Pediatric Drug Development 
Under the Pediatric Research 
Equity Act and the Best 
Pharmaceuticals for Children 
Act:  Scientific Considerations 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Division of Pediatric and Maternal 
Health at 301-796-2200 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 
15548dft.docx 
05/10/23   
Pediatric Drug Development 
Under the Pediatric Research 
Equity Act and the Best 
Pharmaceuticals for Children 
Act:  Scientific Considerations 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
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Draft  Not for Implementation 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.  BACKGROUND ............................................................................................................... 2 
III.  LEGISLATIVE AND REGULATORY CONTEXT ..................................................... 3 
A.  PREA............................................................................................................................................... 3 
1. Pediatric Assessments:  Section 505B(a)(1)(A) of the FD&C Act ................................................... 3 
2. Molecularly Targeted Pediatric Cancer Investigation:  Section 505B(a)(1)(B) of the FD&C Act . 5 
B.  BPCA............................................................................................................................................... 5 
C.  The Pediatric Review Committee ................................................................................................. 6 
IV.  SCIENTIFIC CONSIDERATIONS FOR PEDIATRIC DRUG DEVELOPMENT .. 7 
A.  Considerations Regarding Data in Pediatric Patients ................................................................ 8 
1. Formulation Development ............................................................................................................... 8 
2. Nonclinical Information ................................................................................................................... 9 
3. Clinical Pharmacology .................................................................................................................. 11 
4. Safety Information .......................................................................................................................... 12 
B.  Pediatric Extrapolation ............................................................................................................... 12 
C.  Timing of Pediatric Studies ......................................................................................................... 13 
D.  Drug Development for the Neonatal Population ....................................................................... 15 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Pediatric Drug Development Under the Pediatric Research  
2  Equity Act and the Best Pharmaceuticals for Children Act:  
3  Scientific Considerations 
4  Guidance for Industry1 
5   
6   
7   
8   
9  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
10  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
11  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
12  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
13  for this guidance as listed on the title page. 
14   
15   
16   
17   
18  I.  INTRODUCTION 
19   
20  The purpose of this guidance is to assist industry in developing data and obtaining information 
21  needed to support approval of drug products in pediatric populations.2  This guidance addresses 
22  selected clinical, scientific, and ethical issues regarding the development of drugs for pediatric 
23  use when such drugs are subject to the Pediatric Research Equity Act (PREA)3 and/or the Best 
24  Pharmaceuticals for Children Act (BPCA).4  In 2010, the Biologics Price Competition and 
25  Innovation Act of 2009 extended provisions of the BPCA to biological products.5 
26   
27  This guidance does not address the clinical development of drugs that are not subject to either 
28  PREA or the BPCA.  This guidance, along with the draft guidance for industry Pediatric Drug 
29  Development:  Regulatory Considerations  Complying With the Pediatric Research Equity Act 
 
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)). 
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Draft  Not for Implementation 
30  and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act (May 
31  2023) (draft Regulatory Considerations guidance),6 revises and replaces the draft guidance for 
32  industry How to Comply With the Pediatric Research Equity Act.7  This guidance also addresses 
33  certain additional topics that FDA has not previously addressed in guidance. 
34   
35  This guidance only addresses briefly the Food and Drug Administration Reauthorization Act of 
36  2017s (FDARAs) amendments to PREA8 relating to requirements that sponsors of certain adult 
37  oncology drugs with molecular targets that are determined to be substantially relevant to the 
38  growth or progression of a pediatric cancer submit reports on molecularly targeted pediatric 
39  cancer investigations.9   
40   
41  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
42  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
43  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
44  the word should in Agency guidances means that something is suggested or recommended, but 
45  not required. 
46   
47   
48  II.  BACKGROUND 
49   
50  Many diseases that occur in adults also occur in children, and children are often treated with the 
51  same drugs as adults.  The effects of many drugs may vary considerably for adults and children 
52  or for different pediatric subgroups.  Labeling for many drugs marketed in the United States 
53  lacks information on the safe and effective use in all or certain pediatric age groups.  Indeed, 
54  labeling for many of the drugs that are widely used in pediatric patients specify that safety and 
55  effectiveness in pediatric patients have not been established.   
56   
57  The absence of adequate pediatric use information in labeling poses significant risks for children.  
58  Inadequate pediatric dosing information in labeling may lead to inappropriate dosing that can 
59  increase the risk of adverse reactions and/or lead to ineffective treatments.  The lack of pediatric 
60  safety data may lead to inappropriate use in pediatric patients and expose such patients to the 
61  potential risk of age-specific adverse reactions that are unexpected based on data gathered from 
62  the use of the drug in adults.  The absence of adequate pediatric labeling also may deny pediatric 
 
6 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.  
 
7 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). 
 
8 See section 505B of the FD&C Act (21 U.S.C. 355c). 
 
9 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. 
  2  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
63  patients therapeutic advances because physicians choose to prescribe drugs that are potentially 
64  less effective in pediatric populations due to the lack of information regarding use.  Failure to 
65  develop an age-appropriate pediatric formulation of a drug may also deny pediatric patients 
66  access to important new therapies or may result in pediatric patients taking extemporaneous 
67  formulations where bioavailability may be poor or inconsistent. 
68   
69   
70  III.  LEGISLATIVE AND REGULATORY CONTEXT 
71   
72  This section contains a brief summary of PREA and the BPCA and a description of the Pediatric 
73  Review Committee (PeRC).  A more complete discussion of the requirements under PREA and 
74  the BPCA, as well as recommendations regarding how to comply with them, is available in the 
75  draft Regulatory Considerations guidance.10   
76   
77  A.  PREA 
78   
79  1.  Pediatric Assessments:  Section 505B(a)(1)(A) of the Federal Food, Drug, and 
80  Cosmetic Act 
81   
82  PREA requires that any applications (or supplements to an application)11 falling within the 
83  requirements of section 505B(a)(1) of the Federal Food, Drug, and Cosmetic (FD&C) Act for a 
84  new active ingredient, new indication, new dosage form, new dosing regimen, or new route of 
85  administration must either include a pediatric assessment12 or reports on the molecularly targeted 
86  pediatric cancer investigation (as appropriate),13 or a request for waiver and/or deferral of the 
87  pediatric assessments or reports on the molecularly targeted pediatric cancer investigation.14  
88  There are certain exceptions; for example, PREA requirements generally do not apply to a drug 
89  for an indication for which orphan designation has been granted.15  
90   
 
10 When finalized, the draft Regulatory Considerations guidance will represent FDAs current thinking on the topics 
therein. 
 
11 See section 505B(a)(1)(A) of the FD&C Act (21 U.S.C. 355c(a)(1)(A)).  
 
12 See section 505B(a)(2) of the FD&C Act (21 U.S.C. 355c(a)(2)).   
 
13 See section 505B(a)(3) of the FD&C Act (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.   
 
14 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)). 
 
15 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.  For additional information, see the draft Regulatory Considerations guidance.  When final, this guidance will 
represent the FDAs current thinking on this topic.   
 
  3  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
91  The FD&C Act requires sponsors planning to submit applications subject to PREA to submit an 
92  initial Pediatric Study Plan (iPSP);16 these are typically submitted during the investigational 
93  phase of development, which helps to ensure that sponsors thoroughly consider a pediatric 
94  clinical development program earlier in their overall clinical development program. Section 
95  505B(b) of the FD&C Act also requires holders of approved new drug applications and biologics 
96  license applications for marketed drugs to conduct pediatric assessments under certain 
97  circumstances.17  Drugs developed for use only in pediatric populations may be subject to the 
98  pediatric assessment requirements of PREA.18  The appropriate pediatric age ranges to be studied 
99  may vary, depending on, for example, the pharmacology of the drug, the incidence and the 
100  manifestations of the disease in various age groups, and the ability to measure the response to 
101  therapy.   
102   
103  Under PREA, a pediatric assessment must contain data, gathered using appropriate formulations 
104  for each age group for which the assessment is required, that are adequate to assess the safety 
105  and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, 
106  and that support dosing and administration for each pediatric subpopulation for which the drug is 
107  safe and effective.19  If the course of the disease and the effects of the drug are sufficiently 
108  similar in adults and pediatric patients, FDA may determine that pediatric effectiveness can be 
109  extrapolated from adequate and well-controlled studies in adult subjects.20  
110   
111  In general, PREA requirements do not apply to a drug for an indication for which orphan 
112  designation has been granted.21  Thus, submission of pediatric assessments is not required for an 
113  application to market a drug for an indication for which orphan designation has been granted.22   
114   
115  For more detailed information regarding waivers or deferrals of the requirement to submit 
116  pediatric assessments, see the draft Regulatory Considerations guidance.23 
117   
 
16 See section 505B(e) of the FD&C Act (21 U.S.C. 355c(e)). 
 
17 See section 505B(b) of the FD&C Act (21 U.S.C. 355c(b)). 
 
18 See section 505B(a)(1)(A) of the FD&C Act (21 U.S.C. 355c(a)(1)(A)). 
 
19 See section 505B(a)(2)(A) of the FD&C Act (21 U.S.C. 355c(a)(2)(A)). 
 
20 See section 505B(a)(2)(B) of the FD&C Act (21 U.S.C. 355c(a)(2)(B)). 
 
21 See section 505B(k) of the FD&C Act (21 U.S.C. 355c(k)).  We note that section 505B(k)(1) of the FD&C Act 
states, Unless the Secretary requires otherwise by regulation...this section does not apply to any drug or biological 
product for an indication for which orphan designation has been granted under section 526.  The Secretary has 
delegated this authority to FDA on these issues, and, as of the date of publication of this guidance, FDA has not 
issued any such regulations.  We also note that under section 505B(k)(2) of the FD&C Act, the orphan exemption 
does not apply to drugs that trigger PREA under section 505B(a)(1)(B) of the FD&C Act.   
 
22 See section 505B(k)(1) of the FD&C Act (21 U.S.C. 355c(k)(1)).  
 
23 When final, this guidance will represent the FDAs current thinking on this topic.   
  4  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
118  2.  Molecularly Targeted Pediatric Cancer Investigation:  Section 505B(a)(1)(B) of 
119  the FD&C Act 
120   
121  Pursuant to section 505B(a)(1)(B) of the FD&C Act, a person who submits an original 
122  application on or after August 18, 2020, for a new active ingredient, where the drug that is the 
123  subject of the application is intended for the treatment of an adult cancer and directed at a 
124  molecular target that FDA determines to be substantially relevant to the growth or progression of 
125  a pediatric cancer, must submit reports on the molecularly targeted pediatric cancer investigation, 
126  unless submission of the reports is waived or deferred.24   
127   
128  A molecularly targeted pediatric cancer investigation shall be designed to yield clinically 
129  meaningful pediatric study data, gathered using appropriate formulations for each age group for 
130  which the study is required, regarding dosing, safety, and preliminary efficacy to inform 
131  potential pediatric labeling.25  For a drug that is the subject of a molecularly targeted pediatric 
132  cancer investigation, if the course of the disease and the effects of the drug are sufficiently 
133  similar in adult and pediatric patients, FDA may determine that pediatric effectiveness can be 
134  extrapolated from adequate and well-controlled studies in adult subjects.26 
135   
136  PREA requirements generally do not apply to a drug for an indication for which orphan 
137  designation has been granted; however, this orphan exemption does not apply to drugs that 
138  trigger PREA under section 505B(a)(1)(B) of the FD&C Act. 27  Accordingly, for such drugs 
139  meeting the criteria in section 505B(a)(1)(B), the requirement to submit reports on the 
140  molecularly targeted pediatric cancer investigation applies even if the drug is for an adult 
141  indication for which orphan designation has been granted.28 
142   
143  B.  BPCA 
144   
145  The BPCA provides for additional marketing exclusivity if FDA issues a written request (WR), 
146  the applicant agrees to the request, the applicant completes the requested studies using 
147  appropriate formulations for each age group for which the studies were requested and within the 
148  requested time frame, and the reports of the studies are submitted and accepted by FDA.29  When 
149  accepting or rejecting the reports, FDA determines whether the studies fairly respond to the WR, 
150  have been conducted in accordance with commonly accepted scientific principles and protocols, 
151  and have been reported in accordance with filing requirements.30 
 
24 Sections 505B(a)(1)(B), 505B(a)(3), 505B(a)(4), and 505B(a)(5) of the FD&C Act (21 U.S.C. 355c(a)(1)(B), 21 
U.S.C. 355c(a)(3), 21 U.S.C. 355c(a)(4), and 21 U.S.C. 355c(a)(5)). 
 
25 Section 505B(a)(3)(A) of the FD&C Act (21 U.S.C. 355c(a)(3)(A)). 
 
26 Section 505B(a)(2)(B) and 505B(a)(3)(B) of the FD&C Act (21 U.S.C. 355c(a)(2)(B) and 355c(a)(3)(B)). 
 
27 See section 505B(k) of the FD&C Act (21 U.S.C. 355c(k)). 
 
28 See section 505B(k)(2) of the FD&C Act (21 U.S.C. 355c(k)(2)).   
 
29 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)).  
 
30 See section 505A(d)(4) of the FD&C Act (21 U.S.C. 355a(d)(4)). 
  5  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
152   
153  FDA may issue a WR for pediatric studies either in response to a proposed pediatric study 
154  request (PPSR) or at the initiative of FDA.  A PPSR describes the studies the applicant proposes 
155  to conduct.  The procedures for qualifying for exclusivity and the protections to which that 
156  exclusivity attaches are described in more detail in the draft Regulatory Considerations 
157  guidance.31 
158   
159  It is important to note the distinction between the scope of the studies requested under the BPCA 
160  and those required under PREA.  FDAs authority to issue a WR extends to the use of an active 
161  moiety for indications that may produce health benefits in the pediatric population, regardless of 
162  whether the indications have been previously approved in adults.32  Under PREA, pediatric 
163  assessments are required only for those indications included in the pending (or approved) 
164  application.33  To qualify for pediatric exclusivity, the pediatric studies conducted to satisfy the 
165  requirements of PREA must be the subject of a WR and satisfy all other requirements for 
166  pediatric exclusivity under the BPCA.34  As discussed in the draft regulatory considerations 
167  guidance, FDA does not expect to issue WRs solely for studies or planned studies that are 
168  required under PREA.  For more detailed information regarding WRs for pediatric studies and 
169  PPSRs, see the draft Regulatory Considerations guidance.35 
170   
171  C.  The PeRC 
172   
173  FDAs internal pediatric review committee (i.e., the PeRC) is consulted on all iPSPs, waivers, 
174  deferrals, assessments, deferral extensions, and WRs.36  The PeRC is also provided all responses 
175  to PPSRs, not just WRs that result from those requests.37  Members of this committee include 
176  employees of FDA with expertise in pediatrics (including representation from the Office of 
177  Pediatric Therapeutics), neonatology, biopharmacology (i.e., pharmacology/toxicology), 
 
31 When final, the draft Regulatory Considerations guidance will represent FDAs current thinking on the topics 
therein. 
 
32 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)). 
 
33 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.   
 
34 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)). 
 
35 When final, the draft Regulatory Considerations guidance will represent FDAs current thinking on the topics 
therein. 
 
36 See sections 505C, 505B(f)(1), and 505A(f)(1) of the FD&C Act (21 U.S.C. 355d, 21 U.S.C. 355c(f)(1), and 21 
U.S.C. 355a(f)(1)). 
 
37 See section 505A(f)(7) of the FD&C Act (21 U.S.C. 355a(f)(7)).  
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Draft  Not for Implementation 
178  statistics, chemistry, legal issues, pediatric ethics, the appropriate expertise pertaining to the 
179  pediatric drug under review, and other individuals as needed.38  As a general matter, members of 
180  the relevant drug review division provide background information to the PeRC and are present 
181  during the discussion of the application to provide insight on their reviews and to answer 
182  questions. 
183   
184   
185  IV.  SCIENTIFIC CONSIDERATIONS FOR PEDIATRIC DRUG DEVELOPMENT39 
186   
187  In general, principles that guide pediatric drug development do not differ greatly from the 
188  principles that apply to drugs developed for adults.  Before initiating a development program in 
189  pediatric populations, applicants should consider the condition(s) to be investigated, the drug 
190  under study, and the pediatric subpopulation(s) for whom such a drug would represent a 
191  meaningful therapeutic option.   
192   
193  The information needed to approve a drug for pediatric use includes data from nonclinical 
194  studies, and clinical dosing, safety, and effectiveness information.40  Applicants should consider 
195  whether efficacy could be partially or fully extrapolated from studies in adults or other pediatric 
196  populations (see section IV.B., Pediatric Extrapolation).  Finally, applicants should determine 
197  whether existing data from adult human studies or animal disease models can be used to support 
198  both the safety and preliminary effectiveness of the drug sufficiently to initiate pediatric studies.  
199  If such information does not exist, applicants should plan and initiate necessary studies to obtain 
200  this information. 
201   
202  The intent of the pediatric study plan (PSP), as required under PREA,41 is to identify needed 
203  pediatric studies early in drug development and begin planning for these studies.  An iPSP must 
204  be submitted to FDA before submission of the required assessments or investigation, and no later 
205  than either 60 calendar days after the date of the end-of-phase 2 meeting or such other time as 
206  agreed upon between FDA and the applicant.42  However, FDA encourages applicants to consult 
207  with FDA or submit iPSPs to FDA earlier in development than is required by section 505B(e) of 
208  the FD&C Act, when appropriate.  More information on the timing of iPSPs, the contents of an 
 
38 See section 505C of the FD&C Act (21 U.S.C. 355d). 
 
39 This section generally does not pertain to biological products licensed under section 351(k) of the PHS Act (42 
U.S.C. 262(k)).  For more information regarding biosimilar products and PREA, see the guidance for industry 
Questions and Answers on Biosimilar Development and the BPCI Act (September 2021) and the draft guidance for 
industry New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) (September 
2021).  The draft guidance is available on the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
 
40 For purposes of section 505A of the FD&C Act, the term pediatric studies or studies is defined as at least one 
clinical investigation (that, at the Secretarys discretion, may include pharmacokinetic studies) in pediatric age 
groups (including neonates in appropriate cases) in which a drug is anticipated to be used, and, at the discretion of 
the Secretary, may include preclinical studies (21 U.S.C. 355a(a)).   
 
41 See section 505B(e) of the FD&C Act (21 U.S.C. 355c(e)). 
 
42 See section 505B(e)(2)(A) of the FD&C Act (21 U.S.C. 355c(e)(2)(A)). 
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209  iPSP, the process for reaching agreement with FDA, and the process for amending an agreed 
210  iPSP can be found in guidance for industry Pediatric Study Plans: Content of and Process for 
211  Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020). 
212   
213  A.  Considerations Regarding Data in Pediatric Populations 
214   
215  The following considerations may be relevant to the overall development strategy of a pediatric 
216  development program.  Considerations applicable to both PREA and the BPCA have been 
217  incorporated.   
218   
219  1.  Formulation Development 
220   
221  PREA requires pediatric assessments to be conducted using appropriate formulations for each 
222  age group for which the assessment is required.43  PREA also requires that a molecularly 
223  targeted pediatric cancer investigation gather data using appropriate formulations for each age 
224  group for which the study is required.44  A marketing application that includes a pediatric 
225  indication may need a new dosage form (e.g., a liquid rather than a tablet), addition of a new 
226  strength (e.g., tablet containing a lower dose), or several different dosage forms (e.g., drops, 
227  orally disintegrating tablets, pellets).  The intent of PREA is to require sponsors to develop and 
228  study formulations that allow for use in all relevant pediatric populations, in situations where the 
229  existing dosage form or strength may be unsuitable for use in all or part of the relevant pediatric 
230  populations.   
231   
232  When developing formulations for pediatric populations, applicants should consider the 
233  following, where applicable. 
234   
235    With respect to age appropriateness of the dosage form: 
236   
237   The proposed dosage form in relation to the targeted age group(s).  If adult dosage 
238  form is to be used, the volume and size of the dosage form. 
239   
240   The proposed drug product composition for the pediatric formulation(s) planned to be 
241  used in pediatric studies and how the planned formulations will be dosed (e.g., for an 
242  oral dosage form, whether it will be swallowed, chewed, and/or mixed in soft foods 
243  and/or liquids). 
244   
245   For orally administered dosage forms, the palatability of the dosage form.   
246   
247   If a device is to be used for administration, the type of device and how it will be used 
248  by pediatric populations in all age groups studied (e.g., dropper, syringe, measuring 
249  cup, inhalers). 
250   
251    With respect to toxicity (safety): 
 
43 See section 505B(a)(2)(A) of the FD&C Act (21 U.S.C. 355c(a)(2)(A)). 
 
44 See section 505B(a)(3)(A) of the FD&C Act (21 U.S.C. 355c(a)(3)(A)). 
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252   
253   The use of excipients, including certain dyes, alcohols, flavoring agents, or 
254  preservatives, considering any potential interactions. 
255   
256   The use of a delivery device (e.g., dropper, syringe, measuring cup) copackaged with 
257  the formulation.  Applicants should consider how the device will be calibrated for 
258  accuracy during the proposed in-use period.  Applicants should plan studies to assess 
259  the presence of leachable/extractable components that may be toxic to younger 
260  children or neonates. 
261   
262    With respect to stability of the drug product: 
263   
264   The compatibility and stability assessments of the drug substance with the proposed 
265  excipients under storage conditions during marketing and in-use conditions.    
266   
267   The stability of the formulation, as well as maintenance of intended drug 
268  dissolution/release characteristics when drug products (e.g., disintegrating tablet, 
269  sprinkles, pellets, films, liquids) are given in aqueous solutions, juice, human (breast) 
270  milk, formula, and soft foods such as apple sauce.   
271   
272    With respect to characterizing oral drug products dissolution/release characteristics in 
273  media simulating gastric fluids and environment: 
274   
275   The performing of dissolution/release testing using standard dissolution media as well 
276  as media mimicking in vivo gastric fluids and environment (such as media containing 
277  milk for neonate and infant studies).   
278   
279  Early consultation with FDA is strongly recommended when embarking on pediatric formulation 
280  development. 
281   
282  2.  Nonclinical Information 
283   
284  Nonclinical data, specific to the pediatric population, may be needed to support the initiation of 
285  clinical studies in different pediatric age groups, in addition to traditional toxicology studies 
286  and/or data from adult clinical development programs.  In certain cases, data from clinical 
287  studies in adult subjects, supported by nonclinical studies in adult animals, have been used to 
288  support the initiation of studies in pediatric populations.  However, such studies may not always 
289  assess possible drug effects on developmental processes that occur at specific ages in pediatric 
290  populations.  Developmental processes in pediatric populations may also differentially affect 
291  drug pharmacokinetics and pharmacodynamics, compared to these parameters in adult 
292  therapeutic use.  Juvenile animal studies may assist in identifying postnatal developmental 
293  toxicities that are not assessed in reproductive toxicity testing and that may not be safely 
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294  evaluated in pediatric clinical studies.  The adequacy of nonclinical data to support initiation of 
295  clinical studies in different pediatric age groups should be discussed with FDA.45   
296   
297  If human safety data and previous animal studies are insufficient to inform adequately the likely 
298  safety profile of the drug in the intended pediatric age group, or if the drugs mechanism of  
299  action or its pharmacokinetic (PK) profile suggests that it may affect growth or developmental 
300  processes, juvenile animal studies should be considered to address these concerns.  This section 
301  contains a brief summary of considerations for nonclinical information to support pediatric drug 
302  development.  Additional discussion of juvenile animal studies is available in other guidance.46   
303   
304  When appropriately designed, juvenile animal studies (in vitro and in vivo) can provide a hazard 
305  assessment that specifically addresses identified safety concerns in immature, developing organ 
306  systems; for example: 
307   
308    Specific toxicity studies in juvenile animals can include an assessment of exposure 
309  (toxicokinetics) to address specific developmental endpoints (e.g., neurotoxicity, 
310  immunotoxicity, effects on growth or sexual maturation, nephrotoxicity) at particular 
311  developmental phases consistent with the intended clinical use 
312   
313    Studies in specific animal disease models may be useful when studies in healthy juvenile 
314  animals may not adequately inform the safety in pediatric populations (e.g., inborn errors 
315  of metabolism)  
316   
317  Many investigational cellular and gene therapy drug products are intended to treat severely 
318  debilitating illnesses that exist predominantly in children (e.g., neurodegenerative diseases, 
319  metabolic disorders, lysosomal storage disorders).  These drug products are usually administered 
320  via an invasive route (e.g., intracranial, intraspinal, subretinal, intravenous), can distribute to 
321  nontarget tissues, and can remain in the body for prolonged periods.  Therefore, safety data, as 
322  well as data regarding the prospect of direct clinical benefit, to support an appropriate starting 
323  dose is sometimes obtained from nonclinical studies.  Many of these studies are conducted in 
324  animal disease models that are juveniles or young adults.  Additional information on cellular and 
325  gene therapy drug products can be found in other guidance.47   
326   
 
45 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. 
 
46 Additional information can be found in the guidance for industry Nonclinical Safety Evaluation of Pediatric Drug 
Products (February 2006) and the International Council for Harmonisation (ICH) guidance for industry M3(R2) 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals (January 2010). 
 
47 For example, see the guidance for industry Preclinical Assessment of Investigational Cellular and Gene Therapy 
Products (November 2013).   
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327  3.  Clinical Pharmacology48 
328   
329  Well-designed early phase dosing studies are critical to a successful pediatric development 
330  program.  Inadequate dosing studies in the past have contributed to failed efficacy studies and 
331  have delayed or prevented approval in pediatric age groups.  Modeling and simulation, when 
332  appropriate, should be used to inform dose selection and/or trial design.  Confirmatory PK 
333  studies may be critical, particularly in younger children, in whom dosing is not necessarily 
334  predictable based on the experience in adult or adolescents.   
335   
336  Depending on the approach, PK and/or pharmacodynamic (PD) studies may be needed to 
337  establish dosing recommendations when extrapolating efficacy from adult to pediatric 
338  populations, between different pediatric age groups, or between formulations.   
339   
340  Regarding PK studies, applicants should consider the following:  
341   
342    The sample size for PK studies should be justified, taking into account the expected 
343  variability in PK parameters for that age group. 
344   
345    Matching exposure using pharmacokinetics relies on a reasonable assumption that 
346  exposure-response is similar in adults and the pediatric age group being studied; 
347  therefore, it is most appropriate when pediatric extrapolation is being used.  
348   
349    A dedicated PK study may not be needed in every age group.  For example, prior 
350  experience with dosing in adolescents has demonstrated that knowledge of adult dosing 
351  and appropriate dose scaling may be sufficient for some drugs, with adequate 
352  justification.49 
353   
354    Minimizing blood sampling may be possible using sparse PK sampling techniques and 
355  population pharmacokinetics, when such studies are properly designed. 
356   
357    There is limited information regarding the effect of maturational changes on 
358  pharmacogenetic effects in neonates and infants.  Consideration should be given to the 
359  potential for differences of pharmacogenetic effects in this age group from observed 
360  effects in older children and adults.50 
361   
362    When administration of the investigational drug presents more than a minor increase over 
363  minimal risk, applicants should also consider combining PK studies with safety or 
 
48 Additional information can be found in the draft guidance for industry General Clinical Pharmacology 
Considerations for Pediatric Studies of Drugs, Including Biological Products (September 2022).  When final, this 
guidance will represent FDAs current thinking on this topic. 
 
49 See Momper JD, Mulugeta Y, Green DJ, et al., 2013, Adolescent Dosing and Labeling Since the Food and Drug 
Administration Amendments Act of 2007, JAMA Pediatr, 167(10):926932. 
 
50 Additional information can be found in the guidance for industry General Clinical Pharmacology Considerations 
for Neonatal Studies for Drugs and Biological Products (July 2022).   
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364  efficacy studies that provide the prospect of direct clinical benefit to the enrolled children 
365  (see section IV.C., Timing of Pediatric Studies).51 
366   
367  PD studies are particularly important when drug concentrations cannot be measured in a 
368  pertinent bodily fluid (e.g., plasma, cerebrospinal fluid, urine).  In all cases, however, applicants 
369  should consider the following: 
370   
371    PD differences between adult and pediatric populations (e.g., influence of maturation of 
372  receptors and/or organ systems), especially as related to drug dosing and study endpoints 
373   
374    The use of bridging studies from one population to another (e.g., from adult and older 
375  pediatric age groups to younger children) including, where appropriate, the use of PD 
376  modeling 
377   
378    The potential for changes in PD response between age groups in the pediatric population 
379   
380  4.  Safety Information 
381   
382  Safety information from adult human studies and animal models may provide preliminary 
383  information regarding the expected safety profile of a drug in pediatric populations, but safety 
384  information from administration of the drug to children is almost always needed to establish 
385  safety in the pediatric populations.  Adverse effects of a drug in pediatric populations may not be 
386  predictable based on the adult experience, particularly adverse effects related to behavior, 
387  cognition, or growth.  Nonetheless, pediatric safety information that is available from different 
388  formulations of a drug, or from other closely related drugs within the same class, as appropriate, 
389  should be reviewed.  In addition, because some effects may be measurable only in children of a 
390  certain age or maturity level, long-term follow-up studies, particularly for drugs tested in 
391  neonates, infants or young children, may be needed to assess the effects of the drug.52  If 
392  appropriate, potential risks of the drug should be assessed by age group.  If there is an approved 
393  risk evaluation and mitigation strategy for a drug that is already marketed for use in the adult 
394  population, sponsors should assess what steps should be taken to mitigate risk in the pediatric 
395  population.  Pharmacovigilance programs developed to assess known or potential safety signals 
396  in adult subjects should also include pediatric subjects, when appropriate.   
397   
398  B.  Pediatric Extrapolation 
399   
400  To obtain approval of a new drug application, manufacturers must provide substantial evidence 
 
51 See 21 CFR 50.52 and 50.53.  Additional information can be found in the draft guidance for industry, sponsors, 
and institutional review boards Ethical Considerations for Clinical Investigations of Medical Products Involving 
Children (September 2022).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
52 Additional information can be found in the draft guidance for industry Considerations for Long-Term Clinical 
Neurodevelopmental Safety Studies in Neonatal Product Development (February 2023).  When final, this guidance 
will represent the FDAs current thinking on this topic. 
 
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401  of effectiveness.53  FDAs thinking regarding the quantity and quality of evidence that may be 
402  necessary to support effectiveness is described in other guidance.54   
403   
404  FDA recognizes that in some cases conducting clinical studies in pediatric populations may be 
405  challenging, and study approaches commonly used to generate data in adult populations may not 
406  be feasible.  Pediatric ethical issues, vulnerabilities particular to the study population, limited 
407  number of children available for participation in a study, difficulty in developing age-
408  appropriate endpoints, limited availability of validated patient-reported outcome measurements, 
409  the potential need to use surrogate endpoints, the potential need for alternative study designs, 
410  and other factors may pose unique challenges in the development of protocols for clinical 
411  studies in pediatric populations.   
412   
413  One approach that can increase the efficiency of pediatric drug development, where appropriate, 
414  is the use of pediatric extrapolation.  The use of pediatric extrapolation in drug development is 
415  discussed in other guidance.55   
416   
417  C.  Timing of Pediatric Studies  
418   
419  From a scientific and ethical perspective, the timing of pediatric trials is grounded in 21 CFR 
420  part 50, subpart D, Additional Safeguards for Children in Clinical Investigations.56  FDA-
421  regulated clinical investigations that involve children as subjects generally may be initiated 
422  when, among other things, sufficient data from animal disease models and/or adult human 
423  subjects are available to support either (1) a sufficiently low risk of the intervention or procedure 
 
53 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)).  We note that under section 351 of the PHS Act, licenses 
for biological products have been issued only upon a showing that the products are safe, pure, and potent.  
Potency has long been interpreted to include effectiveness (21 CFR 600.3(s)).  FDA has also generally considered 
substantial evidence of effectiveness to be necessary to support licensure of a biological product under section 351 
of the PHS Act.  For additional information, see the draft guidance for industry Demonstrating Substantial Evidence 
of Effectiveness for Human Drug and Biological Products (December 2019).  When final, this guidance will 
represent FDAs current thinking on this topic. 
 
54 Additional information can be found in the guidance for industry Providing Clinical Evidence of Effectiveness for 
Human Drug and Biological Products (May 1998).   
 
55 Additional information can be found in the draft ICH guidance for industry E11A Pediatric Extrapolation (April 
2022).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
56 See the draft guidance for industry, sponsors, and institutional review boards Ethical Considerations for Clinical 
Investigations of Medical Products Involving Children.  When final, this guidance will represent the FDAs current 
thinking on this topic. 
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424  absent any prospect of direct benefit;57 or (2) a sufficient prospect of direct benefit to justify the 
425  risks.58   
426   
427  Applicants should consider initiation of pediatric studies during the adult development program 
428  if sufficient data on the safety and potential benefit of a drug already exist (e.g., from a 
429  previously approved indication, or a different formulation).  For many drugs with little previous 
430  human exposure, the initial phase of pediatric development (i.e., phase 1) might begin after the 
431  adult phase 2 and/or 3 studies have established evidence of a sufficient prospect of direct benefit 
432  to justify exposing pediatric populations to the risks of the drug.  Dosing, safety, and 
433  effectiveness studies may then be conducted in pediatric populations concurrently with the 
434  effectiveness trial in adult subjects.59 
435   
436  Pediatric studies of drugs for life-threatening diseases for which approved treatment is not 
437  available also should be considered earlier in development than might occur for less serious 
438  diseases.60  For example, pediatric studies of some oncology drugs have begun as early as adult 
439  phase 1 or phase 2 studies, after initial safety data in adult subjects were available.  Even when 
440  no approved therapies are available, initiation of pediatric studies still generally requires, among 
441  other things, either a sufficiently low risk of the intervention or procedure or that the prospect of 
442  direct benefit to the enrolled pediatric populations is sufficient to justify the risks.61  Absent 
443  sufficient adult human data, the nonclinical evidence of benefit and risk from an appropriate in 
444  vitro and/or animal model may be particularly important.  FDA encourages applicants to discuss 
445  with the Agency the plan for the development of such drugs as early as possible (e.g., pre-
446  investigational new drug application, end-of-phase 1 meetings). 
447   
448  FDA recognizes that in certain cases, scientific and ethical considerations dictate that pediatric 
449  studies should not begin until after adequate safety and efficacy data are available in adult 
450  subjects; for example, where a drug has not shown any advantage over other approved drugs in 
451  the class, the therapeutic gain is likely to be low, and the risks of exposing pediatric subjects to 
452  the new drug may not be justified until the drugs safety profile is better established in adult 
453  subjects.  In these cases, the applicant can request a deferral of required pediatric studies (see 
454  section III. A., PREA).  However, if substantial pediatric use may be anticipated after the drug is 
455  approved for use in adults, early initiation of pediatric studies should be considered. 
 
57 See 21 CFR 50.53 (regarding clinical investigations involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but likely to yield generalizable knowledge about the subjects disorder or condition).  
Additionally, approval by an institutional review board of studies presenting no greater than minimal risk to children 
and not offering a prospect of direct benefit also may be considered under 21 CFR 50.51; however, FDA generally 
views the administration of an FDA-regulated drug as presenting more than minimal risk. 
 
58 See 21 CFR 50.52. 
 
59 For discussion on the timing of pediatric studies relative to adult studies in the context of antiretroviral drugs for 
the treatment of human immunodeficiency virus (HIV), see the guidance for industry Pediatric HIV Infection: Drug 
Product Development for Treatment (March 2019). 
 
60 Additional information can be found in the guidance for industry Expedited Programs for Serious Conditions  
Drugs and Biologics (May 2014).   
 
61 See 21 part 50, subpart D. 
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456   
457  D.  Drug Development for the Neonatal Population62 
458   
459  FDA also recognizes that clinical development of drugs for use in the neonatal population poses 
460  additional challenges.  The ability to apply information about the safety and effectiveness of 
461  drugs from older pediatric populations and adult subjects to neonates is extremely limited.  
462  Neonatal physiology may differ considerably from that of older populations.  Moreover, some 
463  disorders occur only in neonates and other disorders that affect older populations may not be 
464  apparent in the neonatal period. 
465   
466  In addition, the neonatal period (generally considered to include birth through 27 days corrected 
467  gestational age) represents an extremely brief window for study enrollment.  Furthermore, 
468  although there may be reluctance to enroll children from all pediatric populations, parents may 
469  be especially reluctant to expose newborns to investigational therapies and invasive tests.  The 
470  relationship among some surrogate endpoints (e.g., need for supplemental oxygen at 30 days) 
471  and longer term outcomes that are meaningful to patients (e.g., improvement in 
472  neurodevelopmental outcome) have not been established.  Clinical or laboratory tests that are 
473  routine in older children may not be standardized or validated in neonates, making the results of 
474  such studies difficult to interpret.  Necessary limits on the volume of blood that may be 
475  withdrawn make testing more difficult.  Data may be lacking to fully elucidate the short- and 
476  long-term risks of a drug because clinical studies in neonates that are not specifically conducted 
477  to provide substantial evidence of efficacy and safety of a drug often have small sample sizes and 
478  are of limited duration.  Finally, neonatal clinical trials face substantial hurdles from within the 
479  practice of neonatology, including the use of unproven therapies that often become standard of 
480  care in the absence of data establishing dosing, safety, and effectiveness. 
481   
482  As a result of increasing attention to the lack of high-quality data for the use of drugs in 
483  neonates, several provisions in the BPCA and PREA address clinical development in neonates.  
484  For example, if FDA issues a WR that does not include a request to study a drug in neonates, the 
485  BPCA requires that FDA include a statement describing the rationale for not requesting studies 
486  in neonates.63  In addition, when pediatric assessments are required under PREA, applicants are 
487  required to submit assessments that are adequate to assess safety and effectiveness for the 
488  claimed indications in all relevant pediatric age groups, which may include neonates.64    
489   
490  When drugs may be appropriate for use in the neonatal population, special consideration should 
491  be given to the timing of neonatal clinical studies relative to studies in older populations.  The 
492  failure to study neonates before approval in older children and/or adults has meant that drugs are 
493  often used in neonates without adequate information about dosing, safety, or effectiveness.  
494  Unless previous animal or human data exist to suggest that use of a drug should not be studied in 
495  the neonatal population because of safety concerns, FDA recommends that applicants consider 
 
62 Additional information can be found in the guidance for industry General Clinical Pharmacology Considerations 
for Neonatal Studies for Drugs and Biological Products.   
 
63 See section 505A(d)(1)(A) of the FD&C Act (21 U.S.C. 355a(d)(1)(A)). 
 
64 See section 505B(a)(2)(A) of the FD&C Act (21 U.S.C. 355c(a)(2)(A)). 
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496  dosing, safety, and efficacy studies, as appropriate, of any drug that may be used in the neonatal 
497  population.  In general, such studies should be undertaken at the same time as studies in older 
498  pediatric populations, unless efficacy or safety data from older pediatric populations are 
499  necessary before initiation of studies in the neonatal population.  Uncertainties regarding 
500  potential developmental or neurocognitive effects of a drug on the neonatal population generally 
501  are not adequate justification for failing to study such effects concurrently with other pediatric 
502  populations.  Long-term safety studies in drugs developed for neonates may be needed to assess 
503  these effects.65 
504   
 
65 Additional information can be found in the draft guidance for industry Considerations for Long-Term Clinical 
Neurodevelopmental Safety Studies in Neonatal Product Development. 
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