Rare Pediatric Disease 
Priority Review Vouchers 
Guidance for Industry 
 
 
 DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication  in the Federal Register of the notice announcing  the availability  of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.   Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration,  5630 
Fishers Lane, Rm. 1061, Rockville,  MD  20852.  All comments should be identified  with the 
docket number listed in the notice of availability  that publishes  in the Federal Register. 
 
 
For questions regarding this draft document, contact (OOPD) Aaron Friedman at 3017962989, 
or (CBER) Stephen Ripley at 240-402-7911,  or (CDER) Althea Cuff at 301-796-4061, or (OPT) 
Terrie Crescenzi at 301-796-8646. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
Office of Orphan Products Development (OOPD) 
Office of Pediatric Therapeutics (OPT) 
 
 
July 2019 
 
Revision 1 
   
Rare Pediatric Disease Priority Review 
Vouchers 
Guidance for Industry
 
 
Additional  copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 
Silver Spring, MD  20993-0002 
Tel: 301-796-3400; Fax: 301-847-8714; E-mail: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, rm. 3128 
Silver Spring, MD  20993-0002 
Tel: 800-835-4709 or 240-402-8010; E-mail: ocod@fda.hhs.gov  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm  
or 
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   
http://www.fda.gov/orphan  
or 
Office of Pediatric Therapeutics 
Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 32 
Silver Spring, MD, 20993 
Tel: 301-796-8659; E-mail: OPT@fda.hhs.gov  
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OfficeofScienceandHealthCo
ordination/ucm2018186.htm 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
Office of Orphan Products Development (OOPD) 
Office of Pediatric Therapeutics (OPT) 
 
July 2019 
 
Revision 1
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND AND OVERVIEW ......................................................................... 1 
III.  DEFINITIONS, POLICIES, AND PROCEDURES  QUESTIONS AND 
ANSWERS ................................................................................................................. 3 
A.  Rare Pediatric Disease Product Applications................................................................... 3 
B.  Requesting Rare Pediatric Disease Designation ..............................................................10 
C.  Requesting a Rare Pediatric Disease Priority Review Voucher ........................................16 
D.  Using and Tranferring a Rare Pediatric Disease Priority Review Voucher ....................18 
E.  Specific Eligibility Questions..............................................................................20  
F.  Relationship between Rare Pediatric Disease Designation and Orphan-Drug 
Designation...................................................................................................22 
G.  Agency's Responsibilities and Roles.....................................................................23  
 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Rare Pediatric Disease Priority Review Vouchers, 
1 
Draft Guidance for Industry 
2 
3   
4  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
5  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
6  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
7  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
8  for this guidance as listed on the title page.   
9   
10   
11  I.  INTRODUCTION 
12   
13  This guidance provides information  on the implementation  of section 908 of the Food and Drug 
14  Administration  Safety and Innovation  Act (FDASIA),1 which added section 529 to the Federal 
15  Food, Drug, and Cosmetic Act (the FD&C Act).2  Under section 529, FDA3 will award priority 
16  review vouchers to sponsors of certain rare pediatric disease product applications  that meet the 
17  criteria specified in that section.   
18   
19  In general, FDAs guidance documents do not establish legally  enforceable responsibilities.   
20  Instead, guidances describe the Agencys current thinking  on a topic and should be viewed only 
21  as recommendations,  unless specific regulatory or statutory requirements are cited.  The use of 
22  the word should in Agency guidances means that something  is suggested or recommended, but 
23  not required.  
24   
25  II.  BACKGROUND AND OVERVIEW 
26   
27  Section 529 of the FD&C Act is intended to encourage development of new drug and biological 
28  products (drugs) for the prevention and treatment of certain rare pediatric diseases.4  Although 
29  there are existing incentive programs to encourage the development and study of drugs for rare 
30  diseases, pediatric populations,  and unmet medical needs, section 529 provides an additional 
31  incentive for rare pediatric diseases, which may be used alone or in combination  with other 
32  incentive programs.  These other incentive programs include:   orphan-drug designation  and the 
33  associated benefits under the Orphan Drug Act for rare disease therapies;5 programs that 
34  encourage or require the study of drugs used in pediatric populations  under the Best 
                                                             
1 Public Law 112-144, enacted July 9, 2012. 
2 21 U.S.C. 360ff.  Unless otherwise noted, references to sections in this guidance are to sections of the FD&C 
Act. 
3 Throughout this document, we use the terms we and FDA interchangeably. 
4 For the purposes of this guidance, references to drugs and drug and biological products include drugs approved 
under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological drug products 
licensed under section 351 of the Public Health Service Act (42 U.S.C. 262). 
5 Public Law 97-414, as amended, codified at sections 526-528 of the FD&C Act (21 U.S.C. 360aa-360ee). 
 
1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
35  Pharmaceuticals for Children  Act (BPCA) and the Pediatric Research Equity Act (PREA);6 and 
36  various programs to facilitate and expedite development and review of new drugs to address 
37  unmet medical needs in the treatment of serious or life-threatening  conditions.7   Even so, 
38  Congress has recognized that there remain unmet medical needs among patients with rare 
39  diseases that occur primarily  in pediatric populations.   By enacting section 529, Congress 
40  intended to stimulate new drug development for rare pediatric diseases by offering additional 
41  incentives for obtaining  FDA approval of these products.   
42   
43  Under section 529, the sponsor of a human drug application  (as defined in section 735(1) of the 
44  FD&C Act8) for a rare pediatric disease drug may be eligible  for a voucher that can be used to 
45  obtain a priority review for a subsequent human drug application  submitted under section 
46  505(b)(1) of the FD&C Act9 or section 351 of the Public Health Service (PHS) Act after the date 
47  of approval of the rare pediatric disease drug.   
48   
49  On September 30, 2016, the Advancing Hope Act of 2016 updated the definition  of rare 
50  pediatric disease (see Question 1) and created a requirement for sponsors seeking a rare 
51  pediatric disease priority  review voucher to request the voucher upon submission  of the rare 
52  pediatric disease product application (see Question 14).  In addition,  the Advancing Hope Act 
                                                             
6 See, e.g., Public Law 107-109 (January 4, 2002) and Public Law 108-155 (December 3, 2003), codified in sections 
505A and 505B of the FD&C Act (21 U.S.C. 355a-355c). 
7 These programs include, among others, fast track designation, breakthrough therapy designation, accelerated 
approval, priority review designation, regenerative medicine advanced therapy designation, and programs for certain 
tropical disease products and antibiotics.  For more information, you may refer to the FDA Guidance, Expedited 
Programs for Serious Conditions  Drugs and Biologics, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf; 
FDA Guidance, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, available at 
https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellul
arandgenetherapy/ucm585414.pdf,  FDA Draft Guidance, Neglected Tropical Diseases of the Developing World: 
Developing Drugs for Treatment or Prevention, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269221.pdf; 
FDA Draft Guidance, Tropical Disease Priority Review Vouchers, available at 
http://www.fda.gov/downloads/Drugs/Guidances/UCM080599.pdf; and Food and Drug Administration Innovation 
and Safety Act (FDASIA), Public Law 112-144, Title VIIIGenerating Antibiotic Incentives Now.  
8 The statutory definition for the term human drug application is an application for--  
(A) approval of a new drug submitted under section 355(b) of this title, or  
(B) licensure of a biological product under subsection (a) of section 262 of Title 42.  
Such term does not include a supplement to such an application, does not include an application with respect to 
whole blood or a blood component for transfusion, does not include an application with respect to a bovine 
blood product for topical application licensed before September 1, 1992, an allergenic extract product, or an in 
vitro diagnostic biologic product licensed under section 262 of Title 42, does not include an application with 
respect to a large volume parenteral drug product approved before September 1, 1992, does not include an 
application for a licensure of a biological product for further manufacturing use only, and does not include an 
application or supplement submitted by a State or Federal Government entity for a drug that is not distributed 
commercially. Such term does include an application for licensure, as described in subparagraph (B), of a large 
volume biological product intended for single dose injection for intravenous use or infusion.  
Section 735(1) of the FD&C Act (21 U.S.C. 379g(1)).  The definition does not cover applications for medical 
devices. 
9 Because 505(b)(2) new drug applications (NDAs) are submitted under section 505(b)(1), all references to NDAs 
submitted under section 505(b)(1) include 505(b)(2) applications. 
 
2 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
53  clarified that no sponsor of a rare pediatric disease product application  may receive more than 
54  one priority  review voucher issued under any section of the FD&C Act for the same drug.  On 
55  December 13, 2016, the 21st Century Cures Act extended the rare pediatric disease priority 
56  review voucher program as follows:  
57   
58  [FDA] may not award any [rare pediatric disease] priority  review vouchers...after 
59  September 30, 2020, unless the rare pediatric disease product application  (A) is for a drug 
60  that, not later than September 30, 2020, is designated...as a drug for a rare pediatric 
61  disease; and (B) is, not later than September 30, 2022, approved under section 505(b)(1) 
62  of [the FD&C Act] or section 351 of the [PHS Act].10   
63   
64  Therefore, under the sunset provisions  as applicable  at the time of issuance of this draft 
65  guidance, after September 30, 2020, FDA may only award a voucher if the drug has rare 
66  pediatric disease designation,  and that designation was granted by September 30, 2020.  After 
67  September 30, 2022, FDA may not award any rare pediatric disease priority  review vouchers.   
68   
69  This guidance revises the draft guidance of the same title issued in November 2014 to reflect 
70  these updates.  This guidance is intended to assist developers of rare pediatric disease products in 
71  assessing whether their product may be eligible  for rare pediatric disease designation  and a rare 
72  pediatric disease priority  review voucher.  It also clarifies the process for requesting such 
73  designations  and vouchers, sponsor responsibilities  upon approval of a rare pediatric disease 
74  product application,  and the parameters for using and transferring a rare pediatric disease priority 
75  review voucher.    
76   
77  III.  DEFINITIONS, POLICIES, AND PROCEDURES  QUESTIONS AND 
78  ANSWERS 
79   
80  A.  Rare Pediatric Disease Product Applications 
81   
82  Q1.  What is a rare pediatric disease?  
83   
84  Section 529(a)(3) defines a rare pediatric disease as a disease that meets each of the following 
85  criteria: 
86   
87  (A) The disease is a serious or life-threatening  disease in which the serious or life-
88  threatening manifestations primarily  affect individuals  aged from birth to 18 years, 
89  including  age groups often called neonates, infants, children,  and adolescents [; and]  
90  (B) The disease is a rare disease or condition,  within the meaning of section 526 [of the 
91  FD&C Act].    
92   
93  Serious or life-threatening manifestations primarily affect children 
                                                             
10 Section 529(b)(5).  Congress may consider whether to extend these time restrictions in the future, so interested 
persons should consult current law with respect to these restrictions. 
 
3 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
94  Of note, section 529 describes the pediatric population  as from birth through 18 years.11  This 
95  age range differs from how FDA defines the pediatric population  in other contexts.  Generally, 
96  for drug and biological  products, FDA considers the pediatric population  to include patients from 
97  birth through 16 years.12  This guidance uses the term children to mean the definition  of the 
98  pediatric population  in section 529: individuals  aged from birth to 18 years. 
99    
100  FDA interprets the current definition  of rare pediatric disease and its reference to serious or 
101  life-threatening  manifestations of the disease or condition  using the following  principles: 
102    A manifestation of the disease or condition  should be serious or life-threatening  in 
103  children aged 0 through 18 years of age.  Manifestations include expressions and 
104  symptoms of the disease or condition.   Note that manifestations  does not mean the 
105  onset of the disease or condition or the onset of treatment.  For example, if a disease or 
106  conditions  onset typically  begins in childhood,  but manifestations of the disease or 
107  condition  do not become serious or life-threatening  until adulthood,  the disease or 
108  condition  is not a rare pediatric disease.  Similarly,  if treatment for the disease or 
109  condition  begins in childhood,  but under current standard of care the manifestations of 
110  the disease or condition  are not serious or life-threatening  in children,  the disease or 
111  condition  is not a rare pediatric disease. 
112    FDA will consider the manifestations  of the disease or condition  in the context of 
113  standard of care for the disease or condition.   Specifically,  FDA will consider what 
114  manifestations of the disease or condition  are serious or life-threatening  in children under 
115  standard treatment for the disease or condition.   Therefore, FDA will not consider the 
116  serious or life-threatening  manifestations of the disease or condition  that only occur when 
117  the disease is left untreated if that is not the standard of care.    
118    FDA will assess the serious or life-threatening  manifestations of the disease or condition 
119  and determine which manifestations primarily  affect children and which primarily  affect 
120  adults.  Factors in determining  if a manifestation primarily  affects children include: 
121  timing  and rate of disease progression (e.g., end-stage organ disease occurs in childhood), 
122  manifestations of abnormal growth or development,  and whether the proportion  of 
123  children is greater than the proportion  of adults with the given manifestation.  If the 
124  disease or condition  has a manifestation that primarily  affects children, FDA will 
125  consider the disease or condition  to be a rare pediatric disease.13   
126    The serious and life-threatening  manifestations of the disease or condition  that primarily 
127  affect children will also be a factor in determining  whether the application  qualifies for a 
128  voucher (see Questions 3 and 4). 
                                                             
11 We interpret from birth to 18 years as including all individuals less than 19 years of age (i.e., as from 0 through 
18 years).  Similarly, FDA interprets 21 CFR 201.57(c)(9)(iv), which describes a pediatric age range as from birth 
to 16 years, as including all individuals less than 17 years of age (i.e., as from 0 through 16 years). 
12 See 21 CFR 201.57(c)(9)(iv).   
13 That is not to say that manifestations that primarily affect adults cannot also be serious or life-threatening in 
children.  But based on the statutory definition, FDA is required to determine which manifestations primarily affect 
children and which primarily affect adults.  For example, FDA has determined that impaired lung function is a 
serious or life-threatening manifestation of cystic fibrosis that primarily affects adults, but can also be serious or life-
threatening in children.  FDA considers cystic fibrosis to be a rare pediatric disease based on other manifestations of 
the disease that do primarily affect children. 
 
4 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
129   
130  Rare disease or condition 
131  Section 526 of the FD&C Act defines a rare disease or condition  as any disease or condition 
132  that affects (1) less than 200,000  persons in the United States (U.S.) or (2) affects more than 
133  200,000  in the U.S. and for which there is no reasonable expectation that the cost of developing 
134  and making available in the U.S. a drug for such disease or condition  will be recovered from 
135  sales in the U.S. of such drug. 
136   
137  A drug may also meet the rare disease or condition  requirement if it is for an orphan subset 
138  of a disease or condition  that otherwise affects 200,000 or more persons in the U.S.14  In order 
139  for such drug to qualify as a drug for a rare pediatric disease, the orphan subset must be serious 
140  or life-threatening  and the serious or life-threatening  manifestations of the orphan subset must 
141  primarily  affect individuals  aged from birth to 18 years.15 
142   
143  The calculation  of prevalence estimates will depend on whether the drug is a therapeutic drug or 
144  a vaccine, diagnostic drug,16 or preventive drug, as follows: 
145    
146    For therapeutic drugs, prevalence estimates of the entire affected U.S. population 
147  should be based on the number of individuals  diagnosed with the disease or condition.   
148  For some diseases and conditions,  individuals  may have an underlying  genetic 
149  abnormality  at birth but may not develop manifestations of the disease until later, if 
150  ever.  In these instances, whether individuals  are considered diagnosed for the 
151  purpose of estimating  prevalence may depend on whether the product is intended to 
152  treat an underlying  genetic abnormality,  attenuate or prevent progression of the 
153  clinical  expression of the disease, or treat the clinical  symptoms or manifestations of 
154  the disease.   
155    For vaccines, diagnostic drugs, and preventive drugs, prevalence estimates should be 
156  based on the number of persons of all ages to whom the drug will  be administered  in 
157  the U.S. annually.   
158   
159  For information  on how to document prevalence in designation  requests, see the responses to 
160  Questions 9 and 15. 
161   
                                                             
14 An orphan subset requires demonstration that use of the drug outside of the subset of interest (in the remaining 
persons with the disease or condition) would not be appropriate owing to one or more properties of the drug, such as 
drug toxicity, mechanism of action, or previous clinical experience with the drug.  See 21 CFR 316.3(b)(13); 21 
CFR 316.20(b)(6).   
15 See Section 529(a)(3)(A). 
16 An application may qualify as a rare pediatric disease product application if it is for a drug or biologic that is a 
diagnostic for the management of a disease or condition.  We note, however, that such diagnostic products must be 
the subject of a NDA or BLA to qualify as a rare pediatric disease product application, as diagnostic products that 
are the subject of medical device applications are not eligible for a rare pediatric diseases priority review voucher.  
An application for a drug for the initial diagnosis of a disease or condition will not qualify as a rare pediatric disease 
product application. 
 
5 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
162  Qualifying  as a drug for a rare pediatric disease is not sufficient to receive a priority  review 
163  voucher.  For sponsors to receive such a voucher, the application  for the drug must meet all of 
164  the remaining  eligibility  criteria described in response to Question 2.17   
165   
166  Q2.  What is a rare pediatric disease product application? 
167   
168  The term rare pediatric disease product application is defined in section 529(a)(4) of the FD&C 
169  Act.  It refers to an application  that: 
170   
171    Is a human drug application  as defined in section 735(1) of the FD&C Act18:  
172   
173    For prevention or treatment19 of a rare pediatric disease (see Questions 1 and 3);  
174    That contains no active ingredient  (including  any ester or salt of the active ingredient) 
175  that has been previously  approved in any other application  under section 505(b)(1), 
176  505(b)(2), or 505(j) of the FD&C Act or section 351(a) or 351(k) of the PHS Act.  
177   
178    That FDA deems eligible  for priority  review.20  
179   
180    Is submitted under section 505(b)(1) of the FD&C Act21 or section 351(a) of the Public 
181  Health Service Act. 
182   
183    Relies on clinical  data derived from studies examining  a pediatric population  and dosages 
184  of the drug intended for that population  (see Question 4). 
185   
186    Does not seek approval for an adult indication  in the original  rare pediatric disease 
187  product application  (see Question 5); and 
188   
189    Is approved after the date of enactment of the Advancing Hope Act of 2016 (September 
190  30, 2016).22 
191   
                                                             
17 See section 529(a)(4). 
18 See footnote 8. 
19 See footnote 15.   
20 Certain applications may receive priority review pursuant to a statutory mandate (i.e., sections 524A and 505A of 
the FD&C Act). However, in determining whether an application qualifies for priority review within the meaning of 
this provision (i.e., section 529(a)(4)(C) of the FD&C Act), if a rare pediatric disease priority review voucher is 
requested, the Agency will determine whether the application satisfies the criteria for eligibility for a priority review 
designation, i.e., whether the drug treats a serious condition and, if approved, would provide a significant 
improvement in safety or effectiveness. For more information on the priority review designation see footnote 7, 
referring to FDAs guidance Expedited Programs for Serious ConditionsDrugs and Biologics (May 2014). 
21 See footnote 9. 
22 Note that there are limitations on when rare pediatric disease priority review vouchers can be awarded:  FDA may 
not award a voucher if the application was submitted to FDA prior to October 7, 2012 (i.e., 90 days after enactment 
of the Prescription Drug User Fee Amendments (PDUFA) of 2012), section 529(b)(3); and see Section II of this 
guidance for a description of the sunset provision for awarding vouchers under the law as applicable at the time of 
issuance of this draft guidance. 
 
6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
192   
193  Q3.  What does it mean to be for prevention or treatment of a rare pediatric disease?23 
194   
195  To be eligible  for a voucher, the drug should be (1) approved for a rare pediatric disease and (2) 
196  treat or prevent a serious or life-threatening  manifestation  of the disease or condition  that affects 
197  children.  These serious or life-threatening  manifestations may be the manifestations  that 
198  primarily  affect children, but they are not required to be, so long as the approved indication  is 
199  clinically  meaningful  to pediatric patients with the disease or condition.  For example: 
200    A drug may meet this standard if the approved indication  is explicitly  for treatment or 
201  prevention of a serious or life-threatening  manifestation  of the disease or condition  that 
202  affects children.   
203    A drug may also meet this standard if the drug treats or prevents the underlying  cause of 
204  the disease or condition  and the approved indication  is for treatment or prevention of the 
205  disease or condition  generally.   
206   
207  The intent of the statute is to award a voucher for a drug that benefits the pediatric patients with 
208  the rare pediatric disease or condition.   FDA will look at the totality  of the evidence to determine 
209  if the approval is clinically  meaningful  for the serious or life-threatening  manifestations of the 
210  disease that affect children. 
211   
212  FDA encourages sponsors to work with the relevant review division  or office in CBER or CDER 
213  to ensure they are studying the drug in a way that establishes safety and efficacy for the drug 
214  for a rare pediatric disease.  The priority  review voucher request should include scientific 
215  justification  of how the approved indication  will be clinically  meaningful  to pediatric patients 
216  with the disease or condition.   We expect a written description of the data and endpoints from the 
217  submitted studies that supports a determination  that the drug is for pediatric patients with the rare 
218  pediatric disease as described above. 
219   
220  Q4.  What does relies on clinical data derived from studies examining a pediatric 
221  population and dosages of the drug intended for that population mean? 
222   
223  We interpret relies on clinical  data derived from studies examining  a pediatric population  and 
224  dosages of the drug intended for that population  to mean that, to be eligible  for a voucher, the 
225  approved product: 
226   
227    should have been studied in a clinically  meaningful  pediatric population  with the rare 
228  disease (although the studies may also include adults in appropriate circumstances), 
229  and  
230    the pediatric data should have been critical to obtaining adequate labeling  for the 
231  pediatric population  in terms of safety, effectiveness, and dosage information 
232  (although data from studies including  adults may also have supported the pediatric 
233  labeling  in appropriate circumstances). 
234   
                                                             
23 See Section 529(a)(4)(A)(i). 
7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
235  It is important that applicants seeking a voucher submit data adequate for labeling  the drug for 
236  use by the full range of affected pediatric patients, within reasonable limits  (i.e., all pediatric 
237  patient age ranges affected by the disease that are reasonable to include in the studies without 
238  undue delays in completing  the studies and submitting  the application).   The studied pediatric 
239  population  should be clinically  meaningful  and represent more than a token pediatric population.   
240  Such labeling  aligns with the intent of section 529, which is to help address the unmet medical 
241  needs of pediatric patients with rare pediatric diseases.   
242   
243  Note that sponsors are not required to study a manifestation  of the disease or condition  that 
244  primarily  affects pediatric patients, but the studies should support approval for a rare pediatric 
245  disease in a way that is clinically  meaningful  to pediatric patients with the disease or condition 
246  (see Question 3). 
247   
248  Q5.  What does Does not seek approval for an adult indication in the original rare 
249  pediatric disease product application mean?    
250   
251  An applicant cannot receive a rare pediatric disease priority  review voucher if the application 
252  seeks approval for an adult indication  in the original  rare pediatric disease product application.   
253  We interpret this criterion to mean that, to preserve voucher eligibility,  the applicant cannot seek 
254  approval for a different adult indication  (i.e., for a different disease/condition)  in the original  rare 
255  pediatric disease application.   If the applicant seeks approval for use by pediatric and adult 
256  populations  with the rare pediatric disease, the applicant will still be eligible  for a voucher if the 
257  approved use includes pediatric use, as described in Questions 3 and 4.   If the applicant obtains 
258  approval for use only in an adult population  with the rare pediatric disease, the applicant is 
259  ineligible  for a voucher.   
260   
261  Thus, under this interpretation,  an applicant can preserve voucher eligibility  even if the applicant 
262  seeks approval for use by adults in addition  to pediatric patients with the rare pediatric disease.  
263  One reason we are interpreting  the statute in this way is to avoid incentivizing  sponsors to 
264  exclude adults affected by the rare pediatric disease from clinical  trials or to exclude adult data 
265  from the subsequent marketing application  solely for the sake of voucher eligibility,  when such 
266  exclusions may not be scientifically  or ethically acceptable for the reasons described below.   
267   
268  Clinical Trial Design  Clinical Trials for a Potential Rare Pediatric Disease Product May Need 
269  to Include Individuals Over 18 Years of Age for Scientific or Ethical Reasons:  Clinical trials for 
270  rare diseases and conditions  are challenging  because, among other factors, the small patient 
271  populations  limit  the opportunities  for study and verification  of results.  Because such clinical 
272  trials are likely  to be small and at risk of being underpowered, FDA expects that rare disease 
273  clinical  development programs will attempt to include all patients with the rare disease or 
274  condition  that are available for study and who could reasonably be expected to benefit from the 
275  intervention,  regardless of the age of the patient (where feasible and appropriate based on the 
276  disease/condition  and expected effects of intervention).24   Indeed, studies using novel therapies 
277  should generally be conducted in young adults (18 to 21 years of age) prior to exposing 
                                                             
24 See, e.g., ICH and FDA Guidance, E11 Clinical Investigation of Medicinal Products in the Pediatric Population, 
Section II.A, available at  http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129477.pdf.  
8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
278  adolescents and younger pediatric patients; for children to be included  in early phase 
279  investigations,  there must be a prospect of direct benefit for an individual  child to be studied in a 
280  clinical  trial in which more than a minor increase over minimal  risk is presented by an 
281  intervention  or procedure.25  For all of these reasons, it may not be scientifically  or ethically 
282  appropriate to exclude those over 18 years of age from a clinical  trial evaluating a potential  rare 
283  pediatric disease product. 
284   
285  Data to Include in a Marketing Application  Available Adult Safety and Effectiveness Data 
286  Must be Included in the Application:   If clinical safety and effectiveness data are available in an 
287  adult population  (i.e., individuals  over 18 years) at the time of the submission  of an original 
288  application  for a potential rare pediatric disease product, these data must be included in the 
289  application  for FDAs review.26  In many cases, if there is a population  over 18 years of age with 
290  the rare pediatric disease that could benefit from the product and for whom there are available 
291  data to support the evaluation of the safety and effectiveness of the product, labeling  for such a 
292  population  should be sought in the original  product application.    
293   
294  As noted, seeking approval for use in both adults and pediatric patients with the rare pediatric 
295  disease will not affect voucher eligibility.   However, we remind applicants seeking a voucher 
296  that  whether or not they seek approval for use in an adult population   we expect them to 
297  submit data adequate for labeling  the drug for use by the full range of affected pediatric patients 
298  (see response to Question 4).   
299   
300  Note that after a sponsor has been awarded a rare pediatric disease priority  review voucher for 
301  approval of a drug, the sponsor can develop the same drug for additional  indications,  including  a 
302  different adult indication,  without losing  the voucher. 
303   
304  Q6.  What user fees apply to a rare pediatric disease product application? 
305   
306  User fees for human drug applications  are described in section 736 of the FD&C Act.27  In 
307  general, a rare pediatric disease product application  is subject to these statutory requirements like 
308  any other application.   Such applications  may, however, be eligible  for exemptions from some 
309  fees if they have received orphan-drug designation.   See FDAs Guidance for Industry User Fee 
310  Waivers, Reductions, and Refunds for Drug and Biological  Products.28  
311   
312  User fees also apply to applications  for which a rare pediatric disease priority  review voucher is 
313  used, as described in Question 22. 
314    
315  Q7.  What are the sponsors responsibilities after approval of a rare pediatric disease 
316  product application? 
317   
                                                             
25 21 CFR 50.52 and 50.53; see also ICH and FDA Guidance, E11 Clinical Investigation of Medicinal Products in 
the Pediatric Population, footnote 19, Section II.C.  
26 21 CFR 314.50(d)(5)(iv); 21 CFR 601.2; 21 U.S.C. 379h. 
27 21 U.S.C. 379h. 
28 Available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079298.pdf . 
9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
318  The sponsor of an approved rare pediatric disease product application  must submit a report to 
319  FDA no later than 5 years after approval that addresses, for each of the first 4 post-approval 
320  years: 
321    the estimated population  in the U.S. with the rare pediatric disease for which the 
322  product was approved (both the entire population  and the population  aged 0 through 
323  18 years), 
324    the estimated demand in the U.S. for the product, and  
325    the actual amount of product distributed  in the U.S.29   
326   
327  Sponsors should submit such reports to the review division  or office within CDER or CBER that 
328  reviewed the new drug application  (NDA)/ biologics  license application  (BLA) for the rare 
329  pediatric disease product.  This report should be prominently  marked, Rare Pediatric Disease 
330  Product Post-Approval Report.  
331   
332  B.  Requesting Rare Pediatric Disease Designation 
333   
334  Q8.  What is the rare pediatric disease designation process?   
335   
336  Under section 529(d), a sponsor may choose to request rare pediatric disease designation.  FDA 
337  strongly recommends that sponsors planning  to request a voucher request rare pediatric disease 
338  designation.   Under the law as applicable  at the time of issuance of this draft guidance, FDA may 
339  not award any vouchers after September 30, 2020, unless the application  is for a drug that was 
340  designated as a drug for a rare pediatric disease by September 30, 2020.30  
341   
342  If a sponsor chooses to request such designation,  section 529(d)(2) provides that it shall do so at 
343  the same time that they submit a request for orphan-drug designation  under section 52631 or a 
344  request for fast track designation  under section 506.32  FDA will recognize a request for rare 
345  pediatric disease designation  to be submitted at the same time as a request for orphan-drug 
346  designation  or fast track designation  if the requests are received by FDA within two weeks of 
347  each other.  
348   
349  Note that, while a request for rare pediatric disease designation  may be submitted at the same 
350  time as a request for orphan-drug designation  or fast track designation,  each request should be 
351  submitted as a separate proposal (i.e., they should not be submitted in one combined package).  
352  The sponsor should indicate in the rare pediatric disease designation  request whether or not it is 
353  requesting orphan-drug designation  or fast track designation  at the same time.  See Question 10 
354  for how to submit a rare pediatric disease designation request. 
355   
356  We remind sponsors of the timing  for orphan-drug and fast track designation  requests: 
357   
                                                             
29 Section 529(e)(2). 
30 Section 529(b)(5).  FDA may not award any rare pediatric disease priority review vouchers after September 30, 
2022, even for applications for drugs granted rare pediatric disease designation by September 30, 2020. 
31 21 U.S.C. 360bb. 
32 21 U.S.C. 356. 
 
10 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
358  Timing of Requests for Orphan-Drug Designation:  Under section 526, orphan-drug 
359  designation  requests must be submitted before the sponsors filing  of a marketing application 
360  for the drug for the orphan use.33   
361   
362  Timing of Requests for Fast Track Designation:  Requests for fast track designation  may be 
363  submitted at the time of original  submission  of the investigational  new drug (IND) 
364  application  or any time thereafter prior to receiving marketing approval of the NDA or BLA, 
365  although FDA encourages that such requests be submitted no later than the sponsors pre-
366  NDA/BLA meeting because many of the features of fast track designation  will no longer be 
367  applicable after that time.34   
368   
369  If sponsors submit a timely request for rare pediatric disease designation,  section 529(d)(3) 
370  directs FDA to make a decision on the request no later than 60 days after submission.35   The 
371  statute directs FDA to decide whether to designate the drug as a drug for a rare pediatric 
372  disease and whether to designate the application  for the drug as a rare pediatric disease product 
373  application,36  as described in response to Question 11.   
374   
375  FDA recognizes that some sponsors may wish to submit a rare pediatric disease designation 
376  request at a different time  for example, if they had already submitted requests for orphan-drug 
377  and/or fast track designation  before the enactment of FDASIA, or if for whatever reason they 
378  have no interest in submitting  either such request but do want to submit a rare pediatric disease 
379  designation  request.  FDA is willing  to accept designation  requests submitted at a different time 
380  than that provided by statute as long as FDA receives the designation  request before FDA has 
381  filed the NDA/BLA for the drug for the relevant indication.   Although we will aim to respond to 
382  such requests in a timely manner, the 60-day response deadline does not apply.  We will not 
383  accept requests for rare pediatric disease designation received after FDA has already filed the 
384  NDA/BLA for the drug for the relevant indication.    
385   
386  Whether or not a sponsor receives rare pediatric disease designation  for its drug, the sponsor 
387  must include a request for a rare pediatric disease priority  review voucher in its original 
388  NDA/BLA submission  (either in the initial  package or up until the point of NDA/BLA filing)  in 
                                                             
33 Section 526(a)(1).  For more information on orphan-drug designation, see 21 CFR part 316 and 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesi
gnation/default.htm.  
34 These features include more frequent interactions with the FDA review team, including meetings to discuss study 
design and other issues, possible rolling review of portions of the marketing application before receipt of the 
complete application, and possible priority review if supported by clinical data at the time of BLA or NDA 
submission.  For more information on fast track designation and priority review, see FDA Guidance, Expedited 
Programs for Serious ConditionsDrugs and Biologics, available at:  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. 
See also 
http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128
291.htm. 
35 FDA interprets this language, not later than 60 days after the request is submitted, to mean that FDA must 
respond within 60 days after receiving the request. 
36 Section 529(d)(3). 
 
11 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
389  order to be eligible  to receive a voucher.37  See responses to Questions 14 and 15 for information 
390  on requesting such a voucher.   
391   
392  Q9.  What information should these designation requests contain?   
393   
394  Sponsors should include the following  information  in rare pediatric disease designation  requests:  
395    
396  (1) The name and address of the sponsor and the name of the sponsors primary contact 
397  person and/or resident agent including  title, address, telephone number, and email 
398  address;  
399   
400  (2) The non-proprietary  and trade name, if any, of the drug, or, if neither is available, the 
401  chemical name or a meaningful  descriptive name of the drug;  
402   
403  (3) The proposed dosage form and route of administration;   
404   
405  (4) A description of the rare pediatric disease for which the drug is being or will be 
406  investigated; the proposed use of the drug; and the IND number if previously  assigned; 
407   
408  (5) A description of the drug to include (i) the identity  of the active moiety, if it is a drug 
409  composed of small molecules, or of the principal  molecular structural features, if it is 
410  composed of macromolecules,  and (ii) its physical and chemical properties, if these 
411  characteristics can be determined; 
412   
413  (6) An explanation  of the mechanism of action, with supportive data, suggesting that the 
414  drug may be effective in the rare pediatric disease;38   
415   
416  (7) The basis for concluding  that the drug is for a rare disease or condition.    This basis 
417  is established when a sponsor provides the following  information,  as described in Section 
418  526 of the FD&C Act:39 
419  (i) Documentation,  with appended authoritative references, to demonstrate that (a) 
420  the estimated prevalence of the affected patient population  in the U.S.  those 
421  diagnosed with the disease or condition   is below 200,000  at the time of 
422  submission  of the request for designation,  or (b) if the drug is a vaccine, 
423  diagnostic drug, or preventive drug, the persons to whom the drug will be 
424  administered in the U.S. are fewer than 200,000 per year.  Please provide a list of 
425  sources for the information,  including  dates of the information  provided and 
                                                             
37 Section 529(b)(4)(A)(i). 
38 As explained in response to Question 31, FDA expects a lesser level of supportive data for rare pediatric disease 
designation than for orphan-drug designation because of the many differences between the two programs.  In vitro 
data supporting the mechanism of action of the drug in the disease or in a related disease may suffice for rare 
pediatric disease designation, whereas that level of data would not generally suffice for orphan-drug designation.  
39 See 21 CFR 316.20. 
12 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
426  literature citations (see response to Question 1 for more information  on estimating 
427  prevalence); or 
428  (ii) For drugs intended for diseases or conditions  affecting 200,000 or more 
429  people in the U.S., or for a vaccine, diagnostic drug, or preventive drug that 
430  would be given to 200,000 or more persons in the U.S. per year, a summary of the 
431  sponsors basis for believing  that the disease or condition  occurs so infrequently 
432  that there is no reasonable expectation that the costs of drug development and 
433  marketing will be recovered in future sales of the drug in the U.S.  We ask that 
434  sponsors include the same sort of cost and related information  as is detailed at 21 
435  CFR 316.21(c). 
436  (8) Documentation,  with appended authoritative references, to demonstrate that the rare 
437  disease or condition  for which the drug is proposed is a rare pediatric disease as 
438  defined in section 529(a)(3)(A), meaning that the disease is a serious or life-threatening 
439  disease in which the serious or life-threatening  manifestations primarily  affect individuals 
440  aged from birth to 18 years (see response to Question 1).  The sponsor should include an 
441  analysis of the serious or life-threatening  manifestations of the disease and evidence 
442  supporting  whether each serious or life-threatening  manifestation primarily  affects 
443  children or adults.  Please provide a list of sources for the information,  including  dates of 
444  the information  provided and literature citations.   
445   
446  (9) Where a sponsor requests designation  of a drug for only a subset of persons with a 
447  particular disease or condition  that otherwise affects 200,000 or more people (orphan 
448  subset of non-rare disease or condition),  a demonstration that, due to one or more 
449  properties of the drug, the remaining  persons with such disease or condition  would not be 
450  appropriate candidates for use of the drug (see Question 1 and footnote 13).  Such 
451  properties of the drug may include drug toxicity,  mechanism of action, or previous 
452  clinical  experience with the drug.   
453   
454  If a sponsor is submitting  a rare pediatric disease designation  request at the same time as or 
455  shortly after a request for orphan-drug designation  for the drug, it can cross-reference any of the 
456  above information  already contained in their orphan-drug designation  request.40  The sponsor 
457  should indicate in the rare pediatric disease designation  request whether or not it is requesting 
458  orphan-drug designation  or fast track designation  at the same time as the request for rare 
459  pediatric disease designation.    
460   
461  Q10.  What is the process for submitting rare pediatric disease designation requests? 
462   
463  Sponsors should submit two copies, with at least one hard copy, of the completed, dated, and 
464  signed rare pediatric disease designation  requests, with the information  specified in response to 
                                                             
40 Cross-referencing of information in previously submitted orphan-drug designation requests may not be 
appropriate if the information is outdated, for example, if prevalence estimates for the disease have changed in the 
intervening time between submission of the orphan-drug designation request and submission of the rare pediatric 
disease designation request.   
13 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
465  Question 9 to the Office of Orphan Products Development, Food and Drug Administration,  Bldg. 
466  32, rm. 5295, 10903 New Hampshire Ave., Silver Spring, MD 20993. 
467   
468  Q11.  How will FDA respond to such designation requests? 
469   
470  The statute requires that FDA, in responding  to rare pediatric disease designation  requests, 
471  decide whether to designate the drug as a drug for a rare pediatric disease and whether to 
472  designate the associated marketing application  as a rare pediatric disease product application.41 
473  The Office of Orphan Products Development (OOPD) and the Office of Pediatric Therapeutics 
474  (OPT) will issue the designation  response in consultation  with the Center for Drug Evaluation 
475  and Research (CDER) and the Center for Biologics  Evaluation and Research (CBER), as 
476  appropriate.  This designation  response will take one of the following  forms: 
477   
478  A Deficiency Letter:  FDA will send a deficiency letter within the timeframe specified in 
479  Question 8 if the request lacks the information  described in Question 9 or contains inaccurate or 
480  incomplete information.   In the deficiency letter, we will ask the sponsor to respond within 60 
481  days or else request an extension of time to respond within that same timeframe; otherwise, FDA 
482  may consider the designation  request voluntarily  withdrawn.   
483   
484  Designating the Drug as a Drug for a Rare Pediatric Disease and Either Denying or 
485  Conditionally Designating the Application as a Rare Pediatric Disease Product Application:  
486  FDA will designate a drug as a drug for a rare pediatric disease within the timeframe specified 
487  in response to Question 8 if the sponsor provides adequate information  to demonstrate that the 
488  drug is for a rare pediatric disease (including  appropriate prevalence estimates with appended 
489  authoritative  references) and an adequate explanation,  with supportive data, of the drugs 
490  mechanism of action suggesting that the drug may be effective in the rare pediatric disease (see 
491  response to Question 9).  FDA will evaluate prevalence as of the time of submission  of the 
492  designation  request.  If FDA designates the drug as a drug for a rare pediatric disease, these 
493  prevalence estimates generally will not be reevaluated at the time of NDA/BLA submission,42 
494  but FDA will evaluate the remaining eligibility  criteria to determine whether the NDA/BLA is 
495  eligible  for a priority  review voucher (see Question 2).   
496   
497  Even if FDA designates the drug as a drug for a rare pediatric disease, FDA cannot 
498  definitively  designate any associated marketing application  as a rare pediatric disease product 
499  application  because eligibility  cannot be determined unless and until the application  is approved 
500  or licensed.  This is because eligibility  depends on the contents of the application  as well as 
501  certain facts at the time of approval or licensure (see Question 2).  Short of designating  the 
502  application,  FDA has two options in responding  to the application  portion of a designation 
503  request:   
504   
                                                             
41 Section 529(d)(3)(A) and (B). 
42 FDA does reserve the right to revisit a decision on prevalence estimates if it becomes apparent that information 
relevant to that question and available at the time of the submitted request for designation was not provided to FDA 
or known by FDA at the time of designation decision. 
14 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
505  (1) to conditionally designate the application as a rare pediatric disease product 
506  application  assuming that, at the time of approval or licensure, it will meet all of the 
507  eligibility  criteria set forth in section 529(a)(4).  The final answer to a conditional 
508  designation  of an application  will  come in the form of a voucher award or non-award at 
509  the time of marketing approval, if the sponsor requests such a voucher in the NDA/BLA.  
510  As described in responses to Questions 14 and 15, even sponsors who receive rare 
511  pediatric disease designation  must include a voucher request in their original  NDA/BLA 
512  submission  if they remain interested in receiving a voucher.43 
513    
514  (2) to deny designating the application if, at the time of submission  of the designation 
515  request, it appears the application  will fail to meet at least one of the criteria to be a rare 
516  pediatric disease product application  (see Question 2).  Even sponsors who have been 
517  denied such designation  may request a voucher in their NDA/BLA submission  if they 
518  believe they are eligible  (see responses to Questions 14 and 15). 
519   
520  Neither Designating the Drug as a Drug for a Rare Pediatric Disease Nor 
521  Designating the Application as a Rare Pediatric Disease Product Application:  If FDA 
522  determines that the drug is not in fact a drug for a rare pediatric disease, FDA will deny rare 
523  pediatric disease designation  of both the drug and the application.   Reasons for such denial 
524  include:    
525    the drug is not for a rare disease or condition  under section 526 (e.g., prevalence in 
526  the U.S. is 200,000  or greater), and the drug is not for an orphan subset of a non-
527  rare disease or condition;   
528    the drug is not for a disease or condition  (or orphan subset of a disease or 
529  condition)  that is a serious or life-threatening  disease in which the serious or life-
530  threatening manifestations primarily  affect individuals  aged from birth to 18 years;  
531    there is insufficient  evidence to support the necessary prevalence estimates or to 
532  demonstrate an orphan subset;  
533    lack of an adequate explanation,  with supportive data, of the drugs mechanism of 
534  action suggesting that the drug may be effective in the rare pediatric disease;  
535    the request contains an untrue statement of material fact, omits material information, 
536  or is otherwise ineligible  for designation. 
537   
538  Even if a sponsor is denied rare pediatric disease designation,  the sponsor can request a rare 
539  pediatric disease priority  review voucher at the time of NDA/BLA submission  if the sponsor 
540  believes the submission  is eligible  (see responses to Questions 14 and 15).   
541   
542  Voluntarily Withdrawn Letter:  FDA may consider a designation  request voluntarily 
543  withdrawn if the sponsor fails to respond to a deficiency letter, or to request an extension of time 
544  to respond, within 60 days of the deficiency letter date.  In the event FDA considers a request 
545  voluntarily  withdrawn, FDA will notify the sponsor in writing.  As above, such sponsors can still 
546  request a voucher in the NDA/BLA submission  if they believe they are eligible. 
547   
                                                             
43 Section 529(b)(4)(A)(i). 
15 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
548  Not Accepted Letter:  As noted in response to Question 8, FDA will not accept requests 
549  for rare pediatric disease designation received after FDA has already filed the NDA/BLA for the 
550  drug for the relevant indication.   Such sponsors may still  receive a voucher if they requested a 
551  voucher in the NDA/BLA submission  and they are otherwise eligible.   
552   
553  Q12.  What if a sponsor chooses not to submit a rare pediatric disease designation request 
554  before submitting the marketing application?   
555   
556  Sponsors who choose not to submit a rare pediatric disease designation  request may nonetheless 
557  receive a priority  review voucher if they request such a voucher in their original  marketing 
558  application,44  meet all of the eligibility  criteria, and (under the law as applicable at the time of 
559  issuance of this draft guidance) the application  is approved by September 30, 2020.  The 
560  determination  of whether the drug is for a rare pediatric disease will occur as described above, 
561  except the prevalence determination  will be based on the prevalence at the time of NDA/BLA 
562  submission  rather than the prevalence at the time of designation  request.   
563   
564  We encourage sponsors who are interested in receiving a rare pediatric disease priority review 
565  voucher to notify FDA early of their interest (e.g., no later than a pre-NDA/BLA meeting).  
566  However, notification  before submission  of the rare pediatric disease product application  is not 
567  required.  The process for requesting a voucher at the time of NDA/BLA submission  is described 
568  in Questions 14 and 15. 
569   
570  C.  Requesting a Rare Pediatric Disease Priority Review Voucher  
571   
572  Q13.  Do sponsors need to receive rare pediatric disease designation before requesting a 
573  priority review voucher? 
574   
575  In general, a sponsor does not need to receive rare pediatric disease designation  for its drug in 
576  order to request a priority  review voucher.  However, under the law as applicable  at the time of 
577  issuance of this draft guidance, FDA may not award a voucher after September 30, 2020, unless 
578  the application  is for a drug that was designated as a drug for a rare pediatric disease by 
579  September 30, 2020 and the application  is approved by September 30, 2022.   
580   
581  Q14.  When should sponsors request a rare pediatric disease priority review voucher? 
582   
583  Whether or not sponsors have requested rare pediatric disease designation,  sponsors seeking a 
584  rare pediatric priority  review voucher must submit a voucher request in the original  submission 
585  of the potential  rare pediatric disease product application   either in the initial  package sent or up 
586  until the point of NDA/BLA filing.45  This voucher request should be prominently  marked, Rare 
587  Pediatric Disease Priority Review Voucher Request, and be included or referenced in a cover 
588  letter. 
589   
590  Q15.  What information should sponsors include in a priority review voucher request? 
                                                             
44 Section 529(b)(4)(A)(i). 
45 Id. 
16 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
591   
592  This request for a voucher should describe how the application  meets the eligibility  criteria in 
593  section 529(a)(4) of the FD&C Act (See Question 2).  The sponsor should address how the 
594  application  meets each of the criteria, even if FDA already designated the application  as a rare 
595  pediatric disease product application  at the designation  stage.   
596   
597  Depending on whether the sponsor has already received rare pediatric disease designation for the 
598  drug, the contents of the voucher request should include the following  to support that the drug is 
599  for the prevention or treatment of a rare pediatric disease: 
600   
601  Sponsors Who Have Received Rare Pediatric Disease Designation for the Drug:  
602  Sponsors who have received rare pediatric disease designation  for the drug should include that 
603  designation  letter with the voucher request and need not re-analyze prevalence estimates at the 
604  time of NDA/BLA submission.    
605   
606  Sponsors Who Have Requested but Not Received Rare Pediatric Disease Designation for 
607  the Drug:  Sponsors who have requested but not received rare pediatric disease designation 
608  should include in a voucher request the latest designation  correspondence from FDA (i.e., an 
609  acknowledgment letter, deficiency letter, denial letter, or voluntarily  withdrawn letter).  Note that 
610  under the law as applicable at the time of issuance of this draft guidance, if sponsor does not 
611  have rare pediatric disease designation  for their drug by September 30, 2020, FDA may not 
612  award a voucher after September 30, 2020. 
613   
614  If the designation  request has been denied or withdrawn, then the voucher request should include 
615  new prevalence estimates as of the time of NDA/BLA submission;  otherwise, the sponsor can 
616  cross-reference the information  in its designation  request and provide additional  information  as 
617  necessary.  In particular:   
618   
619    Sponsors who have received only an acknowledgment letter in response to a 
620  designation  request should cross-reference their designation  request (with associated 
621  prevalence estimates).  
622    Sponsors who have received a deficiency letter should include a response to the 
623  deficiency letter with their voucher requests or else cross-reference a previously 
624  submitted deficiency response.  
625    Sponsors who have received denial letters should explain how their drug is for a rare 
626  pediatric disease despite this denial, based on new information  about the drug or the 
627  disease/condition,  and include new prevalence estimates as of the time of NDA/BLA 
628  submission  (with supporting  documentation described in Question 9 items (7)-(8)).   
629    Sponsors who have received voluntarily withdrawn letters should likewise include 
630  new prevalence estimates as of the time of NDA/BLA submission  (with supporting 
631  documentation  described in Question 9 items (7)-(8)). 
632   
633  Sponsors Who Have Not Requested Rare Pediatric Disease Designation:  Sponsors who 
634  have not requested rare pediatric disease designation should include in a voucher request 
635  prevalence estimates as of the time of NDA/BLA submission,  with supporting  documentation 
17 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
636  described in Question 9 items (7)-(8).  Note that if a sponsor does not have rare pediatric disease 
637  designation  for their drug, FDA may not award a voucher after September 30, 2020. 
638   
639  D.  Using and Transferring a Rare Pediatric Disease Priority Review Voucher 
640   
641  Q16.  What is a priority review? 
642   
643  The priority  review awarded by the voucher is the same as the priority  review referred to in the 
644  current PDUFA goals letter, which commits FDA to a goal of completing  a certain percentage of 
645  priority  reviews within the prescribed time frames.   For example, in a PDUFA goals letter, FDA 
646  may commit to completing  90 percent of priority reviews within the prescribed time frames.  
647  FDAs current PDUFA goals letter is available on its website.46  FDA intends to treat any human 
648  drug application  for which a PRV is used as if it were any other priority review drug application 
649  under the goals letter.  
650   
651  Q17.  What is a priority review voucher and when is it awarded? 
652   
653  Under section 529(a)(2) of the FD&C Act, a priority review voucher is a voucher that FDA 
654  issues to the sponsor of a rare pediatric disease product application  at the time of the marketing 
655  application  approval.  This voucher entitles the holder to designate a single human drug 
656  application  submitted under section 505(b)(1) of the FD&C Act47 or section 351 of the PHS Act 
657  as qualifying  for a priority  review.  Such a subsequent application  would not have to meet the 
658  usual requirements for a priority  review, but it would have to be submitted after the approval of 
659  the rare pediatric disease product application. 
660   
661  Q18.  What form will the voucher take? 
662   
663  We will include information  related to the priority  review voucher in the approval letter for the 
664  rare pediatric disease product application.   This letter will include a priority  review voucher 
665  identification  number, which should be referenced when redeeming or transferring the voucher. 
666   
667  Q19.  How and when can a voucher be used?  
668   
669  The application  using the priority  review voucher must be submitted under section 505(b)(1) of 
670  the FD&C Act48 or section 351 of the PHS Act and is not limited  to drugs for rare pediatric 
671  diseases.  The application  using the voucher may be for a new indication  of the same drug whose 
672  approval led to the award of the voucher.  The sponsor redeeming the voucher must notify FDA 
673  of its intent to submit an application  with a priority  review voucher at least 90 days before 
674  submission  of the application  and must include the date the sponsor intends to submit the 
675  application  (hereinafter the intended submission  date).49  This notification  should be 
676  prominently  marked, Notification  of Intent to Submit an Application  with a Rare Pediatric 
                                                             
46 https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm511438.pdf. 
47 See footnote 9. 
48 See footnote 9. 
49 Section 529(b)(4)(B)(i).   
 
18 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
677  Disease Priority Review Voucher.  Upon submitting  this notification  to FDA, the sponsor is 
678  obligated  to pay the priority  review user fee described in the response to Question 22.50   
679   
680  The voucher cannot be used if the application  is submitted before the intended submission  date.   
681  If a sponsor does not submit the application  on the intended submission  date, the sponsor should 
682  inform FDA as soon as possible of the new intended submission  date.  If the sponsor decides not 
683  to use the voucher for the application  described in the notification,  the sponsor should withdraw 
684  the notification  from FDA.  The sponsor should submit a new notification  informing  FDA, at 
685  least 90 days before application  submission,  of its intent to submit a different human drug 
686  application  with a priority  review voucher and include the intended submission  date.51 
687   
688  Q20.  Will these vouchers be transferable? 
689   
690  Yes.  The sponsor of a rare pediatric disease drug receiving a priority  review voucher may 
691  transfer (including  by sale) the voucher to another sponsor.52  The voucher may be further 
692  transferred any number of times before the voucher is used, as long as the sponsor making the 
693  transfer has not yet submitted the application.53    
694   
695  Q21.  What is the procedure for voucher transfer?  
696   
697  Each person to whom a voucher is transferred must notify FDA of the change of voucher 
698  ownership within 30 days after the transfer.54  This notification  should be prominently  marked, 
699  Transfer of Rare Pediatric Disease Priority Review Voucher and submitted to the NDA/BLA. 
700  It should include a letter from the previous owner to the current owner and a letter from the 
701  current owner to the previous owner, each acknowledging  the transfer.  Any sponsor redeeming a 
702  voucher should include these transfer letters in the application  submitted to FDA (in addition  to 
703  notifying  FDA of the intent to submit an application  with a priority  review voucher, as described 
704  in response to Question 19).  A complete record of transfer must be made available to FDA in 
705  order to redeem a transferred voucher.55   
706   
707  Q22.  What fees apply when using a priority review voucher? 
708   
709  The sponsor of a human drug application  that is the subject of a priority  review voucher must 
710  pay a priority  review user fee in addition  to any other required user fee.56  The amount of the 
711  priority  review user fee will be determined each fiscal year and is based on the difference 
712  between the average costs incurred by FDA, in the previous fiscal year, of reviewing a priority 
713  review NDA/BLA and an NDA/BLA that is not subject to priority  review.57  Payment of this 
                                                             
50 Id. 
51 Id. 
52 Section 529(b)(2). 
53 Section 529(b)(4)(B)(ii).   
54 Section 529(b)(2)(B). 
55 Id.  See also section 529(b)(4)(B). 
56 Section 529(c)(1). 
57 Section 529(c)(2). 
 
19 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
714  extra fee, to which the sponsor is legally committed as a result of the notification  of its intent to 
715  use the voucher, is not subject to waivers, exemptions,  reductions, or refunds.58   
716   
717  FDA will establish the fee amount before the beginning  of each fiscal year and will publish  the 
718  fee schedule in the Federal Register. 
719   
720  Q23.  When do I pay the priority review voucher user fee? 
721   
722  The priority  review voucher user fee is due upon notifying  FDA of the intent to submit an 
723  application  with a priority  review voucher, as described in the response to Question 19.59  It is 
724  payable in accordance with procedures established by FDA, which will be described in the 
725  Federal Register notice that sets the fees for each fiscal year.  The application  will be considered 
726  incomplete if the priority  review voucher user fee and all other applicable  user fees are not paid 
727  in accordance with FDA payment procedures.60   
728   
729  Q24.  If I present a voucher to FDA for priority review, am I guaranteed a 6-month 
730  review on my drug application? 
731   
732  Although FDAs goal is to take action on the application  within 6 months after the 60-day filing 
733  period for an application  involving  a new molecular entity or within 6 months after the date of 
734  receipt of an application  not involving  a new molecular entity,61 this timeframe is not 
735  guaranteed.  Note that take action in this context means that FDA aims to complete its review 
736  of the filed application  and issue an approval or complete response letter within this timeframe; it 
737  does not mean that the application  will be approved within this timeframe.   
738   
739  E.  Specific Eligibility Questions 
740   
741  Q25.  Is eligibility for a priority review voucher affected by whether the sponsor intends to 
742  market the rare pediatric disease drug after approval? 
743   
744  The statute does not describe marketing of a rare pediatric disease drug as a prerequisite to 
745  receiving a priority  review voucher.  However, under section 529(e)(1), FDA may revoke any 
746  priority  review voucher if the rare pediatric disease drug for which the voucher was awarded is 
747  not marketed in the U.S. within 1 year following  the date of approval.   
748   
749  Q26.  Are drug-drug combinations eligible for priority review vouchers?  
750   
751  A drug-drug combination  (also referred to as a fixed-combination  drug) is eligible  for a voucher 
752  if the product meets the criteria established in section 529(a)(4) of the FD&C Act.  In general, an 
753  application  for a fixed-combination  drug submitted under section 505(b) of the FD&C Act will 
754  be eligible  for a voucher if the product contains a drug substance, no active moiety of which has 
                                                             
58 Section 529(c)(4)(C). 
59 Section 529(c)(4)(A).   
60 Section 529(c)(4)(B). 
61 See footnote 45. 
 
20 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
755  been approved in any other application  under section 505(b) of the FD&C Act.62  For example, 
756  an application  for a fixed-combination  drug that contains a drug substance with a single,  new 
757  active moiety may be eligible  for a voucher, even if the fixed-combination  also contained a drug 
758  substance with a previously  approved active moiety. 
759   
760  Q27.  Are drugs eligible for a priority review voucher if they have been approved and 
761  used in other countries but have not been previously approved by FDA?  
762   
763  Yes, as long as they meet all the criteria for a rare pediatric disease product application  described 
764  in section 529(a)(4) (see section III.A.). 
765   
766  Q28.  Is a drug that is already approved by FDA for another indication eligible for a 
767  priority review voucher for a rare pediatric disease product application? 
768   
769  No.  As noted, for an application  to qualify for a rare pediatric disease priority  review voucher, it 
770  must be for a human drug that contains no active ingredient (including  any ester or salt of the 
771  active ingredient) that has been previously  approved in any other application  under section 
772  505(b)(1), 505(b)(2), or 505(j) of the FD&C Act or section 351(a) or 351(k) of the PHS Act.63   
773   
774  Q29.  Would a new pediatric formulation for a drug already approved for adults be 
775  eligible for a rare pediatric disease priority review voucher?  
776   
777  No.  As noted, an application  for a drug containing  a previously  approved active ingredient 
778  (including  any ester or salt of the active ingredient) is not eligible  to receive a rare pediatric 
779  disease priority  review voucher.   
780   
781  Q30.  Would an application for a rare pediatric disease drug submitted to FDA before 
782  enactment of PDUFA of 2012 (under FDASIA) but not yet approved qualify for a 
783  voucher? 
784   
785  No.  The rare pediatric disease product sponsor may not receive a rare pediatric disease priority 
786  review voucher if the application  was submitted to FDA prior to October 7, 2012 (90 days after 
787  the date of the enactment of PDUFA of 2012).64   
788   
789   
                                                             
62 See section 529(a)(4)(A)(ii) of the FD&C Act.  Because section 529(a)(4)(A)(ii) of the FD&C Act contains the 
same phrase (no active ingredient (including any ester or salt of the active ingredient) that has been previously 
approved) as is used in sections 505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act, FDA will follow, for drugs 
approved under the FD&C Act, its guidance on exclusivity for combination drugs under those provisions.  See the 
guidance for industry New Chemical Entity Exclusivity Determinations for Certain Fixed-Drug Combination Drug 
Products (2014).  For biological products approved under the PHS Act, FDA will make decisions on eligibility 
under section 529(a)(4)(A)(ii) of the FD&C Act on a case-by-case basis. 
63 Section 529(a)(A)(ii). 
64 Section 529(b)(3). 
 
21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
790  F.  Relationship between Rare Pediatric Disease Designation and Orphan-Drug 
791  Designation  
792   
793  Q31.  Will a drug that receives rare pediatric disease designation also qualify for orphan-
794  drug designation? 
795   
796  We anticipate that many rare pediatric disease drugs will qualify  for designation  as orphan drugs 
797  (if such designation  is sought) because a rare pediatric disease also must be a rare disease or 
798  condition  as defined in section 526, including  those that affect fewer than 200,000  persons in 
799  the U.S.65  There are instances, however, where a drug may qualify as a drug for a rare pediatric 
800  disease but not qualify for orphan-drug designation,  or vice versa, as explained below.  The 
801  following  examples illustrate  situations in which a drug might receive rare pediatric disease 
802  designation  but not also immediately  qualify  for orphan drug designation: 
803   
804    Assume that a drug receives rare pediatric disease designation but is considered the 
805  same drug under the orphan drug regulations as an already approved drug for the same 
806  orphan use.  21 CFR 316.3(b)(14).  This drug would not be eligible  to receive orphan-
807  drug designation  absent a plausible  hypothesis that it may be clinically  superior to the 
808  already approved drug.  21 CFR 316.20(a) and (b)(5).  Note:  Even though this drug may 
809  receive rare pediatric disease designation,  the application  for the drug may not qualify 
810  as an application  for a rare pediatric disease product application   and hence not be 
811  likely  to receive a priority  review voucher  if it contains a previously  approved active 
812  ingredient  (including  any ester or salt of the active ingredient).  
813   
814    Assume a sponsor plans to develop a drug for a rare pediatric disease but so far has very 
815  little data suggesting that the drug may be effective in that disease (e.g., only in vitro data 
816  supporting  the drugs mechanism of action in a related disease).  It is possible that this 
817  level of data may suffice for rare pediatric disease designation  but generally it would not 
818  suffice for orphan-drug designation. This is because, to qualify for orphan-drug 
819  designation,  an applicant must supply sufficient information  to establish a medically 
820  plausible  basis for expecting the drug to be effective in the prevention,  diagnosis,  or 
821  treatment of the rare disease or condition.66    The sponsor may eventually  obtain orphan 
822  designation  for the drug after developing  or obtaining  more supportive data for use of the 
823  drug for the rare disease or condition,  including  in vivo and/or clinical  data in the rare 
824  disease or condition. 
825   
826  If a drug receives orphan-drug designation,  it may be eligible  for orphan-drug exclusivity,  tax 
827  credits for qualified  clinical  testing, orphan product grant funding,  as well as fee exemptions 
828  under section 736 of the FD&C Act.  For information  regarding these orphan drug incentives, 
829  please contact the OOPD at orphan@fda.hhs.gov or 301-796-8660.   For information  regarding 
830  user fee exemptions, please contact the User Fee staff in CDERs Office of Management at 301-
831  796-7900.   
832   
                                                             
65 Section 529(a)(3)(B).  See also section 526. 
66 See 21 CFR 316.25(a)(2). 
22 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
833  G.  Agencys Responsibilities and Roles 
834   
835  Q32.  What are the Agencys responsibilities if it issues a priority review voucher under 
836  section 529 or if it approves a drug application for which the sponsor used such a 
837  voucher? 
838   
839  As per section 529(f)(1), FDA will publish  a notice in the Federal Register and on its website67 
840  within 30 days after issuing a priority  review voucher under section 529 and within 30 days after 
841  approving  a drug application  for which the sponsor used such a voucher. 
842   
843  Q33.  What are the different roles played by CDER, CBER, OOPD, and OPT? 
844   
845  CDER and CBER 
846   
847  The applicable review divisions  and offices within CDER and CBER have the responsibility  for 
848  premarket review of the rare pediatric disease product applications  and for determining  whether 
849  an application  meets the eligibility  criteria for receiving a priority review voucher.  CDER and 
850  CBER will consult with OOPD and OPT as to whether a disease/condition  is a rare pediatric 
851  disease as defined in section 529(a)(3). 
852   
853  OOPD and OPT 
854   
855  OOPD and OPT, both within the Office of the Commissioner,  are distinct from CDER and 
856  CBER and are responsible for determining  whether a drug (including  a biological  product) 
857  qualifies for designation  as a drug for a rare pediatric disease as defined in section 529(a)(3), if 
858  such designation  is requested.   
859   
860  Specifically,  OOPD determines if the drug is for a rare disease or condition  within the meaning 
861  of Section 526.  OPT determines if the drug is for a disease that is a serious or life-threatening 
862  disease in which the serious or life-threatening  manifestations primarily  affect individuals  aged 
863  from birth to 18 years.  OOPD and OPT will consult with CDER and CBER as appropriate.   
864   
865  OOPD is also responsible for granting orphan-drug designation  to drugs (including  biological 
866  products) under section 526 and 21 CFR part 316.  As noted in Question 31, whether a drug 
867  receives orphan-drug designation  is a different question from whether it receives designation  as a 
868  drug for a rare pediatric disease.  Questions about the orphan designation  program should be 
869  directed to OOPD. 
870   
871  In the event a sponsor does not request rare pediatric disease designation  but does request a rare 
872  pediatric disease priority  review voucher at the time of NDA/BLA submission,  the review 
873  division  or office within CDER and CBER will consult with OOPD and OPT, as appropriate, as 
874  to whether the disease/condition  is a rare pediatric disease as defined in section 529(a)(3). 
                                                             
67 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm375479.htm  
23 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
875   
876  Q34.  Whom should I contact if I have questions about a rare pediatric disease product 
877  application? 
878   
879  Sponsors with questions not addressed in this guidance should contact OOPD for questions 
880  related to designation as a rare disease, OPT for questions related to designation  as a rare 
881  pediatric disease, and the appropriate review division  or office within CDER or CBER for 
882  questions related to rare pediatric disease product applications.   CDER and CBER encourage 
883  early interaction with potential sponsors on these issues (e.g., in a pre-IND meeting or early in 
884  the clinical  development program). 
24