detail below.  
HUD Designation  
HDE applicants  must include a copy of or reference to FDAs HUD designation letter with each  
HDE  application.42  
Amount charged for the  device  
As required by 21 CFR 814.104(b)(5), the  applicant  must state  the amount to be charged for the  
device, and if the amount is more than $250 a report  or attestation must be provided verifying  
that the amount charged does not exceed the costs of the devices research, development, 
fabrication, and distribution. A  report  must be prepared by an independent  certified public  
accountant, made in accordance with the Statement on Standards for Attestation established by  
the American  Institute of Certified Public Accountants. In lieu of such a report, an applicant  may 
submit an attestation by a responsible individual of the organization, verifying that the  amount  
charged does not exceed the costs of the devices research, development, fabrication, and 
distribution. If the amount charged is $250 or less, the requirement for a  report by an 
independent certified public accountant or  an attestation by a  responsible individual of the  
organization is waived. If an HDE applicant requests that FDA consider  whether the HUD meets  
the  eligibility criteria  to qualify  for profit making (see  Section  VIII.A.  regarding how to request  
to make a profit), the  applicant must still include this report or attestation in the HDE application.  
Comparable Devices  
As required by 21 CFR 814.104(b)(2), the  applicant must  provide a statement  that no other  
comparable device, other than another HUD  approved under an HDE or  a device under an 
approved IDE, is available to treat or diagnose the  disease or condition. A comparable device 
does not need to be identical to the device that is the subject of  the HDE application. However, in 
applying the comparable device exemption criterion, FDA takes into account that the purpose  
of the HDE Program is to encourage development of devices intended to treat or diagnose  
diseases or conditions that affect small patient populations. In determining whether a  comparable  
device exists, FDA may  consider:   
   the devices indications for use and technological  characteristics;   
   the patient population to be treated or diagnosed with the device; and  
   whether the device meets the needs of the identified patient population.  
FDA may  refuse to file an HDE application if  FDA determines that a comparable device is  
available (other than under another HDE or  a device under  an approved IDE) to treat or diagnose  
                                                           
42  21 CFR 814.104(b)(1).  
 
10   Contains Nonbinding Recommendations  
such disease or  condition for which the  approval of the HDE application is being sought.43  FDA 
cannot approve an HDE  application for a HUD if  we determine that such a comparable device is  
available.44   
B.   FDA Review  Actions  for an HDE  Application  
After an original HDE  application or HDE supplement  is accepted  for filing and  FDA begins its  
substantive review, the Agency may take the following actions  during the course of review:45  
   Approval order;  
   Approvable letter;  
   Major deficiency letter;  
   Not approvable letter; and 
   Denial order.  
The review timeframe for original HDE  applications and HDE supplements is 75 days.46  In  
addition, if the applicant  submits a major amendment, the review  timeframe may be extended up 
to 75 days.47 Certain changes to the manufacturing  procedure or changes in method of  
manufacture may qualify to be submitted as a 30-day notice.48 For more information regarding  
30-day notices, refer to the  FDA guidance,  30-Day  Notices, 135-Day Premarket Approval  
(PMA) Supplements and 75-Day Humanitarian Device Exemption (HDE) Supplements for  
Manufacturing Method or Process Changes.49  See Section  VII.C below for  additional details on 
HDE supplements.  
1.   Approval Order  
FDA will issue an approval order (letter) informing the  applicant that the  HDE application is 
approved and that the applicant may begin commercial distribution of the  device in accordance  
with any prescribed conditions of approval after we have  completed our review and determined  
that none of the reasons listed in 21 CFR 814.118 for denying approval applies.50    
When FDA issues an approval order, the FDA review clock stops. An approval order marks the  
end of FDAs review, as  it is a final action.  
                                                           
43  See 21 CFR 814.112(a)(2).  
44  See section 520(m)(2)(B) of the FD&C  Act.  
45  See 21 CFR 814.106,  814.116, and 814.118.   
46  See 21 CFR 814.108 and 814.114.  
47  21 CFR 814.106.  
48  See 21 CFR 814.108 and 814.39(f).  
49  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/30-day-notices-135-
day-premarket-approval-pma-supplements-and-75-day-humanitarian-device-exemption.  
50  See 21 CFR 814.116(b).  
 
11   Contains Nonbinding Recommendations  
2.   Approvable Letter  
FDA will issue an approvable letter  to inform the  applicant that we have completed our review of  
the application and determined that one or both of the following  are necessary:51  
   Resolution of minor deficiencies that are identified in the approvable  letter. These 
deficiencies  may include, for example, clarifications of previously submitted information, 
revisions to the labeling, and revisions to or development of a post-approval study  
protocol. 
   Completion of an FDA inspection that finds the manufacturing facilities, methods, and 
controls in compliance with the QS regulation, 21 CFR part 820, and, if applicable, 
verifies records pertinent to the HDE  application. When this is the case, the approvable  
letter states that the device is approvable pending  GMP inspection.  
When FDA issues an approvable letter pending resolution of minor deficiencies, we stop the  
FDA review  clock and place the  application on hold. When FDA receives  a complete response to 
an approvable letter  for an HDE  application, we consider it a major amendment and restart the 
clock with a new  75-day FDA response timeframe.   
When FDA issues an approvable  letter  pending GMP inspection letter, we  stop the FDA review  
clock. Once FDA determines that the GMP issues are resolved, we  will issue an approval order  if 
all other  minor  deficiencies that may have been noted in the approvable letter have also been  
resolved.  
3.   Major Deficiency Letter  
FDA will issue a major deficiency letter to  inform the applicant that the  HDE application lacks  
significant information necessary for  FDA to complete our review and request that  the applicant  
amend the application to provide the necessary information regarding the device,52  such as:  
   Additional clinical experience to demonstrate  probable benefit and/or  that the device  will 
not expose patients to an unreasonable or significant risk of illness or injury;  
   Additional non-clinical data to demonstrate probable benefit and/or that  the device  will 
not expose patients to an unreasonable or significant risk of illness or injury (e.g., 
electromagnetic compatibility,  electrical safety, biocompatibility,  reliability, software,  
labeling,  animal testing53);  
   Scientific rationale for test data provided in the application;  
   New validation data  and analyses (e.g., due to device modifications made during the  
course of the  HDE  application  review); or  
                                                           
51  See 21 CFR 814.116(c).  
52  See 21 CFR 814.106 and 21 CFR 814.37(b).  
53  We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing  when  feasible. We 
encourage applicants to consult  with us if it they  wish to use a non-animal testing method they  believe is suitable,  
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency  
to an animal test  method.  
12   Contains Nonbinding Recommendations  
  A re-analysis of previously submitted data (e.g., alternative  analytical method).
When FDA issues a major deficiency letter, we stop the FDA  review  clock  and place the 
application on hold. When FDA receives a complete response to a major deficiency letter,  we 
consider it a major amendment, restart the clock, and review the amendment  within 75 days.  
4.  Not Approvable  Letter 
FDA will issue a not approvable letter  to inform the applicant that we have completed our review  
and that we do not believe that the application can be approved as-is  because of significant  
deficiencies. The not approvable letter  will describe the deficiencies in the  application, including  
each applicable  ground for not approving and, where practical, will identify  measures required to 
place the application in an approvable form.54 
Generally, before FDA issues a not approvable letter, we will first issue a major deficiency letter  
to provide the applicant  with an opportunity to address concerns. However, if an applicant fails  
to provide an adequate response to a major deficiency letter, or if we have attempted to resolve 
all deficiencies via interactive review  and have not received  adequate responses, FDA  will issue 
a not approvable letter.  
When FDA issues a not approvable letter, we stop the review  clock and place the application on 
hold. If  FDA  receives a  complete response to a not approvable letter, the amendment  will be 
considered  a major amendment, and we restart the clock with  a new 75-day FDA response  
timeframe.55  
5.  Denial Order 
FDA may deny approval  of an HDE  application for any of the reasons identified in 21 CFR  
814.118(a). FDA will issue a denial order (letter)  when we need to inform  the applicant that we 
have denied approval of the  HDE  application. The denial order  will identify all deficiencies in  
the application, including each applicable  ground for  denial  and, where practical, will identify  
measures required to place the application in an  approvable form. The denial order will include  a 
notice of an opportunity to request review under section 515(d)(4) of the  FD&C  Act.56 
When FDA issues a denial order, we end  the FDA review clock if a prior action has not already  
done so. FDA  expects that a denial will normally  be preceded by  another  FDA action that stops  
the review  clock, such as a not approvable letter. However, the FD&C Act does not require  any 
prior FDA  action, and FDA may, in appropriate circumstances, proceed directly to issuing  a 
denial order. A denial order marks the  end of  FDAs  review, as  it is considered a  final action. 
                                                           
54  21 CFR 814.116(d).  
55  See 21 CFR 814.44(f)(1) and 814.116(d).   
56  21 CFR 814.118(b) and 814.45(b).  
 
13   Contains Nonbinding Recommendations  
6.  Acknowledgement of Voluntary  Withdrawal 
An applicant may, on its own initiative, withdraw an HDE  application  at any  time prior to  
approval, and for any  reason, by submitting an amendment informing  FDA  of its intent to 
remove the application from FDAs review.57  A voluntary  withdrawal action will stop the review  
clock on the receipt date  of the amendment.  
Under  FDA  regulations  for review  of  HDE applications, FDA also  considers an original  HDE  
application or HDE supplement to have been voluntarily withdrawn if an applicant fails to 
respond to a not filing letter,  an approvable  letter,  major deficiency  letter, or not approvable letter  
within  75 days  of issuance of the letter.58 However,  if before the end of that 75-day period, an 
HDE applicant  requests additional time to generate data or provide other information to address  
the issues identified in the FDA letter, FDA may  agree to allow  additional time, as appropriate. 
When additional time is requested, FDA generally would  allow  up to 360 days to provide  a 
complete response to the  FDA action letter. We  generally do not find it appropriate to agree to 
requests for  additional time beyond 360 days. FDA intends to notify the applicant with a letter  
acknowledging voluntary withdrawal of the  HDE  application  or HDE supplement.  Any 
amendment submitted in response to an  FDA  action letter after FDAs notification  
acknowledging voluntary withdrawal would be  considered a resubmission of the  HDE  
application. As such, it will be assigned a new  HDE number  and  will be subject to the  
requirements of 21 CFR 814.104.  
VI.  Assessing Probable Benefit  and Risk in an HDE 
Application 
As discussed above, a device that meets the criteria under section 520(m) of the FD&C Act is  
exempt from the effectiveness requirements of sections 514 and 515 of the FD&C Act.59 To 
approve an HDE application, section 520(m) of the FD&C Act requires that FDA find, among  
other things, that the device will not expose patients to an unreasonable or significant risk of  
illness or injury and the probable benefit to health from the 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 device[s] or alternative forms of treatment.60 To make the  required findings, FDA  
performs an assessment  of probable risks  and benefits for a device  as part  of its HDE application 
review.  
                                                           
57  21 CFR 814.116(e)(3).  
58  See 21 CFR 814.106  and 814.116(e)(1)-(2).  FDA considers a not filing letter communicating that an HDE  
application lacks  sufficient information for substantive review to be an FDA request to submit an amendment. 
59  See sections 514, 515, and 520(m) of the FD&C  Act; 21 CFR 814.118(a)(1).  
60  Section 520(m)(2)(C) of the  FD&C  Act.   
 
14   Contains Nonbinding Recommendations  
FDA  also assesses probable benefits and risks as  part of its review of PMAs and De Novo 
requests,61 and the Agency has previously presented a benefit-risk framework for benefit-risk  
determinations in the context of reviewing those  applications in the guidance document  Factors  
to Consider When Making  Benefit-Risk Determinations in Medical Device Premarket Approval  
and De Novo Classifications. FDA believes that the benefit-risk framework and factors used to 
assess PMAs or De Novo requests referenced above is  generally  appropriate for HDE  
applications. FDA therefore intends to consider the same factors described  in FDAs benefit-risk  
framework for  evaluating PMAs or De Novo requests when assessing probable benefits and risks  
for HDE  applications. 
However, given the different standards  and requirements that apply to approval of  an HDE  
application, the weighting of those  factors and the nature of  the evidence available regarding  
those factors  is likely to differ in the HDE context. Among other differences, the HDE pathway  
accepts greater uncertainty  premarket because a reasonable assurance of effectiveness is not  
required for a device  approved under  an HDE  application.62 Therefore, when compared to a  
PMA or De Novo request, both of which require  a demonstration of reasonable assurance of  
safety and  effectiveness,63  it is anticipated that there  will  generally  be greater uncertainty  
surrounding the benefit-risk profile based on the  evidence submitted in an HDE application.   
Moreover, as with the benefit-risk framework for  evaluating PMAs or De  Novo requests, FDA  
considers relevant factors as part of the probable benefit-risk assessment for an HDE application 
in the context of the intended use of  the device, including the target patient  population and the  
size of the population. For example, the smaller the patient population  for  which the device is  
intended, the greater the  uncertainty  FDA would  typically expect  in the review of an HDE  
application  because of the challenges of obtaining clinical data regarding the device. FDAs  
probable  benefit-risk  assessment also takes  into account currently available alternative treatments  
or diagnostics, including  their limitations.  When available, information characterizing patients  
tolerance for risk, tolerance for uncertainty,  and their perspectives on probable benefit may  
provide useful context during the probable benefit-risk  assessment. We encourage applicants to 
collect and submit patient preference  information  as available to assist in this assessment.  In  
addition, we encourage patient advocacy  groups  as well  as academicians and  other  groups to 
collect patient preference  information, which may  be  collected in conjunction with an applicant  
for purposes of  a future  HDE application. Refer to the FDA  guidance document, Patient 
Preference InformationVoluntary Submission, Review in Premarket Approval Applications, 
                                                           
61  See FDAs guidance, Factors to Consider When Making Benefit-Risk Determinations in Medical Device 
Premarket  Approval and De Novo Classifications,  (https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/factors-consider-when-making-benefit-risk-determinations-medical-device-premarket-
approval-and-de) for a discussion of how FDA benefit-risk assessments relate to the Agencys safety and  
effectiveness evaluation of a device in the context of reviewing PMAs and De Novo requests. 
62  Section 520(m)(2) of the FD&C  Act.  
63  To meet the statutory  standard for approval of a PMA, there must be a showing of reasonable assurance that the 
device is safe and effective. See section 515(d)  of the FD&C  Act.  The De Novo classification process is appropriate  
for devices that  would otherwise be subject to PMA but for which general controls or general and special controls  
provide a reasonable assurance of safety and effectiveness.  See section 513(f)(2) of the FD&C  Act.  
 
15   Contains Nonbinding Recommendations  
Humanitarian Device Exemption Applications, and De Novo Requests, and  Inclusion in 
Decision Summaries and Device Labeling.64 
The Agencys probable  benefit-risk framework provides for flexibility  and use of scientific  
judgment in assessing the totality of the  evidence  to determine if a specific  device meets the  
standard for  HDE application approval. This flexibility  allows 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. To do so, FDA  has  
developed tools to assist in assessing probable benefit and risk for an HDE application. Refer to  
the supplementary Considerations for the  Probable Benefit-Risk Assessment in Appendix B and 
the Probable Benefit-Risk Assessment  Summary in Appendix C. These tools are intended to 
reflect differences in  probable benefit-risk determinations for an HDE  application when 
compared to other types  of device marketing submissions. Note that the tools in this guidance  
also  present  questions to consider  regarding  the factors for the probable benefit-risk assessment.   
FDA has  also published guidance with respect to making benefit-risk determinations for  IDE  
applications.65 However, unlike an IDE, which permits a device to be shipped lawfully for the  
purpose of conducting  a clinical  investigation of the devices  safety and/or  effectiveness, an  
approved HDE  application is  a marketing  authorization. Accordingly, the two applications have  
different statutory  and regulatory standards and, as a general matter, earlier stages of device 
development and investigational study under  an IDE  are typically  associated with greater  
uncertainty than an HDE. Approval of  an IDE application to permit investigational use of a  
device  may be  appropriate where it  is unknown if  subjects are likely to  benefit from the  use of  
the device, if  the risks to the subjects are outweighed by the anticipated benefits to the subjects  
and the importance of the knowledge to be  gained,  and  the IDE application otherwise  satisfies  
the requirements of 21 CFR part 812.66  In contrast, approval of the  HDE  application, which 
authorizes  the marketing  of a device,  requires, among other things, a demonstration that there is  
probable benefit and that  the probable benefit 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.  
For HDE  applications, probable benefit is present  when there is  evidence for FDA to reasonably  
conclude that patients  are likely to  benefit from the use of the device. The probable benefit-risk  
decision support tools prompt  FDA review staff to consider probable  benefit in terms of:  
  Type  of benefit(s) 
  Magnitude  of benefit(s); 
  Probability  of the patient  experiencing one or more benefit(s); 
                                                           
64  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-preference-
information-voluntary-submission-review-premarket-approval-applications.  
65  See Factors to Consider When Making Benefit-Risk  Determinations for Medical Device Investigational Device 
Exemptions, (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-consider-when-
making-benefit-risk-determinations-medical-device-investigational-device).  
66  FDA  may disapprove or  withdraw approval of an IDE application if, among other reasons, [t]here is reason to 
believe that the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance 
of the  knowledge to be gained . . . .  21 CFR 812.30(b)(4).  
16   Contains Nonbinding Recommendations  
  Duration of effect(s);  
  Patient perspectives; and/or 
  Care-partner  (e.g., parent or aide)  perspectives.
In addition, the probable  benefit-risk decision support tools prompt  FDA review staff to consider  
risk in terms of:  
  Severity, types, number and rates of harmful events associated with use of the device; 
  Probability  of a harmful  event; 
  Duration of harmful events; 
  Risk from false-positive  or false-negative results for diagnostics;  and 
  Patient  perspectives; and/or 
  Care-partner  perspectives.
As with benefit-risk assessments for PMAs and De Novo requests, FDA  considers additional  
factors, including uncertainty  and available alternative treatments or diagnostics, as part of  
assessing whether probable benefits outweigh the  probable risks in the context of an HDE  
application. Sources of  evidentiary  uncertainty  could include, but are not limited to:   
  Sample size; 
  Duration of follow-up; 
  Use of a surrogate outcome;  and/or  
  Use of  non-clinical performance data such as animal testing or computer  modeling  rather 
than or in addition to a clinical or surrogate outcome.
The types of evidence that may be used to support approval of an HDE application  include  
investigations using laboratory animals, investigations involving human subjects, nonclinical  
investigations, and analytical studies for in vitro diagnostics.  FDA  recognizes that in some 
instances there may be little or no clinical experience with the device that is the subject of an  
HDE application. Depending upon the nature of  the device and its associated risks, FDA  may 
request  that clinical data be collected in support of an HDE  application.  However, it is also  
important to recognize that non-clinical data may  play  a critical role in  probable benefit-risk  
assessments in the context of HDE. Medical devices often have attributes  that cannot be tested  
by clinical methods alone and that play a major role in the performance, safety, or effectiveness  
of the device. In some cases, non-clinical testing (e.g.,  engineering performance studies,  animal 
studies, analytical testing,  or computer modeling and simulation) can obviate or reduce the need 
for clinical testing to evaluate certain aspects of device design or performance. Both  clinical and  
non-clinical testing methods may be used to assess  the probable  benefit (including consideration 
of its  likelihood, magnitude and duration), the probability or severity of a  given risk, and/or the  
success of  risk control measures, including risk mitigation measures. 
The document at Appendix B, Considerations for the  Probable Benefit-Risk Assessment,  is 
intended to complement the Probable  Benefit-Risk Assessment  Summary  at Appendix C. FDA 
staff should use the two tools  together  while  reviewing the HDE application. FDA staff  should 
also refer to this guidance to assist them in making their determinations.  HDE applicants may  
17   Contains Nonbinding Recommendations  
also consider these tools, but inclusion of these documents as part of  an application is not a  
requirement.   
VII. Post-Approval Requirements 
HDE  applications are subject to a number of post-approval requirements, as described  below. In  
addition to these requirements, a post-approval study (PAS) may be required and described in the  
approval order.67 The  guidance document, Procedures for Handling Post-Approval Studies  
Imposed by PMA Order, includes recommendations for PMA post-approval studies.68 
However, most of the information in this guidance document also applies to post-approval  
studies imposed for an approved HDE  application.  
A.  IRB  or  Appropriate Local Committee  Oversight and
Approval 
A HUD with an approved HDE  application is approved by FDA  for marketing. The  HDE holder  
is responsible for ensuring that a  HUD under an approved HDE is administered only in facilities  
having  IRB oversight in accordance with the Agencys regulation governing  IRBs.69  In addition,  
approval  by an  IRB or  an appropriate local committee is required before a HUD  under an 
approved HDE  can be used at a facility  for clinical  care, with the  exception of emergency use.70 
See Section  VIII.G., Emergency  Use of  HUDs. Note that we do not interpret the statute to 
require an  IRB or appropriate local committee to review and approve  each individual use of a  
HUD, and the IRB  may  grant a generalized approval to use the HUD  at  a facility. In such 
circumstances,  FDA does not require  the facility,  HDE holder, or practitioner to  seek approval  
from the  IRB or appropriate local committee  for each use, provided the use of the HUD is within 
the  terms of the  generalized approval.  
FDA interprets the statutory term appropriate local committee to mean a  standing committee  
for the facility that has  expertise and experience in reviewing and making treatment decisions for  
clinical care, particularly  in applying innovative medical device technologies to clinical care.  As  
such, a standing committee for the facility that includes physicians  with experience in the  
treatment of rare diseases or conditions would be considered an appropriate  local committee by  
the Agency. Depending on the facility  and the charters of its committees, examples of an  
appropriate local committee may include a  peer review committee, a credentialing committee, or  
a Quality Care Committee. We recommend that the committee include  a senior executive level  
medical staff or faculty  member (e.g.,  the Chief  Medical  Officer, Physician-in-Chief, Surgeon-
in-Chief, Department Chair). In addition, FDA interprets the term appropriate to mean that  
members of the appropriate local committee are free of financial and other  conflicts of interest in  
decisions pertaining to the use of  the HUD in clinical care or they recuse themselves from such  
                                                           
67  21 CFR 814.126(a) and 814.82(a)(2).   
68  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/procedures-handling-
post-approval-studies-imposed-pma-order.  
69  See section 520(m)(4)(A) of the FD&C  Act. FDA regulations  governing IRBs are in 21 CFR part 56.  
70  See section 520(m)(4)(B) of the FD&C  Act and 21 CFR 814.124(a).  
18   Contains Nonbinding Recommendations  
decisions in which they have a conflict of interest. Merely because a facility has a standing  
committee does not mean the committee is appropriate to review use of  a  HUD in clinical care.  
The HDE holder is not required to submit the names and addresses of the  reviewing  IRBs  or 
appropriate local committees  to FDA. However, as required in 21 CFR 814.126(b)(2), the  HDE  
holder must maintain records of:   
   The names and  addresses of the facilities to which the HUD was  shipped (which FDA 
interprets to mean information for facilities to which the HUD was shipped to treat or  
diagnose patients  within the U.S.);  
   Correspondence with reviewing  IRBs; and  
   Any other information requested by a reviewing  IRB or FDA.   
FDA recommends that HDE holders likewise maintain correspondence  with reviewing  
appropriate local committees as well as other information that such committees may require.  
Additional information regarding the role of  IRBs and  appropriate local  committees with respect  
to HUDs  is available in Section  VIII.E, below.  
B.   Adverse Event Reporting  
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 are  required to submit medical device reports to FDA and to the  IRB of record (i.e., 
the  IRB that oversees use of  the HUD  at the facility  where the adverse event occurred) after  
HDE approval.71  In the event that an appropriate local committee approved the use of the HUD  
for routine clinical care at that facility, instead of an IRB, we recommend that manufacturers  
submit MDRs to that committee.  
Accordingly, manufacturers must submit  MDRs to FDA and the  IRB  of record (with submission 
to  the appropriate local committee that approved the use of the HUD  recommended, if 
applicable)  when  they become aware of information reasonably suggesting that  a HUD may have 
caused or  contributed to a death or serious injury, or has malfunctioned and would be likely to 
cause or  contribute to a death or serious injury if the malfunction were to recur.72  
User facilities must submit MDRs to FDA, the  IRB of record (with submission to the appropriate  
local committee that approved the use of the  HUD  recommended, if applicable), and, if known, 
the manufacturer  when they become  aware of information reasonably suggesting that  a HUD 
may have caused  or  contributed to the  death  of a patient, and must submit reports to the  
manufacturer (or to FDA and the  IRB of record if  the manufacturer is unknown) when they 
become aware of information reasonably suggesting that a  HUD may have  caused or  contributed 
                                                           
71  See section 519(a) and (b) of the FD&C  Act; 21 CFR 803.30, 803.50, and 814.126(a). See 21 CFR 803.3(d) for  
the definition of a device user  facility.  
72  See 21 CFR 803.50  and 814.126(a).  
 
19   Contains Nonbinding Recommendations  
to a serious injury to a patient  of the facility.73 As defined by 21 CFR 803.3(w), a serious injury  
means an injury or illness that:  
  Is life-threatening;  
  Results in permanent impairment of a body function or permanent damage  to a body 
structure;  or  
  Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.  
Adverse events  for  HUDs that are approved and labeled for pediatric patients or in a pediatric  
subpopulation, as described in section 520(m)(6)(A)(i)(I) of the  FD&C Act, and exempt from the 
profit prohibition will be reviewed periodically by  FDAs Pediatric Advisory  Committee  
(PAC).74 Additional information on upcoming PAC meetings  is available on the FDA website.75  
If the HUD is being investigated in a clinical study  under an  IDE, adverse events that occur  
during the study should be reported in accordance  with  21 CFR 812.150(a)(1) and 812.150(b)(1).  
C.  HDE  Supplements 
After  FDA approval of  an original HDE  application, an applicant shall submit an HDE  
supplement for review and approval by  FDA before making  a change  affecting the  safety  or 
probable benefit of the device.76  
If you wish to request new indications for use for  a device  under an  HDE (e.g., for a different  
disease or condition)  you must obtain a new HUD  designation and submit a  new original HDE  
application in compliance with 21 CFR 814.110. If  you are submitting  a new original  HDE  
application, please  contact OOPD to discuss obtaining a new HUD designation. In the new HDE  
application, any relevant  information or data submitted in the HDE application for the original  
indication may be incorporated by reference.  
D.  HDE  Periodic Reports 
You must submit periodic  reports for HDEs  in accordance  with the approval order under  21 CFR  
814.126(b). HDE  periodic  reports  must include the following information  unless FDA specifies 
otherwise:  
  An update of the information required under 21 CFR 814.102(a)  to demonstrate that the 
HUD designation is still valid.77 An updated annual  incidence reassessment  (AIR)  based 
on updated numbers to show that the target population for the disease or condition for 
which the device has been designated is not more  than 8,000 per  year provides this 
information. The AIR refers to the HUD designated population, which in some cases may 
                                                           
73  21 CFR 803.30  and 814.126(a).  
74  Section 520(m)(7) of the FD&C  Act.  
75  https://www.fda.gov/advisory-committees/committees-and-meeting-materials/pediatric-advisory-committee  
76  21 CFR 814.108 and 814.39.  
77  See 21 CFR 814.126(b)(1)(i).  
20   Contains Nonbinding Recommendations  
be larger than the approved indication under the HDE (i.e., if the HDE approval covers  
only a  certain indication within the designated disease or  condition). In reviewing this  
information, the reviewing center, CDRH or CBER, may refer the AIR to  OOPD for 
further evaluation if necessary.  
   An update to the explanation of why the device would not be available unless an HDE  
were granted, a statement that no other comparable device (other than another HUD 
under an HDE  or a device under an approved IDE) is  available  to treat or diagnose the  
disease or condition, and an updated discussion of  the risks and benefits of currently  
available devices or alternative forms of treatment in the United States.78  Information on 
HDE approvals can be found on the publicly accessible search engine on the FDA 
website.79  
   An update to the explanation of why the probable  benefits  to health from the 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.80  
   An update to the amount  to be charged for the device and, if over $250, a report by an 
independent certified public accountant  or  an attestation by a responsible individual of  
the organization verifying that the  amount charged does not exceed the costs of the  
devices research, development, fabrication, and distribution.81  
   The number of devices that have been shipped or sold since initial marketing approval  
and, if the number shipped or sold exceeds 8,000, an explanation and estimate of the  
number of devices used per patient.82  FDA interprets this regulation to require HDE  
holders to report the total number of HUDs shipped or sold per year pursuant to the  
approved HDE application in the U.S., no matter how the HUDs are used (whether for  
the approved indication(s), emergency use, or otherwise). However,  for devices that have 
both an HDE application approval and a PMA approval for a different indication, you 
need  report only the number of devices that are shipped or sold pursuant to the HDE  
unless specifically required otherwise by the PMA Approval Order.  
   Information describing the clinical experience with the  approved device,  including  safety 
information that is known or reasonably should be known to the applicant, and any  
medical device  report made under 21 CFR  part  803.83  
   A summary of any  changes made to the device in accordance with supplements submitted 
under 21 CFR 814.108.84  
                                                           
78  See 21 CFR 814.126(b)(1)(ii) and  814.104(b)(2).  
79  https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/hde.cfm   
80  See 21 CFR 814.126(b)(1)(ii) and 814.104(b)(3).  
81  See 21  CFR 814.126(b)(1)(ii) and 814.104(b)(5).  
82  See 21 CFR 814.126(b)(1)(iii).  
83  See 21 CFR 814.126(b)(1)(iv).  
84  See 21 CFR 814.126(b)(1)(v).  
 
21   Contains Nonbinding Recommendations  
E.  HUD Designation  Re-Evaluation  and/or HDE
Withdrawal 
If, based on information contained in the HDE  periodic reports, FDA is concerned  that the HUD 
designation may no longer apply to your device, we may contact  you for  additional information, 
re-evaluate  and possibly  revoke  your  HUD designation, and/or  withdraw HDE approval.85  
If we make the determination that more than 8,000 individuals in the United States  are affected  
by or manifest a certain disease or condition per  year, we may  consider  whether  your HUD  
designation should be revoked in accordance with 21 CFR 814.102(c) and  your  HDE withdrawn 
in accordance with 21 CFR 814.118. In making this determination, we intend to consider factors  
such as the number of patients with the disease or  condition and the public health need for the  
device. The investigational use of a HUD outside  of the HUD designation would not count  
toward the limit of 8,000 individuals per  year. Per section 520(m)(5) of the  FD&C Act, FDA 
may suspend or withdraw an HDE only after providing notice and an opportunity for  an informal  
hearing. We intend to discuss the regulatory options with the HDE holder  before revoking a 
HUD designation.  
If  FDA subsequently approves  a PMA  or grants  a De Novo request  for the  HUD or another  
comparable device with the same indication(s), we may withdraw the HDE  because the HUD  
would no longer meet the requirements of section 520(m)(2)(B) of the FD&C Act.86 
VIII.  Special  Considerations for Devices  Marketed Under an
HDE 
A.  Eligibility  for Profit 
Except in certain circumstances, 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).87  If  a HUD is studied in a clinical investigation for a new indication, the sponsor of the  
clinical investigation cannot charge subjects or investigators  a price higher than necessary to  
recover the costs of manufacture, research, development, and handling.88  Any costs for which a 
subject in a clinical investigation is responsible must, when appropriate, be provided in the  
informed consent document.89 
Under section 520(m)(6)(A)(i) of the FD&C Act, as amended by  FDASIA, a HUD under an 
HDE is only eligible to be sold for profit if the device meets the following  criteria (i.e., the  
eligibility criteria):  
                                                           
85  See 21 CFR 814.102(c),  814.118(a)(9), and 814.126(b)(1).   
86  See 21 CFR 814.118(a).  
87  Section 520(m)(3) of the FD&C  Act.  
88  See 21 CFR 812.7(b).  
89  21 CFR 50.25(b)(3).  
22   Contains Nonbinding Recommendations  
  The device is intended for the treatment or diagnosis of a disease or  condition that occurs 
in pediatric patients or in a pediatric subpopulation, and such device is labeled for use in
pediatric patients or in a  pediatric subpopulation in which the disease or condition occurs; 
or 
  The device is intended for the treatment or diagnosis of a disease or  condition that does 
not occur in pediatric patients or that occurs in pediatric patients in such numbers that the 
development of the device for such patients is impossible, highly impracticable, or 
unsafe. 
If a device under an HDE  does not meet either of the eligibility criteria, the device  cannot be sold  
for profit. FDA reviews the financial information in the HDE holders initial application and  
periodically thereafter. When approving the use  of a HUD  for treatment or diagnosis of patients  
in clinical care, the IRB  or appropriate local committee is not required to review a justification  
for the amount charged for the  HUD.  For the purposes of this guidance, the descriptions below  
are intended to provide additional clarity regarding each component of the  eligibility criteria.  
Occurs  in pediatric patients or in a  pediatric subpopulation  This would be a disease  
or condition that can  occur in patients who are  younger than 22 years of  age. 
Does not occur in pediatric patients   This would be a disease or condition that occurs  
only in patients who are  22 years of  age or older. An example of a disease that does not  
occur in pediatric patients is Alzheimers disease.  
Impossible or highly impracticable  When determining whether the development of a  
HUD in pediatric patients is impossible or highly impracticable,  FDA considers  
information provided by  the applicant to FDA, including publicly-available information 
such as published literature, which demonstrates that the sponsor would not be able to 
conduct the necessary  clinical investigation(s) in the pediatric population for the device.  
For example, FDA may  determine that the development of a particular device is  
impossible or highly impracticable in pediatric patients if  the device is intended to 
treat a disease or  condition that has a pediatric annual incidence that is so small, or if the  
prevalence of the pediatric patients living with the  disease is  so small, or if the pediatric  
population is so geographically dispersed to prevent sufficient patient recruitment in the  
pediatric population for  a clinical investigation.  Because of the speed  and efficiency of  
modern communications  tools, geographic dispersion will  typically  justify a  
determination that development is impossible or highly impracticable  only in 
extraordinary circumstances and will  generally have to be coupled with very  small  
population size. FDA does not consider economic factors (such as the  costs associated 
with conducting  a clinical investigation) as a basis for being impossible or highly  
impracticable.  
Unsafe  FDA may determine that the  development  of a HUD in pediatric  patients is  
unsafe if the applicant  has provided information, including publicly-available 
information such as published literature, to FDA that demonstrates that the  device would 
expose pediatric patients  to an unreasonable or significant risk of illness or  injury. If FDA  
determines that the HUD is eligible to be sold for  profit because development of the  
23   Contains Nonbinding Recommendations  
device in pediatric patients would be unsafe, the labeling (e.g., warnings or  
contraindications) for the device should reflect the safety concern.  
An  HDE applicant whose device meets  one of the eligibility criteria and  who wishes  to sell its  
HUD for profit should provide adequate supporting documentation to FDA  in its original HDE  
application to demonstrate to FDA that the HUD meets  the  eligibility criteria. An HDE holder  
whose HDE  application was approved prior to the enactment of  FDASIA on July 9, 2012, and  
who wishes  to sell its HUD for profit should provide adequate supporting documentation to FDA  
in an HDE supplement  to demonstrate to FDA that the HUD meets the  eligibility  criteria. If FDA 
determines that the HUD meets the eligibility  criteria, FDA will then determine the ADN for the 
HUD when  FDA approves the HDE application or supplement.90  
B.   The  Annual Distribution Number (ADN)  
Under section 520(m)(6)  of the FD&C Act, if  FDA makes a determination that a HUD meets the  
eligibility criteria,  in any  given calendar  year, a  HUD can be sold for a profit up until the number  
of devices sold exceeds the annual distribution number (ADN).  
The ADN is determined  by  FDA:  
   When the Agency approves the original HDE application; or  
   When the Agency approves an HDE supplement for an HDE application approved before  
the enactment of  FDASIA on July 9, 2012, if the  HDE holder seeks a determination for  
the HUD in an HDE supplement based upon the profit-making eligibility criteria,  and  
FDA determines that the  HUD meets the  eligibility  criteria.91   
Under section 520(m)(6)(A)(ii) of the  FD&C Act, the ADN is defined, with  respect to a device 
under an HDE, as the number of devices reasonably needed to treat, diagnose, or cure a  
population of 8,000 individuals in the United States. The applicant should provide the number  
of devices per  year reasonably needed for each individual in the HDE application or HDE  
supplement and provide  adequate documentation to support such number in order to provide  a  
basis for FDA to calculate the ADN.  
When determining the ADN, FDA considers the number of devices per  year reasonably needed 
to treat, diagnose, or  cure an individual (first multiplier) and multiplies that value by  8,000 
(second multiplier). By law, the second multiplier is always  8,000. Therefore, the ADN will be 
equal to or  greater than 8,000, depending on the value of the first multiplier. For  example, the 
target population estimate for the intended use may  be 3,000 individuals, but if 2 devices are  
reasonably needed per  year to treat, diagnose or cure a patient, the ADN would be 16,000 (i.e., 2 
multiplied by  8,000 because the second multiplier for the ADN is  always 8,000, regardless of the 
actual population estimate).  After FDA has determined the ADN, an HDE holder may submit an 
                                                           
90  See section 613(b) of FDASIA and Section VIII.B.  for more discussion on the  ADN.  
91  See section 520(m)(6)(A)(ii)  of the FD&C  Act and section  613(b) of FDASIA.  
 
24   Contains Nonbinding Recommendations  
HDE supplement requesting that FDA modify the  ADN based upon additional information, and 
FDA may modify the number.92  
As required under 21 CFR 814.126(b)(1)(iii), the  HDE applicant is responsible for monitoring  
how many devices  are shipped or sold in the U.S. each year,  and if that number exceeds 8,000, to 
provide an explanation and estimate to FDA of how the device is being used by patients. 
Similarly, the  HDE holder is responsible for monitoring when the number of devices shipped or  
sold in a year exceeds the ADN, when  the HUDs are approved by  FDA to  make a profit.93  An  
IRB or appropriate local  committee is not responsible for monitoring the number of uses per  year  
of the HUD.  
If the HDE holder ships multiple sizes of a device to help ensure that one of the devices is the 
appropriate size for the patient(s) when used, it would not be necessary to count all of these  
devices toward the ADN  tally if the additional sizes of the devices  (that did not properly fit the  
patient(s)) are returned to the HDE holder. Unused devices should be returned to the HDE holder  
to appropriately account  for them. The HDE holder should document in its periodic report how  
many devices are returned to the HDE holder if multiple sizes are shipped. Additionally, HDE  
holders should keep in mind that if they distribute  devices in excess of the  ADN, they will not be  
able to make a profit on those devices.  
HDE holders assigned an ADN must immediately  notify the Agency if the  number of devices  
distributed in a  calendar  year exceeds the ADN.94 HDE holders  should make this  immediate  
notification to the Agency  by submitting an HDE  report whenever the number of HUDs shipped 
or sold in a  calendar  year, however the HUD is used, exceeds the ADN.  The statutory  
notification requirement is generally consistent with the reporting requirement in 21 CFR  
814.126(b)(1)(iii)  concerning the number of devices shipped or sold regardless of their ultimate  
use (even if outside their  approved indications). However, the statutory provision requires  
immediate notification when the number shipped or sold in a  calendar  year exceeds the ADN,  
whereas the current  HDE  regulations require periodic reports on a timeframe specified in the  
HDE approval order.  
Once this notification occurs, or once FDA discovers through an inspection that 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), and the amount charged for the device must not exceed the cost of research and 
development, fabrication, and distribution of the device.95   
In those cases in which a device is approved  for a certain  indication  under an HDE application 
and is approved under a  PMA or has a De  Novo request granted for a different indication, sales  
or shipments of the device pursuant to the PMA or  the De Novo request are  not subject to the  
ADN reporting  requirement. The ADN  relates only  to those devices that are marketed  under an  
HDE. Therefore, the manufacturer is required to notify  FDA only when sales or shipments  
                                                           
92  See section 520(m)(6)(C) of the FD&C  Act.  
93  See section 520(m)(6)(A)(iii) of the FD&C  Act.  
94  See section 520(m)(6)(A)(iii) of the FD&C  Act.  
95  See section 520(m)(6)(D) of the FD&C  Act.  
25   Contains Nonbinding Recommendations  
pursuant to the HDE  exceed the ADN. If  a  manufacturer  must report the number of sales or  
shipments of  a device approved for  certain indications under  a PMA, the manufacturer  would be   
responsible for  separately  reporting  sales or shipments of devices  marketed for different  
indications under an HDE per 21 CFR 814.126(b)(1)(iii).  
C.   Information  to Patients   
Neither the  FD&C Act nor FDA  regulations require informed consent from patients who are  
treated or diagnosed with an HDE-approved  HUD  in the course of their clinical care. An IRB or  
appropriate local committee may, however, choose to require that patients receive certain  
information about the HUD when the  committee approves use of the HUD  for clinical care at a 
facility.  If a  committee requires that patients receive a written document prior to use of the HUD  
in clinical care, the document should include much of the information found in the HDE  patient 
labeling. If no patient information packet is available, the HDE holder may consider including  
the following in any written information provided to patients: an explanation that the HUD is  
designed to diagnose or treat the disease or  condition described in the HDE  labeling  and that no 
comparable device is available to treat the disease or condition; a description of any ancillary  
procedures associated with  the use of the HUD;  a  description of the use of the HUD; all known 
risks or discomforts; and an explanation of the postulated mechanism of action of the HUD in 
relation to the disease or  condition. The  IRB or  appropriate local  committee may decide to   
require inclusion of this  or other information explicitly as part of a  written document provided to 
patients.  
The labeling for  a HUD  approved under an HDE, including any labeling provided to patients, 
must be truthful and non-misleading.96  The device labeling  must also include the following  
statement clarifying that effectiveness has not been demonstrated: 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.97 Additional  
labeling requirements appear under 21 CFR 814.20(b)(10).  
D.   HDEs and Pediatric Patients  
As discussed above, under section 520(m)(6)(A)(i)(I) of the FD&C Act, a  HUD is eligible to be  
sold for profit if, among  other things, the device is intended for the treatment or diagnosis of a  
disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and such 
device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease  
or condition occurs.  This provision permits  HDE holders to receive  a profit from the sale of 
HUDs that are indicated  and labeled for pediatric  use, subject to the limit of the ADN.  
HUDs  marketed  under  an HDE may be  indicated and labeled for pediatric  use only or  for use in 
both pediatric and adult patients. Devices that  are intended to treat both a pediatric population 
and an adult population may be included in a single HDE application, but the indications for use  
should specify use in pediatric patients, or pediatric subpopulation(s), as well as use in adults. In  
                                                           
96  See section 502(a) of the FD&C  Act, 21 U.S.C. 352(a).  
97  21 CFR 814.104(b)(4)(ii).  
26   Contains Nonbinding Recommendations  
some cases, the probable benefit-risk profile for devices intended for use in a pediatric  
population, or in a pediatric subpopulation, may differ  from its profile when intended for use in 
an adult population. Therefore,  we recommend that HDE applications for devices intended for  
use in pediatric populations and in 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. For more information about  
extrapolating data,  refer to the FDA  guidance,  Leveraging Existing Clinical Data for  
Extrapolation to Pediatric Uses of Medical Devices.98  
As defined in section 520(m)(6)(E)(i) of the FD&C Act, pediatric patients  for purposes of  
section 520(m) of the  FD&C Act are 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.99 As defined by section 
520(m)(6)(E)(ii) of the FD&C Act,  pediatric subpopulation means one of the following  
populations: neonates, infants, children, or  adolescents. Additional information about the  
definition of pediatric patients and pediatric use as it relates to medical devices can be found in  
the FDA  guidance, Premarket Assessment of Pediatric Medical Devices.100  
HUDs that are approved and labeled for pediatric  patients or in a pediatric  subpopulation as  
described  in section 520(m)(6)(A)(i)(I) of the  FD&C Act  are required, under section 520(m)(8)  
of the FD&C Act, to be reviewed annually  by FDAs PAC.101  The PAC annually  reviews these 
HUDs to ensure that the HDE remains  appropriate for the pediatric populations for which it was  
approved. The PAC also conducts periodic review of adverse events  for these devices when they  
are exempt from the profit prohibition.102  
E.   Review and Approval  of the Use  of HUDs in Clinical 
Care  
As summarized above, an IRB or appropriate local committee must approve the use of  a HUD  at  
a given facility before it can be used  at that facility.103  Therefore, a  healthcare professional  
wishing to use an HDE-approved HUD to treat or  diagnose  a patient at  a facility should obtain 
approval  from  the facilitys  IRB or  the appropriate local  committee before  use of the HUD, 
except in certain emergencies where prior  approval is not required. See Section VIII.G., 
Emergency  Use of  HUDs.  In reviewing the use of the HUD  in clinical care, the  IRB or  
appropriate local  committee should be cognizant that FDA has made  a determination that the  
                                                           
98  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/leveraging-existing-
clinical-data-extrapolation-pediatric-uses-medical-devices.  
99  See also 21 CFR 814.3(s). 
100  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-assessment-
pediatric-medical-devices.  
101  For more information on the  PAC, see https://www.fda.gov/advisory-committees/committees-and-meeting-
materials/pediatric-advisory-committee.  
102  See section 520(m)(7) of the  FD&C  Act.   
103  See section 520(m)(4)(B) of the FD&C  Act.   
 
27   Contains Nonbinding Recommendations  
probable benefits to health outweigh the probable  risks for use of the  HUD  only within its  
approved indication(s). The HDE holder is responsible for ensuring that the HUD is administered  
in facilities that have oversight by an IRB constituted and functioning in accordance with 21 
CFR part 56.104  Note that an IRBs or  appropriate local committees approval for the use of  a  
HUD at a facility to treat  or diagnose patients in the course of providing clinical care does not  
mean that there has been IRB approval of a  clinical investigation involving  the HUD.  
The IRB or appropriate local  committee is not required to review  and approve each individual  
use of a HUD, nor is it required to audit medical records of patients who receive a HUD. Rather,  
the IRB or  appropriate local committee may use its discretion to determine  how to approve use  
of a HUD, including  consideration of professionals qualifications through training and expertise  
to use the  device.105 For example, with the input of members with the appropriate expertise in the  
clinical area, an IRB or  appropriate local  committee may specify limitations on the use of the  
device based upon one or more measures of disease progression, prior use and failure of  any  
alternative treatment modalities, reporting  requirements to the committee or committee  
chairperson, appropriate  follow-up precautions and evaluations, or other  criteria the committee  
determines to be appropriate. 
1.   Process  and Considerations  for  Reviewing the 
Use of HUDs in Clinical Care  
For initial review of a HUD,  the IRB or appropriate local  committee should perform its  review at  
a convened meeting of the committee.106 The  IRB or appropriate local committee should have  
policies and procedures in place for the receipt and evaluation of the materials necessary for  
initial approval and continuing review of the  HUDs use at that facility. The policies and 
procedures should also specify  whether the committee requires  a consent document for the use  of 
the HUD at that facility.  
FDA recommends that  the  IRB or  appropriate local  committee follow the review criteria in 21  
CFR 56.111 and elsewhere in part 56, where applicable. For example, the  IRB or appropriate  
local  committee should review the risks to  patients that are found in the HDE-approved product  
labeling,  ensure the risks are minimized, and evaluate whether the risks are reasonable in relation  
to the proposed use of the device  at the facility. FDA also recommends that the  IRB or  
appropriate local  committee review the following  materials, as applicable,  during initial review  
of a request to use a HUD:  
   A copy of the HDE approval order;  
   A description of the device;  
   The product labeling;  
                                                           
104  See section 520(m)(4)(A) of the FD&C  Act and 21 CFR 814.124(a).  
105  For many  HDE-approved HUDs, the HDE  holder is required to provide training on the use of the device prior to 
the healthcare professional  using the device. Such requirements  would be specified in the HDE application approval  
order.  See  21 CFR 814.126(a) and 814.82(a). 
106  See 21 CFR 56.108,  which describes a convened meeting of an IRB for purposes of reviewing FDA-regulated  
clinical investigations.  
28   Contains Nonbinding Recommendations  
   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  
appropriate local  committee or  by facility policy; and  
   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.  
A list of approved HDE  applications may be found at  https://www.fda.gov/medical-
devices/device-approvals-denials-and-clearances/hde-approvals. The approval order, labeling, 
and patient information may be found by selecting the submission number of the appropriate  
HDE application.  
FDA does not require submission of a protocol to the  IRB or  appropriate local  committee for  
review when the committee is evaluating a request to use the HUD in the clinical care of patients  
at a facility. However, the IRB, appropriate local  committee, or institution may require one under  
its own policies and procedures.  
In addition, FDA does not require committees other than the IRB or appropriate local  committee  
to approve the use of a HUD. However, the institution may require additional review. For  
example, the use of another committee to provide assessments of specific risks posed by the  
technology or software compatibility may supplement the  IRB or  appropriate local  committee  
review.  
If a physician wants to use a HUD outside its approved indication(s), FDA  recommends that the  
physician follow the  IRB or appropriate local committees requirements for use of a HUD at that  
facility, which may include separate approval requirements for use outside the approved 
indication(s). The  IRB or appropriate local committee may also require that the physician obtain 
informed consent107  from the patient and ensure that reasonable patient protection measures are 
followed, such as devising schedules to monitor the patient, taking into consideration the  
patients specific needs, and the limited information available about the  risks and probable  
benefits of the device. The extent of oversight in these circumstances is up to the  IRB or  
appropriate local committee. As discussed above, MDRs must be submitted to FDA and to the  
IRB of record  if the device may have caused or  contributed to death or serious injury and for  
certain malfunctions. If an appropriate local committee approved the use  of the HUD  at the  
facility, FDA  recommends that MDRs be submitted to that committee.  
2.   Continuing Review of the  Use of  HUDs in 
Clinical Care  
Under  FDAs  current regulations, an  IRB that reviews a request to use a HUD at a facility is  
responsible for initial as  well as continuing  review of  the HUD.108  When an appropriate local  
committee conducts such an initial review instead  of an  IRB, that appropriate local committee  
                                                           
107  As  noted above, informed consent required by a facility in the context of clinical care does not refer to  
informed consent subject to the requirements in FDAs regulations at 21 CFR part 50. 
108  21 CFR 814.124(a).  
29   Contains Nonbinding Recommendations  
should also conduct continuing review of the  HUD. For continuing review, an  IRB  may use an  
expedited review procedure in which a chairperson or one or more experienced reviewers carries  
out the review, similar to the expedited review procedure described at 21 CFR 56.110(b). When 
an IRB conducts the initial review, a facility  may decide to  utilize an appropriate local committee  
to conduct continuing review of the use of the HUD in clinical care.  
Appropriate local committees may develop their own policies and procedures for continuing  
review of  a HUD  and should determine what type of review  procedure is appropriate for each 
HUD. An expedited procedure, such as that  described under 21 CFR 56.110, may be appropriate  
for continuing  review  because a HUD marketed under an HDE is a legally  marketed device, and  
its use in clinical care does not constitute research.  An expedited review  does not mean a less-
than-substantive review. The individual(s) conducting an expedited review  for use of  a HUD  at a 
facility should thoughtfully consider the risk and benefit information available and any MDRs.  
In addition, FDA does not require that the  IRB or  appropriate local committee  serve as a Data 
Monitoring Committee. The  IRB or appropriate local committee may, however, ask the HDE  
holder for copies of the  safety  information submitted to FDA in the periodic reports required by  
21 CFR 814.126(b)(1). In this way, information that could have  a bearing  on human safety  
would be considered at the time of continuing  review.  
When an IRB  or  appropriate local committee is deciding whether to approve the use of  a HUD  
for clinical care of patients at a facility,  it does not make  a Significant Risk/Non-Significant Risk  
(SR/NSR) determination. As  noted above, use of a legally marketed HUD  within its HDE-
approved indication at a facility to treat or diagnose patients is not a clinical investigation  of a 
device under 21 CFR part 812. 
F.   Review and  Approval for  Clinical  Testing  of HUDs  
A clinical investigation of a HUD that requires submission of an IDE application to FDA or is  
conducted under the  abbreviated requirements for  NSR devices at 21 CFR  812.2(b) must be  
approved and supervised by an IRB.109  Data may be  collected in a clinical investigation  for the 
HDE-approved indication(s)  without an IDE. An approved IDE permits  a device to be shipped 
lawfully  for the purposes of conducting investigations of the device  without complying with 
certain other requirements of the FD&C Act that  would apply to devices in commercial  
distribution.110 As long  as the HUD is being studied for the indication(s) in its approved labeling, 
the HUD is not subject to  IDE requirements because the HUD is a legally  marketed device and  
therefore can be lawfully shipped without an IDE. However,  regardless of the applicability of the  
IDE regulation at 21 CFR part 812, other FDA regulatory  requirements may  still apply,  including  
                                                           
109  See 21 CFR 56.103, 812.2(b)(1)(ii),  and 812.42.  
110  See 21 CFR 812.1.  
 
30   Contains Nonbinding Recommendations  
requirements  for IRB  review and  approval, financial disclosure,  informed consent111 and, if  
applicable, additional safeguards for children.112  
If the IRB receives a request to review an investigation  to determine safety  or effectiveness  of 
the HUD for  a different indication than the HDE-approved indication(s), then the  IRB should be  
aware that this type of clinical investigation is subject to the  IDE regulations at 21 CFR  part 812. 
If the device is a SR device, the sponsor of the investigation must submit an IDE application to 
FDA and obtain FDA approval of that application before starting  the clinical investigation.113  A 
physician who wants to study a HUD may be the sponsor, investigator, or both for the study. In 
sum, the investigational  use of a HUD under these circumstances must be  conducted in 
accordance with 21 CFR parts 812, 50, 54, and 56.114  
Significant Risk/Non-Significant Risk Determinations  
An IRB does not have to make a SR/NSR determination when it receives a  request to review a  
clinical investigation of  a HUD (e.g.,  collection of  safety and  effectiveness  data) when that  
clinical investigation concerns the HDE-approved indication(s) only. As noted above, FDA does  
not consider such investigations  to require an  IDE  under 21 CFR part 812.  
For  an investigation  of the HUD for indications other than the HDE-approved indication(s), the  
IRB would need to make a SR/NSR determination if that determination has not already been 
made by FDA.115  In practice, most sponsors have  submitted and obtained FDA approval of  an 
IDE application before submitting such investigations of HUDs to IRBs for review, so IRBs  
have not needed to make  the SR/NSR determination (i.e., FDA had already  determined  the 
device was a SR device). However, in the event that a sponsor seeks  IRB approval for  
investigational use of  a HUD for an indication other than its approved indication(s) without first 
obtaining  a determination from FDA  regarding whether the study is a SR or NSR study, then the  
IRB should make the SR/NSR determination as required in 21 CFR 812.66.   
G.   Emergency Use  of HUDs  
If a physician in an  emergency situation determines that IRB or  appropriate local committee 
approval for the use of the HUD at the  facility cannot be obtained in time to prevent serious harm  
or death to a patient, a HUD may be used without prior approval. In this situation, the HDE  
                                                           
111  Specific requirements for obtaining informed consent  from  human subjects apply to FDA-regulated clinical  
investigations. See 21 CFR part 50, subpart B. Note that, in some cases, facilities  may  have specific requirements for  
obtaining informed consent for  the use of the HDE-approved HUD in the routine clinical  care of patients, but these 
would not be FDA regulatory  requirements.  
112  See 21 CFR  part 56 for IRB requirements;  see 21 CFR part 54 for requirements  for financial disclosure by  
clinical investigators; and  see 21 CFR part 50 for  requirements for  the protection of human subjects, including 
additional safeguards for children. 
113  21 CFR 812.20(a).  
114  Note that 45 CFR part 46 may be applicable to research involving HUDs  under certain circumstances. The 
applicability of those regulations is outside the scope of this  guidance. 
115  See 21 CFR 812.66.  
 
31   Contains Nonbinding Recommendations  
holder  may ship the HUD, based on the physicians certification of the emergent need and 
representation that the physician  will follow the requirements  regarding reporting such use to the  
chairperson of the  IRB or appropriate local committee. The physician must  provide  notification  
of the use to the chairperson of the  IRB or  appropriate local  committee, and the notification must 
include the identification of the patient involved, the date of the use, and the reason for the  
use.116 FDA regulations require that physicians provide such notification to the chairperson of  an 
IRB in writing  within 5 days of the emergency use of the device.117  For facilities at which an  
appropriate local committee reviews the use of  HUDs instead of an IRB, FDA recommends that  
physicians provide the same required notification of the emergency use  to the committee in 
writing and within 5 days. 
FDA further recommends that the physician submit a follow-up report on the patients condition 
to the HDE holder. The  HDE holder is required under 21 CFR 814.126(b)  to submit periodic  
reports, including the applicants clinical experience with the device and the number of devices  
shipped or sold in the US. 
IX.  Paperwork Reduction  Act of 1995  
 
This guidance contains information collection provisions that are subject  to review by the Office of  
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520).  
 
The time required to complete this information collection is estimated to average 100 hours per 
response, including the time to review instructions, search existing data sources, gather the data  
needed, and complete  and review the  information collection. Send comments regarding this burden 
estimate or suggestions for reducing this burden to:   
FDA PRA Staff   
Office of Operations   
Food and Drug  Administration  
PRAStaff@fda.hhs.gov   
An agency may not conduct or sponsor, and a person is not required to respond to, a  collection of  
information unless it displays a currently  valid OMB control number. The OMB control number 
for this information collection is 0910-0661 (expires 09/30/202 2).   
                                                           
116  See section 520(m)(4) of the FD&C  Act.  
117  21 CFR 814.124(a).  
32   Contains Nonbinding Recommendations  
Appendix A  Checklist for  Filing Review for  HDEs 
(should be completed within 30 days of DCC receipt)  
 
HDE Number:  _____________________________  Date Received:   ___________  
HUD Number (from OOPD):   _________________  
Device:  _______________________________________________   Procode:   ___________  
Company  Name/ Address:   _______________________________________________________ 
Contact Name/Phone Numbers:   ___________________________________________________ 
FDA Staff Member  Name:   _______________________________________________________ 
Decision: FDA Staff Recommendation:  File  ___     Not File ___ 
Within 15 calendar days of receipt of the HDE application,  FDA staff  should answer the preliminary questions  
below,  which are used as an initial screening of the HDE application. Depending  upon the answers to these 
preliminary questions, the remainder of the  filing review  may or  may  not be necessary. If the responses to the 
preliminary questions and subsequent consultation  with FDA staff identified below indicate that the HDE filing  
review should not continue, the  FDA staff member  or the CBER regulatory project manager (RPM) should promptly  
inform the  FDA team (including consulting reviewers  and management) and notify the requester using proper  
administrative procedures.  
Preliminary Questions  
Answers in the shaded blocks indicate consultation with an identified Center  advisor is needed.   Yes   No  
1.   Is the product a device [per  201(h) of the FD&C  Act]  or a combination product  (per 21 CFR 3.2(e))     
with a device constituent part? If it appears not to be a device (per 201(h) of the FD&C  Act) or such a 
combination product  (per 21  CFR 3.2(e)), or you are unsure, consult  with the CDRH  Product  
Jurisdiction Officer or CBER  Product  Jurisdiction  Officer  to determine the appropriate action and  
inform management.  Provide  summary of  Product  Jurisdiction Officers  
determination/recommendation/action in the comments section below.  
  If the product  does not appear  to be a device or a combination product  with a device constituent part, 
mark No.  
NOTE: If the product is a combination product  with a device constituent part, it  may  not be appropriate for  
review under an HDE. If the product is a combination product, consult  with the  CDRH  Product  
Jurisdiction  Officer  (cdrhproductjurisdiction@fda.hhs.gov) or CBER Product Jurisdiction  Officer  and  
inform management.  
Comments:   
2.   Is there a copy of,  or reference to the determination  made by  the Office of Orphan Product      
Development that the device qualifies as a HUD? [814.104(b)(1)]  
 
  If there is  no copy of, or reference to the HUD determination, mark  No.  
33   Contains Nonbinding Recommendations  
3.   If a Request for Designation (RFD)  was  submitted for the device and assigned to  your center, identify      
the RFD # and confirm the following:  
   Is the device the same (e.g., design, formulation) as that presented in the RFD submission?  
   Are the indications  for use for the device identified in the HDE  the same as those identified in  
the RFD submission?  
 
If  you believe the product or the indications presented in the HDE have changed from  the  RFD, or  you 
are unsure, consult  with the CDRH  Product  Jurisdiction Officer  
(cdrhproductjurisdiction@fda.hhs.gov)  or CBER Product  Jurisdiction  Officer  to determine the 
appropriate action and inform  management. Provide summary of  Product  Jurisdiction Officers  
determination/recommendation/action in the comments section below.  
 
If the answer to either question above is no,  mark No.   
Comments:  
4.   Is  the device eligible for  HDE  ?        
 
NOTE: If the device does not appear to  be eligible for review through the HDE program  because there is a 
comparable device available  (e.g., a predicate device exists,  a De Novo request has been granted for a 
similar device,  or an approved PMA  exists  for a similar device),  you  should consult  with management   
and  the appropriate CDRH or CBER  staff during the filing review  to determine the appropriate action.   
 
If  you believe  an application is for a device that  is eligible for review through the HDE program and an 
exemption from  the effectiveness provisions,  you should (1) complete the 510(k)  decision tree to  
document  why the device  would be found NSE (attach copy) and (2) obtain concurrence from the 
appropriate CDRH  or CBER staff  prior to the  filing the original HDE.  
Comments:  
5.   Is the applicant the subject of  an  Application Integrity Policy (AIP)?  If Yes, consult with the  CDRH      
Office of Product Evaluation and Quality/Office of  Clinical Evidence/Division of Clinical Evidence  &  
Analysis 1 (CDRH/OPEQ/OCEA/DCEA1) or CBER Office  of Compliance and Biologics 
Quality/Division of Inspections and Surveillance/Bioresearch Monitoring Branch 
(CBER/OCBQ/DIS/BMB),  to  determine the appropriate action  and provide a summary of the  
discussion/recommendation/action in the comments  section  below. Check on  web at  
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/application-
integrity-policy/application-integrity-policy-list  
Comments:  
  
 
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
A.   HDE Content        
  1.   Are all required sections in English or accompanied  with an  English translation?      
   
  2.   Is  there a table of contents? [814.104(b)(4) and 814.20(b)(2)]    
   
  Inclusion of information in an HDE application that is  not in English and is not accompanied by an English translation is not  an  
independent basis for a Refuse to File  decision;  however, we recommend providing the sections of  your HDE application in  34  
English (or accompanied with an English translation) in order to avoid significant delay of review of your submission.   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
  3.   HDE / HUD Information        
    a.   Is there an explanation of  why the device would  not be available unless an  HDE    
   
was granted? [814.104(b)(2)]  
    b.   Is there a statement that  no other comparable device, other than another  approved   
   
HUD  under an HDE or a device under an approved IDE, is available to treat or  
diagnose the disease or condition? [814.104(b)(2)]  
    c.   Is there a discussion of the risks  and benefits of currently available devices or    
   
alternative forms of treatment? [814.104(b)(2)]  
    d.   Is there an explanation of  why the probable benefit to health  from the 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? [814.104(b)(3)]  
    e.   Has  the amount to be charged  for the device been provided, and if  greater than    
   
$250.00, is a report  or attestation  provided verifying that the  amount charged does  
not exceed the costs of the devices research, development, fabrication, and  
distribution? [814.104(b)(5)]  
  4.   Is a bibliography provided?  [814.104(b)(4) and 814.20(b)(8)(i)]  
     
    a.   Have copies of  key articles been provided and are English translations included, if  
     
appropriate?    
Check N/A if applicant includes a statement that upon searching they  found no  
literature related to their device  
  5.   If a device sample has been requested by FDA,  has it been provided or if impractical to        
submit, has the applicant offered alternatives to allow FDA staff to view or access the        
device? [814.104(b)(4) and 814.20(b)(9)]  
  6.   Is there a summary of the contents of the HDE? [814.104(b)(4) and 814.20(b)(3)]    
   
  7.   Device Characteristics        
    a.   Is a description of  the  device included? [814.104(b)(4) and 814.20(b)(4)]    
   
      i.   Pictorial representations? [814.104(b)(4) and 814.20(b)(4)(i)]    
   
      ii.   Materials specifications?  [814.104(b)(4) and 814.20(b)(4)(ii)]    
   
            If there is a color additive present:  
     
   has the color additive been identified by common  name and  
chemical name, and  
   has the amount of each color additive in the formulation by  
weight percent of the colored  component and total amount (e.g.,  
ppm, g) in the device been provided?  
    b.   Is a description of the principles of operation of the device (including    
   
components) and properties relevant to clinical  function present? [814.104(b)(4)  
and 814.20(b)(4)(iii)-(iv)]  
  While submission of key articles that are not in English and are not accompanied by an English translation is not an independent  
basis for a Refuse to File decision, we recommend that copies of  submitted articles are provided  in  English (or accompanied  with  
35  
an English translation) in order to avoid significant delay of review of your submission.   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
  8.   Is the Device Manufacturing Section included?  [814.104(b)(4) and 814.20(b)(4)(v)]   (See   
   
the  guidance  entitled, Quality System Information  for Certain Premarket Application  
Reviews, available at  https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/quality-system-information-certain-premarket-application-reviews)  
    a.   Has a description of the methods, facilities, and controls  used in the manufacture,    
   
processing, packing,  storage, and,  where appropriate,  installation of the device  
been provided?   
  9.   The application includes a summary  and full study report*  for each nonclinical study  
     
provided?  [814.104(b)(4)  and 814.20(b)(6)(i)]  
 
Note:  the applicant can reference data located in other applications. Check Yes if  
nonclinical data is  not provided in the current application but found in another  
application. State where the data were provided (e.g., modular application, master file).  
 
*Full  study report includes objective of the test, description of test methods and  
procedures, study endpoint(s), pre-defined pass/fail criteria,  results summary,  and  
discussion of conclusions. In the event that an applicant is appropriately declaring  
conformity  with a  voluntary consensus  standard that FDA  has recognized pursuant to  
section 514(c) of the FD&C  Act  to meet applicable requirements,  it may not be  
necessary to submit  full test reports  with respect to those requirements. Refer to 13(a).   
See FDAs guidance Appropriate Use of Voluntary  Consensus Standards in  
Premarket  Submissions for Medical Devices, available at  
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/appropriate-use-voluntary-consensus-standards-premarket-submissions-
medical-devices.     
    a.   Sterilization  
     
    b.   Biological/Microbiological  
     
    c.   Immunological  
     
    d.   Toxicological/Biocompatibility  
     
    e.   Engineering (stress,  wear, etc.)  
     
    f.   Chemistry/Analytical (typically for IVDs)  
     
    g.   Shelf Life  
     
    h.   Animal Studies   
     
    i.   Other Essential Laboratory Testing  
     
  10.   Is a summary of clinical  experience and  investigation(s) and results provided?  
     
[814.104(b)(4)(i)]  
36   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
    a.   Are the final  versions of the clinical protocols included?  (If performed  under IDE,  
     
these  should be the final FDA-approved versions of the  clinical protocols,  
incorporating any Notices of  Changes.)  
    b.   Is a description of study population demographics provided?  
     
    c.   Is a description of adverse events (e.g., adverse reactions, complaints,  
     
discontinuations, failures,  replacements)  provided?  
    d.   Have report forms  for patients  who died or who did not complete the investigation  
     
been provided (i.e., to resolve potential bias)?    
 
Check  N/A only if no patients died or were discontinued.  
  11.   Are statistical  analyses of the clinical investigations provided, if appropriate?  
     
[814.104(b)(4)(i)]  
    a.   Are the results of all analyses identified in the protocol provided?    
   
  12.   Has appropriate  draft labeling  been submitted? [814.104(b)(4) and 814.20(b)(10)]        
    a.   Physician Labeling    
   
      i.   Are indications  for use included?    
   
      ii.   Are contraindications,  warnings, and precautions included?    
   
      iii.   Are instructions for use included?    
   
      iv.   Does the labeling 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 [814.104(b)(4)(ii)]  
    b.   Patient Labeling  Check  
     
 
Check  N/A only if  the relevant lead Center  has previously indicated that patient 
labeling is not  necessary.  
    c.   Technical/Operators Manual, if applicable  
     
  13.   Statements/Certifications/Declarations of Conformity         
    a.   Does the application  utilize  voluntary consensus standard(s) (See section 514(c)  of 
     
the FD&C  Act).  This includes both FDA-recognized and non-recognized 
consensus standards.  Select N/A if the submission does not utilize voluntary  
consensus standards.   
      i.   If the application cites FDA-recognized voluntary consensus  standard(s),  
     
does the application include:  
a Declaration of Conformity (DOC) as outlined in FDAs  guidance 
Appropriate Use of Voluntary Consensus Standards in Premarket  
Submissions  for Medical  Devices, available at   
37   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/appropriate-use-voluntary-consensus-standards-premarket-
submissions-medical-devices   
OR  
if citing general use of a standard, an explanation of any deviation from  the 
standard?    [814.104(b)(4) and 814.20(b)(5)]  
      ii.   If the application cites non-FDA-recognized voluntary consensus  
     
standard(s), does the application  explain any deviation from  the standard?  
[814.104(b)(4) and 814.20(b)(5)]  
    b.   Investigator Financial Disclosure         
For additional information refer to  the guidance document  Financial Disclosure        
by  Clinical Investigators, available at        
https://www.fda.gov/regulatory-information/search-fda-guidance-      
documents/financial-disclosure-clinical-investigators.        
       
As required by 21 CFR Part 54, has the applicant  submitted  for each  clinical       
investigator either:  
     
1. A signed and dated Certification Form (3454) or        
 
     
2. A signed and dated Disclosure Form (3455)  
 
Note:  the signature should be from a responsible corporate official or  
representative of the applicant.   
i.   For a Certification Form (3454):  Is the required list of all investigators and  
     
subinvestigators attached to the Form?  
ii.   If box 3 of  Form 3454 is checked, does the Form include an attachment  
     
with the reason(s)  why  financial disclosure information could not be  
obtained?   
iii.   For a Disclosure Form (3455):  Does the application provide details of the  
     
financial arrangements and interests of the investigator(s) or  
subinvestigator(s), along with a description of any  steps taken to  minimize  
potential bias?  
    c.   Environmental  Assessment under 21 CFR 25.20(n) [814.104(b)(4) and   
   
814.20(b)(11)]  
      i.   If claiming a categorical exclusion, information to justify  the exclusion, OR  
     
      ii.   An environmental assessment  (ONLY  required for devices that  present new  
     
environmental concerns)  
  If citing general use of a FDA-recognized standard  or citing a non-FDA recognized  voluntary consensus standard, we recommend that the basis of  
such use, along with the  underlying information or  data that supports how the standard was used, be included in the application.  
38   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
    d.   Did the application include a completed FORM FDA 3674,  Certification with    
   
Requirements of ClinicalTrials.gov Data Bank? (42 U.S.C.  282(j)(5)(B)  and 42      
CFR part 11)      
     
Note: Enter the NCT number(s) in  the  Center Tracking System (CTS)   
      Data from FORM FDA 3674 (mark  Yes for the applicable one):        
      i.   No clinical trials referenced in application.    
   
      ii.   Requirements are not applicable to referenced clinical trials.    
   
      iii.   Requirements are applicable and have been  met.    
   
    f.   Statements of  Compliance for Clinical Investigations  [814.104(b)(4) and   
   
814.20(b)(6)(ii)(A)-(C)]  
Select N/A if the application  does not contain any clinical data from  
investigations (as defined in 21 CFR 812.3(h)).  
 
For multicenter clinical investigations involving both United States (US) and  
outside the United States (OUS) sites, part (i) should be addressed for the US  sites  
and  part (ii) should be addressed for the OUS sites.  21 CFR  812.28 applies to all  
OUS clinical investigations that enroll the  first subject on or after February 21,  
2019.  
Please refer to the guidance document entitled  Acceptance of Clinical Data to  
Support  Medical Device  Applications and Submissions  - Frequently Asked  
Questions,  available at  https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/acceptance-clinical-data-support-medical-device-
applications-and-submissions-frequently-asked, for more information.  
      i.   For all clinical investigations  conducted in the US, the application includes one of  
   
the following for each  investigation  (check all that apply):  
  A statement of compliance  with 21 CFR parts 50, 56, and 812.   
  A brief statement of the reason for noncompliance  with  21 CFR parts 50, 56,  
and 812.  
Select N/A if the clinical investigations were conducted solely OUS.  
      ii.   For all clinical investigations  conducted  OUS, the application includes one of the 
   
following  for each  investigation (check all  that apply):  
  A statement that the clinical investigations  were conducted in accordance with  
good clinical practice (GCP) as described in 21 CFR 812.28(a)(1).  
39   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
  A brief statement of the reason for not conducting the investigation in 
accordance with  GCP and a description of steps taken to ensure that the data and  
results are credible and accurate and that the rights,  safety, and  well-being of  
subjects have been adequately protected.   
  A  waiver request in accordance with 21 CFR 812.28(c).  
Select  N/A if the clinical investigations were conducted solely inside the US.  
  14.   Pediatric Use - Per 515A(a)(2) of the  FD&C  Act, did the application include, if readily        
available: [814.104(b)(6) and 814.20(b)(13)]  
    a.   A description of any pediatric subpopulations that  suffer from the disease or    
   
condition that the device is intended to treat, diagnose, or cure, or statement that 
no pediatric subpopulation exists  for the disease or condition for  which the device  
is intended. This statement does not  mean the device is indicated for treating  
pediatric patients. For additional information refer to the guidance document  
Providing Information about Pediatric Uses of Medical Devices  - Guidance for  
Industry and Food and Drug Administration Staff, available  at 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/providing-information-about-pediatric-uses-medical-devices.  
    b.   The number of affected pediatric patients.    
   
B.   Issues Identified by FDA  Prior to receipt of the HDE  Application  - history of the applicant  with        
this device  [814.104(b)(4) and  814.20(b)(8)(ii)-(iii)]  
  1.   Does the applicant list prior applications or state that there  were no prior applications?    
   
(may be located in  CDRH  Coversheet Form FDA 3514, Section F)        
       
If the applicant lists prior applications, address the applicable questions below:        
    a.   510(k) #______________________________________    
   
      i.   If this device has been the subject of an NSE decision,  does  the HDE  
     
application  take into account any concerns  related to  safety  or probable  
benefit that  were previously communicated during the review of the prior  
510(k) or through 510(k) correspondence?  
    b.   IDE  #_________________________________________    
   
      i.   Have the data presented in the HDE taken into account  any safety  or 
     
probable benefit concerns (e.g., future considerations) previously  
communicated during the review of prior IDE(s) or through  IDE  
correspondence?  
    c.   PMA #________________________________________    
   
40   Contains Nonbinding Recommendations  
Inventory of  Organizational and Administrative Elements  
(Requirements per 21 CFR 814.112 unless otherwise indicated)  
Check Yes if item  is present, N/A if it is not needed and Not Present if it is not included but needed.  
     A  Not Present answer  may  result in a  Refuse  to File decision.   Present   Not  
   Each element on the checklist  should be addressed within the application. An applicant     Present  
may provide a rationale for omission  for any criteria that are deemed not applicable. If   (No)  
Yes   N/A  
a rationale is provided, the criteria is considered Present  (Yes). An assessment of the  
rationale  will be considered during the review of the application.   
      i.   If a previously submitted PMA  for this device has been withdrawn or  
     
denied, does the current HDE  application take into account any issues  
related  to  safety  or probable  benefit raised during review of  the prior  
PMA(s) or through PMA correspondence?  
    d.   HDE #________________________________________    
   
      i.   If a previously submitted HDE application for this device has been  
     
withdrawn or denied, does the current HDE application take  into account 
any issues related to  safety  or probable benefit raised during  review of  
the prior HDE application  or through HDE correspondence?  
    e.   Modular HDE #________________________________    
   
      i.   If Yes, how  many  modules  submitted? ____________        
 
How many modules were  closed?  _______________  
      ii.   If there are  modules that are on hold, does the HDE address outstanding  
     
deficiencies?  
  2.   Does the applicant list Q-Submission(s) regarding the device or this application in  which    
   
FDA feedback regarding data or information related to  safety  and/or probable  benefit in the        
HDE  was provided electronically  or during a  meeting (in person or by phone), or state that        
there were no prior Q-Submission interactions  with the FDA regarding this application?        
   
If the applicant lists  Q-Submissions, address the applicable questions below:  
    a.   Q-Submission #____________________        
Meeting date(s), if applicable_____________________________  
    b.   Copy of  minutes from each  meeting or other  written feedback?  
     
    c.   Were all FDA concerns or action items previously presented to the applicant in  
     
  the  Q-Submission  minutes or feedback addressed in the HDE or has the applicant  
provided a detailed scientific  or clinical justification  for an  alternative approach?  
 
Filing  Decision Questions  
A No answer  will  typically  result in a  Not-Filed  decision.  
    Yes   No  
Decision 1   Is the HDE complete?  
   
 
If, on its face, the HDE is  missing one or more required elements (identified above),  such that  
the application is not sufficiently complete to permit substantive review,  answer No.  
 
41   Contains Nonbinding Recommendations  
Filing  Decision Questions  
A No answer  will  typically  result in a  Not-Filed  decision.  
    Yes   No  
       
Decision 2   From only an administrative review, does the HDE include information that appears  to 
   
constitute valid scientific  evidence?    
 
Only answer No if it is clear that the HDE is supported solely by information that 21 CFR  
860.7 identifies as not constituting valid scientific evidence:  
   isolated case reports  
   random experience  
   reports lacking sufficient details to permit scientific evaluation  
   unsubstantiated opinions  
 
Comments:  
Decision 3        
Does the HDE address the  key nonclinical and clinical issues identified by FDA prior to  
   
submission of the HDE application?       
     
OR      
     
Has the applicant provided a detailed scientific or clinical justification for the alternate 
   
approach?  
 
Section B of the checklist outlines questions intended to identify  when the  FDA has  
previously provided specific  feedback  to the applicant relevant to  an evaluation of the risks  
and probable benefits of the device  through one or  more  mechanisms, such as a  prior HDE or  
PMA application, a prior Not Substantially Equivalent decision on a 510(k), Investigational 
Device Exemption (IDE) letters, feedback  through the Q-submission Program, a 
Determination or  Agreement meeting(s), or other substantive communication  with FDA. If  
such information  has been communicated to the applicant through one or  more of these  
mechanisms, and the HDE application addresses each of the key  nonclinical and clinical  
issues identified by  FDA, the answer to the above question is Yes. Furthermore, if some of  
these key issues previously identified by FDA are not addressed, but the HDE application  
contains a scientific or clinical justification  for the omission  or  an alternative approach, the  
answer to the above question is Yes.  These cases do not preclude the responsible  review  
Division  from accepting the HDE application.  
 
In this context, the term  key issues is  meant to refer to issues that are central to  FDAs  
review of  the  devices  risks  and probable benefit  under sections 515 and  520(m)  of the  FD&C  
Act.  Examples of key issues include:  need for long-term nonclinical studies (e.g.,  
biocompatibility, carcinogenicity, or other animal studies), and certain clinical study 
parameters (e.g., sample size, patient population, study design,  and endpoints). These key  
issues are typically device-specific.  As a result, the decision  of  FDA  to Refuse to File an  
HDE  application based on this criterion can only be made after carefully considering the 
following questions:  
 
Are the types of necessary nonclinical and clinical studies well-known in the scientific and  
medical communities for the particular device?  
For an established device type, the types of  nonclinical and clinical studies that  we would  
expect in a PMA are likely  to be well-known both  within FDA and in the scientific and  
medical communities and, as such, are often included as part of an FDA  guidance document  
and/or consensus standard.  You should bear in mind that, for HDEs, the device  may  not be of  
an established device type.  
  For example, this information could be  in the form of results of nonclinical laboratory studies with the device or results  of  clinical 
42  
experience or investigations that  are relevant to an assessment of the risks and probable benefits of the device.   Contains Nonbinding Recommendations  
Filing  Decision Questions  
A No answer  will  typically  result in a  Not-Filed  decision.  
    Yes   No  
 
Were the  issues conveyed to the applicant as part of  a documented regulatory process?  
Examples of a documented regulatory process include:  
   interaction  through the Q-submission process,  
   prior PMA  or HDE  application,  
   prior Not Substantially Equivalent decision on  a 510(k),  
   IDE letters, or  
   letter(s) issued as a result of Determination or Agreement  meetings.  
 
Were the issues conveyed to the applicant related  to insufficient effectiveness data?  
Devices approved under an HDE  application  are exempt from the requirement to demonstrate  
a  reasonable assurance of effectiveness. If an issue that is not addressed in the current HDE  
application  relates to insufficient effectiveness data,  filing the  HDE  may be appropriate  in 
cases for  which  accepting a  PMA would not.  
 
FDA staff should only designate  an HDE  Refuse to  File based on a No response to  Acceptance 
Decision 3 in instances  where the key issues  were identified by  FDA staff as part of a documented 
regulatory process.  
 
 
Digital Signature Concurrence Table  
Reviewer Sign-Off    
Team Lead/Assistant Director    
Sign-Off  
Division Sign-Off    
Office Sign-Off    
(for NOFI only)  
43   Contains Nonbinding Recommendations  
Appendix  B  Considerations  for  the  Probable Benefit-Risk  
Assessment  
As discussed in Section VI of this guidance, FDA considers the same  factors described in FDAs  
benefit-risk framework for evaluating PMAs or De Novo requests when assessing probable  
benefits and risks for HDE applications. Refer to the FDA  guidance document, Factors to  
Consider when Making  Benefit-Risk Determinations in Medical Device Premarket Approval and  
De Novo Classifications,1 for a description of those factors.  It should be clearly noted, 
however, that probable benefit and probable benefit-risk determinations under an HDE are  
different  from those under a PMA or a De Novo request. Please refer to Sections V and VI of the  
guidance for  further discussion related to these differences and  the probable  benefit-risk  
assessment. The tools identified in Appendices  B and C are meant to serve complementary roles, 
and both should be completed as part of the probable benefit-risk assessment.   
Instructions for FDA Staff: You should make your recommendation regarding the probable  
benefit-risk assessment  based on the totality of the  evidence. The probable benefit-risk  
assessment is part of the  decision whether to approve the application, but it does not include an 
assessment of all applicable requirements for approval. An indication from  these tools that the  
probable benefits outweigh the probable risks does not mean that the application satisfies other  
applicable requirements  for an HDE  application.  
The following questions are intended as a sequential method to help weigh  various  factors  as part  
of the probable benefit-risk assessment. As such, the questions are intended to help identify and 
explain  which factors and considerations are critical in  making a probable  benefit-risk  
assessment  for a particular device. However, the  questions are not intended to suggest that   
considerations other than those listed in the completed worksheet  are irrelevant. This checklist 
should be used when non-clinical and/or  clinical evidence has been submitted in the form of  
valid scientific evidence.  
Consider questions 1-8 for the proposed Indications  for Use,  until  you reach a recommendation  
either  that the probable benefits outweigh the probable risks or to move to question 9, which 
prompts  you to consider  a narrowed Indications for Use. When considering an acceptable, 
narrowed Indications for  Use, interact with the  applicant to reach agreement on a narrowed 
Indications for Use. However, as  reflected under question 1, if the evidence does not support a  
finding of probable benefit under the proposed Indications for Use  (or narrowed Indications  for 
Use), or  evidence  does not support a finding of probable benefit for the proposed Indications  for 
Use and  agreement on  narrowed Indications for Use is not achievable  or applicable, the  
application  would not  be approvable.  
   
                                                           
1  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-consider-when-making-
benefit-risk-determinations-medical-device-premarket-approval-and-de   
44   Contains Nonbinding Recommendations  
Assessment of Probable Benefit  
1.   Is there any evidence of  clinical benefit?  
 
Note that  in lieu of summaries, conclusions, and results of clinical  investigations required under  21 
CFR  814.20(b)(3)(v)(B), (b)(3)(vi), and  (b)(6)(ii), HDE applicants are required to submit summaries, 
conclusions, and results of  all  clinical  experience or investigations (whether adverse or 
supportive) reasonably obtainable by the applicant that are relevant  to an assessment of the risks 
and probable benefits of  the device  (see 21 CFR 814.104(b)(4)(i)). 
 
Is a  probable  clinical benefit demonstrated for the  device for this indication (e.g., from 
any one or more of the primary  and/or secondary datasets or from  associated real-world  
evidence)?  Probable benefit may be considered in terms of how a patient feels, functions, 
survives, or an acceptable surrogate outcome. This information may be collected using  
validated tools such as  quality of life questionnaires, if appropriate. Probable benefit may  
also be considered in terms of convenience in managing or diagnosing  a disease or  
condition. Probable benefit should be considered based on the assessment of the data.  
Select any of the following that demonstrate probable  benefit, and then answer the  
question in the box below.  
 
  A favorable change in at  least 1  clinical assessment  that is equal  to or greater than seen  in  the 
control group  
  A favorable change in at  least 1  clinical assessment  that meets a predetermined  performance 
goal  
  A favorable change in at  least 1  clinical assessment  that  meets or surpasses a minimally  
important clinical difference  
  A favorable change in at  least 1  clinical assessment  that is equal  to or greater than  changes 
seen with other  available modalities for the disease or  condition  
  A favorable change that would be meaningful  to patients considering the  severity, chronicity,  
etc., of the condition, taking  into consideration patient-reported outcomes (PRO)  and health-
related quality of life  
  A favorable change in non-clinical data or modeling that is deemed to be predictive of  
clinical outcomes  
  A favorable clinical performance characteristic (e.g., sensitivity/PPA12, specificity/NPA23, 
etc.) for screening, diagnosis, prognosis, monitoring, or treatment selection  
  Acceptable performance characteristics for analytical validation of  the device  
  Other(s)  
  None  
 
Question 1:  Is there any evidence of  probable  clinical benefit?  
     
  YES  Continue to Question 2  

  NO  Move to Question 9 

   
                                                           
2  PPA: Positive Percent Agreement  
3  NPA: Negative Percent  Agreement  
45   Contains Nonbinding Recommendations  
2.   2What is the extent  of uncertainty  for the probable  benefits?  
Recognizing that  some extent of  uncertainty always exists,  select the sources of uncertainty, if  
applicable,  in  the data that  affect your assessment of the clinical benefit. Consider  sources of  
uncertainty  related to  clinical and/or analytical performance characteristics (e.g.,  sensitivity,  
specificity, accuracy, precision, reproducibility, as applicable). Select any of the following  that 
demonstrate sources of uncertainty for  the probable benefits, and then answer the  question in the  
box below.  
     I nconsistent or conflicting results between studies  
    W  ide confidence intervals surrounding the point  estimate(s)  and/or odds ratio(s)  
     High  subject  or specimen loss-to-follow-up at critical  assessment point(s)  
     Large amount of missing data at critical assessment time(s) +/- imputation  
     Significant number of major protocol deviations  
     Impact of  confounding interventions  or physiological factors  
     Inconsistent user  experience or user  experience not representative of likely real-world user  
     Unclear correlation between  non-clinical data, pre-selected enriched  data, or  computer  
modeling and clinical performance  
    Surrogate endpoint has not  been demonstrated to correlate with a clinical outcome  
     Real-World Evidence (RWE) is not  relevant or reliable for the purposes of the proposed 
analysis  
     Inspectional findings  
     Study design or results  lead to lack of generalizability for the intended use population or  
specific  clinical subpopulations  
    Physiological or clinically  meaningful range of the diagnostic  output is  unknown, or  
generalizability of proposed clinical cut-off is unknown 
    Imperfect comparator method used  to  calculate performance characteristics  
     Other(s)  
    None  
 
Question 2:  What is the  extent  of  uncertainty for the 
probable benefits?  
   
  Low  Continue  to Question 3; consider suggesting a 

different kind of marketing  application. 
  Med   Continue  to Question 3  

  High   Continue  to Question 3  

 
 
Summary of the  Assessment  of Probable Benefit  
For the  Proposed Indications  for Use:  
Considering responses to Questions 1 and 2, summarize  the Assessment of  Probable  Benefit for the 
proposed Indications for Use.  Include  a description of  your assessment of  the extent of  probable benefit, 
considering the  type, magnitude, and probability  of benefit(s);  and the duration of effects. Include  a 
description of  the impact of uncertainty  on your Assessment  of Probable Benefit. If no benefit is  
identified, briefly explain why.  
46   Contains Nonbinding Recommendations  
Assessment of Risk  
3.   Are known/probable risks more than minimal?   
Select any of the following  elements that demonstrate sources of  known/probable risks  that are  
more than minimal, and then answer  the question in the box below.  
 
    Adverse events (AEs) or  outcomes related  to the device itself  
    AEs or outcomes related  to  the use of the device or  procedure to use the device  
    AEs or outcomes related to anesthesia  or sedation to use the  device  
    AEs or outcomes due  to subsequent  tests/treatments needed (e.g., radiation from CT scans)  
    AEs or outcomes, not seen  in the study/data, but probable based  on class effect or events 
known to occur with similar technologies  
    False positive/false negative/failed to provide a  result for diagnostics  
    Treatment or diagnostic  intended to be used as  a standalone rather than an adjunctive use  
    Other(s)  
    None  
 
Question 3: Are known/probable risks  more than 
minimal?  
  
   YES  Continue  to Question 4  

   NO  Continue  to Question 4  

 
 
4.   What is  the  extent  of  uncertainty for the probable  risks?   
Recognizing that  some extent of uncertainty  always exists, select  the sources of  uncertainty, if  
applicable, in the data regarding the  adverse events/outcomes or  risks.  Select any  of the following  
that  demonstrate sources of uncertainty for the probable risks, and then answer  the question in 
the box below.  
 
   Insufficientpatient numbers to detect  serious events  or false positives/false negatives  
   Insufficientduration of follow-up to detect  delayed/late events  
   Lackof data on repeated exposure to the device/use  
   Inconsistentor conflicting results between studies  
   Properevaluations not performed as part of the study protocol  to adequately detect certain AEs  
   Pooror inconsistent adverse event definitions and documentation  
   Eventslikely confounded by, and attributed to, other  comorbidities or  treatment modalities  
   High subject loss-to-follow-up at critical  assessment point(s)  
   Largeamount of missing data at critical assessment time(s) +/- imputation  
   Significantnumber of major protocol deviations  
   Inconsistentuser  experience or user  experience not representative of likely real-world user  
   Concerns related to performance characteristics  (e.g., sensitivity/PPA, specificity/NPA)  
   Imperfectcomparator method used  to  calculate performance characteristics  
   Other(s)  
   None  
47   Contains Nonbinding Recommendations  
 
 
Question 4: What is the  extent  of  uncertainty for the  
probable  risks?  
  
  Low  Continue to Question 5  
  Med   Continue  to Question 5  

  High   Continue  to Question 5  

 
 
Summary of the  Assessment of  Probable  Risk  
If you answered No to Question 3 but High to Question 4, please explain here.  
 
For the  Proposed Indications  for Use:  
Summarize  the Assessment of  Probable  Risk for  the proposed Indications  for Use.  Include  a description 
of  your assessment of  the extent of  probable risk considering  the severity, types, number and rates of  
harmful events associated  with use of the device;  probability of a harmful event;  duration  of harmful  
events; and risk  from  false-positive or false-negative results for diagnostics.  Include a description of  the  
impact of uncertainty  on your Assessment  of Probable  Risk.  
Assessment of Probable Benefit-Risk  
Instructions for FDA Staff:   Provide a recommendation  based on the totality of the evidence.  As  noted above,  
the probable benefit-risk assessment is part of the decision  regarding whether to approve  an HDE application  
but is not an assessment of all applicable requirements.   
To approve  an HDE application, FDA must  make,  among other things,  a determination  that  the  device will not 
expose patients to an unreasonable or significant risk of illness or injury  and that the  probable benefit to health 
from the use of the device outweighs  the  risk of injury or illness from its  use  taking into account the  probable  
benefits and risks of currently available devices or alternative forms of treatment.   
If you answer yes for any  Q5-8, explain your rationale for how the probable benefits outweigh the probable  
risks. You should also  consider and recommend actions that  would enhance the probable  benefit-risk  profile  of 
the device, such  as  modifications to the  proposed labeling, which  may include  additional  appropriate warnings,  
and precautions, instructions for use,  or  presentation of data  to  help ensure the product labeling is transparent  
with respect to the  probable  benefits  and risks.   
If you answer unable to conclude for Q5-8, please provide the information that you believe would be needed 
to support a determination that probable  benefits outweigh the probable risks for the Indications for Use under  
consideration in the summary text boxes and also proceed to  Q9.  
Question 5:  Do the Probable Benefits outweigh  the Risks,  considering  the 
 
assessment of the Probable Benefit  and Risk  and the extent  of uncertainty  
identified above?  
 
  Yes  The probable benefits outweigh the risks such that, for this device,  

additional consideration of  relevant factors would not  change that determination. 
  Unable to conclude that  probable  benefits  outweigh  the risks   further discussion  

and consideration of  relevant factors  is appropriate   Continue to Question 6  
48   Contains Nonbinding Recommendations  
 
 
Summary of the  Assessment  of Probable Benefit-Risk  
For the  Proposed Indications  for Use:  
Summarize the probable  benefit(s)  that have been demonstrated for  the proposed Indications  for Use  and  
your assessment of  how Probable Benefit(s) compare to  Risks. Include a description of how  available  
alternative modalities, including their probable benefits and risks, affect your  assessment. Include a  
description of  how uncertainty  regarding Probable Benefit(s)  and Risk(s)  affects your assessment.  
 
6.   Do the Probable Benefits outweigh the Risks,  when  taking into  account  the following  
additional considerations? Select relevant considerations, and then answer the question in the  box  
below.  
  Understanding  of patient  willingness  or unwillingness  to accept a large extent  of uncertainty in   
 
the probable  benefits  and/or  risks  
   Availablepatient preference information (PPI) showing patient willingness or unwillingness  to  
accept  the probable risks in exchange for  the probable benefits.  In  circumstances where it is not  
feasible  to obtain PPI (e.g., some pediatric or impaired  patient populations), care-partner  
perspectives may be considered.   
   Understandingof  care-partner perspectives on  the  probable  benefits and risks  for a device 
where applicable (e.g., ease of care  that may affect patient care and outcomes)  
   Availablequalitative or quantitative PPI on the relative desirability or  acceptability to patients  
of outcomes or other attributes  that differ  among alternative  health interventions  
   Understandingthat the device represents novel technology for which the current  device 
technology is different  
   Abilityto manage  or diagnose the condition and consideration of  natural history of disease  
progression in the absence of  the  intervention or diagnostic information with the device under  
review  
   Thedevice avoids serious harm associated with available therapies for  the disease or  condition  
   Theadverse events associated with use of  the device are reversible  
   Typeof  intervention required to address  the harmful event (e.g., medication, surgery)  
   Understandingof mechanistic  plausibility and/or class effect  (e.g., familiarity  with similar  
technology)  
   Other(s)  
   None  
 
Question 6:  Do the Probable Benefits  outweigh the Risks, when taking  into  
account additional  relevant considerations?  
  Yes  The probable benefits outweigh the risks such that, for this device,  

additional  consideration of  relevant factors would not  change that determination.  
  Unable to conclude that  probable  benefits outweigh the  risks  further discussion  

and consideration of risk mitigation measures is appropriate  Continue to 
Question 7  
   
49   Contains Nonbinding Recommendations  
 
 
Summary of the  Assessment  of Probable Benefit-Risk,  taking into account  additional  relevant  
considerations  
For the  Proposed Indications  for Use:  
Summarize the probable  benefit(s)  that have been demonstrated for  the proposed Indications  for Use and  
your assessment of  how Probable Benefit(s) compare to  Risks. Include a description of how  available  
alternative modalities, including their probable benefits and risks, affect  your assessment. Include a  
description of  how uncertainty regarding Probable Benefit(s)  and Risks affects your assessment.   Include  
a description of how patient perspectives affected your  assessment.  
 
7.   Can the risks be  mitigated, so that  Probable Benefits  outweigh the Risks? Consider if the  
Probable Benefits outweigh the Risks if  risk mitigation  strategies are incorporated  to  lower 
the probability  of a harmful event occurring and improve  the probable benefit-risk profile  of  
the device.   Select  relevant considerations, and then answer the question in the box below.  
 
    Additional descriptions of  known and probable benefits and risks in physician and patient  
labeling, including appropriate Contraindications, Warnings, and Precautions and description of  
the  clinical events  
    Additional warnings noting limitations of safety information (e.g., The safety of the use of this  
device in [situation] has not been evaluated.)  
    Labeling  the device for prescription use  only  
    Training:  
    Limitation to  caregivers with certain qualifications or clinical training  
    Limit to users with a minimum set of qualifications and/or  training  
    Physician/user training program  
    Other:  
    Device tracking  
    Other(s)  
    None  
 
Question 7:  Can the  risks be mitigated,  so that Probable Benefits outweigh  the 
Risks?  
  
  Yes  The probable benefits outweigh the risks such that, for this device,  

additional  consideration of  relevant factors would not  change that determination.  
  Unable to conclude that  probable  benefits outweigh the  risks  further discussion  

and consideration of postmarket actions  is  appropriate   Continue  to Question 8  
   
50   Contains Nonbinding Recommendations  
 
 
 
Summary of the  Assessment  of Probable Benefit-Risk,  considering  risk mitigation strategies  
For the  Proposed Indications  for Use:  
Summarize the probable benefit(s)  that have been demonstrated for  the proposed Indications  for Use and  
your assessment of  how Probable Benefit(s) compare to  Risks. Include a description of how  available  
alternative modalities, including their probable benefits and risks, affect  your assessment. Include a  
description of  how uncertainty regarding Probable Benefit(s)  and Risks affects your assessment.  Include 
a description of how patient perspectives affected your  assessment.   
 
 
8.   Do the Probable Benefits outweigh the Risks considering  the use of postmarket actions?  Select  
appropriate postmarket action(s), and then answer  the question in the  box below.  
   Collection of additional  and/or  confirmatory non-clinical performance data in  the postmarket  
space  (e.g., post-approval study, postmarket surveillance)  
   Collectionof additional  and/or  confirmatory clinical data in  the postmarket space  (e.g., post-
approval study,  postmarket surveillance)  
 
   If  either non-clinical or  clinical performance data collections in the postmarket space are 
checked, consider:  
      The feasibility  of postmarket data collection  and likelihood that postmarket  data collection  

will be  completed  within  a reasonable timeframe   
     Whether  it would be appropriate  for  labeling to include description of postmarket  data 
collection and its purpose  
 
   Other(s)  
   None  
 
 
Question 8: Do the  Probable  Benefits outweigh the Risks considering the use of  
postmarket actions?  
   
  Yes  The  probable benefits outweigh the risks.  

  Unable to conclude that  probable  benefits outweigh the  risks   Continue  to Question 9  

   
51   Contains Nonbinding Recommendations  
 
 
 
Summary of  the Assessment  of Probable Benefit-Risk, considering postmarket actions  
For the  Proposed Indications  for Use:  
Summarize the probable benefits(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of  how Probable  Benefit(s) compare to  Risks. Include a description of how  available  
alternative modalities, including their probable benefits and risks, affect your  assessment.  Include a  
description of  how uncertainty regarding Probable Benefit(s)  and Risks affects your assessment.  Include  
a description of how patient perspectives affected your  assessment.  
 
 
Question 9: Is there  any evidence of  probable  clinical benefit  for a narrowed  Indications  
for Use?  
   
  Yes  Return to Question 1 and proceed with narrowed Indications  for Use  

  No   Do not  approve the application  

 
52   Contains Nonbinding Recommendations  
 
Appendix C   Probable Benefit-Risk  Assessment  Summary 
 
HDE  Probable Benefit-Risk  Proposed Indications for Use.  
Assessment  Summary  
HDE Questions  
 
Based on  the totality of  the data  
Device Name:  
 
HDE Number:   
Considering benefit in terms of  
Assessment  of Probable      Type      Duration  of effects   
   Magnitude      Patient perspective (or care-partner, if 
Benefit  
   Probability   applicable)  
 
1. Is there  any evidence  of clinical     YES   Q2  
benefit?     NO   Do not approve for  proposed Indications for Use;  proceed to Q9  
2. What is the  extent  of uncertainty     High    Medium Low  
for the  Probable  Benefits?1   Continue to Q3  
Considering risk in terms of  
   Severity, types,      Duration  of harmful events  
number and     Risks from false-positive or false-negative 
Assessment  of Risk 
  rates of harmful   results   
events      Patient perspective (or  care-partner, if 
   Probability  of a  applicable)  
harmful event    
3. Are known/probable  risks more     YES   Q4  
than minimal?     NO  Q4 
 
4. What is  the  extent  of uncertainty     High    Med  Low  
for the  Probable  Risks?    Continue to Q5  
Assessment  of Probable  Benefit-Risk 
 
5. Do the  Probable Benefits     YES   Worksheet complete  
outweigh the Risks?2     Unable to conclude that  probable  benefits outweigh the risks   Q6  
6. Do the  Probable Benefits  
  YES   Worksheet complete  
outweigh the Risks, taking into  
Unable to conclude that  probable  benefits outweigh the risks   Q7  
account additional considerations?  
7. Can the risks be mitigated, so  that 
  YES   Worksheet complete  
Probable Benefits  outweigh the  
  Unable to conclude that  probable  benefits outweigh the risks Q8  
Risks?  
8. Do the  Probable Benefits  
  YES   Worksheet complete  
outweigh the Risks considering the  
  Unable to conclude that  probable  benefits outweigh the risks   Q9  
use of postmarket actions?  
                                                           
1  Instructions:  If the  extent  of uncertainty is low, then  consider whether a  different  kind of marketing application  would be appropriate. However,  
low uncertainty does not  necessarily imply clinically meaningful  benefit. 
2  Instructions: For an HDE,  take into account  the probable benefits and risks of currently available devices or alternative forms of treatment.  
 
53   Contains Nonbinding Recommendations  
 
9. Is there  any evidence  of clinical  
  YES   Return to Q1 and proceed with  narrowed  Indications  for Use3  
benefit for a  narrowed Indications   
  NO  Do not approve  the application  
for Use?   
    
                                                           
3  Instructions: The term indications for use describes the disease or condition  that  the device will diagnose, treat, prevent, cure, or mitigate, 
including a description  of  the patient population  for  which the device  is intended.  See  21 CFR  814.20(b)(3)(i)  and 814.104(b)(4). Consider  the  
probable benefits  and risks for a modified population for the proposed  use,  a modified  indication for the proposed  population, or  both a modified  
indication and modified  population, which would translate into  a narrowing of the Indications for Use from what was originally proposed. Note  
that  probable benefit and probable benefit-risk  determinations for HDEs are different from those  under PMAs. For more information, refer to  
Section VI of this guidance.    
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