Clarification of Orphan 
Designation of Drugs and 
Biologics for Pediatric 
Subpopulations of Common 
Diseases
  
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Orphan Products Development (OOPD) 
 
July 2018 Clarification of Orphan 
Designation of Drugs and 
Biologics for Pediatric 
Subpopulations of Common 
Diseases 
 
 
 
Guidance for Industry 
 
 
 
 
Additional copies are available from: 
Office of Orphan Products Development 
Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 32, Rm. 5295 
Silver Spring, MD 20993 
Tel: 301-796-8660; E-mail: orphan@fda.hhs.gov 
https://www.fda.gov/orphan  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Orphan Products Development (OOPD) 
 
July 2018 Contains Nonbinding Recommendations 
 
Clarification of Orphan Designation of Drugs and Biologics for 
Pediatric Subpopulations of Common Diseases 
Guidance for Industry 
 
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 office responsible for this guidance as listed on the 
title page.   
 
 
I.  INTRODUCTION 
 
This guidance is intended for sponsors of drugs and biological products (hereafter drugs1) who 
are considering submitting requests for orphan-drug designation for their drugs under section 526 
of the Federal Food, Drug, and Cosmetic Act (FD&C Act).  The Food and Drug Administration 
(FDA) does not expect to grant any additional orphan-drug designation to drugs for pediatric 
subpopulations of common diseases (i.e., diseases or conditions with an overall prevalence of 
200,000 or greater). Pediatric-subpopulation designations that have already been granted will not 
be affected by this change. 
 
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 FDAs guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
Congress enacted the Orphan Drug Act (ODA) to give sponsors incentives to develop drugs to 
prevent, diagnose, or treat rare diseases and conditions, including in pediatric patients with such 
diseases.2  Orphan-drug designation may cover diseases in pediatric patients in several ways, 
including the following: 
1.  If a disease is rare (i.e., the prevalence of the disease is less than 200,000), a drug may be 
eligible for designation for the entire disease.  The pediatric population, as part of the 
population being affected by that disease, would be covered under that orphan 
designation. 
                                                 
1 For the purposes of this guidance, the term drugs refers to both human drug and biological products regulated by 
the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research. 
2 Pub. L. 97-414 (1983), codified as amended at 21 U.S.C.  360aa - 360ee.  The ODA generally defines a rare 
disease or condition as any disease or condition that affects fewer than 200,000 persons in the United States.   
 
1 
  Contains Nonbinding Recommendations 
 
2.  If a disease is common (i.e., the prevalence of the disease is 200,000 or greater), a drug 
may be eligible for orphan designation for a valid orphan subset of the disease.3  For 
example, if the prevalence of the pediatric population affected by the disease is less than 
200,000 and if it would not be appropriate to use the drug in the adult population of the 
disease, the drug may be eligible for orphan designation for the pediatric population as an 
orphan subset. 
3.  If the disease in the pediatric population is in fact a different disease from the disease in 
the adult population, and the prevalence of that pediatric population is less than 200,000, 
the disease in the pediatric population is itself a rare disease for which a drug may be 
eligible for orphan-drug designation.   
For each orphan-drug designation request, FDA determines whether a given medical condition 
constitutes a distinct disease or condition based on a number of factors assessed cumulatively, 
including: pathogenesis of the disease or condition; course of the disease or condition; prognosis 
of the disease or condition; and resistance to treatment.  These factors are analyzed in the context 
of the specific drug for which designation is requested.4   
 
In addition, FDA had historically granted orphan-drug designation to drugs intended for use in 
pediatric subpopulations of common diseases or conditions (i.e., diseases or conditions with an 
overall prevalence of 200,000 or greater in the U.S.) if the prevalence in the pediatric 
subpopulation in the U.S. is below 200,000.5  For example, if a given common disease occurs in 
both adults and children, the pediatric subpopulation would be the portion of those individuals 
with the disease who are younger than 17 years of age.6  And if the prevalence of this given 
disease in the pediatric subpopulation were less than 200,000 in the U.S., this subpopulation 
would be considered a rare pediatric subpopulation.  In such a case, upon a sponsors request, 
FDA has granted pediatric-subpopulation designation to the sponsors drug.  This was a specific 
type of orphan-drug designation, in which FDA granted designation to a drug for use in a rare 
pediatric subpopulation of a common disease or condition. 
 
                                                 
3 The orphan drug regulations define an orphan subset to mean that use of the drug in a subset of persons with a 
non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons 
with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug....  See 21 
CFR  316.3(b)(13).  Therefore, a sponsor requesting orphan-drug designation for a drug for use in an orphan subset 
must demonstrate that, due to one or more properties of the drug, the remaining persons with such disease or 
condition would not be appropriate candidates for use of the drug.  See 21 CFR  316.20(b)(6).  For more on 
factors that may inform whether or not an appropriate orphan subset exists, see FDA, Orphan Drug Regulations, 
Final Rule, 78 Fed. Reg. 35117, 35119-35120 (June 12, 2013). 
4 See FDA, Orphan Drug Regulations, Final Rule, at 35120. 
5 The term common disease or condition is used interchangeably with non-rare disease or condition in this 
document; both refer to diseases or conditions with an overall prevalence of 200,000 or greater in the U.S. 
6 The regulation governing labeling requirements defines the pediatric population as including patients aged birth 
to 16 years, including age groups often called neonates, infants, children, and adolescents.  See 21 CFR  
201.57(c)(9)(iv).  FDA has interpreted this regulation to mean birth to younger than 17 years (i.e., birth through 16 
years of age).  For the purposes of orphan-drug designation, FDA also defines pediatric as birth through 16 years of 
age. 
 
2 
  Contains Nonbinding Recommendations 
 
Two examples of pediatric-subpopulation designations include designations of drugs to treat 
pediatric ulcerative colitis and pediatric HIV.  Each of these diseases (e.g., ulcerative colitis or 
HIV) is common (i.e., the total prevalence is 200,000 or greater in the U.S.), but because the 
prevalence of the disease in the pediatric population in the U.S. falls below 200,000, FDA has 
granted pediatric-subpopulation designation for drugs for use in pediatric subpopulations with 
these two diseases.   
 
FDA began the practice of pediatric-subpopulation designation before the enactment of 
legislation to specifically promote the study of drugs in the pediatric population.  Sponsors had 
historically failed to include pediatric populations in the research and development of their drugs 
for common diseases or conditions at that time.  To foster research in pediatric populations, FDA 
decided to apply orphan drug development incentives to promote the development of drugs for 
indications with a prevalence of 200,000 or greater in the total population, but with less than 
200,000 in the pediatric population for use in those pediatric populations.7 
 
In the meantime, Congress has created several programs intended to promote pediatric studies:   
 
  In 1997, the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
created a pediatric exclusivity provision that provided an additional six months of market 
exclusivity when a sponsor submits reports of pediatric studies that fairly respond to a 
written request from FDA and are conducted in accordance with generally applicable 
scientific principles and protocols.8 
  In 2002, this incentive program was reauthorized under the Best Pharmaceuticals for 
Children Act (BPCA).9   
  In 2003, the Pediatric Research Equity Act (PREA) was enacted, codifying a similar 
FDA regulation that had been struck down by the courts that required that certain 
marketing applications for new active ingredients, new indications, new dosage forms, 
new dosing regimens or new routes of administration contain an assessment of safety and 
effectiveness (including dosing information) for the proposed indication in all relevant 
pediatric subpopulations.10   
  In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) 
permanently reauthorized the BPCA and PREA.11  In addition, the FDA Reauthorization 
Act of 2017 (FDARA) extended the scope of PREA to require pediatric studies of certain 
                                                 
7 The financial incentives provided by orphan-drug designation include tax credits to defray the cost of conducting 
clinical trials and eligibility for seven years of market exclusivity.  Additionally, no user fee is required for orphan 
drug product submissions, except when an application also includes an indication for a non-rare disease or 
condition. 
8 See Pub. L. 105-115 (1997), codified at section 505A of the FD&C Act (21 U.S.C. 355a). 
9 See Pub. L. 107-109 (2002), codified at section 505A of the FD&C Act (21 U.S.C. 355a). 
10 See Pub. L. 108-155 (2003), codified at section 505B of the FD&C Act (21 U.S.C. 355c).  Section 505B, which 
has been amended several times since 2003, is often still referred to as PREA, a convention we will adopt in this 
guidance. 
11 Pub. L. No. 112-144 (2012).   
 
3 
  Contains Nonbinding Recommendations 
 
adult oncology drugs that are directed at a molecular target that the Secretary determines 
to be substantially relevant to the growth or progression of a pediatric cancer.12 
 
Sections 505A and 505B of the FD&C Act, as added by BPCA and PREA, and subsequently 
reauthorized without sunset dates, have proven successful in promoting pediatric studies of drugs 
that are used in children.  Since their enactment, the successful completion of pediatric studies 
has led to the addition of new pediatric information in labeling for more than 700 products.13  
Additionally, the rare pediatric disease (RPD) priority review voucher (PRV) program, 
established under FDASIA, rewards sponsors that attain marketing approval for new drugs for 
use in rare pediatric diseases with vouchers for priority review of future marketing applications, 
intending to provide an added incentive for studies of rare pediatric diseases.14 
 
III.  CLARIFICATION 
 
Despite their successes, these statutory provisions have also resulted in substantial changes to the 
regulatory landscape.  Thus, not only have they rendered pediatric-subpopulation designation no 
longer necessary to promote pediatric studies, they have inadvertently introduced complications 
that could potentially inhibit the achievement of that goal.   
 
Section 505B(k) of the FD&C Act contains a statutory exemption from the requirement to 
conduct pediatric studies under PREA for certain drugs with orphan designation (i.e., the PREA 
orphan exemption). 15  Under this exemption, PREA does not apply to any application for a drug 
for an indication for which orphan designation has been granted when that application would 
otherwise trigger PREA because the application contains a new active ingredient, new indication, 
new dosage form, new dosing regimen or new route of administration.16  As a result, this 
                                                 
12 See Pub. L. 115-52 (2017), codified at section 505B(a)(1)(B) of the FD&C Act (21 U.S.C. 355c(a)(1)(B)).  We 
note that FDARA also included other changes to section 505B, including a removal of the PREA orphan exemption 
for molecularly targeted oncology drugs for which pediatric studies are required under the new provision.  These 
changes are outside of the scope of this guidance. 
13 See FDA, New Pediatric Labeling Information Database located at 
https://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase.   
14 See Pub. L. 112-144 (2012), codified at section 529 of the FD&C Act (21 U.S.C. 360ff). 
15 Section 505B(k) of the FD&C Act (21 U.S.C. 355c(k)), as amended by FDARA, reads as follows: 
(k) Relation to Orphan drugs -- 
(1) In General; Exemption for Orphan Indications  Unless the Secretary requires otherwise by regulation 
and except as provided in paragraph (2), this section does not apply to any drug or biological product for an 
indication for which orphan designation has been granted under section 526. 
(2) Applicability Despite Orphan Designation of Certain Indications  This section shall apply with respect 
to a drug or biological product for which an indication has been granted orphan drug designation under 
section 526 if the investigation described in subsection (a)(3) applies to the drug or biological product as 
described in subsection (a)(1)(B).   
FDA has interpreted section 505B(k)(1) to mean that if a sponsor holds orphan-drug designation for a pediatric 
subpopulation of a disease, the PREA orphan exemption applies to the sponsor seeking marketing approval for 
the adult population of that same disease. 
16 Section 505B(k)(2), as created by section 504 of FDARA, substantially resolves this issue for applications subject 
to section 505B(a)(1)(B). 
 
4 
  Contains Nonbinding Recommendations 
 
provision would exempt a sponsor holding pediatric-subpopulation designation for a disease 
from the requirement to conduct the pediatric studies normally required under PREA when 
seeking approval of an adult indication of that same disease. 
 
To better illustrate this example, if FDA granted pediatric-subpopulation designation to a 
sponsors drug for pediatric ulcerative colitis and the sponsor submitted an NDA or BLA for the 
drug to treat ulcerative colitis in adults, under PREA, the sponsor would be exempt from the 
requirement to conduct pediatric studies in ulcerative colitis.  Although some sponsors with 
pediatric-subpopulation designation for their drugs have completed (or plan to complete) 
pediatric studies in the disease for which they hold designation, other sponsors with pediatric-
subpopulation designation for their drugs may never conduct pediatric studies in the disease for 
which they hold designation.17   
 
The interaction between granting pediatric-subpopulation designation and the PREA orphan 
exemption has created a kind of loophole.  This is because obtaining pediatric-subpopulation 
designation provides orphan incentives to study a drug in the pediatric population with the 
disease but does not mandate the conduct of those studies.  As a result, a sponsor could use 
pediatric-subpopulation designation to obtain an exemption from the requirement to conduct the 
very studies the designation program was meant to incentivize.  FDA has concluded that the 
pediatric-subpopulation designation is no longer necessary to promote the conduct of pediatric 
studies and could ultimately inhibit the achievement of that goal, possibly even jeopardizing the 
Agencys ability to require those studies under PREA. 
 
To close this loophole, FDA does not expect to grant any additional pediatric-subpopulation 
designation (i.e., designation for rare pediatric subpopulations of common diseases).  Pediatric-
subpopulation designation is no longer necessary to stimulate the study of drugs in pediatric 
populations now that various programs, such as PREA and BPCA, have proven to be effective in 
achieving those ends. 
 
However, as discussed in Section II of this guidance, orphan-drug designation may otherwise 
cover diseases in pediatric patients and this remains unchanged.  As a result, assuming a given 
drug meets all other criteria for designation, FDA intends to still grant orphan-drug designation 
to a drug to prevent, diagnose, or treat the following: 
 
1.  A rare disease that includes a rare pediatric subpopulation; 
2.  A pediatric subpopulation that constitutes a valid orphan subset;18 and  
3.  A rare disease that is in fact a different disease in the pediatric population as compared to 
the adult population.   
 
                                                 
17 Section 505(g) of FDARA required FDA to report to Congress on any drugs with orphan designation for which a 
marketing application has been submitted without containing important pediatric information in the product 
labeling. 
18 See footnote 3.  Moreover, as scientific understanding evolves, FDA will continue to consider how targeted 
therapies and the diseases they treat may qualify as orphan subsets. 
 
5 
  Contains Nonbinding Recommendations 
 
Pediatric-subpopulation designations that have already been granted will not be affected.  
Therefore, a sponsor that holds orphan-drug designation for a drug for use in a pediatric 
subpopulation of a common disease is still eligible for the applicable benefits of orphan 
designation.19  
 
                                                 
19 FDA may revoke orphan-drug designation in accordance with 21 CFR  316.29. 
6