Pediatric Drug Development:  Regulatory 
Considerations  Complying With the 
Pediatric Research Equity Act and 
Qualifying for Pediatric Exclusivity Under 
the Best Pharmaceuticals for Children Act 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Rosemary Addy at 301-796-1640 
or (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-
402-8010.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
Administrative/Procedural 
 
Revision 1 
15032dft.docx 
04/26/23   
Pediatric Drug Development:  Regulatory 
Considerations  Complying With the 
Pediatric Research Equity Act and 
Qualifying for Pediatric Exclusivity Under 
the Best Pharmaceuticals for Children Act 
Guidance for Industry 
 
 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
Administrative/Procedural 
 
Revision 1 
  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  OVERVIEW OF REGULATORY STRATEGY FOR PEDIATRIC DRUG 
DEVELOPMENT ............................................................................................................. 3 
A.  General Approach .......................................................................................................................... 3 
B.  Developing Drugs for Pediatric Use ............................................................................................. 5 
1. Drugs for Life-Threatening or Severely Debilitating Conditions and Unmet Medical Needs ......... 5 
2. Drugs for Diseases or Conditions That Occur Primarily in Pediatric Populations ........................ 6 
3. Neonates ........................................................................................................................................... 6 
4. Orphan Products .............................................................................................................................. 6 
5. Drug Development in Foreign Countries ........................................................................................ 8 
6. Drugs for Diseases or Conditions That Only Occur in Adults ........................................................ 8 
III.  PEDIATRIC RESEARCH EQUITY ACT ..................................................................... 8 
A.  Overview  Requirements of PREA ........................................................................................... 8 
1. PREA Applicability .......................................................................................................................... 8 
2. Scope of Requirements  Generic drugs ........................................................................................ 9 
B.  Development of Drugs for Pediatric Use...................................................................................... 9 
1. Pediatric Study Plans ....................................................................................................................... 9 
2. Developing a Pediatric Formulation ............................................................................................. 10 
C.  Pediatric Assessments and Molecularly Targeted Pediatric Cancer Investigations Under 
PREA ..................................................................................................................................................... 10 
1. Definitions ...................................................................................................................................... 10 
2. Submission of Pediatric Assessments or Reports on the Molecularly Targeted Pediatric Cancer 
Investigation ................................................................................................................................... 11 
D.  Waivers and Deferrals Under PREA ......................................................................................... 12 
1. Waivers .......................................................................................................................................... 12 
a.  Criteria for full waiver ............................................................................................................ 12 
b.  Criteria for partial waiver ........................................................................................................ 13 
c.  Information for requesting a waiver ........................................................................................ 14 
d.  Waiver decision ...................................................................................................................... 14 
2. Deferrals ........................................................................................................................................ 14 
a.  Timeline .................................................................................................................................. 15 
b.  Criteria for deferral ................................................................................................................. 15 
c.  Information for requesting a deferral ...................................................................................... 16 
d.  Deferral review and decision .................................................................................................. 16 
e.  Deferral extensions .................................................................................................................. 16 
3. Annual Review ............................................................................................................................... 17 
E.  Compliance With PREA.............................................................................................................. 18 
IV.  BEST PHARMACEUTICALS FOR CHILDREN ACT ............................................ 19 
A.  Written Requests .......................................................................................................................... 19 
1. Description of the Written Request ................................................................................................ 19 
2. Written Request Studies ................................................................................................................. 20 
3. Amended Written Requests ............................................................................................................ 22 
i  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
B.  How to Obtain a Written Request .............................................................................................. 23 
1. Submitting a PPSR ......................................................................................................................... 24 
2. Issuance and Acceptance of a WR ................................................................................................. 25 
C.  How to Submit Study Reports in Response to a Written Request .......................................... 25 
D.  Qualifying for Pediatric Exclusivity ........................................................................................... 26 
1. For a Drug Product That Is the Subject of a New Drug Application or Biologics License 
Application ..................................................................................................................................... 26 
2. Nonprescription Drugs .................................................................................................................. 27 
E.  Determining Eligibility For Pediatric Exclusivity ..................................................................... 27 
F. Attaching the Period of Pediatric Exclusivity After a Determination That a Drug Qualifies for 
Pediatric Exclusivity......................................................................................................................... 29 
1. Drug Products ................................................................................................................................ 29 
a.  An initial 6-month period of pediatric exclusivity .................................................................. 29 
b.  A second 6-month period of pediatric exclusivity .................................................................. 30 
c.  Later-filed applications containing the same drug .................................................................. 31 
2. Biological Products ....................................................................................................................... 32 
V.  ELEMENTS COMMON TO PREA AND THE BPCA .............................................. 32 
A.  The Pediatric Review Committee ............................................................................................... 32 
B.  Publishing Information About Pediatric Studies ...................................................................... 33 
1. Pediatric Exclusivity Determinations ............................................................................................ 33 
2. Medical, Statistical, and Clinical Pharmacology Reviews ............................................................ 33 
3. Other Pediatric Information .......................................................................................................... 34 
C.  PREA and Pediatric Exclusivity ................................................................................................. 35 
D.  Considerations for Labeling of Drug Products ......................................................................... 36 
1. Labeling Study Results ................................................................................................................... 36 
2. Dispute Resolution ......................................................................................................................... 37 
3. Priority Review of Applications and Labeling Supplements .......................................................... 37 
E.  Adverse Event Reporting for Drug Products Subject to the BPCA and PREA .................... 38 
VI.  ADDITIONAL INFORMATION .................................................................................. 38 
GLOSSARY................................................................................................................................. 39 
 
ii  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1  Pediatric Drug Development:  Regulatory Considerations  
2  Complying With the Pediatric Research Equity Act and  
3  Qualifying for Pediatric Exclusivity Under the  
4  Best Pharmaceuticals for Children Act  
5  Guidance for Industry1 
6   
7   
8   
9   
10  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
11  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
12  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
13  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
14  for this guidance as listed on the title page. 
15   
16   
17   
18   
19  I.  INTRODUCTION 
20   
21  This guidance is intended to assist industry developing drug products2 to comply with the 
22  pediatric study requirements under the Pediatric Research Equity Act (PREA),3 and to describe 
23  the process for qualifying for pediatric exclusivity and the protections that pediatric exclusivity 
24  offers under the Best Pharmaceuticals for Children Act (BPCA).4  In 2010, the Biologics Price 
25  Competition and Innovation Act of 2009 extended provisions of the BPCA to biological 
26  products.5 
27   
 
1 This guidance has been prepared by the Division of Pediatrics and Maternal Health in the Center for Drug 
Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration.   
 
2 For the purposes of this guidance, unless otherwise specified, references to drugs or drug products include drugs 
approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) and 
biological products licensed under section 351 of the Public Health Service (PHS) Act (42 U.S.C. 262) that are 
regulated as drugs. 
 
3 Public Law 108-155 (2003), codified at section 505B of the FD&C Act (21 U.S.C. 355c).  Although section 505B 
has been amended since the passage of PREA, by convention, that section of the FD&C Act is often referred to by 
the acronym for the Act that created it, PREA.  We adopt that convention in this guidance. 
 
4 Public Law 107-109 (2002), codified at section 505A of the FD&C Act (21 U.S.C. 355a). Although section 505A 
has been amended since the passage of the BPCA, by convention, that section of the FD&C Act is often referred to 
by the acronym for the Act that created it, the BPCA.  We adopt that convention in this guidance. 
 
5 See section 351(m) of the PHS Act (42 U.S.C. 262(m)). 
  1  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
28  Note that section 505B(b) of the Federal Food, Drug, and Cosmetic (FD&C) Act on already-
29  marketed drugs and section 409I of the Public Health Service (PHS) Act are only briefly 
30  addressed in this guidance.  Future guidance may address these issues in greater detail.  
31  Furthermore, this guidance only briefly addresses the Food and Drug Administration 
32  Reauthorization Act of 2017s (FDARAs) amendments to section 505B of the FD&C Act 
33  relating to requirements that sponsors of certain adult oncology drugs with molecular targets that 
34  are determined to be substantially relevant to the growth or progression of a pediatric cancer 
35  submit reports on molecularly targeted pediatric cancer investigations.6,7   
36   
37  The scientific aspects of a pediatric program (e.g., considerations regarding data in pediatric 
38  subjects, timing of pediatric studies) are addressed in the draft guidance for industry Pediatric 
39  Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for 
40  Children Act:  Scientific Considerations (May 2023).8 
41   
42  This guidance, along with the draft guidance for industry Pediatric Drug Development Under the 
43  Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act:  Scientific 
44  Considerations,9 revises and replaces the draft guidance for industry How to Comply With the 
45  Pediatric Research Equity Act.10  In addition to addressing the PREA topics covered in the 
46  earlier draft guidance (i.e., the pediatric assessment, pediatric plan, waivers and deferrals, 
47  compliance issues, and pediatric exclusivity provisions), this guidance addresses statutory 
48  changes relating to adverse event reporting, pediatric study plans (PSPs), deferral extensions, 
49  and noncompliance.   
50   
51  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
52  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
53  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
54  the word should in Agency guidances means that something is suggested or recommended, but 
55  not required. 
56   
57   
 
6 Certain terms used in this guidance, which appear in bold italics at first mention, are defined for purposes of this 
guidance in the Glossary. 
 
7 For additional information on FDAs implementation of these amendments to section 505B of the FD&C Act, see 
the guidance for industry FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology 
Drugs: Amendments to Sec. 505B of the FD&C Act (May 2021).  We update guidances periodically.  To make sure 
you have the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
8 When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.  
 
9 When final, this guidance will represent the FDAs current thinking on this topic.   
 
10 This guidance also addresses certain topics previously addressed in the guidance for industry Qualifying for 
Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act.  That guidance was 
withdrawn August 7, 2013 (78 FR 48175).   
  2  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
58  II.  OVERVIEW OF REGULATORY STRATEGY FOR PEDIATRIC DRUG 
59  DEVELOPMENT  
60   
61  A.  General Approach 
62   
63  For purposes of pediatric drug development, FDA generally considers the pediatric population to 
64  include those patients from birth to younger than 17 years (i.e., birth through 16 years of age), 
65  and to include the subpopulation age groups of neonates, infants, children, and adolescents.11  
66  Consistent with International Council for Harmonisation (ICH) guidelines,12 FDA considers 
67  these subpopulation age groups to be divided as follows: 
68   
69    Neonates:  birth through 27 days (corrected gestational age) 
70    Infants:  28 days to 23 months 
71    Children:  2 years to 11 years 
72    Adolescents:  12 years to younger than 17 years   
73   
74  The BPCA defines pediatric studies to mean at least one clinical investigation in pediatric age 
75  groups (including neonates in appropriate cases) in which a drug is anticipated to be used, and, at 
76  the discretion of the Secretary, may include preclinical studies.13  For purposes of satisfying the 
77  requirements of PREA, assessments of safety and effectiveness must be performed in all relevant 
78  pediatric age groups, unless the assessments are waived or deferred.14   
79   
80  The BPCA and PREA are designed to work together to encourage the development of data to 
81  inform the safe and effective use of drugs in pediatric populations.  Under PREA, pediatric 
82  assessments are required for drug products with a new active ingredient, new indication, new 
83  dosage form, new dosing regimen, or new route of administration unless the drug is for an 
84  indication for which orphan designation has been granted.15  Also under PREA, molecularly 
85  targeted pediatric cancer investigations are required for original new drug applications (NDAs) 
86  or biologics license applications (BLAs) submitted on or after August 18, 2020, for a new active 
87  ingredient, if the drug that is the subject of the application is intended for the treatment of an 
 
11 See 21 CFR 201.57(c)(9)(iv)(A) (the terms pediatric population(s) and pediatric patient(s) are defined as the 
pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and 
adolescents).  FDA interprets birth to 16 years in 21 CFR 201.57(c)(9)(iv)(A) to mean from birth to younger than 
17 years old.  See, for example, the guidance for industry Pediatric Information Incorporated Into Human 
Prescription Drug and Biological Product Labeling (March 2019). 
 
12 For additional information, see the ICH guidances for industry E11 Clinical Investigation of Medicinal Products 
in the Pediatric Population (December 2000) and E11(R1) Addendum: Clinical Investigation of Medicinal Products 
in the Pediatric Population (April 2018). 
 
13 See section 505A(a) of the FD&C Act (21 U.S.C. 355a(a)). 
 
14 See sections 505B(a)(2)(A), 505B(a)(4), and 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(2)(A), 21 U.S.C. 
355c(a)(4), and 21 U.S.C. 355c(a)(5)). 
 
15 See sections 505B(a)(1)(A) and 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(a)(1)(A) and 21 U.S.C. 
355c(k)(1)). 
 
  3  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
88  adult cancer, and directed at a molecular target that FDA determines to be substantially relevant 
89  to the growth or progression of a pediatric cancer.16  Studies conducted under the BPCA, on the 
90  other hand, are optional because sponsors have the option of declining to undertake them in 
91  response to a written request (WR).  Nevertheless, it is critical that sponsors consider both laws 
92  when planning their pediatric clinical development programs. 
93   
94  PREA requires that any application falling within the requirements of section 505B(a)(1) of the 
95  FD&C Act for a new active ingredient, new indication, new dosage form, new dosing regimen, 
96  or new route of administration must either include pediatric assessments or reports on the 
97  molecularly targeted pediatric cancer investigation (as appropriate);17 or a request for waiver 
98  and/or deferral of the pediatric assessments or reports on the molecularly targeted pediatric 
99  cancer investigation.18  There are certain exceptions; for example, PREA requirements generally 
100  do not apply to a drug for an indication for which orphan designation has been granted (see 
101  section II.B.4., Orphan Products).19   
102   
103  The FD&C Act requires sponsors to submit an initial pediatric study plan (iPSP) during the 
104  investigational phase of development, which helps to ensure that sponsors thoroughly consider a 
105  pediatric clinical development program earlier in their overall clinical development program.20  
106  See sections III., Pediatric Research Equity Act, and V., Elements Common to PREA and the 
107  BPCA, for additional information about PREA.  
108   
109  While addressing PREA, sponsors should also consider whether to seek a WR under the BPCA.  
110  It is important to note that sponsors may qualify for pediatric exclusivity under the BPCA for 
111  completed PREA studies when those studies are described in a WR,21 and the WR is issued by 
112  FDA before the sponsor submits any reports about the studies described in the WR.22  If FDA 
113  determines that information relating to the use of a new drug in the pediatric population may 
114  produce health benefits in that population and issues a WR, a sponsor may qualify for 6 months 
115  of exclusivity under the BPCA for conducting studies that are required under PREA.23  However, 
116  as discussed in Section IV. A. 2., Written Request Studies, FDA does not expect to issue WRs 
117  solely for studies or planned studies that are required under PREA.    
 
16 Section 505B(a)(1)(B) of the FD&C Act (21 U.S.C. 355c(a)(1)(B)). 
 
17 For additional information, see the guidance for industry FDARA Implementation Guidance for Pediatric Studies 
of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act. 
 
18 See sections 505B(a)(1), 505B(a)(4), and 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(1), 21 U.S.C. 
355c(a)(4), and 21 U.S.C. 355c(a)(5)). 
 
19 See section 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(k)(1)).  Under section 505B(k)(2) of the FD&C Act, 
this orphan exemption does not apply to products that trigger PREA under section 505B(a)(1)(B) of the FD&C Act.  
 
20 See section 505B(e) of the FD&C Act (21 U.S.C. 355c(e)). 
 
21 See section 505A(h) of the FD&C Act (21 U.S.C. 355a(h)). 
 
22 See section 505A(b)(1) of the FD&C Act (21 U.S.C. 355a(b)(1)). 
 
23 See section 505A(b)(1) of the FD&C Act (21 U.S.C. 355a(b)(1)). 
  4  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
118   
119  In addition, sponsors should consider other indications for development in the pediatric 
120  population based on the current understanding of the effect of the drug (e.g., mechanism of 
121  action), and include them as appropriate when seeking a WR.  FDA reviews adult safety and 
122  effectiveness data and, in some instances, information from postmarketing safety reports, 
123  information regarding unapproved uses, and the scientific literature to identify a potential health 
124  benefit in pediatric populations when contemplating a WR.  This knowledge not only informs 
125  FDAs decision to issue a WR for a given indication, but also whether to include a request to 
126  study additional indications in children beyond those already approved in adults.  See sections 
127  IV., Best Pharmaceuticals for Children Act, and V., Elements Common to PREA and the BPCA, 
128  for more information about the BPCA. 
129   
130  B.  Developing Drugs for Pediatric Use 
131   
132  During clinical development programs, a sponsor should consider whether the eventual 
133  marketing application will trigger the requirements of PREA.  FDA encourages sponsors to 
134  interact with FDA early, including, when applicable, to discuss studies to meet PREA and other 
135  requirements.  See section III., Pediatric Research Equity Act, for information about the 
136  requirements of PREA. 
137   
138  FDA has identified a number of scenarios and considerations that may affect a sponsors 
139  approach to developing a drug product for use in pediatric patients.  Some common ones are 
140  described below. 
141   
142  1.  Drugs for Life-Threatening or Severely Debilitating Conditions and Unmet 
143  Medical Needs 
144   
145  Early consultation and discussions are particularly important for drugs intended for life-
146  threatening or severely debilitating conditions.24  For these drugs, FDA encourages sponsors to 
147  discuss the pediatric plan at pre-investigational new drug application (pre-IND) and end-of-phase 
148  1 meetings.25  In some cases, pediatric studies of drugs for life-threatening or severely 
149  debilitating conditions that lack adequate therapies might begin earlier than usual in the drug 
150  development process.  The need for new therapies might justify early trials despite the relative 
151  lack of safety and effectiveness information in humans.  Pediatric studies might be considered 
152  appropriate when prospects of direct benefit to the enrolled children are sufficient to justify the 
153  risks.26   
154   
 
24 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014) for 
more information.  
 
25 See section 505B(e)(2)(C)(i)(I) of the FD&C Act (21 U.S.C. 355c(e)(2)(C)(i)(I)).   
 
26 See 21 CFR 50.52. 
  5  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
155  2.  Drugs for Diseases or Conditions That Occur Primarily in Pediatric Populations 
156   
157  Sponsors developing drug products for diseases or conditions that primarily or substantially 
158  occur in the pediatric population should discuss their plans with FDA as early as possible (e.g., 
159  pre-IND meeting).  They should consider submitting an iPSP earlier than is required under 
160  PREA because the initial clinical studies will likely include pediatric subjects (see section 
161  III.B.1., Pediatric Study Plans).  
162   
163  3.  Neonates  
164   
165  The complex medical state of neonates makes it critical to evaluate drugs specifically for their 
166  use.  However, FDA is aware that studies in neonates present special challenges, including the 
167  short time period to conduct studies during the neonatal period (e.g., birth through 27 days 
168  corrected gestational age), the differences in neonatal physiology that may affect dose and 
169  endpoint selection, as well as ethical issues that may be age-specific.  Under PREA, studies in 
170  neonates may be required.  However, it is possible that partial waivers for this and other specific 
171  age groups might be appropriate under certain circumstances.27  
172   
173  FDA encourages specific activities regarding neonates.  Under PREA, if a sponsor does not plan 
174  to study an investigational drug in neonates, the rationale and supporting data explaining why the 
175  drug is not appropriate for use in this population should be included in the iPSP.28  Under the 
176  BPCA, similar rationale and supporting data explaining why the investigational drug is not 
177  appropriate for use in this population should be included in the proposed pediatric study request 
178  (PPSR) if a sponsor does not plan to study the drug in neonates.  When FDA issues a WR that 
179  does not include studies in neonates, the WR must state the rationale for not including 
180  neonates.29  See sections IV.A.1., Description of the Written Request, and IV.B., How to Obtain 
181  a Written Request, as well as the draft guidance for industry Pediatric Drug Development Under 
182  the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act:  Scientific 
183  Considerations30 for more information regarding clinical studies in neonates.  
184   
185  4.  Orphan Products   
186   
187  PREA requirements generally do not apply to any drug or biological product for an indication 
188  for which orphan designation has been granted; however, this orphan exemption does not apply 
189  to drugs that trigger the PREA requirement for submission of reports on the molecularly targeted 
 
27 See section 505B(a)(5)(B) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)). 
 
28 See section 505B(e)(2)(B) of the FD&C Act (21 U.S.C. 355c(e)(2)(B)) and the guidance for industry Pediatric 
Study Plans:  Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric 
Study Plans (July 2020).   
 
29 See section 505A(d)(1)(A) of the FD&C Act (21 U.S.C. 355a(d)(1)(A)). 
 
30 When final, this guidance will represent FDAs current thinking on this topic. 
 
  6  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
190  pediatric cancer investigation.31  Thus, PREA does not require submission of pediatric 
191  assessments for an application (or supplemental application) to market a drug for an indication 
192  for which orphan designation has been granted.32  As FDA has interpreted PREA, if orphan 
193  designation is granted after approval of a drug, and postmarketing studies were required under 
194  PREA at the time of the drugs approval, the granting of orphan designation does not alter the 
195  already existing requirement for such studies.33  The PREA orphan exemption is not revisited to 
196  retroactively abrogate a PREA requirement that was properly imposed before orphan designation 
197  was granted.  Additionally, if marketing approval is sought for multiple indications for a drug 
198  product, some of which have not been granted orphan designation, the sponsor must submit 
199  pediatric assessments for all indications that do not have an orphan designation, unless the 
200  assessments are waived or deferred.34  If the orphan-designated indication(s) involve the 
201  pediatric population, we encourage sponsors to conduct studies in the relevant age group(s) 
202  whenever appropriate.   
203   
204  Despite this orphan exemption under PREA, a sponsor that submits an application to market a 
205  drug for an indication for which orphan designation has been granted may be eligible to qualify 
206  for pediatric exclusivity if FDA issues a WR to the sponsor in connection with the application 
207  and the sponsor accepts.  Sponsors should contact FDA about the feasibility and timing of a WR 
208  and about submitting a PPSR, if appropriate.  For more information, see sections III.C.2., 
209  Submission of Pediatric Assessments or Reports on the Molecularly Targeted Pediatric Cancer 
210  Investigation, IV.F.2., Biological Products, and V.B.1., Pediatric Exclusivity Determinations, as 
211  well as FDAs Office of Orphan Products Development web page on developing drug products 
212  for rare diseases and conditions,35 and the guidance for industry Clarification of Orphan 
213  Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases (July 
214  2018). 
215   
 
31 See sections 505B(a)(1)(B), 505B(a)(3), and 505B(k) of the FD&C Act (21 U.S.C. 355c(a)(1)(B), 21 U.S.C. 
355c(a)(3), and 21 U.S.C. 355c(k)).  Note that, although section 505B(k) authorizes FDA to issue regulations that 
would alter the orphan exemption, as of the date of publication of this guidance, FDA has not issued any such 
regulations. 
 
32 See section 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(k)(1)).  For products meeting the criteria in section 
505B(a)(1)(B) of the FD&C Act, the requirement to submit reports on the investigation described in section 
505B(a)(3) of the FD&C Act applies even if the drug is for an adult indication for which orphan designation has 
been granted.  See section 505B(k)(2) of the FD&C Act (21 U.S.C. 355c(k)(2)).  See also the guidance for industry 
FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to 
Sec. 505B of the FD&C Act.   
 
33 Because the orphan exemption in section 505B(k)(1) of the FD&C Act can affect whether PREA applies to a 
particular application or supplement submitted to the Agency for review, FDA evaluates whether the orphan 
exemption is applicable at the time it evaluates whether PREA would otherwise be triggered for any application or 
supplement under section 505B(a)(1)(A). 
 
34 See sections 505B(a)(1)(A), 505B(a)(4), 505B(a)(5), and 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(a)(1)(A), 
21 U.S.C. 355c(a)(4), 21 U.S.C. 355c(a)(5), and 21 U.S.C. 355c(k)(1)). 
 
35 See the Medical Products for Rare Diseases and Conditions web page at 
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm. 
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Draft  Not for Implementation 
216  5.  Drug Development in Foreign Countries 
217   
218  Many sponsors conduct their entire clinical programs in other countries and occasionally submit 
219  a marketing application with little, if any, prior interaction with FDA.  All sponsors who seek to 
220  market their drugs in the United States are strongly encouraged to contact FDA as early as 
221  possible to avoid any delay in providing any required pediatric information in their applications.  
222  Sponsors should include an agreed iPSP in any NDA, BLA, or supplement that is required by 
223  PREA to include pediatric assessments or reports on the molecularly targeted pediatric cancer 
224  investigation.  PREA requirements are described in more detail in section III., Pediatric Research 
225  Equity Act. 
226   
227  6.  Drugs for Diseases or Conditions That Only Occur in Adults 
228   
229  Sponsors focusing on clinical development programs for drugs for diseases and conditions that 
230  only occur in adults must submit an iPSP, assuming the application triggers PREA.36  A list of 
231  diseases and conditions that rarely or never occur in pediatrics can be found on FDAs website.37  
232  Generally, applications for drugs for such diseases or conditions that rarely or never occur in 
233  pediatrics will qualify for a waiver because the necessary studies would be impossible or highly 
234  impracticable.38  However, sponsors should consider all potential pediatric indications for their 
235  drugs.  FDA may consider issuance of a WR for other indications that may have health benefits 
236  in the pediatric population.   
237   
238   
239  III.  PEDIATRIC RESEARCH EQUITY ACT   
240   
241  A.  Overview  Requirements of PREA 
242   
243  1.  PREA Applicability 
244   
245  With limited exception (for example, the orphan exemption described in section II.B.4., Orphan 
246  Products), PREA applies to the following: 
247   
248    Applications (or supplements to an application) submitted under section 505 of the 
249  FD&C Act or section 351 of the PHS Act for a new active ingredient, new indication, 
250  new dosage form, new dosing regimen, or new route of administration, and  
251   
 
36 See section 505B(e)(1) of the FD&C Act (21 U.S.C. 355c(e)(1)); see also section 505B(a)(1) of the FD&C Act 
(21 U.S.C. 355c(a)(1)). 
 
37 See Adult-Related Conditions That Qualify for a Waiver Because They Rarely or Never Occur in Pediatrics, 
available at https://www.fda.gov/media/101440/download. 
 
38 See section 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(5)).  FDA anticipates that there will be additional 
considerations for applications described in section 505B(a)(1)(B) of the FD&C Act that require submission of 
reports on the molecularly targeted pediatric cancer investigation described in section 505B(a)(3) of the FD&C Act.  
For additional information, see the guidance for industry FDARA Implementation Guidance for Pediatric Studies of 
Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act.   
 
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252    Original applications for a new active ingredient submitted under section 505 of the 
253  FD&C Act or section 351 of the PHS Act on or after August 18, 2020, if the drug that is 
254  the subject of the application is intended for the treatment of an adult cancer and is 
255  directed at a molecular target that FDA determines to be substantially relevant to the 
256  growth or progression of a pediatric cancer.39   
257   
258  PREA also authorizes FDA to require holders of already approved applications to conduct 
259  pediatric assessments under certain circumstances.40   
260   
261  2.  Scope of Requirements  Generic drugs 
262   
263  Abbreviated new drug applications (ANDAs) submitted under section 505(j) of the FD&C Act 
264  most often are applications for drugs containing the same active ingredient(s), strength(s), 
265  indication(s), dosage form(s), dosing regimen(s), and route(s) of administration as the listed 
266  drugs they reference and are not subject to PREA.  ANDA applicants may petition the Agency to 
267  request a change from a listed drug per section 505(j)(2)(C) of the FD&C Act and 21 CFR 
268  314.93, a process referred to as a suitability petition.  The regulation at 314.93 limits the types of 
269  changes that may be permitted to changes in strength, dosage form, route of administration, or of 
270  a single active ingredient in a combination drug subject to the restrictions identified in 
271  314.93(d)(1) through (3).  ANDAs submitted pursuant to an approved suitability petition for 
272  changes in dosage form, route of administration, or for a change in active ingredient in a 
273  combination drug do trigger PREA, but they are only eligible for submission as ANDAs if the 
274  pediatric assessment or molecularly targeted pediatric cancer investigation requirements are 
275  waived.41  If a change proposed in a suitability petition triggers PREA and FDA does not waive 
276  the requirement to submit pediatric assessments or reports on the molecularly targeted pediatric 
277  cancer investigation, the suitability petition will be denied, and the proposed drug product will 
278  not be eligible for submission as an ANDA.42   
279   
280  B.  Development of Drugs for Pediatric Use   
281   
282  1.  Pediatric Study Plans 
283   
284  A sponsor planning to submit a marketing application or supplement that is subject to PREA is 
285  required to submit an iPSP before submission of pediatric assessments or reports on the 
286  molecularly targeted pediatric cancer investigation.43  A sponsor should submit an iPSP to its 
287  investigational new drug application (IND) for review by the appropriate review division as early 
 
39 See section 505B(a)(1) of the FD&C Act (21 U.S.C. 355c(a)(1)). 
 
40 See section 505B(b) of the FD&C Act (21 U.S.C. 355c(b)). 
 
41 See section 505(j)(2)(C) of the FD&C Act (21 U.S.C. 355(j)(2)(C)) and section 505B(a)(1) of the FD&C Act (21 
U.S.C. 355c(a)(1)). 
 
42 See, for example, 21 CFR 314.93.  
 
43 See section 505B(e)(1) of the FD&C Act (21 U.S.C. 355c(e)(1)). 
 
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288  as practicable and must submit it no later than 60 calendar days after the date of the end-of-phase 
289  2 meeting or such other time as agreed upon between FDA and the applicant.44  More 
290  information on the timing and contents of iPSPs, the process for reaching agreement with FDA 
291  on iPSPs, and the process for amending an agreed iPSP can be found in the guidance for industry 
292  Pediatric Study Plans:  Content of and Process for Submitting Initial Pediatric Study Plans and 
293  Amended Initial Pediatric Study Plans (July 2020).  Sponsors are also encouraged to consider the 
294  possibility of submitting a PPSR to obtain a WR during the PSP process.  An iPSP and a PPSR 
295  are different documents and have different considerations for submission; the former is a 
296  requirement for compliance with PREA and the latter may be submitted at a sponsors discretion 
297  to seek a WR under the BPCA.  See sections IV.A., Written Requests, and IV.B., How to Obtain 
298  a Written Request, for further discussion about PPSRs and WRs. 
299   
300  2.  Developing a Pediatric Formulation 
301   
302  Under PREA, sponsors are required to conduct pediatric studies using appropriate formulations 
303  for each age group for which the assessment or investigation is required.45  However, FDA may 
304  grant a partial waiver if a sponsor is unable to develop an age-appropriate formulation after 
305  reasonable attempts to do so.46  (See discussion of waivers in section III.D., Waivers and 
306  Deferrals Under PREA.)  Under PREA, sponsors must submit a request for approval of a 
307  pediatric formulation used in their pediatric studies, and if a sponsor fails to submit such a 
308  request, the drug may be considered misbranded.47  Accordingly, sponsors should submit an 
309  application or supplemental application for any formulation(s) not previously approved that were 
310  used during pediatric studies and for which the sponsor has data to assess the safety and 
311  effectiveness and to support dosing and administration.  To avoid delays in initiation of pediatric 
312  clinical studies, sponsors should begin the development of an age-appropriate formulation as 
313  early as possible.  
314   
315  C.  Pediatric Assessments and Molecularly Targeted Pediatric Cancer 
316  Investigations Under PREA 
317   
318  1.  Definitions 
319   
320  Pediatric assessments must contain data, gathered using appropriate formulations for each age 
321  group for which the assessment is required and that are adequate to: 
322   
323    Assess the safety and effectiveness of the drug for the claimed indications in all relevant 
324  pediatric subpopulations; and 
325   
 
44 See section 505B(e)(2)(A)(ii) of the FD&C Act (21 U.S.C. 355c(e)(2)(A)(ii)). 
 
45 See section 505B(a)(2)(A) and 505B(a)(3)(A) of the FD&C Act (21 U.S.C. 355c(a)(2)(A) and 355c(a)(3)(A)). 
 
46 See section 505B(a)(5)(B)(iv) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)(iv)). 
 
47 See section 505B(d) of the FD&C Act (21 U.S.C. 355c(d)). 
 
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326    Support dosing and administration for each pediatric subpopulation for which the drug is 
327  safe and effective.48   
328   
329  A molecularly targeted pediatric cancer investigation shall be designed to yield clinically 
330  meaningful pediatric study data, gathered using appropriate formulations for each age group for 
331  which the study is required, regarding dosing, safety, and preliminary efficacy to inform 
332  potential pediatric labeling.49 
333   
334  2.  Submission of Pediatric Assessments or Reports on the Molecularly Targeted 
335  Pediatric Cancer Investigation 
336   
337  Sponsors must submit pediatric assessments or reports on the molecularly targeted pediatric 
338  cancer investigation with any application for which such assessments or reports are required by 
339  PREA, unless FDA defers and/or waives the requirement.50  (For pediatric assessments, if the 
340  drug is for an indication for which orphan designation has been granted, the requirements of 
341  PREA do not apply.)51  See section III.D., Waivers and Deferrals Under PREA, for discussion of 
342  waivers and deferrals.  In general, sponsors should include pediatric studies at the time of 
343  submission of an application when there is sufficient knowledge to proceed and it is feasible to 
344  complete studies in children in parallel with adult studies.  
345   
346  Information about the results of pediatric assessments under PREA must be included in product 
347  labeling whether findings are positive, negative, or inconclusive.52  Labeling changes for 
348  approved products must be submitted in accordance with applicable requirements in 21 CFR 
349  601.12 and 21 CFR 314.70.  For more information about labeling, see section V.D., 
350  Considerations for Labeling of Drug Products, and the guidance for industry Pediatric 
351  Information Incorporated Into Human Prescription Drug and Biological Product Labeling 
352  (March 2019).  
353   
354  For information about the specific types of data that may be needed to complete a pediatric 
355  assessment, refer to the draft guidance for industry Pediatric Drug Development Under the 
356  Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act:  Scientific 
357  Considerations.53  
358   
 
48 See section 505B(a)(2)(A) of the FD&C Act (21 U.S.C. 355c(a)(2)(A)). 
 
49 Section 505B(a)(3)(A) of the FD&C Act (21 U.S.C. 355c(a)(3)(A)). 
 
50 See sections 505B(a)(1), 505B(a)(4), and 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(1), 21 U.S.C. 
355c(a)(4), and 21 U.S.C. 355c(a)(5)). 
 
51 See section 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(k)(1)). 
 
52 See section 505B(g)(2) of the FD&C Act (21 U.S.C. 355c(g)(2)). 
 
53 When final, this guidance will represent FDAs current thinking on this topic. 
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359  D.  Waivers and Deferrals Under PREA 
360   
361  1.  Waivers 
362   
363  PREA authorizes FDA to waive the requirement to submit pediatric assessments or reports on 
364  the molecularly targeted pediatric cancer investigation, based on established criteria, for some or 
365  all pediatric age groups.54  FDA can grant a full or partial waiver of the requirements on its own 
366  initiative or at the request of an applicant.55  Any applicant requesting a waiver should provide 
367  written justification for the waiver and evidence to support the request.  
368   
369  a.  Criteria for full waiver 
370   
371  FDA will, as appropriate, grant a full waiver of the requirement to submit pediatric assessments 
372  or reports on the molecularly targeted pediatric cancer investigation if the applicant certifies and 
373  FDA finds one or more of the following criteria:  
374   
375    Necessary studies are impossible or highly impracticable (because, for example, the 
376  number of patients is so small or the patients are geographically dispersed).56 For further 
377  information, see Section II.B.6., Drugs for Diseases or Conditions That Only Occur in 
378  Adults. 
379   
380    There is evidence strongly suggesting that the drug would be ineffective or unsafe in all 
381  pediatric age groups.57 
382   
383    The drug (1) does not represent a meaningful therapeutic benefit over existing therapies 
384  for pediatric patients; and (2) is not likely to be used in a substantial number of pediatric 
385  patients.58   
386   
387   Importantly, we note that both criteria must be met for this waiver justification to 
388  apply.  A drug is considered to represent a meaningful therapeutic benefit over 
389  existing therapies if FDA determines that (1) if approved, the drug or biological 
390  product could represent an improvement in the treatment, diagnosis, or prevention of 
391  a disease, compared with marketed products adequately labeled for that use in the 
392  relevant pediatric population; or (2) the drug or biological product is in a class of 
393  products or for an indication for which there is a need for additional options.59  FDA 
394  anticipates that improvement over marketed drugs might be demonstrated by 
 
54 See section 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(5)). 
 
55 See section 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(5)). 
 
56 See section 505B(a)(5)(A)(i) of the FD&C Act (21 U.S.C. 355c(a)(5)(A)(i)). 
 
57 See section 505B(a)(5)(A)(ii) of the FD&C Act (21 U.S.C. 355c(a)(5)(A)(ii)). 
 
58 See section 505B(a)(5)(A)(iii) of the FD&C Act (21 U.S.C. 355c(a)(5)(A)(iii)). 
 
59 See section 505B(c) of the FD&C Act (21 U.S.C. 355c(c)). 
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395  showing, for example (1) evidence of increased effectiveness in treatment, 
396  prevention, or diagnosis of disease; (2) an improved safety profile; (3) enhancement 
397  of compliance (e.g., by virtue of less frequent dosing or mode of delivery); or (4) 
398  safety and effectiveness in a new subpopulation for which marketed drugs are not 
399  currently labeled. 
400   
401  b.  Criteria for partial waiver 
402   
403  FDA will, as appropriate, grant a partial waiver of the requirement to submit pediatric 
404  assessments or reports on the molecularly targeted pediatric cancer investigation with respect to 
405  a specific pediatric age group, if the applicant certifies and FDA finds one or more of the 
406  following criteria:   
407   
408    Necessary studies are impossible or highly impracticable (because, for example, the 
409  number of patients in that age group is so small or patients in that age group are 
410  geographically dispersed);60 
411   
412    There is evidence strongly suggesting that the drug would be ineffective or unsafe in that 
413  age group;61 
414   
415    The drug (1) does not represent a meaningful therapeutic benefit over existing therapies 
416  for pediatric patients in that age group; and (2) is not likely to be used in a substantial 
417  number of pediatric patients in that age group;62 
418   
419    The applicant can demonstrate that reasonable attempts to produce a pediatric 
420  formulation necessary for that age group have failed.63   
421   
422  We note that if a partial waiver is granted on the basis that it is not possible to develop a pediatric 
423  formulation, the waiver will cover only the pediatric age groups requiring that formulation.64   
424   
425  FDA believes that a partial waiver granted based on the inability to develop a pediatric 
426  formulation generally should apply to situations in which the applicant can demonstrate that 
427  unusually difficult technological problems prevented it from developing a pediatric formulation.  
428  In certain cases, FDA may seek appropriate external expert opinion (e.g., from an advisory 
429  committee) to help assess whether to grant such a waiver.  
430   
 
60 See section 505B(a)(5)(B)(i) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)(i)). 
 
61 See section 505B(a)(5)(B)(ii) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)(ii)). 
 
62 See section 505B(a)(5)(B)(iii) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)(iii)). 
 
63 See section 505B(a)(5)(B)(iv) of the FD&C Act (21 U.S.C. 355c(a)(5)(B)(iv)). 
 
64 See section 505B(a)(5)(C) of the FD&C Act (21 U.S.C. 355c(a)(5)(C)). 
 
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431  If the sponsor seeks a partial waiver on the grounds that it is not possible to develop a pediatric 
432  formulation, the sponsor must submit documentation detailing why a pediatric formulation 
433  cannot be developed.65  This should include a detailed description of the sponsors efforts to 
434  develop a pediatric formulation.66  If FDA grants such a waiver, the sponsors submission will be 
435  made publicly available.67   
436   
437  c.  Information for requesting a waiver  
438   
439  To request a waiver, sponsors should provide the following:  
440   
441    The drug name, applicant name, and indication. 
442   
443    The age group(s) included in the waiver request. 
444   
445    The statutory reason(s) for requesting a waiver, including reference to the applicable 
446  statutory authority.68 
447   
448    Evidence that the request meets the statutory reason(s) for waiver.69  All relevant 
449  scientific/clinical justifications for the waiver request should be included.  
450   
451  d.  Waiver decision 
452   
453  FDA grants a waiver at the time of approval of an application that triggers PREA if it determines 
454  that the application satisfies the statutory requirements for a waiver.  FDA generally includes a 
455  preliminary evaluation of the sponsors plan to request a waiver in FDAs comments on the iPSP 
456  (see section III.B.1., Pediatric Study Plans).  This evaluation reflects FDAs best judgment at that 
457  time. 
458   
459  2.  Deferrals 
460   
461  PREA authorizes FDA to defer the requirement to submit pediatric assessments or reports on the 
462  molecularly targeted pediatric cancer investigation, based on established criteria.70  A deferral 
463  acknowledges that pediatric assessments or reports on the molecularly targeted pediatric cancer 
464  investigation are required, but permits the applicant to submit the assessments or reports after the 
 
65 See section 505B(a)(5)(C) of the FD&C Act (21 U.S.C. 355c(a)(5)(C)). 
 
66 A partial waiver on this basis hinges on whether the applicant can demonstrate the failure of reasonable 
attempts to produce a pediatric formulation (section 505B(a)(5)(B)(iv) (21 U.S.C. 355c(a)(5)(B)(iv)). 
 
67 See section 505B(a)(5)(C) of the FD&C Act (21 U.S.C. 355c(a)(5)(C)).   
 
68 See sections 505B(a)(5) and 505B(e)(2)(B)(ii) of the FD&C Act (21 U.S.C. 355c(a)(5) and 21 U.S.C. 
355c(e)(2)(B)(ii)). 
 
69 See, for example, section 505B(e)(2)(B)(ii) of the FD&C Act (21 U.S.C. 355c(e)(2)(B)(ii)). 
 
70 See section 505B(a)(4) of the FD&C Act (21 U.S.C. 355c(a)(4)). 
  14  Contains Nonbinding Recommendations  
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465  approval of an NDA, BLA, or supplement.  FDA may, on its own initiative or at the request of 
466  an applicant, defer the submission of some or all of the pediatric assessments or reports on the 
467  molecularly targeted pediatric cancer investigation until a specified date after approval of the 
468  drug.71  
469   
470  a.  Timeline 
471   
472  Sponsors can discuss a plan for a deferral and the status of a deferred study with FDA as follows: 
473   
474    Premarketing  It is important to include in the iPSP any plans for a deferral request.  In 
475  certain cases it may be appropriate to initiate early discussion of a plan for deferral, for 
476  example, as part of a pre-IND meeting or during phase 1 of clinical development.  
477   
478    Application review  FDA grants the deferral, as appropriate, upon approval of the 
479  application or supplement. 
480   
481    Postmarketing  The applicant must submit an annual review of the status of a deferred 
482  pediatric study (PREA postmarketing requirement) to FDA until it has submitted the final 
483  study report.72  The final due date of a deferred pediatric study may be extended under 
484  certain circumstances (see section III.D.2.e., Deferral extensions). 
485   
486  b.  Criteria for deferral 
487   
488  FDA may defer the timing of submission of some or all required assessments or reports on the 
489  molecularly targeted pediatric cancer investigation if the applicant submits certain required 
490  information to FDA, as discussed below, and FDA finds one or more of the following:73 
491   
492    The drug is ready for approval for use in adults before pediatric studies are complete; 
493   
494    Pediatric studies should be delayed until additional safety or effectiveness data have been 
495  collected; or 
496   
497    There is another appropriate reason for deferral 
498   
499  An appropriate reason for deferral may include, for example, that development of a pediatric 
500  formulation is not complete. 
501   
 
71 See section 505B(a)(4) of the FD&C Act (21 U.S.C. 355c(a)(3)). 
 
72 See section 505B(a)(4)(C) of the FD&C Act (21 U.S.C. 355c(a)(4)(C)). 
 
73 See section 505B(a)(4)(A)(i) of the FD&C Act (21 U.S.C. 355c(a)(4)(A)(i)). 
 
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502  c.  Information for requesting a deferral  
503   
504  To request a deferral, an applicant must provide the following:74 
505   
506    A certification of the grounds for deferral; 
507   
508    A pediatric study plan as described in section 505B(e) of the FD&C Act (see section 
509  III.B.1., Pediatric Study Plans); 
510   
511    Evidence that the studies are being conducted or will be conducted with due diligence 
512  and at the earliest possible time; and  
513   
514    A timeline for completion of such studies. 
515   
516  d.  Deferral review and decision 
517   
518  The decision to defer and the deferral date are determined on a case-by-case basis.  FDA may, as 
519  appropriate, consider the following in determining whether and how long to defer submission of 
520  a pediatric assessment: 
521   
522    The need for the drug in pediatric patients; 
523    Availability of sufficient safety data to initiate pediatric clinical studies; 
524    The nature and extent of pediatric data needed to support pediatric labeling; 
525    The existence of clearly documented difficulties in enrolling subjects; and/or 
526    Evidence of technical problems in developing pediatric formulations. 
527   
528  For additional information on the circumstances in which a deferral may be appropriate for a 
529  molecularly targeted pediatric cancer investigation, see the guidance for industry FDARA 
530  Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: 
531  Amendments to Sec. 505B of the FD&C Act.  
532   
533  The iPSP, agreed iPSP, and any subsequent amendments should include the key elements of any 
534  planned deferred studies.  FDA does not intend to make recommendations on planned deferral 
535  requests that are submitted in the absence of an iPSP, except under rare circumstances (e.g., 
536  urgent public health need). 
537   
538  FDA grants a deferral, as appropriate, in the approval letter for an NDA, BLA, or supplement.    
539   
540  e.  Deferral extensions 
541   
542  The FD&C Act provides a mechanism for FDA to grant an extension of the timeline for a 
543  deferral granted by FDA.75  Examples of reasons assessments or investigations may be delayed 
 
74 See section 505B(a)(4)(A)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(A)(ii)). 
 
75 See section 505B(a)(4)(B) of the FD&C Act (21 U.S.C. 355c(a)(4)(B)). 
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544  include, but are not limited to, unexpected difficulties with enrollment, unexpected delays in 
545  reaching agreement with FDA on protocols for the pediatric clinical studies, or an unanticipated 
546  need for additional safety or effectiveness data before proceeding with studies in children.  
547  During consideration of the deferral extension request, in general, FDA considers whether the 
548  applicant could have prevented or foreseen the delay.  FDA also generally considers the 
549  likelihood that studies can be completed given the circumstances.  
550   
551  To request a deferral extension, an applicant must submit a new timeline for the completion of 
552  pediatric studies along with any significant updates to the following information from the 
553  original deferral request:76 
554   
555    A certification of the grounds for deferral; 
556   
557    PSP; and 
558   
559    Evidence that the studies are being conducted or will be conducted with due diligence 
560  and at the earliest possible time. 
561   
562  Applicants should submit information to support the need for an extension of the timeline for 
563  deferred studies.  For example, if an applicant needs additional time to complete the deferred 
564  pediatric studies because of difficulty recruiting subjects, the applicant should provide 
565  information outlining the reasons for the difficulties, evidence supporting the reasons outlined 
566  (including information on the incidence of the condition and global geographic distribution, if 
567  applicable), and information outlining its efforts to increase enrollment such as the number of 
568  clinical sites contacted and the number of subjects screened and enrolled. 
569   
570  An applicant must submit a request for deferral extension, along with the required information, at 
571  least 90 days before the date that the studies are due.77  FDA will respond to such request within 
572  45 days of receipt of the request.78  If FDA grants the deferral extension, the specified date will 
573  be the new due date for submission of the deferred assessments or deferred reports on the 
574  molecularly targeted pediatric cancer investigation.79  
575   
576  3.  Annual Review 
577   
578  Pediatric assessments deferred under PREA are required postmarketing studies subject to annual 
579  status reporting requirements under PREA and FDA regulations.80 
 
76 See section 505B(a)(4)(B)(i)(II) of the FD&C Act (21 U.S.C. 355c(a)(4)(B)(i)(II)). 
 
77 See section 505B(a)(4)(B)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(B)(ii)). 
 
78 See section 505B(a)(4)(B)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(B)(ii)). 
 
79 See section 505B(a)(4)(B)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(B)(ii)). 
 
80 See section 505B(a)(4)(C) of the FD&C Act (21 U.S.C. 355c(a)(4)(C)); 21 CFR 314.81(b)(2)(vii), and 21 CFR 
601.70. 
 
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580   
581  An applicants annual status report under PREA must contain the following:81 
582   
583    Information detailing the progress made in conducting pediatric studies 
584   
585    If no progress has been made in conducting such studies, evidence and documentation 
586  that such studies will be conducted with due diligence and at the earliest possible time 
587   
588    The projected completion date for pediatric studies 
589   
590    The reason(s) that a deferral or deferral extension continues to be necessary 
591   
592  E.  Compliance With PREA 
593   
594  If an applicant submits an application or supplement subject to PREA and fails to comply with 
595  applicable PREA requirements, FDA may, as appropriate, refuse to file the application or issue a 
596  complete response letter after reviewing the application.82  If an applicant fails to fulfill required 
597  deferred pediatric studies under PREA that were established in the approval letter, FDA will 
598  issue to the applicant a noncompliance letter that informs it of such failure.83  The applicant must 
599  respond to this letter in writing within 45 days and may request a deferral extension as part of 
600  that response.84   
601   
602  FDA will post the noncompliance letter and the applicants response on the FDA public website 
603  after redacting any information protected by applicable law.85  If FDA grants a deferral extension 
604  before the initial study due date, FDA does not intend to issue a noncompliance letter unless and 
605  until the newly established due date has passed.  
606   
607  After FDA issues a noncompliance letter, it may take additional steps to ensure compliance if 
608  needed.  The drug may be considered misbranded solely because of the applicants failure to 
609  comply with PREA and subject to relevant enforcement action.86  For an approved drug, the 
610  failure to submit pediatric assessments or reports on the molecularly targeted pediatric cancer 
611  investigation, or a request for waiver or deferral of those studies, will not be the basis for 
 
81 See section 505B(a)(4)(C)(i) of the FD&C Act (21 U.S.C. 355c(a)(4)(C)(i)). 
 
82 See 21 CFR 314.101(d), 21 CFR 314.110, and 21 CFR 601.3. 
 
83 See section 505B(d)(1) of the FD&C Act (21 U.S.C. 355c(d)(1)). 
 
84 See section 505B(d)(1) of the FD&C Act (21 U.S.C. 355c(d)(1)). 
 
85 See 505B(d)(1) of the FD&C Act (21 U.S.C. 355c(d)(1)).  See also the Noncompliance Letters Under 505B(d)(1) 
of the FD&C Act web page at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm343203.htm.  
 
86 See section 505B(d)(2) of the FD&C Act (21 U.S.C. 355c(d)(2)). 
 
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612  withdrawing approval of a drug or revoking a license for a biological product.87  However, if 
613  FDA finds a drug to be misbranded, the drug could be subject to an injunction or seizure 
614  proceedings.88  
615   
616   
617  IV.  BEST PHARMACEUTICALS FOR CHILDREN ACT 
618   
619  A.  Written Requests 
620   
621  1.  Description of the Written Request 
622   
623  A WR is a document issued by FDA requesting submission of a study or studies intended to 
624  provide meaningful health benefits in the pediatric population.  The WR specifies the elements 
625  of the study or studies that the sponsor or application holder must complete to qualify for 
626  pediatric exclusivity.89  FDA can issue a WR at the request of an interested party or on its own 
627  initiative.  Completion of studies described in a WR is voluntary.90  FDA does not limit issuance 
628  of a WR to a specific drug product, and the WR can result in only one 6-month period of 
629  pediatric exclusivity for that sponsor, as described in section IV.F., Attaching the Period of 
630  Pediatric Exclusivity After a Determination That a Drug Qualifies for Pediatric Exclusivity.  
631  FDAs authority to issue a WR extends to use of an active moiety for indications that may 
632  produce health benefits in the pediatric population, regardless of whether the indications have 
633  been previously approved in adults.91 
634   
635  Generally, a WR seeks all applicable information necessary to establish safety and effectiveness 
636  of a drug for use in all relevant pediatric populations, including study information (e.g., type, 
637  timing, endpoints), drug-specific safety concerns to be monitored, statistical analysis plan, and 
638  timeline for completing the studies.   
639   
640  FDA can use a PPSR to develop a WR or use alternative information (see section IV.B., How to 
641  Obtain a Written Request).  As a greater understanding of the indication or of the mechanism of 
642  action of a particular drug or drug class develops, WRs, including elements within a study or 
643  studies necessary to qualify for pediatric exclusivity, may evolve. 
644   
 
87 See section 505B(d)(2) of the FD&C Act (21 U.S.C. 355c(d)(2)). 
 
88 See sections 302 and 304 of the FD&C Act (21 U.S.C. 332 and 21 U.S.C. 334). 
 
89 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
 
90 Section 505A of the FD&C Act does not require the sponsor or application holder to conduct pediatric studies; 
instead, it creates an exclusivity incentive to encourage such studies.  However, the sponsor or application holder 
may be required to conduct pediatric studies of certain new and marketed drugs under section 505B of the FD&C 
Act. 
 
91 See sections 505A(a), 505A(b)(1), 505A(c)(1), and 505A(d)(1)(B) of the FD&C Act (21 U.S.C. 355a(a), 21 
U.S.C. 355a(b)(1), 21 U.S.C. 355a(c)(1), and 21 U.S.C. 355a(d)(1)(B)). 
 
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645  In addition, the BPCA requires that, in issuing a WR, FDA take into account adequate 
646  representation of children of ethnic and racial minorities.92  If a WR does not request studies in 
647  neonates, the request will include a statement describing the rationale for not requesting such 
648  studies.93 
649   
650  A sponsor will not be eligible for pediatric exclusivity based on requirements or requests to 
651  conduct postmarketing studies (e.g., studies required under PREA) or other communications 
652  about pediatric studies unless it is in receipt of a WR.94 
653   
654  2.  Written Request Studies 
655   
656  In general, FDA decides what studies to include in a WR by determining what information is 
657  needed to use the drug appropriately in the pediatric population.  When making this 
658  determination, in general, FDA obtains the following from the sponsor:   
659   
660    Information on any other indications for this product that may have health benefits in 
661  children.  For example, the sponsor should provide information on any indications for 
662  which there are ongoing clinical studies in adults and/or children or for which the sponsor 
663  has opened an IND. 
664   
665    Information that exists in the literature on the drug or on pharmacologically related drugs. 
666   
667  In some instances, FDA may ask a sponsor to submit information to an IND before issuing a 
668  WR.  Similarly, in some cases, a sponsor may wish to submit pediatric study data to its IND in 
669  support of an amendment to its WR.  Pediatric studies previously submitted to an IND can be 
670  used as the basis of a PPSR or can be submitted to an NDA or BLA to qualify for pediatric 
671  exclusivity in response to a WR; however, FDA does not consider pediatric studies a sponsor 
672  submits to an NDA or BLA (either in an original application, amendment, or supplement) before 
673  FDA issues a WR as being responsive to that WR. 
674   
675  In certain situations, FDA may determine that a WR for additional pediatric studies will not be 
676  issued.  Such situations may include the following:  
677   
678    Sufficient pediatric information has already been submitted to the NDA or BLA, even if 
679  the pediatric information is not yet included in the labeling; 
680   
681    Study of the drug for the specified indication(s) in the pediatric population would not 
682  offer a health benefit in that population; 
683   
 
92 See section 505A(d)(1)(A) of the FD&C Act (21 U.S.C. 355a(d)(1)(A)). 
 
93 See section 505A(d)(1)(A) of the FD&C Act (21 U.S.C. 355a(d)(1)(A)). 
 
94 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
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684    It is not possible to conduct a study or studies of the drug for the specified indications in 
685  the pediatric population in a manner that would provide useful information (e.g., the 
686  study population is too small to yield interpretable results); and/or 
687   
688    Outstanding safety concerns from studies or significant theoretical concerns need to be 
689  clarified with additional studies to support conducting studies in the pediatric population. 
690   
691  Historically, FDA has at times issued WRs solely for studies required under PREA, even if there 
692  were no other indications that may produce health benefits in the pediatric population.  However, 
693  over time, data on pediatric labeling changes pursuant to BPCA and/or PREA have been 
694  collected.  Between 2002 and 2019, there were 768 products with pediatric labeling changes 
695  under BPCA and/or PREA.  Sixty-three percent of these labeling changes were based on studies 
696  conducted under PREA/Pediatric Rule alone; 21 percent were based on studies conducted under 
697  BPCA alone; 16 percent were based on studies conducted under both the BPCA and PREA.  
698  These data suggest that studies required under PREA are successfully completed, and that PREA 
699  requirements have resulted in an increase in pediatric labeling, even without the added incentive 
700  of the BPCA.   
701   
702  The BPCA provides FDA with discretion to determine whether to issue, and the appropriate 
703  scope of, WRs based on the information that may produce health benefits in the pediatric 
704  population.95  In light of the data on pediatric labeling changes pursuant to the BPCA and/or 
705  PREA, FDA believes WRs should be reserved for those sponsors who conduct additional 
706  pediatric studies  beyond what is required under PREA  that may produce health benefits in 
707  children.  Thus, upon finalization of this guidance, FDA does not expect to issue WRs solely for 
708  studies or planned studies that are required under PREA.  In general, FDA expects that a WR 
709  that includes studies or planned studies required under PREA will also include additional 
710  indications or populations.  If there are no additional studies for indications or populations that 
711  may produce health benefits in the pediatric population beyond the studies or planned studies 
712  required under PREA, then FDA does not expect to issue a WR for that drug.  For example, if a 
713  sponsor has an iPSP that includes a plan for deferred studies of a drug for pediatric juvenile 
714  idiopathic arthritis (pJIA), FDA does not expect to issue a WR solely for studies of pJIA in the 
715  same pediatric population.  However, if FDA determines that this drug may produce health 
716  benefits in pediatric systemic juvenile idiopathic arthritis (sJIA), and there are no studies or 
717  planned studies required under PREA for this indication, then it may be appropriate for FDA to 
718  issue a WR for pediatric studies for both pJIA and sJIA.   
719   
720  In general, when considering issuance of a WR, FDA evaluates the need for studies for all 
721  pediatric subpopulations and for all indications for which the drug is being used or could be used 
722  in the pediatric population.   In general, FDA considers the indications already approved for 
723  adults, indications pending for adults, and unapproved uses including uses that might be specific 
724  to the pediatric population.  A single WR may address multiple indications and uses that are both 
725  approved and unapproved.96 
 
95 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
 
96 See section 505A(d)(1)(B) of the FD&C Act (21 U.S.C. 355a(d)(1)(B)). 
 
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726   
727  FDA can issue a WR that includes nonclinical studies.97  Section 505A(a) of the FD&C Act 
728  defines the term pediatric studies to mean at least one clinical investigation (that, at the 
729  Secretarys discretion, may include pharmacokinetic studies) in pediatric age groups (including 
730  neonates in appropriate cases) in which a drug is anticipated to be used, and, at the discretion of 
731  the Secretary, may include preclinical studies.  FDA may need certain toxicology studies in 
732  immature animals to evaluate the safety of drugs for use in pediatric populations.98  Accordingly, 
733  FDA may request that a sponsor or holder of an approved application conduct nonclinical studies 
734  before completing pediatric studies in humans.  FDA may need to review such studies before it 
735  can determine whether information relating to use of the drug could produce health benefits in 
736  the pediatric population; thus, FDA may need these studies to determine if it will issue a WR. 
737   
738  In response to a WR, sponsors may, as appropriate, submit studies conducted by a third party.  
739  However, the sponsor should submit reports of studies that it has not conducted only if (1) the 
740  data from the studies appear to provide useful pediatric information that fairly responds to the 
741  WR issued by FDA; and (2) the sponsor obtains a right of reference to submit the reports of 
742  studies along with the underlying data. 
743   
744  A sponsor can use data it collects before or after FDA issues a WR to respond to the WR.  
745  Although FDA can request literature reviews as part of a larger WR, reviews of published 
746  literature alone are not pediatric studies that will qualify a drug for pediatric exclusivity.99 
747   
748  Although a sponsor may, as appropriate, use studies it conducts to meet PREA requirements to 
749  qualify also for pediatric exclusivity,100 as mentioned, FDA does not consider pediatric studies a 
750  sponsor submits to an NDA or BLA (either in an original application, amendment, or 
751  supplement) before FDA issues a WR as being responsive to that WR.  To qualify for pediatric 
752  exclusivity, sponsors and holders of an approved application should obtain a WR or an 
753  amendment to an existing WR before submitting the pediatric studies to an application. 
754   
755  3.  Amended Written Requests 
756   
757  Each WR states that the WR may be amended.  A sponsor may request an amendment to the 
758  WR, or FDA may issue an amendment on its own initiative.  However, FDA does not anticipate 
759  amending WRs in the absence of scientific, medical, or regulatory justification.  
760   
 
97 See section 505A(a) of the FD&C Act (21 U.S.C. 355a(a)). 
 
98 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  The FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  The FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
99 See sections 505A(a), 505A(b), and 505A(c) of the FD&C Act (21 U.S.C. 355a(a), 21 U.S.C. 355a(b), and 21 
U.S.C 355a(c)). 
 
100 As noted earlier in this section, going forward, FDA does not expect to issue WRs solely for studies or planned 
studies that are required under PREA.  
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761  Sponsors can request a change in the studies due date in the WR by submitting a proposed 
762  amendment to the WR.  If a sponsor believes it will be unable to meet the time frames in a WR, 
763  it should contact FDA to request such a change as soon as possible.  If FDA agrees to the 
764  change, it intends to notify the sponsor in writing regarding the extension time.  Any request for 
765  an extension of time should take into consideration that completed reports of all studies should 
766  be submitted for filing at least 15 months before the expiration of the patent or exclusivity to 
767  which the pediatric exclusivity would attach.  Sponsors should be aware that if they choose to 
768  submit within less than 15 months, FDA may not be able to complete the review and make a 
769  determination in time to meet the 9-month deadline.101   
770   
771  FDA intends to issue all amendments to a WR in writing.  Sponsors should also request any 
772  amendments to a WR in writing.  Discussion of a proposed amendment at a meeting with FDA 
773  does not constitute a request to amend a WR nor does it constitute FDAs amendment of the WR.  
774  In addition, if a sponsor has submitted a protocol that is inconsistent with the WR, and FDA has 
775  not commented on the protocol, the sponsor should not assume FDA agrees that the protocol is 
776  consistent with the WR.  Even a minor change to a study, such as a change in the number of 
777  subjects, the age groups enrolled, or the elimination of certain testing requirements, may warrant 
778  a change in the protocol and a revision of the WR if it relates to a specified term of the WR. 
779   
780  Sponsors can submit preliminary data to an IND in support of a request for amendment.  
781  Sponsors that believe that their studies may not fairly respond to the WR as issued but 
782  nonetheless provide valuable pediatric information should (1) seek to obtain an amended WR 
783  before submitting any pediatric study reports to their NDAs or BLAs; and (2) submit proposed 
784  amendments to their WRs early enough to ensure enough time for FDA to issue an amended WR 
785  and to ensure the sponsor has enough time to submit its studies at least 15 months before the 
786  expiration of any patent or exclusivity to which pediatric exclusivity would attach.   
787   
788  Sponsors should not submit the requested study reports to their NDAs or BLAs until after they 
789  have received FDAs response to requested amendments in writing.  Reports of studies that do 
790  not fairly respond to the existing WR will not qualify for pediatric exclusivity (see sections 
791  IV.C., How to Submit Study Reports in Response to a Written Request, IV.D., Qualifying for 
792  Pediatric Exclusivity, and IV.E., Determining Eligibility For Pediatric Exclusivity).102 
793   
794  B.  How to Obtain a Written Request 
795   
796  Historically, WRs have generally been issued after a drug is approved for use in adults.  
797  However, there may be situations in which it is appropriate to issue a WR before such an action.  
798  See sections II., Overview of Regulatory Strategy for Pediatric Drug Development, and III.B.1., 
799  Pediatric Study Plans, and previous subsections of this section for additional considerations 
800  relating to timing of a WR.  Additionally, the appropriate timing of the submission of a specific 
 
101 See sections 505A(b)(2), 505A(c)(2), and 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(b)(2), 21 U.S.C. 
355a(c)(2), and 21 U.S.C. 355a(d)(4)).   
 
102 See sections 505A(b)(1), 505A(c)(1), 505A(d)(4), and 505A(h) of the FD&C Act (21 U.S.C. 355a(b)(1), 21 
U.S.C. 355a(c)(1), 21 U.S.C. 355a(d)(4), and 21 U.S.C. 355a(h)). 
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801  PPSR can be discussed with the relevant review division(s).  FDA may issue a WR either in 
802  response to a PPSR or on its own initiative (see sections IV.A., Written Requests).  
803   
804  1.  Submitting a PPSR 
805   
806  If a sponsor has exclusivity or patent protection for a drug or exclusivity for a biological product, 
807  or anticipates that it will have such exclusivity or patent protection, the sponsor can submit a 
808  PPSR to the appropriate review division (such a proposal can help to expedite FDAs issuance of 
809  a WR).  Sponsors should mark PPSRs with the header PROPOSED PEDIATRIC STUDY 
810  REQUEST and submit it to the appropriate IND.  Sponsors that seek to qualify for pediatric 
811  exclusivity to attach to existing patents and/or exclusivities should plan to submit their PPSRs 
812  with sufficient time to:  
813   
814    Permit FDA to review the PPSR, confer with the party submitting the PPSR as necessary, 
815  and issue the WR (including review by the FDAs internal pediatric review committee 
816  (the PeRC) as required before issuance103); 
817   
818    Allow time for the sponsor, after the WR is issued, to initiate the studies, complete the 
819  studies, and submit the reports for filing; and  
820   
821    Provide FDA 180 days to review the studies and make an exclusivity determination, with 
822  a remaining, nonoverlapping 9 months before expiration of the patent or exclusivity 
823  period.104 
824   
825  The PPSR should describe the studies the sponsor or application holder proposes to conduct to 
826  qualify for pediatric exclusivity.  The PPSR should include (1) a background section, (2) 
827  nonclinical studies, (3) drug information, (4) clinical studies, (5) known drug safety concerns and 
828  monitoring, (6) statistical information, including power of studies and statistical assessments, and 
829  (7) time frame for submitting reports of the study or studies. 
830   
831  It is important to note that a PPSR is not a substitute for an iPSP (section III.B.1., Pediatric Study 
832  Plans).  Although these submissions may have some similarities, each one is submitted under a 
833  different statutory scheme and serves a distinct purpose.  See sections II., Overview of 
834  Regulatory Strategy for Pediatric Drug Development, III., Pediatric Research Equity Act, and 
835  V.C., PREA and Pediatric Exclusivity, for additional information.  
836   
837  FDA intends to consider PPSRs that include requests to study multiple pediatric age groups in 
838  the same study, as appropriate.  FDA recognizes that studies defined by age may be 
839  inappropriate when it is reasonable to define subgroups using methods other than age, such as 
840  development stage.  If the sponsor submits data as part of a PPSR to indicate that a drug should 
 
103 See section 505A(f) of the FD&C Act (21 U.S.C. 355a(f)). 
 
104 See sections 505A(b)(2), 505A(c)(2), and 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(b)(2), 21 U.S.C. 
355a(c)(2), and 21 U.S.C. 355a(d)(4)).   
 
  24  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
841  be studied in pediatric groups identified by characteristics other than age, in general, FDA 
842  intends to consider that data when developing the WR. 
843   
844  FDA has 120 days after a sponsor submits a PPSR to review and act on the submission.105  Our 
845  response to the PPSR is either a WR or a PPSR inadequate letter, in which we inform the 
846  sponsor of the reasons we will not issue a WR at this time.  In general, FDA also makes 
847  suggestions as to what the sponsor should include in a resubmitted PPSR that might support our 
848  issuance of a WR. 
849   
850  2.  Issuance and Acceptance of a WR 
851   
852  The sponsor or application holder must respond to FDA within 180 days after receiving the WR 
853  indicating whether it will conduct the studies and, if so, indicate when it will initiate the 
854  studies.106   
855   
856  The procedure for qualifying for exclusivity and the protections that exclusivity will confer are 
857  described in more detail in sections IV.E., Determining Eligibility For Pediatric Exclusivity, and 
858  IV.F., Attaching the Period of Pediatric Exclusivity After a Determination That a Drug Qualifies 
859  for Pediatric Exclusivity.   
860   
861  If a sponsor declines a WR that is issued by FDA, the sponsor must provide the reasons it 
862  declined the request.107  If the sponsor declines the WR because it is not possible to develop an 
863  appropriate pediatric formulation, the sponsor must submit to FDA the reasons such pediatric 
864  formulation cannot be developed.108  If a sponsor declines a WR, the sponsor is not eligible to 
865  qualify for pediatric exclusivity for the studies under that WR. 
866   
867  C.  How to Submit Study Reports in Response to a Written Request  
868   
869  To qualify for pediatric exclusivity, sponsors or application holders must submit study reports in 
870  accordance with FDA requirements for filing.109  Studies submitted in an application or 
871  supplement that does not meet requirements for filing of an NDA, BLA, or supplement (i.e., 
872  FDA refuses to file the application or supplement) are not considered submitted to FDA.   
873   
874  In general, sponsors should also submit study reports in accordance with the guidance for 
875  industry Guideline for the Format and Content of the Clinical and Statistical Sections of an 
876  Application (July 1988) and the ICH guidance for industry E3 Structure and Content of Clinical 
877  Study Reports (July 1996).  
 
105 See section 505A(d)(3) of the FD&C Act (21 U.S.C. 355a(d)(3)). 
 
106 See section 505A(d)(2)(A)(i) of the FD&C Act (21 U.S.C. 355a(d)(2)(A)(i)). 
 
107 See section 505A(d)(2)(A)(i) of the FD&C Act (21 U.S.C. 355a(d)(2)(A)(i)). 
 
108 See section 505A(d)(2)(A)(ii) of the FD&C Act (21 U.S.C. 355a(d)(2)(A)(ii)). 
 
109 See section 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(d)(4)).  For additional information on filing 
requirements and refusal to file, see, for example, 21 CFR 314.50, 21 CFR 314.101, and 21 CFR 601.2.  
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878   
879  To help ensure that pediatric study reports are evaluated for eligibility for pediatric exclusivity in 
880  a timely manner, sponsors should include the following with the application or supplement:  
881   
882    A header that states SUBMISSION OF PEDIATRIC STUDY REPORTS  
883  PEDIATRIC EXCLUSIVITY DETERMINATION REQUESTED; 
884   
885    A copy of the WR and any amendments; 
886   
887    A summary of the pediatric studies conducted in response to the WR; 
888   
889    An annotated WR indicating how and where in the submitted study reports each term of 
890  the WR has been addressed; and 
891   
892    Proposed labeling that includes information regarding the results of the study or studies. 
893   
894  If there is information that is adequate to support the evaluation of dosing, safety, and efficacy in 
895  a subpopulation of the population included in the WR, FDA encourages the sponsor to submit an 
896  NDA, BLA, or supplement to incorporate that information into labeling for the drug before the 
897  determination of exclusivity.  If making multiple submissions in response to a single WR, the 
898  sponsor should, in the final submission, reference prior submissions (including relevant 
899  submission dates) and mark only the last submission as described above.  
900   
901  D.  Qualifying for Pediatric Exclusivity 
902   
903  We note at the outset that a commitment to complete a study at some future date is not sufficient 
904  to qualify a drug for pediatric exclusivity.110  Rather, to qualify for an initial period of pediatric 
905  exclusivity, a sponsor must submit study reports that fairly respond to an issued WR, were 
906  conducted in accordance with commonly accepted scientific principles and protocols, and have 
907  been reported in accordance with filing requirements.111  It is not necessary for the uses studied 
908  under the WR to be approved.112 
909   
910  1.  For a Drug Product That Is the Subject of a New Drug Application or Biologics 
911  License Application 
912   
913  A drug product qualifies for pediatric exclusivity when all of the following have occurred:113 
 
110 See sections 505A(b) and 505A(c) of the FD&C Act (21 U.S.C. 355a(b) and 21 U.S.C. 355A(c)). 
 
111 See sections 505A(b), 505A(c), and 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(b), 21 U.S.C. 355a(c), and 21 
U.S.C. 355a(d)(4)). 
 
112 Approval is required for a sponsor to qualify for a second 6-month period of pediatric exclusivity under section 
505A(g) of the FD&C Act (21 U.S.C. 355a(g)).  See section IV.F.1.b., A second 6-month period of pediatric 
exclusivity, for further discussion of that process.   
 
113 See sections 505A(b), 505A(c), and 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(b), 21 U.S.C. 355a(c), and 21 
U.S.C. 355a(d)(4)). 
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914   
915    FDA issued a WR for pediatric studies, and the sponsor or holder of an approved 
916  application agreed to the request. 
917   
918    The sponsor or the holder of an approved application has submitted reports of the 
919  requested studies.  Such reports should be submitted to the NDA or BLA after FDA 
920  issues the WR. 
921   
922    The studies were completed using appropriate formulations for each age group and within 
923  the requested time frame.  
924   
925    FDA has determined the studies fairly respond to the WR, have been conducted in 
926  accordance with commonly accepted scientific principles and protocols, and have been 
927  reported in accordance with filing requirements.  
928   
929    FDA makes an exclusivity determination at least 9 months before the expiration date of 
930  the patent and/or exclusivity protection to which the pediatric exclusivity will attach.114   
931   
932  2.  Nonprescription Drugs 
933   
934  Nonprescription drugs marketed under an approved application may be eligible for pediatric 
935  exclusivity, and the recommendations in this guidance apply to those nonprescription drugs.  
936   
937  Nonprescription drugs that are marketed pursuant to a monograph developed under the over-the-
938  counter drug review are not eligible for exclusivity under section 505A of the FD&C Act.  
939   
940  E.  Determining Eligibility For Pediatric Exclusivity  
941   
942  For a drug to be considered eligible for pediatric exclusivity, FDA recommends that the sponsor 
943  submit a complete report of all studies to FDA at least 15 months before the expiration of any 
944  existing patent or exclusivity it wishes to protect (i.e., the 9-month time period115 plus the 180-
945  day exclusivity determination review period116).  If sponsors choose to submit within less than 
946  15 months, FDA may not be able to complete its review of such studies and make a 
947  determination about the drugs eligibility for pediatric exclusivity in time to meet the 9-month 
948  deadline.  
949   
950  In making an eligibility determination, FDA will evaluate whether the studies fairly respond to 
951  the WR, were conducted in accordance with commonly accepted scientific principles and 
 
114 See section 505A(b)(2) and 505A(c)(2) of the FD&C Act (21 U.S.C. 355a(b)(2) and 21 U.S.C. 355a(c)(2)) and 
section 351(m)(4) of the PHS Act (42 U.S.C. 262(m)(4)).   
 
115 See section 505A(b)(2) and 505A(c)(2) of the FD&C Act; 21 U.S.C. 355a(b)(2) and 21 U.S.C. 355a(c)(2).  
 
116 See section 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(d)(4)). 
 
  27  Contains Nonbinding Recommendations  
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952  protocols, and have been reported in accordance with filing requirements.117  FDAs pediatric 
953  exclusivity boards (Boards), which are comprised of representatives from the Center for Drug 
954  Evaluation and Research or the Center for Biologics Evaluation and Research, including 
955  representatives with pediatric expertise, make this determination.  In general, the Boards 
956  consider the following when assessing, as required by statute, whether the studies fairly respond 
957  to a WR:   
958   
959    The purpose of the pediatric exclusivity provision as described in the statute, with 
960  reference to the legislative history.  The statute makes clear that its purpose is to generate 
961  meaningful clinical information on the use of drug products in children that will result in 
962  a health benefit to pediatric populations.118   
963   
964    Whether the sponsor met the terms of a WR.   
965   
966    The information sought in the WR and the objectives stated in the WR.  
967   
968  In general, the Boards ask whether the studies were designed and carried out by the sponsor in a 
969  way likely to meet those objectives specified in the WR and underlying the exclusivity provision 
970  as a whole.  When a sponsor meets the terms of a WR, the resulting studies fairly respond to that 
971  WR because studies that are carried out in accordance with the trials plans and objectives, as 
972  expressed in the WR, generally satisfy the statutory goal of obtaining meaningful pediatric use 
973  information.  Sometimes, a sponsor fails to produce meaningful pediatric information despite 
974  conducting the studies in the manner requested.  Under such circumstances, FDA nevertheless 
975  considers the sponsor to have fairly responded to the WR.  FDA understands that the failure to 
976  generate meaningful information in such cases is at least partially attributable to study design, 
977  and FDA and the sponsor generally design studies described in a WR jointly. 
978   
979  Where the sponsor has not met the terms of the WR, FDA evaluates whether the information 
980  generated by the studies is nevertheless sufficient to meet the objectives of the WR in light of the 
981  information sought in the WR.  If FDA determines that the objectives of the WR were met, then 
982  FDA concludes that the sponsor has fairly responded, even if it did not meet the terms of the 
983  WR.  FDA considers studies that do not meet the terms of the written request to have fairly 
984  responded if, considering the data provided by the sponsor as a whole (i.e., by considering all 
985  relevant data, and not just data generated by those studies), the sponsor meets the objectives of 
986  the WR by generating clinically meaningful information of the general type (quality and 
987  quantity) the WR contemplates. 
988   
 
117 See section 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(d)(4)). 
118 See, for example, section 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 
355a(c)(1)) requiring FDA to determine that information relating to the use of a new drug in the pediatric 
population may produce health benefits, section 505A(f)(2) of the FD&C Act (21 U.S.C. 355a(f)(2)) requiring 
review by the PeRC before FDA issues a WR, section 505A(f)(3) of the FD&C Act, providing that the same 
committee may review the reports of studies conducted in response to a WR before FDA makes a determination 
regarding pediatric exclusivity, section 505A(f)(6)(E) of the FD&C Act (21 U.S.C. 355a(f)(6)(E)) requiring FDA to 
publicly report, among other things, labeling changes made as a result of studies conducted in response to a WR, and 
section 505A(k)(2) of the FD&C Act (21 U.S.C. 355a(k)(2)) requiring sponsors to distribute the same to physicians 
and other health care providers. 
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989  For example, if a specific number of subjects is requested or a specific study duration or 
990  endpoint is specified to ensure that the study will generate adequate data to provide a health 
991  benefit, failure to comply with these elements of the WR may result in a denial of exclusivity.  
992  Denial is likely if, in the absence of compliance with the terms of the WR, the studies are not 
993  expected to be interpretable or will not provide information that otherwise yields a health benefit 
994  to the pediatric populations addressed in the WR. 
995   
996  Where a WR is capable of more than one interpretation, the Boards generally consider a fair 
997  response to be one that interprets the WR in a manner likely to generate information that will 
998  provide a health benefit (including meaningful pediatric labeling) in the relevant populations that 
999  the WR asked the sponsor to study.  If the studies submitted fairly respond to the WR, the Boards 
1000  will recommend that the drug is eligible for pediatric exclusivity (assuming the other statutory 
1001  requirements for pediatric exclusivity are met).119  If, on the other hand, the sponsor responds to 
1002  the WR in such a way that the possibility of a health benefit (including meaningful pediatric 
1003  labeling in relevant age groups) from the studies conducted is not likely, the Boards are likely to 
1004  conclude that the submission does not fairly respond to the WR. 
1005   
1006  Generally, FDA expects to notify sponsors or holders of an approved application within the 180-
1007  day period after the study reports are submitted whether the study reports fairly responded to the 
1008  WR and the drug qualifies for pediatric exclusivity.120  
1009   
1010  F.  Attaching the Period of Pediatric Exclusivity After a Determination That a 
1011  Drug Qualifies for Pediatric Exclusivity  
1012   
1013  1.  Drug Products121 
1014   
1015  a.  An initial 6-month period of pediatric exclusivity 
1016   
1017  Pediatric exclusivity will attach to all unexpired exclusivities and patents122 listed in the 
1018  Approved Drug Products With Therapeutic Equivalence Evaluations publication (the Orange 
 
119 See sections 505A(b)(1), 505A(c)(1), and 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(b)(1), 21 U.S.C. 
355a(c)(1), and 21 U.S.C. 355a(d)(4)). 
 
120 See section 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(d)(4)).   
 
121 For the purposes of this section IV.F.1., references to drugs or drug products do not include biological products 
licensed under section 351 of the PHS Act (42 U.S.C. 262).  Although the considerations in this section are 
generally relevant to such biological products, pediatric exclusivity for biological products differs in certain ways 
from pediatric exclusivity for other drug products.  For more information see section IV.F.2., Biological Products, 
below. 
 
122 Pediatric exclusivity that has attached to the end of the patent term will block for an additional 6 months after the 
patent expires approval of an ANDA or 505(b)(2) application if (1) the ANDA or 505(b)(2) sponsor did not seek 
approval until the end of the patent term; or (2) the ANDA or 505(b)(2) sponsors patent challenge has been 
unsuccessful.  See, for example, sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 
U.S.C. 355a(c)(1)).  In addition, if an ANDA or 505(b)(2) sponsor files a paragraph IV certification challenging a 
listed patent, and the patent litigation is ongoing when the patent expires, the pediatric exclusivity will attach at the 
 
  29  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1019  Book)123 for any drug product containing the drug the sponsor studies and for which it holds the 
1020  approved NDA.124  For studies a sponsor conducts on a previously unapproved drug, pediatric 
1021  exclusivity will attach to any exclusivities or patents that will be listed in the Orange Book upon 
1022  approval of that drug and to certain later listed patents or exclusivities.125  For studies a sponsor 
1023  conducts on a previously approved drug, pediatric exclusivity will attach to protections listed for 
1024  the previously approved drug at the time the drug qualifies for pediatric exclusivity and to certain 
1025  later listed patents and exclusivities,126 as described further in section IV.F.1.c., Later-filed 
1026  applications containing the same drug.  Pediatric exclusivity for combination drugs may raise 
1027  additional considerations that are not addressed in this guidance. 
1028   
1029  b.  A second 6-month period of pediatric exclusivity 
1030   
1031  Each WR may result in only one 6-month period of pediatric exclusivity.127  However, after a 
1032  drug has qualified for an initial period of pediatric exclusivity, a sponsor submitting a 
1033  supplement to an application can submit additional pediatric studies meeting the relevant 
1034  statutory requirements in response to a second WR.128  The second 6-month period of pediatric 
1035  exclusivity will attach only to any new 3-year exclusivity period for which the supplemental 
1036  application qualifies.129  In addition, several other considerations regarding a second period of 
1037  pediatric exclusivity are presented as follows:130  
1038   
1039    A second WR can result in a 6-month period of exclusivity only if the response to the 
1040  WR results in an approved supplemental application for a new use.  
1041   
1042    A new use is a use not included in the approved labeling of an approved drug.131  For 
1043  example, expansion of the labeling to include a new pediatric population constitutes a 
1044  new use. 
1045   
 
end of the patent term to block approval of that ANDA or 505(b)(2) application for an additional 6 months after the 
patent expires (Ranbaxy Labs. v. FDA). 
 
123 The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. 
 
124 See section 505A(c) of the FD&C Act (21 U.S.C. 355a(c)). 
 
125 See section 505A(b) of the FD&C Act (21 U.S.C. 355a(b)). 
 
126 See section 505A(c) of the FD&C Act (21 U.S.C. 355a(c)). 
 
127 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
 
128 See section 505A(g) of the FD&C Act (21 U.S.C. 355a(g)). 
 
129 See section 505A(g) of the FD&C Act (21 U.S.C. 355a(g)). 
 
130 See section 505A(g) of the FD&C Act (21 U.S.C. 355a(g)). 
 
131 See 21 CFR 99.3(g). 
 
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1046    The supplement for a new use submitted in response to the second WR must qualify for 
1047  3-year exclusivity132 or no 6-month period of pediatric exclusivity will attach. 
1048   
1049    The second 6-month period of pediatric exclusivity attaches only to the 3-year exclusivity 
1050  applied to the supplement for a new use containing the studies submitted in response to 
1051  the second WR and not to any other exclusivity or patent protections applicable to the 
1052  drug. 
1053   
1054    No more than two 6-month periods of exclusivity under the BPCA are possible for any 
1055  specific drug product. 
1056   
1057  c.  Later-filed applications containing the same drug 
1058   
1059  In situations where a sponsor submits an application or supplement containing an active moiety 
1060  for which the sponsor previously qualified for pediatric exclusivity, pediatric exclusivity does 
1061  not attach to new (not previously listed) patents or exclusivity covering the later filed 
1062  applications or supplements unless the subsequent drug product could not be labeled without the 
1063  data that qualified the previously approved drug product for the prior pediatric exclusivity.133 
1064   
1065  FDA notes that if pediatric exclusivity for which a drug product previously qualified has attached 
1066  to a listed patent or exclusivity protecting the previously approved application that also protects 
1067  the new application or new supplement held by the same sponsor, the pediatric exclusivity also 
1068  attaches to that patent in conjunction with the new application or supplement.134  For example, if 
1069  a sponsor qualifies for a 6-month pediatric exclusivity that attaches to a 5-year exclusivity, that 
1070  exclusivity attaches to each of the sponsors NDAs protected by that 5-year exclusivity, 
1071  regardless of when the new application or supplement is filed or what it contains.  The following 
1072  examples are provided: 
1073   
1074    Example 1  Drug 1 (D1) qualifies for pediatric exclusivity.  The sponsor or holder of 
1075  an approved application for D1 later files a different application for a drug product 
1076  containing D1 or a supplement to an existing application for a drug product containing 
1077  D1.  FDA does not need any of the data the sponsor or holder of an approved application 
1078  submitted for pediatric exclusivity to approve the new application or new supplement.  
1079  The pediatric exclusivity does not attach to any exclusivities or patents that apply solely 
1080  to the new application or the new supplement.   
1081   
1082    Example 2  D1 qualifies for pediatric exclusivity.  The sponsor or holder of the 
1083  approved application for D1 later files a different application for a drug product 
1084  containing D1 or a supplement to an existing application for a drug product containing 
1085  D1.  The drug product could not be labeled with the data submitted in the later-filed 
1086  applications or supplements without the data the sponsor or holder of an approved 
 
132 See sections 505(c)(3)(E)(iv) and 505(j)(5)(F)(iv) of the FD&C Act (21 U.S.C. 355(c)(3)(E)(iv) and 21 U.S.C. 
(j)(5)(F)(iv)). 
133 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
 
134 See sections 505A(b)(1) and 505A(c)(1) of the FD&C Act (21 U.S.C. 355a(b)(1) and 21 U.S.C. 355a(c)(1)). 
  31  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1087  application previously submitted for pediatric exclusivity.  The pediatric exclusivity 
1088  attaches to any exclusivities or patents that apply to the new application or the new 
1089  supplement.  In addition, if the pediatric exclusivity attaches to a patent or exclusivity 
1090  that also protects the new application or new supplement, the pediatric exclusivity applies 
1091  to the new application or supplement to the same extent it applies to the previously 
1092  approved application. 
1093   
1094  2.  Biological Products 
1095   
1096  Pediatric exclusivity for biological products differs in some ways from provisions applicable to 
1097  other drug products.  First, as described below, pediatric exclusivity only attaches to reference 
1098  product and orphan drug exclusivity periods.  Second, unlike other drug products, pediatric 
1099  exclusivity does not attach to patents for biological products.135   
1100   
1101  Under section 351(k)(7)(A) of the PHS Act, approval of an application for a biosimilar or 
1102  interchangeable biological product submitted under section 351(k) of the PHS Act may not be 
1103  made effective until 12 years after the date on which the reference product was first licensed 
1104  under section 351(a) of the PHS Act.  Moreover, under section 351(k)(7)(B) of the PHS Act, an 
1105  application for a biosimilar or interchangeable biological product submitted under section 351(k) 
1106  of the PHS Act may not be submitted for review until 4 years after the date on which the 
1107  reference product was first licensed under section 351(a) of the PHS Act.  An additional 6-month 
1108  period of pediatric exclusivity will attach to the 12- and 4-year periods if the sponsor meets the 
1109  requirements for pediatric exclusivity pursuant to section 505A of the FD&C Act.136  
1110  Furthermore, an additional 6-month period of pediatric exclusivity will also attach to the 7 years 
1111  of orphan drug exclusivity for a biological product designated under section 526 of the FD&C 
1112  Act for a rare disease or condition.137 
1113   
1114   
1115  V.  ELEMENTS COMMON TO PREA AND THE BPCA  
1116   
1117  A.  The Pediatric Review Committee 
1118   
1119  Section 505C of the FD&C Act directed FDA to establish the PeRC that must review all WRs 
1120  and all requests for deferrals, deferral extensions, and waivers.138  The PeRC also provides 
1121  consultation on pediatric assessments and on iPSPs, agreed iPSPs, and any significant 
1122  amendments to such plans.139   
 
135 See section 351(m) of the PHS Act (42 U.S.C. 262(m)). 
 
136 See section 351(m) of the PHS Act (42 U.S.C. 262(m)). 
 
137 See section 527(a) of the FD&C Act and section 351(m) of the PHS Act (21 U.S.C. 360cc(a); 42 U.S.C. 262(m)). 
 
138 See sections 505C, 505A(f), and 505B(f) of the FD&C Act (21 U.S.C. 355d, 21 U.S.C. 355a(f), and 21 U.S.C. 
355c(f)). 
 
139 See section 505B(f) of the FD&C Act (21 U.S.C. 355c(f)). 
 
  32  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1123   
1124  As a general matter, the PeRC also reviews significant amendments to WRs and PPSR 
1125  inadequate letters to ensure consistency. 
1126   
1127  Members of the PeRC include FDA employees with expertise in pediatrics (including 
1128  representation from the Office of Pediatric Therapeutics (OPT)), neonatology, biopharmacology 
1129  (i.e., pharmacology/toxicology), statistics, chemistry, legal issues, pediatric ethics, the 
1130  appropriate expertise pertaining to the pediatric drug under review, and other individuals as 
1131  needed.140  In addition to the responsibilities above, the PeRC also provides consultation on 
1132  tracking information regarding pediatric assessments and labeling changes.141  As a general 
1133  matter, members of the relevant drug review division provide background information to the 
1134  PeRC and are present during the discussion of an application. 
1135   
1136  B.  Publishing Information About Pediatric Studies 
1137   
1138  1.  Pediatric Exclusivity Determinations 
1139   
1140  FDA posts on its website a list of exclusivity determinations on approved drugs that have 
1141  qualified for pediatric exclusivity.142  FDA also publishes pediatric exclusivity information for 
1142  drugs in the Patent and Exclusivity Information section of the Orange Book and its supplements 
1143  in the same manner as FDA publishes information regarding 5-year exclusivity, 3-year 
1144  exclusivity, patent listings, and orphan drug exclusivity.143  
1145   
1146  2.  Medical, Statistical, and Clinical Pharmacology Reviews 
1147   
1148  Sections 505A(k) and 505B(h) of the FD&C Act require that FDA publish the medical, 
1149  statistical, and clinical pharmacology reviews of pediatric studies conducted under the BPCA 
1150  and of pediatric assessments under PREA.  For studies submitted in response to a WR, FDA 
1151  must do so within 210 days after the submission.144  For most pediatric assessments submitted 
1152  under PREA, FDA must do so within 330 days after the submission.145  FDA makes such 
 
140 See section 505C of the FD&C Act (21 U.S.C. 355d). 
 
141 See sections 505A(f)(6) and 505B(f)(6) of the FD&C Act (21 U.S.C. 355a(f)(6) and 21 U.S.C. 355c(f)(6)). 
 
142 See the FDAs Pediatric Exclusivity Granted web page at https://www.fda.gov/drugs/development-
resources/pediatric-exclusivity-granted. 
 
143 See the Orange Book available at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.   
 
144 See section 505A(k)(1) of the FD&C Act (21 U.S.C. 355a(k)(1)).  For drug products for which exclusivity 
determinations were made before September 27, 2007, we have posted summaries of medical and clinical 
pharmacology reviews of studies conducted under section 505A of the FD&C Act, consistent with applicable BPCA 
requirements at that time. 
 
145 See section 505B(h)(1) of the FD&C Act (21 U.S.C. 355c(h)(1)).  This provision of the law first went into effect 
on September 27, 2007. 
 
  33  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1153  information publicly available consistent with section 301(j) of the FD&C Act, the Freedom of 
1154  Information Act, and the Trade Secrets Act.146   
1155   
1156  Before disclosure, the medical, statistical, and clinical pharmacology reviews are redacted, as 
1157  appropriate, for trade secret information and for confidential commercial information.147 
1158   
1159  As FDA interprets section 505A(k) of the FD&C Act, the 210-day BPCA disclosure requirement 
1160  is triggered when a sponsor or holder of an approved application submits an application or a 
1161  supplement in response to a WR that FDA determines meets filing requirements (see section 
1162  IV.C., How to Submit Study Reports in Response to a Written Request).  FDA interprets the 
1163  disclosure requirement to apply to such applications and supplements submitted in response to a 
1164  WR under the BPCA, regardless of whether (1) the application process is completed or it is later 
1165  withdrawn; (2) the drug qualifies for pediatric exclusivity; or (3) the application or supplement is 
1166  approved or the sponsor receives a complete response letter.  In addition, FDA interprets the 
1167  disclosure requirement to apply to partial responses to a WR under the BPCA that meet the filing 
1168  requirements.  (See section IV.C., How to Submit Study Reports in Response to a Written 
1169  Request, for a discussion of partial responses.) 
1170   
1171  3.  Other Pediatric Information 
1172   
1173  FDA maintains a web page148 containing extensive information about pediatric studies 
1174  conducted under sections 505A and 505B of the FD&C Act.  The web page includes, among 
1175  other things, statistics and other information regarding the relevant studies, drugs, labeling 
1176  changes, and reports.  Statistics we post include the number of waivers, deferrals, and deferral 
1177  extensions granted; the number of pediatric formulations developed; and the number of 
1178  formulations not developed (including the reason they were not developed).149  The web page 
1179  also identifies drugs approved for use in a pediatric population for which a pediatric formulation 
 
146 See 5 U.S.C. 552 and 18 U.S.C. 1905. 
147 21 CFR 314.430 is FDAs regulation regarding the public disclosure of information in a drug application or 
abbreviated application.  21 CFR 601.51 is FDAs regulation regarding the public disclosure of information in a 
biological product file.  Under 21 CFR 314.430(b), we will not publicly disclose the existence of an application or 
abbreviated application before an approval or tentative approval letter is sent, unless the existence of the application 
or abbreviated application has been previously publicly disclosed or acknowledged.  Under 21 CFR 601.51(b), we 
will not disclose the existence of a biological product file before the application has been approved if the existence 
of the file has not been previously publicly disclosed or acknowledged.  Under 21 CFR 314.430(d)(1) and 
601.51(d)(1), if the existence of the application or biological product file has been publicly disclosed or 
acknowledged, as a general matter, no data or information contained in the application, abbreviated application, or 
biological product file is available for public disclosure before we send an approval letter or before a license is 
issued.  We note that 21 CFR 314.430 and 601.51 were promulgated before the passage of PREA and the BPCA and 
do not specifically discuss the disclosure of medical, statistical, and clinical pharmacology reviews of pediatric 
studies conducted under the BPCA and of pediatric assessments under PREA.  As a general matter, FDA discloses 
such reviews only to the extent the drug product studied has already been approved.  Additionally, the protected 
status of particular information in the reviews is determined on a case-by-case basis. 
 
148 See the Pediatric Reports, Statistics, Reviews, and Databases web page at https://www.fda.gov/science-
research/pediatrics/reports-statistics-reviews-and-databases.   
 
149 See section 505B(f)(6) of the FD&C Act (21 U.S.C. 355c(f)(6)). 
 
  34  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1180  was developed and that qualified for pediatric exclusivity, but the formulation was not marketed 
1181  within 1 year of the exclusivity determination.150  FDA also maintains a web page containing 
1182  information about section 409I of the PHS Act.151 
1183   
1184  A list of approved drugs for which WRs have been issued is published on the FDA website.152  
1185  In addition, WRs, including any amendment(s) if not otherwise incorporated into one document, 
1186  are posted on the FDA website within 30 days of the determination that the requirements for 
1187  exclusivity have been met.153   
1188   
1189  Information from a required annual review following the granting of a deferral will be posted 
1190  publicly within 90 days of submission.154  The posting will include the information submitted 
1191  through the annual review, the name of the applicant, the date on which the drug was approved, 
1192  and the date of each deferral or deferral extension.155  
1193   
1194  Finally, FDA posts guidances, relevant regulations, relevant presentations from conferences, 
1195  press releases, and reports, among other information.  Transcripts from Pediatric Advisory 
1196  Committee meetings, beginning September 2004, are posted as well, as are transcripts from past 
1197  meetings of the Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory 
1198  Committee, held between April 1999 and June 2004.156  FDA intends to update these sites 
1199  regularly.   
1200   
1201  C.  PREA and Pediatric Exclusivity 
1202   
1203  To qualify for pediatric exclusivity, the pediatric studies conducted to satisfy the requirements of 
1204  PREA must be the subject of a WR and satisfy all other requirements for pediatric exclusivity 
 
150 See section 505A(e)(2) of the FD&C Act (21 U.S.C. 355a(e)(2)). 
 
151 See the Off-Patent Studies Under BPCA web page at https://www.fda.gov/drugs/development-resources/patent-
studies-under-bpca. 
 
152 See the Written Requests Issued web page at https://www.fda.gov/drugs/development-resources/written-requests-
issued.  On occasion, information obtained by FDA subsequent to issuance of a WR causes FDA to rescind the WR.  
This list is not updated to indicate when a WR has been rescinded. 
 
153 See section 505A(e)(1) of the FD&C Act (21 U.S.C. 355a(e)(1)).  See also the FDAs Pediatric Exclusivity 
Granted web page at https://www.fda.gov/drugs/development-resources/pediatric-exclusivity-granted. 
 
154 See section 505B(a)(4)(C)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(C)(ii)).  See also FDAs Postmarket 
Requirements and Commitments web page at https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm.  
 
155 See section 505B(a)(4)(C)(ii) of the FD&C Act (21 U.S.C. 355c(a)(4)(C)(ii)). 
 
156 See https://www.fda.gov/advisory-committees/pediatric-advisory-committee/past-meeting-materials-pediatric-
advisory-committee. 
 
  35  Contains Nonbinding Recommendations  
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1205  under the BPCA.157  As discussed in section IV.A.2., Written Request Studies, FDA does not 
1206  expect to issue WRs solely for studies or planned studies that are required under PREA.    
1207   
1208  For already marketed drugs, FDA may require pediatric assessments under PREA if it finds, for 
1209  example, that the drug is used for a substantial number of pediatric patients for the labeled 
1210  indications and adequate pediatric labeling could confer a benefit on pediatric patients.158  In 
1211  some cases, FDA may first issue a WR under section 505A of the FD&C Act before requiring 
1212  studies under section 505B(b).  In those cases, if the sponsor declines the WR for the labeled 
1213  indication(s), FDA may still require those studies under PREA.159  
1214   
1215  It is important to note the distinction between the scope of the studies FDA requests under the 
1216  BPCA and those required under PREA.  The scope of studies described in a WR may be broader 
1217  than those required under PREA.  FDAs authority to issue a WR extends to the use of an active 
1218  moiety for indications that may produce health benefits in the pediatric population, regardless of 
1219  whether it has previously approved the indications in adults.160  Under PREA, pediatric 
1220  assessments are required only for those indications the sponsor has included in the pending 
1221  application.161  To learn more about eligibility for pediatric exclusivity, see section IV., Best 
1222  Pharmaceuticals for Children Act, or contact the relevant review division.   
1223   
1224  D.  Considerations for Labeling of Drug Products  
1225   
1226  1.  Labeling Study Results 
1227   
1228  Study results submitted in response to PREA or a WR must be described in labeling regardless of 
1229  whether these findings support safety and/or effectiveness, do not support safety and/or 
 
157 See sections 505A(b)(1), 505A(c)(1), 505A(d) and 505A(h) of the FD&C Act (21 U.S.C. 355a(b)(1), 21 U.S.C. 
355a(c)(1), 21 U.S.C. 355a(d), and 21 U.S.C. 355a(h)). 
 
158 See section 505B(b)(1) of the FD&C Act (21 U.S.C. 355c(b)(1)). 
 
159 See section 505B(b) of the FD&C Act (21 U.S.C. 355c(b)).  This section states that the Secretary may require a 
sponsor or holder of an approved application to submit pediatric assessments as described under section 505B(a)(2) 
of the FD&C Act if the Secretary finds that (A) (i) the drug or biological product is used for a substantial number 
of pediatric patients for the labeled indications; and (ii) adequate pediatric labeling could confer a benefit on 
pediatric patients; (B) there is reason to believe that the drug or biological product would represent a meaningful 
therapeutic benefit over existing therapies for pediatric patients for 1 or more of the claimed indications; or (C) the 
absence of adequate pediatric labeling could pose a risk to pediatric patients. 
 
160 See sections 505A(a), 505A(b)(1), 505A(c)(1), and 505A(d)(1)(B) of the FD&C Act (21 U.S.C. 355a(a); 21 
U.S.C. 355a(a), 21 U.S.C. 355a(b)(1), 21 U.S.C. 355a(c)(1), and 21 U.S.C. 355a(d)(1)(B)). 
 
161 See sections 505B(a)(1)(A) and 505B(a)(2) of the FD&C Act (21 U.S.C. 355c(a)(1)(A) and 21 U.S.C. 
355c(a)(2)).  Note, however, that molecularly targeted pediatric cancer investigations are based on molecular 
mechanism of action rather than clinical indication.  See sections 505B(a)(1)(B) and 505B(a)(3) of the FD&C Act 
(21 U.S.C. 355c(a)(1)(B) and 21 U.S.C. 355c(a)(3)).  For additional information, see the guidance for industry 
FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to 
Sec. 505B of the FD&C Act.   
 
  36  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1230  effectiveness, or are inconclusive.162  If a full or partial waiver is granted because there is 
1231  evidence that a drug would be unsafe or ineffective in pediatric populations, applicants must 
1232  include this information in labeling.163 
1233   
1234  Applicants must distribute information to health care providers describing any labeling changes 
1235  that are approved as a result of these studies as required by FDA.164   
1 236 
1237  2.  Dispute Resolution 
1238   
1239  The BPCA and PREA provide for a dispute resolution process when FDA and the applicant fail 
1240  to agree on appropriate labeling changes.165  If the applicant does not agree within the specified 
1241  time period after FDAs request to make labeling changes, FDA must refer the matter to the 
1242  Pediatric Advisory Committee (PAC).166  The PAC then has 90 days after receiving the referral 
1243  to review the pediatric study reports and make a recommendation to FDA.167  FDA will consider 
1244  the recommendation, and, if appropriate, within 30 days after receiving the recommendation, 
1245  make a request to the applicant to make the labeling changes FDA determines to be 
1246  appropriate.168  If the applicant fails to agree to make the labeling changes within 30 days after 
1247  receiving such a request, the drug may be deemed misbranded.169 
1248   
1249  3.  Priority Review of Applications and Labeling Supplements  
1250   
1251  Any application or supplement to an application that proposes a labeling change as a result of 
1252  pediatric studies a sponsor conducts under section 505A of the FD&C Act will be considered a 
1253  priority application or supplement.170  This priority status applies even if the studies submitted 
 
162 See sections 505A(j) and 505B(g)(2) of the FD&C Act (21 U.S.C. 355a(j) and 21 U.S.C. 355c(g)(2)).  See also 
the guidance for industry Pediatric Information Incorporated Into Human Prescription Drug and Biological 
Product Labeling. 
 
163 See section 505B(a)(5)(D) of the FD&C Act (21 U.S.C. 355c(a)(5)(D)). 
 
164 See sections 505A(k)(2) and 505B(h)(2) of the FD&C Act (21 U.S.C. 355a(k)(2) and 355c(h)(2)). 
 
165 See sections 505A(i)(2) and 505B(g)(1) of the FD&C Act (21 U.S.C. 355a(i)(2) and 355c(g)(1)). 
 
166 See sections 505A(i)(2)(A) and 505B(g)(1)(A) of the FD&C Act (21 U.S.C. 355a(i)(2)(A) and 355c(g)(1)(A)). 
 
167 See sections 505A(i)(2)(B) and 505B(g)(1)(B) of the FD&C Act (21 U.S.C. 355a(i)(2)(B) and 355c(g)(1)(B)). 
 
168 See sections 505A(i)(2)(C) and 505B(g)(1)(C) of the FD&C Act (21 U.S.C. 355a(i)(2)(C) and 355c(g)(1)(C)). 
 
169 See sections 505A(i)(2)(D) and 505B(g)(1)(D) of the FD&C Act (21 U.S.C. 355a(i)(2)(D) and 355c(g)(1)(D)).  
 
170 See section 505A(i)(1) of the FD&C Act (21 U.S.C. 355a(i)(1)).  This priority review provision applies only to 
applications and supplements containing studies conducted under section 505A of the FD&C Act; it does not apply 
to an application or supplement solely because it contains pediatric information.  Note that NDAs and BLAs may be 
otherwise eligible for priority review.  For information on Prescription Drug User Fee Act VI performance goals and 
procedures, see https://www.fda.gov/industry/fda-user-fee-programs/prescription-drug-user-fee-amendments.  
 
  37  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1254  did not respond completely to the WR or did not otherwise qualify for pediatric exclusivity.171  
1255  Applications that include a pediatric assessment submitted with the sole intention of responding 
1256  to PREA requirements do not necessarily receive priority review.   
1257   
1258  For more information about priority review, see FDAs Prescription Drug User Fee Act 
1259  reauthorization performance goals and procedures document.172    
1260   
1261  E.  Adverse Event Reporting for Drug Products Subject to the BPCA and PREA 
1262   
1263  At the same time that a sponsor submits reports of studies responding to a WR, the sponsor must 
1264  also provide FDA with all available postmarketing adverse event reports regarding the studied 
1265  drug.173  The format of the postmarketing adverse event report should follow the model for a 
1266  periodic safety update report described in the ICH guidance for industry E2C(R2) Periodic 
1267  Benefit-Risk Evaluation Report (PBRER) (July 2016).  In addition, the sponsor may contact the 
1268  review division for further information. 
1269   
1270  Eighteen months after the date of a labeling change made to reflect studies conducted under 
1271  PREA or the BPCA, the applicable center refers to OPT a report of all adverse events received 
1272  by FDA for the drug product.174  As a general matter, OPT presents a report and analysis to the 
1273  PAC, and the PAC reviews this analysis and recommends whether additional monitoring (other 
1274  than the usual surveillance) is necessary.  When the PAC considers additional monitoring 
1275  necessary after the 18-month period, the center generally continues to refer adverse event reports 
1276  to OPT. 
1277   
1278   
1279  VI.  ADDITIONAL INFORMATION 
1280   
1281  The Division of Pediatrics and Maternal Health can provide general information about 
1282  complying with PREA and the BPCA.  Additional pediatric information and contact information 
1283  is available on the Pediatric Product Development web page.175   
1284   
 
171 See section 505A(i)(1) of the FD&C Act (21 U.S.C. 355a(i)(1)).   
 
172 See PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 at 
https://www.fda.gov/media/81306/download.  
173 See section 505A(d)(2)(B) of the FD&C Act (21 U.S.C. 355a(d)(2)(B)). 
 
174 See sections 505A(l) and 505B(i) of the FD&C Act (21 U.S.C. 355a(l) and 355c(i)). 
 
175 Available at https://www.fda.gov/drugs/development-resources/pediatric-and-maternal-health-product-
development. 
  38  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1285  GLOSSARY 
1286   
1287  Assessment  Contains data, gathered using appropriate formulations for each age group for 
1288  which the assessment is required, that are adequate to assess the safety and effectiveness as well 
1289  as support the dosing and administration of a drug product for each relevant pediatric age group 
1290  (see section 505B(a)(2) of the FD&C Act (21 U.S.C. 355c(a)(2))). 
1291   
1292  Certify/Certification  In general, a certification is a statement from the applicant that the data 
1293  provided to support a deferral1 and/or waiver2 request are accurate and complete. 
1294   
1295  Deferral  Defers submission of some or all of the required assessments or reports on the 
1296  molecularly targeted pediatric cancer investigation until a specified date (see section 505B(a)(4) 
1297  of the FD&C Act (21 U.S.C. 355c(a)(4))). 
1298   
1299  Pediatric Study Plan (PSP)  An outline of planned pediatric studies, along with any deferral 
1300  and/or waiver requests, that is submitted by a sponsor for an application subject to PREA before 
1301  the submission of assessments or reports on the molecularly targeted pediatric cancer 
1302  investigation (see section 505B(e) of FD&C Act (21 U.S.C. 355c(e))).  For more information, 
1303  see the guidance for industry  Pediatric Study Plans: Content of and Process for Submitting 
1304  Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020).3   
1305   
1306  Proposed Pediatric Study Request (PPSR)  In general, a PPSR is a submission describing 
1307  what pediatric studies a sponsor or application holder believes will yield information about the 
1308  use of a drug that may produce health benefits in the pediatric population.   
1309   
1310  Molecularly Targeted Pediatric Cancer Investigation  An investigation of a drug described in 
1311  section 505B(a)(1)(B) of the FD&C Act that must be designed to yield clinically meaningful 
1312  pediatric study data, gathered using appropriate formulations for each age group for which the 
1313  study is required, regarding dosing, safety, and preliminary efficacy to inform potential pediatric 
1314  labeling (see section 505B(a)(3) of the FD&C Act (21 U.S.C. 355c(a)(3))).  
1315   
1316  Waiver  Waives the requirement to submit assessments or reports on the molecularly targeted 
1317  pediatric cancer investigation for the entire pediatric population or specific age group(s) (see 
1318  section 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(5))). 
1319   
1320  Written Request (WR)  In general, a WR is a document from FDA, signed by the applicable 
1321  office director(s), requesting submission of a certain study or studies to determine whether the 
1322  use of a drug could provide a meaningful health benefit in the pediatric population that is issued 
1323  under section 505A of the FD&C Act (21 U.S.C. 355a) or section 351(m) of the PHS Act (42 
1324  U.S.C. 262(m)).   
 
1 See section 505B(a)(4)(A)(ii)(I) of the FD&C Act (21 U.S.C. 355c(a)(4)(A)(ii)(I)). 
 
2 See section 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(5)). 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
39