Guidance for Industry and 
Food and Drug 
Administration Staff 
 
 
Humanitarian Use Device (HUD) 
Designations 
 
 
Revision 1 issued:  September 5, 2019 
 
The final guidance was issued on: January 24, 2013 
The draft of this document was issued on:  December 13, 2011 
 
Written comments and suggestions may be submitted at any time for Agency consideration to the 
Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, 
(HFA-305), Rockville, MD, 20852.  Alternatively, electronic comments may be submitted to 
http://www.regulations.gov.  All comments should be identified with the docket number listed in the 
notice of availability that publishes in the Federal Register.  Comments may not be acted upon by the 
Agency until the document is next revised or updated.   
 
For questions regarding this document contact Dr. Erika Torjusen at 301-796-2278 or 
Erika.Torjusen@fda.hhs.gov.  
  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Orphan Products Development (OOPD) 
Center for Devices and Radiological Health (CDRH) 
Center for Biologics Evaluation and Research (CBER) 
   
Guidance for Industry and 
Food and Drug 
Administration Staff 
 
 
Humanitarian Use Device (HUD) 
Designations
  
 
Additional copies are available from: 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
WO71-3128 
Silver Spring, MD 20993  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
Email:  ocod@fda.hhs.gov   
(Tel) 800-835-4709 or 240-402-8010 
 
and/or 
 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave. 
WO66-5431 
Silver Spring, MD 20993  
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products  
Email: CDRH-Guidance@fda.hhs.gov  
 
 and/or 
 
Office of Orphan Products Development 
Office of Clinical Policy and Programs 
Food and Drug Administration 
10903 New Hampshire Ave. 
Bldg. 32, rm. 5271 
Silver Spring, MD 20993 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm 
Email:  orphan@fda.hhs.gov   
(Tel) 301-796-8660 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CONTENTS OF HUD REQUESTS ................................................................................ 3 
A.  Description of the Disease or Condition ....................................................................................... 5 
B.  Population Estimates ..................................................................................................................... 6 
B.1  Therapeutic Devices ....................................................................................................................... 7 
B.2  Diagnostic Devices .......................................................................................................................... 8 
B.3  Devices Intended For Repeat or Multiple Use ............................................................................. 9 
C.  Orphan Subset of a Non-Rare Disease or Condition .................................................................. 9 
D.  Device Description and Scientific Rationale for its Proposed Use ........................................... 11 
D.1  Device Description ....................................................................................................................... 11 
D.2  Scientific Rationale ...................................................................................................................... 12 
E.  Supporting Documentation ......................................................................................................... 12 
IV.  PEDIATRIC CONSIDERATIONS ............................................................................... 13 
V.  HUD DECISION FLOWCHART ................................................................................. 13 
  Contains Nonbinding Recommendations 
 
Guidance for Industry and 
Food and Drug Administration Staff 
 
 
 
Humanitarian Use Device (HUD) 
Designations 
 
 
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  
 
This guidance document is intended to assist applicants in the preparation and submission of 
Humanitarian Use Device (HUD) designation requests to the U.S. Food and Drug 
Administrations (FDA or Agency) Office of Orphan Products Development (OOPD).  It is also 
designed to assist FDA reviewers in their evaluation and analysis of HUD designation requests 
(HUD requests or requests).  Topics addressed in this guidance include: 
 
  demonstrating in HUD requests that the device is designed to treat or diagnose a disease 
or condition that affects or is manifested in not more than 8,000 individuals in the United 
States per year; 
 
  how this demonstration varies depending on whether the device is intended for 
therapeutic or diagnostic purposes; 
 
  how properties of the device may affect this demonstration; and  
 
  for the purpose of a HUD request, identifying a medically plausible subset (orphan 
subset) of persons with a given disease or condition that affects or is manifested in more 
than 8,000 individuals in the United States per year. 
 
This guidance addresses only HUD requests, which are the first step in seeking marketing 
approval of a HUD.  This guidance does not address the second step in this marketing approval 
processnamely, the submission of a Humanitarian Device Exemption (HDE) application to the 
Center for Devices and Radiological Health (CDRH) or to the Center for Biologics Evaluation 
and Research (CBER).  For more information on the preparation and submission of HDE 
  1  Contains Nonbinding Recommendations 
 
applications, see Humanitarian Device Exemption (HDE) Program: Guidance for Industry and 
Food and Drug Administration Staff.1   
 
This guidance is responsive to the congressional mandate in section 740 of the fiscal year 2010 
U.S. Appropriations Act (Agriculture, Rural Development, Food and Drug Administration, and 
Related Agencies Appropriations Act, 2010, Public Law 111-80) dated October 21, 2009.  
Among other things, the congressional mandate required that the Commissioner of Food and 
Drugs establish a review group within FDA to describe its findings and make recommendations 
on issues related to rare and neglected diseases and, in part, to develop guidance document(s) 
based upon these recommendations.   
 
In general, FDAs guidance documents 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 guidances means that something is suggested or recommended, but 
not required.  
 
II.  BACKGROUND 
 
HUD designations are requirements of the HDE provisions in the Safe Medical Devices Act 
(SMDA) of 1990 (Public Law 101-629), as amended.2  See section 520(m) of the Federal Food, 
Drug, and Cosmetic Act (FD&C Act), 21 USC  360j(m).  As defined in 21 CFR 814.3(n), a 
HUD is a medical device intended to benefit patients in the treatment or diagnosis of a disease 
or condition that affects or is manifested in not more than 8,000 individuals in the United States 
per year.3   
  
Devices that receive HUD designation may be eligible for marketing approval under an HDE 
application.  A device that has received HUD designation is eligible for an HDE approval if, 
among other criteria, evidence is provided 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.  4  FDA 
approval of an HDE application authorizes the applicant to market the device in accordance with 
                                                 
1 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/humanitarian-device-
exemption-hde-program.   
2 The HDE provisions have been amended several times since 1990, including in the FDA Modernization Act of 
1997 (FDAMA), in the FDA Amendments Act of 2007 (FDAAA), in the FDA Safety and Innovation Act 
(FDASIA) of 2012, in the 21st Century Cures Act (Cures Act) of 2016, and in the FDA Reauthorization Act of 2017 
(FDARA).  The Cures Act increased the threshold for HUD designation from fewer than 4,000 individuals in the 
United States to not more than 8,000 individuals in the United States. 
3 If there are questions about whether your product is subject to regulation as a medical device, you should contact 
the Office of Combination Products (OCP) by e-mail at combination@fda.gov or by phone at 301-796-8930. 
4 Additionally, to be eligible for HDE approval, the applicant must certify that no comparable device, other than 
another device approved under the HDE provision or a device approved under an Investigational Device Exemption, 
is available to treat or diagnose the disease or condition, and explain why the device would not be available to a 
person with the disease or condition in question without the HDE approval.  Section 520(m) of the FD&C Act; 21 
CFR 814.104(b)(2). 
  2  Contains Nonbinding Recommendations 
 
approved labeling and indication(s) for use.  This marketing approval is subject to certain profit 
and use restrictions set forth in section 520(m) of the FD&C Act.   
 
Although a HUD designation from OOPD is a prerequisite for submitting an HDE marketing 
application to CDRH or CBER, it does not by itself guarantee approval of the HDE application. 
 
The required contents of a HUD request are set forth in 21 CFR 814.102, and described in detail 
in Section III of this guidance document.  Once a HUD request is ready for submission to 
OOPD, the applicant should send two signed and dated submissions (the original and a copy) to 
the address below.   
 
Office of Orphan Products Development 
Food and Drug Administration 
WO32-5271 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
 
Section 745A of the FD&C Act requires applicants to include an electronic copy of certain 
submission types, including presubmissions and submissions under section 520(m) of the FD&C 
Act, after issuance of final guidance implementing that provision.  FDA has issued the final 
Guidance for Industry and FDA Staff: eCopy Program for Medical Devices.5  We recommend 
applicants include an eCopy as one of the two required copies of their HUD request.  
 
Upon receipt of a HUD request, OOPD will issue an acknowledgement letter to the applicant and 
assign a reference number for any future correspondence related to that HUD request.  The 
review process for a HUD request takes up to 45 calendar days from the date of receipt by 
OOPD.  Within this 45-day timeframe, OOPD will approve the request, request additional 
information, or disapprove the request.6  The receipt of additional information from the applicant 
may trigger a new 45-day review clock for OOPD. 
 
If OOPD approves the HUD request, the applicant becomes eligible to submit an HDE marketing 
application to the appropriate assigned center (CDRH or CBER).  The HDE application must 
include a copy of or reference to OOPDs HUD designation letter for the device.7   
 
If questions arise regarding HUD requests or the program in general, OOPD may be contacted at 
orphan@fda.hhs.gov or 301-796-8660.  
 
III.  CONTENTS OF HUD REQUESTS  
 
As set forth in 21 CFR 814.102, a HUD request includes the following: 
 
                                                 
5 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ecopy-program-medical-
device-submissions.  
6 21 CFR 814.102(b).  
7 21 CFR 814.104(b)(1). We encourage applicants to submit an actual copy of the designation letter with their HDE 
application. 
  3  Contains Nonbinding Recommendations 
 
(1)  A statement that the applicant requests HUD designation for a rare disease or condition or 
a specifically identified orphan subset of a non-rare disease or condition.  For the purpose 
of HUD requests, a rare disease or condition is one that affects or is manifested in not 
more than 8,000 individuals in the United States per year; a non-rare disease or 
condition is one that affects or is manifested in more than 8,000 individuals in the 
United States per year. 8  For further explanation of population estimates in HUD 
requests, and specifically how these estimates vary depending on whether the device is 
intended for therapeutic or diagnostic purposes, see Section III.B below. 
(2)  The title, name, address, and telephone number of the applicant and the primary contact 
person(s).  An e-mail address for the primary contact person(s) is recommended. 
(3)  A description of the rare disease or condition that the device treats or diagnoses, ideally 
with particular emphasis on the specific aspects of the disease or condition relevant to the 
functionality of the device, as well as the proposed indication(s) for use of the device 9 
and the reasons why such therapy is needed. 
  If the device treats or diagnoses a non-rare disease or condition, then the applicant 
o
must demonstrate an orphan subset for the device (see Section III.C). 10 
(4)  A description of the device and a discussion of the scientific rationale for the use of the 
device for the rare disease or condition or an orphan subset of a non-rare disease or 
condition (see Section III.D).   
(5)  Documentation, with appended authoritative references, to demonstrate that the device is 
designed to treat or diagnose a rare disease or condition that affects or is manifested in 
not more than 8,000 people in the United States per year (see Sections III.B and III.E).  
Similar documentation is required to demonstrate that not more than 8,000 people in the 
United States per year make up a valid orphan subset for a non-rare disease or condition 
(see Section III.C). 
  If the device is intended for diagnostic purposes,11 including devices intended to 
o
assess the state of a patients health, the population documentation must 
demonstrate that not more than 8,000 patients per year would be subjected to 
                                                 
8 See section 520(m)(2)(A) of the FD&C Act,; 21 CFR 814.102(a)(5).   
9 As described elsewhere in this guidance, OOPD designates a device for use in a rare disease or condition or in an 
orphan subset of a non-rare disease or condition, not for particular indication(s) for use or proposed labeling.  The 
proposed indication(s) for use of the device are nonetheless relevant to a HUD request to help OOPD assess what 
disease or condition the device treats or diagnoses. 
10 FDA uses the same terminology, orphan subset, when evaluating requests for HUD and orphan-drug 
designations.  It is important to note, however, that Congress created different eligibility criteria for HUD 
designations than for orphan-drug designations.  For HUD designations, one eligibility criterion is that the disease or 
condition in question affects not more than 8,000 individuals in the United States (rare disease or condition for the 
purpose of HUD requests), whereas for orphan-drug designations one such criterion is that the disease or condition 
affects fewer than 200,000 individuals in the United States (rare disease or condition for the purpose of orphan-
drug designation requests).  FDA nonetheless employs the same terminology, orphan subset, for HUD 
designations as for orphan-drug designations because the limiting principle is the same: some property or properties 
of the device or drug preclude its use outside of an orphan subset of a non-rare disease or condition (e.g., adverse 
event profile of the product, mechanism of action of the product, etc.).  For more on orphan subsets in HUD 
requests, see Section III.C of this guidance. 
11 See, for example, 21 CFR 809.3(a) (definition of in vitro diagnostic products). 
  4  Contains Nonbinding Recommendations 
 
diagnosis by the device for the disease or condition in the United States.12  This 
population estimate would include all patients who would be tested with the 
diagnostic device annually, including all who test positive or negative for the 
disease or condition (see Section III.B.2). 
 
We recommend that applicants include a cover letter in their HUD requests containing a 
statement that requests either HUD designation for a rare disease or condition, or a specifically 
identified orphan subset of a non-rare disease or condition.  For the remaining information listed 
below, we recommend that applicants include a table of contents, with pagination, identifying 
information in the following order:   
 
  title, name, address, telephone number, and e-mail address of the applicant and 
primary contact person(s);  
  adequate description of the rare disease or condition or documentation of an orphan 
subset of a non-rare disease or condition; 
  proposed indication(s) for use of the device;  
  adequate description of the device and the scientific rationale for its use as proposed; 
  population estimate;  
  bibliography;  
  copies of all cited references separated by tabs; and  
  appendices, if applicable.   
 
Below, we provide clarity on particular elements of HUD requests that have historically caused 
confusion among applicants.  In particular, we focus on the disease or condition that the device 
treats or diagnoses, population estimates, orphan subsets, device descriptions, scientific 
rationales, and supporting documentation. 
 
A.  Description of the Disease or Condition 
 
A HUD request must include a description of the rare disease or condition that the device 
treats or diagnoses, or the non-rare disease or condition in the case of an orphan subset.13  
As noted above, a rare disease or condition for the purpose of HUD requests is one that 
affects or is manifested in not more than 8,000 individuals in the United States per year.14  
Ideally, the description of the rare disease or condition should focus on specific aspects of 
the disease or condition relevant to the functionality of the device, as well as any 
information that assists in defining the patient population.  
 
OOPD designates a device for a rare disease or condition (or for an orphan subset of a 
non-rare disease or condition, as described in Section III.C), not for a specific indication 
or proposed labeling for the device.15  In general, when OOPD gives a HUD designation 
to a device for a rare disease or condition (or orphan subset), it will designate the device 
for use by all persons with that rare disease or condition (or orphan subset), even if the 
                                                 
12 See 21 CFR 814.102(a)(5).   
13 21 CFR 814.102(a)(3). 
14 See supra note 10. 
15 See supra note 9. 
  5  Contains Nonbinding Recommendations 
 
applicant may eventually obtain HDE marketing approval for only select indications 
within that rare disease or condition (or orphan subset).  That is, whatever the scope of 
HUD designation, the scope of marketing approval is governed by the data and 
information submitted in the marketing application for the device.  It is therefore not 
uncommon for the HUD designation to be broader than the indication(s) for which the 
device is eventually approved via HDE.  For example, at the HUD stage, a device may be 
designated for treatment of fetal bladder obstruction regardless of gestational age, but at 
the HDE stage, the device may be approved for treatment of fetal bladder obstruction 
only in fetuses of 18 to 32 weeks gestational age, based on the data and information 
submitted in the HDE marketing application.   
 
When reviewing HUD requests, OOPD first asks what disease or condition the device 
treats or diagnoses.  Assume, for example, that an applicant states in a HUD request that 
a device treats multiple myeloma.  Upon reviewing the HUD request, OOPD will 
consider how the device works to treat or diagnose the disease or condition.  OOPD may 
determine that the device does not in fact treat multiple myeloma, but instead treats a 
manifestation of multiple myeloma, where the device, for example, is intended to fill 
osteolytic lesions in patients with multiple myeloma, but does not treat the multiple 
myeloma itself.   
 
In this example, for designation purposes, OOPD may initially consider the disease or 
condition that the device treats or diagnoses to be the lytic lesions and not the multiple 
myeloma.  OOPD may then ask the sponsor for additional information to determine 
whether lytic lesions due to multiple myeloma should be considered a distinct disease or 
condition from lytic lesions due to other causes (e.g., bone metastasis or hemangioma).  
Showing that a disease or condition is distinct for designation purposes generally entails a 
cumulative assessment of a number of factors, including:  pathogenesis of the disease or 
condition; course of the disease or condition; prognosis of the disease or condition; and 
resistance to treatment.  Absent information justifying that lytic lesions from multiple 
myeloma should be considered a different condition than lytic lesions from other causes, 
OOPD may consider the disease or condition treated by this device to be lytic lesions 
regardless of cause and the sponsor may be asked to provide a population estimate that 
includes patients with lytic lesions from all causes. 
 
Identifying the appropriate disease or condition that the device treats or diagnoses (e.g., 
multiple myeloma, lytic lesions regardless of cause, or lytic lesions due to multiple 
myeloma) is critical to estimating the affected patient population, as described below. 
 
B.  Population Estimates 
 
In seeking HUD designation, it is important to understand the difference between disease 
prevalence and disease incidence.  Prevalence is generally understood as the total number 
of patients with a disease or condition in the population at a given time (e.g., point 
prevalence).  Incidence is generally understood as the number of new patients diagnosed 
with a disease or condition during a particular time period, such as annually (e.g., annual 
incidence).  As described in the preamble to the 1996 Final Rule on HUD designations, 
FDA added the qualifying phrase per year to the regulation (not more than 8,000 
  6  Contains Nonbinding Recommendations 
 
individuals in the United States per year) in an attempt to clarify that it interprets the 
statutory provision as annual incidence, not as point prevalence.16   
 
The method for estimating the affected population in HUD requests varies depending on 
whether the device is intended for therapeutic or diagnostic purposes.  For therapeutic 
devices, as described below, the population estimate is generally the number of new 
patients per year diagnosed with the relevant disease or condition and eligible for 
treatment with the device.  For diagnostic devices, as described below, the population 
estimate is generally the number of patients per year who would be subjected to diagnosis 
with the device, regardless of whether the test result is positive or negative.  Because of 
this difference, each applicant should identify in a HUD request whether the device is 
intended for therapeutic or diagnostic purposes.   
 
B.1  Therapeutic Devices  The Number of New Patients Per Year Who 
Are Diagnosed with the Disease or Condition and Who Would be 
Eligible for Treatment with the Device   
 
Therapeutic devices are eligible for HUD designation if they treat a disease or condition 
with an annual incidence of not more than 8,000 individuals in the United States.  Annual 
incidence in this context generally means the number of new patients per year who are 
diagnosed with the disease or condition and who would be eligible for treatment with the 
device, given the characteristics of the disease or condition and the properties of the 
device.   
 
Below are three examples of annual incidence estimates for therapeutic devices that 
exemplify the ways in which incidence is impacted by differences in the characteristics of 
the device and of the disease or condition in question: 
 
  Sample Incidence Estimate for HUD Request Involving All New Patients 
Diagnosed with a Disease or Condition:  Assume a HUD request is submitted 
for a device designed to treat patients with cystic fibrosis by reducing respiratory 
complications.  The incidence estimate for this request would generally include all 
new patients diagnosed with cystic fibrosis per year.  
 
  Sample Incidence Estimate for HUD Request to Reduce Flare-ups of a 
Disease or Condition:  Assume a HUD request is submitted for a device 
designed to treat patients with multiple sclerosis (MS) by reducing MS flare-ups.  
The incidence estimate for this request would generally include all new patients 
                                                 
16 61 Fed. Reg. 33232, 33233 (June 26, 1996).  As FDA described in this rulemaking, this interpretation serves the 
primary purpose of section 520(m) of the FD&C Act, to provide an incentive for the development of devices to be 
used in the treatment or diagnosis of diseases or conditions that affect small patient populations.  Id.  Adopting a 
point prevalence definition would have been considerably more restrictive and would have provided less of an 
incentive for the development of such devices.  Id. Note that at the time of the rulemaking, the statutory threshold 
was less than 4,00 individuals in the United States per year.  The statute and regulation have been updated to 
reflect the threshold of not more than 8,000 individuals in the United States per year.  See 82 Fed. Reg. 26348 
(June 7, 2017).   
  7  Contains Nonbinding Recommendations 
 
diagnosed with MS per year, no matter how many flare-ups each patient with MS 
may have in a given year.  
 
  Sample Incidence Estimate for HUD Request of a Disease or Condition 
Where the Manifestation Treated by the Device May Develop After Initial 
Disease Diagnosis:  Assume a HUD request is submitted for a device designed to 
treat respiratory failure in patients with amyotrophic lateral sclerosis (ALS).   If 
OOPD determines respiratory failure in ALS to be different than respiratory 
failure in other diseases, then the incidence estimate for this request would 
generally include those patients with ALS who develop respiratory failure in a 
given year no matter when they were first diagnosed with ALS. 
 
B.2  Diagnostic Devices  Patients Per Year Who Would be Subjected to 
Diagnosis by the Device in the United States (Regardless of Test 
Result) 
 
As stated in 21 CFR 814.102(a)(5), the population estimate for diagnostic devices 
depends on the number of patients per year who would be subjected to diagnosis by the 
device in the United States.  This calculation includes not only those who test positive for 
the disease or condition, but also those who test negative for the disease or condition.   
 
The number of patients per year who would be subjected to diagnosis with the device 
depends on the disease or condition that the device diagnoses and the circumstances of 
use.  The number of patients would differ, for example, depending on whether the 
diagnostic is (1) an initial diagnostic or screening test used to diagnose or screen a 
population, (2) a confirmatory test used to confirm the diagnosis of individuals who have 
already screened positive for the disease or condition, (3) a treatment guide used to help 
select or exclude a given therapy for patients with a given disease or condition, or (4) a 
monitoring test used to monitor progression of a given disease or condition. 
 
Below are examples of population estimates for various diagnostic devices: 
 
  An example of a diagnostic device that may qualify for HUD designation is a 
device that identifies a specific gene rearrangement in patients with a rare 
malignancy.  If the annual incidence of the rare malignancy is not more than 
8,000 new cases per year, then not more than 8,000 patients per year would be 
subjected to diagnosis with the device.  The device may therefore be eligible for 
HUD designation. 
 
  An example of a diagnostic device that may qualify for HUD designation is a 
device that monitors a particular blood chemistry or hematology parameter which 
is indicative of disease activity.  In order to qualify for HUD designation, the 
number of patients subjected to the device must be not more than 8,000 patients 
per year (i.e., all new patients diagnosed with the disease or condition as well as 
existing patients with the disease or condition surviving from previous years). 
 
  8  Contains Nonbinding Recommendations 
 
  An example of a diagnostic device that would not qualify for HUD designation is 
a device used to screen all newborn babies to identify certain serious or life-
threatening conditions before symptoms begin.  Even if the serious life-
threatening disease or condition ultimately affects not more than 8,000 patients in 
the United States per year, the diagnostic device would not be eligible for HUD 
designation because the number of newborn babies subjected to the screening test 
would exceed the not more than 8,000 patient per year limit.  
 
  An example of a diagnostic device that may not qualify for HUD designation is a 
device used to screen patients who exhibit certain symptoms associated with a 
rare disease or condition, if the same symptoms are also associated with a non-
rare disease or condition.  The number of patients screened per year would 
include all patients who exhibit those symptoms; if that number exceeds the not 
more than 8,000 patient per year limit, then the diagnostic device would not 
qualify for HUD designation. 
 
B.3  Devices Intended For Repeat or Multiple Use 
 
We recognize that an individual may use a device more than once a year.  Devices 
intended for repeat or multiple use may include a device implanted in more than one 
organ, multiple devices implanted in a single organ (either simultaneously or sequentially 
within a given year), or a diagnostic used on the same patient on a regular basis (e.g., as a 
monitoring test).  HUD designations for therapeutic devices depend on the total number 
of new patients with the disease or condition who would be eligible for use of the device 
in a given year, not on the total number of devices expected to be used in a given year.  
Thus, for example, if there are 3,000 individuals with a given disease or condition who 
would each use (on average) a given device four times per year, that device may still be 
eligible for HUD designation.  Likewise, HUD designations for diagnostic devices 
depend on the total number of new patients subjected to diagnosis by the device in a 
given year, not on the total number of devices expected to be used in a given year.17   
 
C.  Orphan Subset of a Non-Rare Disease or Condition 
 
If a device is designed to treat or diagnose a non-rare disease or condition, it is eligible 
for HUD designation only if the sponsor can show that the device is in fact designed to 
treat or diagnose an orphan subset of this population that occurs in not more than 8,000 
people in the United States per year.18  
 
Orphan subset is a regulatory phrase used to describe the subset of individuals with a 
non-rare disease or condition on whom use of a device is appropriate, where use of the 
device on the remaining individuals with that disease or condition would be inappropriate 
given some intrinsic feature of the device (e.g., adverse event profile or mode of 
action).19  An orphan subset cannot be considered without reference to the device, 
                                                 
17 See 21 CFR 814.126(b)(1)(iii). 
18 See 21 CFR 814.102(a)(3).   
19  See supra note 10. 
  9  Contains Nonbinding Recommendations 
 
specifically to the property or properties of the device that render it medically or 
scientifically inappropriate to use outside of the subset of interest in the remaining 
persons with the non-rare disease or condition.  Factors that may inform whether an 
appropriate orphan subset exists for this purpose include the following inherent properties 
of a device: 
 
  Mechanism of Action of the Device:  The mechanism of action of a device may 
render it scientifically or medically appropriate to limit use of the device to only a 
subset of patients with a non-rare disease or condition.  It may be reasonable to 
expect that certain targeted therapies would be used in only a subset of patients 
based on device functionality.  For example, it may be appropriate to limit use of 
a rigid stent to treatment of only certain locations in the brain in a disease that is 
otherwise non-rare, because in other locations of the brain, the tortuosity of the 
vessels may prevent adequate deployment of the stent. 
 
  Adverse Event Profile:  The adverse event profile of a device for a non-rare 
disease or condition may mean that the device should not be used to treat all 
persons with the disease or condition who can be treated with other, less risky 
therapies.  Consider, for example, an implantable device that treats a non-rare 
disease or condition and is known to have a serious adverse event profile because 
of the risks associated with the implantation process.  It may be possible to 
establish an orphan subset for this device by showing that it would be medically 
or scientifically appropriate, based on the adverse event profile, to restrict use of 
the device to only those patients who are refractory to drug therapy.  The serious 
adverse event profile may preclude use of the device in patients who have not 
failed drug therapy, when therapies with fewer risks are available to these 
patients. 
 
  Other Clinical Experience with the Device:  Information on the devices 
activity, available from completed clinical trials or published in clinical literature 
may be used to establish an orphan subset.  For example, if relevant data show 
that the device has no significant activity in the subset of patients with high grade 
tumors but there is some reason to expect that it might have activity in patients 
with low grade tumors, then patients with low grade tumors may constitute an 
orphan subset within a given disease or condition. 
 
It is important to understand that an orphan subset does not simply mean any 
medically recognizable or clinically distinguishable subset of persons with a non-
rare disease or condition.  For a HUD designation, device property(ies) must 
preclude its use in the remaining persons with the non-rare disease or condition.  
HUD designation facilitates the pathway to market for devices truly designed for 
small populations by making those devices eligible for exemption from the 
reasonable assurance of effectiveness requirement.20  Accepting limitations of this 
                                                 
20 HDEs are 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. See sections 514, 515, and 520(m) of the 
FD&C Act. 
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sort, without further justification (i.e., reference to feature(s) of the device that 
render use outside of the subset of interest scientifically or medically inappropriate), 
would allow for artificially narrow subsets for the purpose of HUD designation and 
would be inconsistent with the purpose of the HDE provision.  Factors that do not 
inform whether an orphan subset exists include, for example: 
 
  Clinical Trial Eligibility:  An orphan subset would not be appropriate where the 
subset of interest is defined only by eligibility to enroll in a given clinical trial to 
support a specific indication for use of a device, and where there is no scientific or 
medical reason to preclude use of the device in the remaining persons with the 
same non-rare disease or condition.  Similarly, patients who do not meet inclusion 
or exclusion criteria for a trial do not automatically qualify as an orphan subset 
because it could be medically appropriate to evaluate the same device for use in 
the remaining persons with the non-rare disease or condition, outside of the subset 
of interest.   
 
  Sponsors Plan to Study the Device for a Select Indication:  An orphan subset 
does not exist simply because the sponsor plans to study the device for only a 
select indication within a non-rare disease or condition, absent a plausible 
argument why the device could not be used to safely or effectively treat the 
remaining persons with the non-rare disease or condition. 
 
  Unmet Medical Need:  Patients with a non-rare disease or condition who have an 
unmet medical need do not automatically constitute an orphan subset unless the 
applicant can justify limiting use of the device to only that subset, based on 
limiting feature(s) of the device, as described above.  
  Current Standard of Care:  Opinions regarding the current standard of care 
as it relates to the use of a device on certain individuals cannot be the basis for 
identifying an orphan subset.  The standard of care will evolve with study of the 
new treatment option and it may be determined, at some point, that it is medically 
or scientifically appropriate to use the device in a larger population with the non-
rare disease or condition. 
  Price:  An orphan subset of a non-rare disease or condition does not exist because 
of price considerations.  The applicant would instead need to justify limiting use 
of the device to the subset of interest based on feature(s) of the device that 
preclude its use in the broader population with the same non-rare disease or 
condition. 
 
D.  Device Description and Scientific Rationale for its Proposed Use  
 
D.1  Device Description   
 
The description of the device should include adequate details to fully describe the device 
under consideration, i.e., a comprehensive list and description of all aspects of the device 
with relevant dimensions, reagents, and/or specifications noted.  Drawings, photographs, 
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or other visual representations are encouraged, as well as a description of the mechanistic 
and operative aspects of the device.   
 
D.2  Scientific Rationale  
 
The scientific rationale supporting use of the device for the rare disease or condition, or 
orphan subset of a non-rare disease or condition (see Section III.C) in the HUD request 
should contain all relevant nonclinical, clinical, and/or proof-of-principle data pertaining 
to the device as applicable  whether positive, negative, or inconclusive.  It should be 
noted that the nonclinical information on whether a device has been verified and 
validated against the proposed device design specifications is reviewed in the HDE 
marketing application and not in the HUD request. 
 
E.  Supporting Documentation 
 
The applicant must include documentation, with appended references, to demonstrate that 
the device is intended to treat or diagnose a disease or condition that affects or is 
manifested in not more than 8,000 people per year in the United States.  Incidence data 
should be based on patients in the United States.  For therapeutic devices, this 
documentation must demonstrate that the annual incidence of the disease or condition is 
not more than 8,000 patients per year.  For diagnostic devices, this documentation must 
demonstrate that not more than 8,000 patients per year would be subjected to diagnosis 
by the device in the United States.  See Sections III.B.1 and III.B.2 for population 
estimates and 21 CFR 814.102(a)(5).  Authoritative references in this context include 
literature citations in specialized medical journals, textbooks, specialized medical 
society proceedings, or governmental statistics publications.  21 CFR 814.102(a)(5).   
 
We recommend including in HUD requests all relevant documentation on the population 
estimate  whether supportive, non-supportive, or inconclusive.  If literature and other 
resources are inadequate to document the annual incidence of the disease or condition, 
the applicant should document the effort to obtain such information and may then provide 
a credible incidence estimate, with methodology, through the use of appropriate research, 
surveys, or consultation with independent experts in the relevant field.  Generally, for an 
estimate from experts to be considered credible in this context, at least three independent 
experts in the relevant field should be consulted.  Each expert should provide his/her 
estimate, and methods used to reach this estimate, of the annual incidence of the disease 
or condition that the device treats or, if the device is a diagnostic, the number of patients 
that would be subjected to diagnosis per year by the device in the United States.  See 
Sections III.B.1 and III.B.2 for population estimates.  Regardless of the total number of 
experts consulted, the findings of each expert should be provided, whether supportive, 
non-supportive, or inconclusive.   
 
Simply stating that the incidence of the disease is not more than 8,000 patients per year in 
the United States or that not more than 8,000 patients per year in the United States would 
be subjected to diagnosis by the device is not adequate for HUD designation.  Insufficient 
evidence of the population estimate may result in disapproval of the HUD request.  21 
CFR 814.102(b)(3)(i).   
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IV.  PEDIATRIC CONSIDERATIONS 
 
For the purposes of HUD requests, the pediatric population is defined as those younger 
than 22 years of age (i.e., inclusive of the patients 21st year of life).21  Generally, OOPD 
will designate for the entire population (i.e., pediatric and adult) if the incidence of the 
disease or condition affects or is manifested in not more than 8,000 patients per year in 
the United States.  However, in situations where the entire population is greater than 
8,000 patients per year, a device may be eligible for HUD designation in the pediatric 
population if the pediatric population affected by the disease or condition in question is 
not more than 8,000 in the United States per year.   
 
V.  HUD DECISION FLOWCHART 
 
The HUD Decision Flowchart serves as a quick guide and outlines the OOPD review 
process for a HUD request but does not include other issues or considerations that may 
arise during a HUD request review and are otherwise discussed in this guidance 
document.  This guide shows that in its review, OOPD identifies the disease or condition 
that the device treats or diagnoses, evaluates the population estimate, and reviews the 
scientific rationale for the device.  OOPD has 45 days to review the submission and 
provide official communication to the applicant. 
                                                 
21 See section 520(m)(6)(E)(i) of the FD&C Act and FDA Guidance on Premarket Assessment of Pediatric Medical 
Devices, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-
assessment-pediatric-medical-devices.   
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