General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

General Clinical Pharmacology
Considerations for Pediatric
Studies of Drugs, Including
Biological Products
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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_OCP_GPT@fda.hhs.gov
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2022
Clinical Pharmacology
Revision 1

General Clinical Pharmacology
Considerations for Pediatric
Studies of Drugs, Including
Biological Products
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
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2022
Clinical Pharmacology
Revision 1

Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	CLINICAL PHARMACOLOGY CONSIDERATIONS .............................................. 3
A. 	Pharmacokinetics .................................................................................................................5
B. 	Pharmacodynamics...............................................................................................................7
C. 	Pharmacogenomics ...............................................................................................................7
IV. 	ETHICAL CONSIDERATIONS ..................................................................................... 7
A. 	Case 1: IRB Review of a Clinical Pharmacology Study Involving Pediatric Participants
Under 21 CFR 50.53 .....................................................................................................................9
B. 	Case 2: IRB Review of a Clinical Pharmacology Study Involving Pediatric Participants
Under 21 CFR 50.52 ................................................................................................................... 10
C. 	Ethical Justification for Pediatric Pharmacology Studies ................................................... 10
V. 	THE PEDIATRIC STUDY PLAN DESIGN AND POINTS TO CONSIDER ......... 11
A. 	Approaches to Pediatric Studies ......................................................................................... 12
B. 	Alternative Approaches to Conventional PK Studies .......................................................... 15
C. 	Pediatric Dose Selection ...................................................................................................... 17
D. 	Pediatric Dosage Formulation............................................................................................. 18
E. 	Sample Size ......................................................................................................................... 19
F. 	Sample Collection ............................................................................................................... 20
G. 	Covariates and Phenotype Data .......................................................................................... 21
H. 	Drug-Drug Interactions ...................................................................................................... 23
I. 	Sample Analysis .................................................................................................................. 24
J. 	Data Analysis ...................................................................................................................... 24
K. 	Clinical Study Report ......................................................................................................... 25
L. 	Data Submission ................................................................................................................. 25

Contains Nonbinding Recommendations
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1
General Clinical Pharmacology Considerations for Pediatric Studies	1
of Drugs, Including Biological Products	2
Guidance for Industry1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
14
I. 	INTRODUCTION	15
16
This guidance assists sponsors of investigational new drug applications (INDs) and applicants of	17
new drug applications (NDAs) under section 505 of the Federal Food, Drug, and Cosmetic Act	18
(the FD&C Act), biologics license applications (BLAs) under section 351(a) of the Public Health	19
Service Act (PHS Act), and supplements to such applications who are planning to conduct	20
clinical studies in pediatric populations.2,3,4 In addition, this guidance assists clinical	21
investigators in the design and planning of, and Institutional Review Boards (IRBs) in the	22
assessment of, clinical studies in pediatric populations.	23
24
Effectiveness, safety, or dose-finding studies in pediatric populations involve gathering clinical	25
pharmacology information, such as information regarding a product’s pharmacokinetics and	26
pharmacodynamics, to inform dose selection and individualization. This guidance addresses	27
general clinical pharmacology considerations for conducting studies so that the dosing and safety	28
1 This guidance has been prepared by the Pediatric Working Group of the Office of Clinical Pharmacology in
conjunction with the Pediatric Subcommittee of the Medical Policy Coordinating Committee in the Center for Drug
Evaluation and Research at the Food and Drug Administration.
2 For the purposes of this guidance, the term sponsor refers to both sponsors and applicants.
3 For purposes of this guidance, references to drugs includes drugs approved under section 505 of the FD&C Act (21
U.S.C. 355) and biological products licensed under 351(a) of the PHS Act (42 U.S.C. 262(a)) that are regulated as
drugs. Hereafter, the term drug will be used to refer to all such products.
4 This guidance is applicable to BLAs submitted under section 351(a) of the PHS Act. For the Agency’s thinking
regarding clinical pharmacology considerations for BLAs submitted under section 351(k), see the FDA guidance
entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
(December 2016). We update guidances periodically. For the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. Additionally, for
information about the Pediatric Research Equity Act (PREA) (section 505B of the FD&C Act) in the context of
biosimilar applications, see the FDA guidance entitled Questions and Answers on Biosimilar Development and the
BPCI Act (Revision 2) (September 2021).

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information for drugs in pediatric populations can be sufficiently characterized, leading to well-	29
designed trials to evaluate effectiveness.	30
31
In general, this guidance focuses on the clinical pharmacology information (e.g., exposure-	32
response, pharmacokinetics, and pharmacodynamics) that supports findings of effectiveness and	33
safety and helps identify appropriate doses in pediatric populations. This guidance also describes	34
how quantitative approaches (i.e., pharmacometrics) can use disease and exposure-response	35
knowledge from relevant prior clinical studies to help design and evaluate future pediatric	36
studies.	37
38
This guidance does not describe: (1) the standards for the approval of drugs in the pediatric	39
population; (2) the determination that the course of a disease is the same in adults and pediatric	40
populations; or (3) the clinical pharmacology studies for the development of vaccine therapies,	41
blood products, or other products not regulated by the Center for Drug Evaluation and Research.	42
43
In general, FDA’s guidance documents do not establish legally enforceable	44
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and	45
should be viewed only as recommendations, unless specific regulatory or statutory	46
requirements are cited. The use of the word should in Agency guidance means that	47
something is suggested or recommended, but not required.	48
49
50
II. 	BACKGROUND	51
52
Over the past several decades, the FDA has tackled the problem of inadequate testing of drugs in	53
pediatric patients and inadequate pediatric use information in drug labeling. The Food and Drug	54
Administration Modernization Act of 1997 (FDAMA) addressed the need for improved	55
information about the use of drugs in the pediatric population by establishing incentives for	56
conducting pediatric studies on drugs for which exclusivity or patent protection exists.5	57
Congress subsequently passed the Best Pharmaceuticals for Children Act (BPCA)6 in 2002 and	58
the Pediatric Research Equity Act (PREA) in 2003.7 Both BPCA and PREA were reauthorized	59
in 2007.8 In 2010, the Biologics Price Competition and Innovation Act extended certain	60
provisions of the BPCA to biological products.9 In 2012, BPCA and PREA were made	61
permanent under Title V of the FDA Safety and Innovation Act (FDASIA).10	62
63
5 Public Law No. 105-115, 111 Stat. 2296 (November 21, 1997).
6 Public Law No. 107-109, 115 Stat. 1408 (January 4, 2002).
7 Public Law No. 108-155, 117 Stat. 1936 (December 3, 2003).
8 Food and Drug Administration Amendments Act of 2007 (FDAAA), Public Law No. 110-85, 121 Stat. 823
(September 27, 2007).
9 See section 351(m) of the PHS Act (42 U.S.C. 262(m)).
10 Public Law No. 11 2-144, 126 Stat. 993 (July 9, 2012).

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Under BPCA, sponsors of certain applications and supplements filed under section 505 of the	64
FD&C Act and under section 351(a) of the PHS Act can obtain an additional six months of	65
exclusivity if, in accordance with the requirements of the statute, the sponsor submits	66
information responding to a Written Request from the Secretary relating to the use of a drug in	67
the pediatric population.11	68
69
Under PREA, sponsors of certain applications and supplements filed under section 505 of the	70
FD&C Act or section 351(a) of the Public Health Service Act are required to submit pediatric	71
assessments, unless they receive an applicable waiver or deferral of this requirement.12,13 If	72
applicable, sponsors must submit a request for a deferral or waiver as part of an initial pediatric	73
study plan (iPSP)14 (see section V of this guidance).	74
75
The FD&C Act requires a description of pediatric study data in labeling arising from study data	76
submitted in response to a Written Request under BPCA and/or data from studies required under	77
PREA, whether the findings are positive, negative, or inconclusive.15 The PREA requirements	78
are triggered by the submission of an application or supplement for a drug under section 505 of	79
the FD&C Act or section 351 of the PHS Act for a new active ingredient, new indication, new	80
dosage form, new dosing regimen, or new route of administration.16 If a full or partial waiver is	81
granted under PREA because there is evidence that the drug would be ineffective or unsafe in	82
some or all pediatric populations, the information must be included in the product’s labeling.17	83
84
This guidance addresses the clinical pharmacology considerations of any planned pediatric study,	85
whether or not it is conducted pursuant to BPCA or PREA.18	86
87
88
III. 	CLINICAL PHARMACOLOGY CONSIDERATIONS	89
90
Clinical pharmacology studies in the pediatric population should be conducted in individuals	91
with the disease which the drug is intended to treat, or in rare instances, in those who are at risk	92
of this disease. Identifying the appropriate pediatric population to study should take into	93
11 Section 505A of the FD&C Act, 21 U.S.C. 355a.
12 Section 505B of the FD&C Act, 21 U.S.C. 355c.
13 For more information, see the FDA draft guidance entitled How to Comply with the Pediatric Research Equity Act
(September 2005). When final, this guidance will represent the Agency’s current thinking on this topic.
14 Section 505B(e)(2)(B) of the FD&C Act, 21 U.S.C. 355c(e)(2)(B).
15 Section 505A(j) of the FD&C Act, 21 U.S.C. 355a(j); Section 505B(g)(2) of the FD&C Act, 21 U.S.C.
355c(g)(2).
16 Section 505B(a)(1) of the FD&C Act, 21 U.S.C. 355c(a)(1).
17 Section 505B(a)(5)(D) of the FD&C Act, 21 U.S.C. 355c(a)(5)(D).
18 For more information, please see the FDA guidance entitled General Clinical Pharmacology Considerations for
Neonatal Studies for Drugs and Biological Products (July 2022).

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consideration: 1) the disease; 2) the profile of the drug under study; 3) scientific and ethical	94
justifications; and 4) developmental changes in the pediatric population.	95
96
Sponsors should address the entire pediatric age range (birth to <17 years of age19) in their iPSP	97
(waivers and deferrals of the requirements under PREA may be appropriate for specific age	98
ranges). The pharmacokinetics of a drug is typically evaluated over the entire pediatric age	99
range in which the agent will be used. See the FDA guidance entitled E11 Clinical Investigation	100
of Medicinal Products in the Pediatric Population (December 2000) for more information. The	101
Center for Drug Evaluation and Research generally divides the pediatric population into the	102
following groups:20	103
104
• 	Neonates: Birth up to 1 month21,22	105
• 	Infants: 1 month up to 2 years	106
• 	Children: 2 years up to 12 years	107
• 	Adolescents: 12 years up to younger than 17 years	108
109
If other categorizations such as physiologic categories based upon systems ontogeny or disease	110
pathophysiology are used, they should be supported with scientific and developmental data.	111
These categories should not be arbitrarily applied for trial enrollment but can help ensure	112
adequate inclusion of participants across the pediatric age range.	113
114
The measurement or prediction of a drug’s pharmacokinetics (exposure) and pharmacodynamics	115
(response) is essential to the clinical pharmacology assessment. It is important to describe the	116
exposure-response relationship of a drug in the pediatric population when possible to enhance	117
the understanding of effective dose ranges or support the ability to extrapolate information from	118
older pediatric participants. A pediatric drug development program should consider the time	119
course of development of the drug metabolizing enzymes, drug excretory systems, transporters	120
and drug target/receptors relevant (if known) to the drug being studied. This can be addressed by	121
characterizing the pharmacokinetics and/or pharmacodynamics of the drug across the appropriate	122
pediatric age range.	123
124
19 See 21 CFR 201.57(c)(9)(iv).
20 In 1994, the FDA revised its regulations to include more complete information about the use of a drug in pediatric
populations. See the final rule on Specific Requirements on Content and Format of Labeling for Human
Prescription Drugs; Revision of “Pediatric Use” Subsection in the Labeling, 59 FR 64240, 64241-42, (December 13,
1994). Pediatric age groups are described in the preamble to that final rule. Although the Agency has since further
revised those labeling requirements (see the final rule on Requirements on Content and Format of Labeling for
Human Prescription Drug and Biological Products, 71 FR 3922 (January 24, 2006)), the Agency’s general thinking
regarding these pediatric subpopulations has remained the same.
21 In this guidance, as in the FDA guidance entitled E11(R1) Addendum: Clinical Investigation of Medicinal
Products in the Pediatric Population (April 2018), the neonatal period is defined for the term and post-term
newborn as the day of birth plus 27 days, and for the preterm newborn, as the day of birth, through the expected date
of delivery plus 27 days.
22 For more information, please see the FDA guidance entitled General Clinical Pharmacology Considerations for
Neonatal Studies for Drugs and Biological Products (July 2022).

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A. 	Pharmacokinetics	125
126
Pharmacokinetic (PK) measures, such as area under the curve (AUC) and maximum	127
concentration (Cmax), and parameters such as clearance (CL), half-life, and volume of	128
distribution, reflect the absorption (A), distribution (D), and excretion (E) of a drug from the	129
body. Drugs can be eliminated in the unchanged (parent) form or undergo metabolism (M) to	130
one or more active and inactive metabolites. This overall set of processes is often referred to as	131
ADME, which ultimately determines the systemic exposure to a drug and its metabolites after	132
drug administration. This systemic exposure, reflected as drug or metabolite concentrations or	133
both, is generally correlated with both beneficial and adverse drug effects. All drugs show inter-	134
and intra-individual variability in PK measures and parameters.	135
136
In the pediatric population, growth and developmental changes in the factors that influence	137
ADME can lead to changes in PK parameters which can lead to changes in drug	138
response/adverse effects. Specifically, the ontogeny of drug metabolizing enzymes, transporters,	139
and receptors should be taken into account when planning and analyzing data from pediatric PK	140
studies.	141
142
The methodological issues in designing pediatric PK studies have been reviewed previously.23	143
Special areas of importance in planning pediatric PK studies are discussed in the following	144
paragraphs.	145
146
1. 	Absorption	147
148
Developmental changes in the pediatric population that can affect absorption include effects on	149
gastric acidity, rates of gastric and intestinal emptying, surface area of the absorption site,	150
gastrointestinal drug-metabolizing enzyme systems, gastrointestinal permeability, biliary	151
function, and transporter expression. Similarly, developmental changes in skin, muscle, and fat,	152
including changes in water content and degree of vascularization, can affect absorption patterns	153
of drugs delivered by intramuscular, subcutaneous, or percutaneous absorption.24 See section	154
V.D for a discussion on the effect of the formulation on drug absorption.	155
156
2. 	Distribution	157
158
Distribution of a drug can be affected by changes in body composition, such as changes in total	159
body water and adipose tissue, which are not necessarily proportional to changes in total body	160
weight. Plasma protein binding and tissue-binding changes arising from changes in body	161
composition with growth and development can also influence distribution. Differences between	162
the pediatric and adult populations in blood flow to an organ, such as the brain, can also affect	163
the distribution of a drug in the body.	164
23 Burckart, GJ, KE Estes, R Leong, Y Mulugeta, V Tandon, J Wang, DR Abernethy, and PR Jadhav, 2012,
Methodological Issues in the Design of Pediatric Pharmacokinetic Studies, Pharm Med, 26:13-22.
24 Hong, L and S Rosenbaum, 2014, Developmental Pharmacokinetics in Pediatric Populations, J Pediatr Pharmacol
Ther, 19(4):262-276.

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165
3. 	Metabolism	166
167
Drug metabolism commonly occurs in the liver, but can also occur in the blood, gastrointestinal	168
wall, kidney, lung, and skin. Developmental changes in metabolizing capacity can affect both	169
bioavailability and elimination, depending on the degree to which intestinal and hepatic	170
metabolic processes are involved.25 Developmental changes in drug metabolism are well	171
recognized, and information on the ontogeny of drug metabolism in newborns, infants, and	172
children is now included in modeling approaches to predicting drug elimination in these groups.	173
Both the rates of metabolite formation and the principal metabolic pathway can be different in	174
the pediatric population compared to adults and within the pediatric population. In vitro studies	175
performed early in drug development can be useful in identifying the metabolic pathways for a	176
drug. See the FDA guidance entitled In Vitro Drug Interaction Studies - Cytochrome P450	177
Enzyme- and Transporter-Mediated Drug Interactions (January 2020) for more information.	178
179
4. 	Excretion	180
181
Drug excretion by the kidney is the net result of glomerular filtration, tubular secretion, and	182
tubular reabsorption. Because these processes mature at different rates in the pediatric	183
population, age can affect the systemic exposure of drugs when renal excretion is a dominant	184
pathway of elimination. The maturation of other excretory pathways, including biliary and	185
pulmonary routes of excretion, is also important.	186
187
5. 	Protein Binding	188
189
Protein binding to a drug or its metabolites can change with age and concomitant illness. In	190
certain circumstances, an understanding of protein binding is important to interpret the data from	191
a blood level measurement and to determine appropriate dose adjustments.26 In vitro plasma	192
protein binding studies can determine the extent of binding of the parent and the major active	193
metabolite(s) and identify specific binding proteins, such as albumin and alpha-1 acid	194
glycoprotein.	195
196
6. 	Clearance	197
198
Clearance of drugs as a function of age and body weight is generally a valuable parameter for	199
determining the dose in the pediatric population, and drug clearance has provided a valuable tool	200
in the assessment of pediatric clinical pharmacology studies. Scaling of drug clearance from one	201
age group to another is a commonly used approach.	202
203
25 Leeder, JS, 2004, Translating Pharmacogenetics and Pharmacogenomics into Drug Development for Clinical
Pediatrics and Beyond, Drug Disc Today, 9(13):567-573.
26 Kearns, GL, SM Abdel-Rahman, SW Alander, DL Blowey, JS Leeder, and RE Kauffman, 2003, Developmental
Pharmacology - Drug Disposition, Action, and Therapy in Infants and Children, NEJM, 349;12:1157-1167.

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B. 	Pharmacodynamics	204
205
Sponsors should collect and analyze PK and, whenever possible, pharmacodynamic (PD) data in	206
pediatric studies to determine how the two are linked (i.e., the PK-PD or exposure-response	207
relationship). PD data can include the effect of the drug on biomarkers or clinical endpoints for	208
both effectiveness and safety. These measurements can allow a better understanding of whether	209
the PK-PD relationships of the drug in pediatrics are similar to those observed in adults and can	210
help derive rational dosing strategies in pediatrics.	211
212
If the clinical endpoint cannot be measured directly because the effect is delayed or infrequent,	213
then the selection of an appropriate biomarker to substitute for the clinical effectiveness or	214
toxicity endpoint is essential. Endpoint selection is a critical part of pediatric study design.27	215
216
C. 	Pharmacogenomics	217
218
Documentation that genetic differences can impact drug exposure and response is increasing,28	219
but the relationship between genomic profiles and developmentally regulated gene expression	220
has not been extensively studied in pediatric populations. Genotype-phenotype relationships	221
observed in adults are not always representative of those observed in pediatric populations,	222
particularly neonates and infants.29 Nevertheless, if drug exposure and/or response is dependent	223
on a well-known pharmacogenomic biomarker (e.g., cytochrome P4502D6), collecting and	224
analyzing pharmacogenetic samples in a pediatric clinical pharmacology study could provide	225
additional information for the interpretation of the PK and PD results. See the FDA guidance	226
entitled Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-	227
Mediated Drug Interactions (January 2020) for more information.	228
229
230
IV. 	ETHICAL CONSIDERATIONS	231
232
FDA-regulated clinical investigations are governed, in part, by IRB regulations in 21 CFR Part	233
56 and the human subject protection regulations in 21 CFR Part 50. The requirements in 21 CFR	234
Part 50, subpart D, Additional Safeguards for Children in Clinical Investigations, apply to FDA-	235
regulated clinical pharmacology studies that enroll pediatric participants. If the proposed	236
intervention or procedure does not offer a prospect of direct clinical benefit to the individual	237
child, these safeguards restrict the allowable risk to which a pediatric participant can be exposed	238
in a clinical investigation to minimal risk (21 CFR 50.51) or no more than a minor increase over	239
27 Green, DJ, JM Burnham, P Schuette, XI Liu, BM Maas, L Yao, SK McCune, J Chen, JN van den Anker, and GJ
Burckart, 2018, Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA, J Clin Pharmacol
58(7):885-890.
28 Food and Drug Administration: Table of Pharmacogenomic Biomarkers in Drug Labeling (June 2021)), available
at: https://www.fda.gov/media/124784/download (Accessed December 21, 2021).
29Green, DJ, P Mummaneni, IW Kim, JM Oh, M Pacanowski, and GJ Burckart, 2016, Pharmacogenomic
Information in FDA-Approved Drug Labels: Application to Pediatric Patients, Clin Pharmacol Ther, 99(6):622-632.

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minimal risk (21 CFR 50.53) unless the protocol is referred to the FDA by the IRB and allowed	240
to proceed under 21 CFR 50.54 (see further description below).	241
242
Clinical pharmacology studies generally do not provide a direct clinical benefit to individual	243
pediatric participants and must therefore present minimal risk (21 CFR 50.51) or no more than a	244
minor increase over minimal risk (21 CFR 50.53) in order to be approved by an IRB under 21	245
CFR Part 50, subpart D. However, if a clinical pharmacology study offers the prospect of direct	246
benefit to the participant, such as by ensuring that serum levels of a drug remain within the	247
therapeutic range, then the study potentially could be approvable by an IRB under 21 CFR 50.52.	248
249
Before initiation of the clinical trial, an IRB must determine that the proposed trial is in	250
compliance with the requirements of 21 CFR 50, subpart D.30 However, if FDA has concerns	251
that the rights and safety of pediatric participants may not be adequately protected, such concerns	252
could present sufficient grounds for the FDA to impose a clinical hold because the investigation	253
could present an unreasonable and significant risk of illness or injury to the pediatric participants	254
(21 CFR 312.42(b)).	255
256
The assessment of a clinical pharmacology protocol under 21 CFR part 50, subpart D depends on	257
whether the investigational drug is being administered: (1) solely for the purposes of obtaining	258
PK data; or (2) in such a way that it offers the pediatric participant a prospect of direct clinical	259
benefit. The two scenarios are discussed further in the case studies below.	260
261
Regardless of the scenario, administration of an investigational drug would generally be	262
considered to represent more than minimal risk and thus would not meet the requirements for	263
approval by an IRB under 21 CFR 50.51 (clinical investigations not involving greater than	264
minimal risk). For IRB approval under 21 CFR 50.53, the pediatric participants must have a	265
disorder or condition that is the focus of the clinical investigation, the investigational drug must	266
present experiences to those subjects that are reasonably commensurate with those inherent in	267
their actual or expected medical, dental, psychological, social, or educational situations, and the	268
clinical investigation must be likely to yield generalizable knowledge about the disease or	269
condition that is of vital importance for the understanding or amelioration of that disorder or	270
condition. For IRB approval of a clinical investigation under 21 CFR 50.52, the pediatric	271
participants must have a prospect of direct clinical benefit from administration of the	272
investigational product, the risk to the pediatric participants must be justified by the anticipated	273
benefit, and the relation of the anticipated benefit to the risk must be at least as favorable to the	274
pediatric participants as that presented by available alternative approaches. Accordingly, healthy	275
pediatric participants (i.e., without a disorder or condition which is the focus of the research)	276
cannot be enrolled in FDA-regulated clinical pharmacology studies unless the Commissioner	277
determines, after consultation with a panel of experts in pertinent disciplines and opportunity for	278
public review and comment, that the conditions in 21 CFR 50.54 are met.31 That regulation	279
applies to clinical investigations that are not approvable under 21 CFR 50.51, 50.52, or 50.53 but	280
30 See 21 CFR 56.109(h) and 21 CFR 56.111(c).
31 See the FDA guidance entitled Process for Handling Referrals to FDA Under 21 CFR 50.54 - Additional
Safeguards for Children in Clinical Investigations (December 2006).

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that present an opportunity to understand, prevent, or alleviate a serious problem affecting the	281
health or welfare of children.	282
283
A. 	Case 1: IRB Review of a Clinical Pharmacology Study Involving Pediatric	284
Participants Under 21 CFR 50.53	285
286
When the investigational drug is being administered to a pediatric participant with the disease or	287
condition for which the drug is being developed, but the intent of the study is solely for the	288
purpose of obtaining PK data, the risk(s) presented by the investigational drug, the route of	289
administration, and the PK sampling schedule must represent no more than a minor increase over	290
minimal risk (21 CFR 50.53(a)) in order to be approvable by the IRB. Pediatric participants may	291
be exposed to no more than a minor increase over minimal risk if, among other criteria, the	292
intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder	293
or condition that is of vital importance for the understanding or amelioration of that disorder or	294
condition (21 CFR 50.53(c)). Thus, for a clinical investigation to be approved by an IRB under	295
this category, the enrolled pediatric participant must have a disorder or condition that meets these	296
requirements. The FDA interprets “condition” to include being at risk for the disease (disorder)	297
based on, for example, epidemiologic, genetic, and other factors.	298
299
Furthermore, sufficient empirical data regarding the risks of the proposed interventions or	300
procedures should be available to ascertain that the risks are no more than a minor increase over	301
minimal risk (21 CFR 50.53(a)). If available, adult data (including dose-response information)	302
should be considered for this purpose. When there are not enough human data to adequately	303
characterize the risk, then the intervention or procedure generally would not be considered to	304
present no more than a minor increase over minimal risk because the risks of the intervention or	305
procedure would not be known with sufficient accuracy.	306
307
The risks of any blood and/or fluid sampling procedures also must represent no more than a	308
minor increase over minimal risk (21 CFR 50.53(a)). The limited venipunctures to obtain	309
specimens for PK analyses would generally be considered either minimal risk or a minor	310
increase over minimal risk, and therefore could be approvable by the IRB even without the	311
prospect of direct benefit (see 21 CFR 50.51(a) and 50.53(a)). This approach to the analysis of	312
clinical trials is often called a component analysis of risk, whereby to determine the overall	313
acceptability of the clinical investigation, the risks and anticipated direct clinical benefits of the	314
interventions included in a protocol are analyzed individually as well as collectively.32,33,34	315
316
An example of a clinical pharmacology study that generally would fall under 21 CFR 50.53 is	317
the pharmacokinetics of the oral administration of a single dose of an over-the-counter cough and	318
cold product. To be enrolled in such a study, a child would either be symptomatic from an upper	319
32 See the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research,
Research Involving Children: Report and Recommendations of the Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research, (43 FR 2084, 2086), January 13, 1978.
33 See Preamble to the Final Rule, Additional Safeguards for Children in Clinical Investigations of Food and Drug
Administration-Regulated Products, (78 FR12937, 12937-12950), February 26, 2013.
34 See the FDA guidance entitled Acute Bacterial Otitis Media: Developing Drugs for Treatment (October 2012).

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respiratory infection (URI) or be at risk for a future URI based on the presence of criteria such as	320
the frequency of past infections, number of people living in the home, or exposure to others in a	321
preschool or school setting. As stated above, the associated blood draws to collect PK samples	322
would generally be considered to be minimal risk (21 CFR 50.51(a)) or no more than a minor	323
increase over minimal risk (21 CFR 50.53(a)) and a single oral dose of the over-the-counter	324
cough and cold product would generally be considered as no more than a minor increase over	325
minimal risk (21 CFR 50.53(a)), thus allowing the study to proceed under 21 CFR 50.53.	326
327
If administration of a single dose of an investigational drug exceeds a minor increase over	328
minimal risk (or there are insufficient data available to make that determination), the clinical	329
pharmacology study either would be required to meet the requirements in 21 CFR 50.52 (as	330
discussed below) or would require referral for review under 21 CFR 50.54 (assuming that the	331
other requirements of that regulation were met).	332
333
B. 	Case 2: IRB Review of a Clinical Pharmacology Study Involving Pediatric	334
Participants Under 21 CFR 50.52	335
336
The administration of an investigational drug with more than a minor increase over minimal risk	337
could be approved by an IRB if the level of risk exposure is justified by a sufficient prospect of	338
direct clinical benefit to the participants (21 CFR 50.52(a)). For example, dose-monitoring	339
studies that ensure serum levels of an investigational drug remain within a therapeutic range	340
generally would fall under 21 CFR 50.52 when the investigational drug presents the prospect of	341
direct benefit to the enrolled pediatric participants and the investigational drug is administered	342
under the protocol using a dosing regimen (including duration) that offers a sufficient prospect of	343
direct clinical benefit to justify the risks (21 CFR 50.52(a)).	344
345
Multiple-dose PK-PD studies can be designed to offer a prospect of direct benefit, but the dose	346
and duration of exposure to the investigational product should be sufficient to result in potential	347
changes in the clinical manifestations of the condition or in disease-specific biomarkers that	348
reflect a clinical benefit. For example, the duration of the PK-PD study could be extended, or	349
perhaps combined as the lead-in phase to an efficacy trial, to provide a suitable duration of drug	350
exposure that offers a sufficient prospect of direct clinical benefit to justify the risks.35	351
352
C. 	Ethical Justification for Pediatric Pharmacology Studies	353
354
Adequate information from clinical pharmacology studies to support pediatric dosing is critical	355
to the development of ethically sound confirmatory trials. Inadequate pediatric dosing may lead	356
35 Roth-Cline, M and RM Nelson, 2015, Ethical Considerations in Conducting Pediatric and Neonatal Research in
Clinical Pharmacology, Curr Pharm Design, 21:5619-5635.

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to failed pediatric clinical trials.36 The FDA considers the public health need for adequate	357
pediatric dosing in its assessment of the ethical propriety of proposed studies.37,38	358
359
360
V. 	THE PEDIATRIC STUDY PLAN DESIGN AND POINTS TO CONSIDER	361
362
A sponsor who is planning to submit a marketing application (or supplement to an application)	363
for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route	364
of administration is required to submit an iPSP39 unless the drug is for an indication for which	365
orphan designation has been granted.40 In addition, a sponsor who is planning to submit, on or	366
after August 20, 2020, an original application for a new active ingredient that is subject to the	367
molecularly targeted cancer drug provision of PREA (i.e., the drug that is the subject of the	368
application is intended for the treatment of an adult cancer and is directed at a molecular target	369
that the FDA determines to be substantially relevant to the growth or progression of a pediatric	370
cancer) is also required to submit an iPSP,41 regardless of whether the drug is for an indication	371
for which orphan designation has been granted.42 By statute, a biosimilar product that has not	372
been determined to be interchangeable with the reference product is considered to have a new	373
active ingredient for purposes of PREA.43	374
375
The submission of the iPSP is intended to encourage sponsors to consider pediatric studies early	376
in product development and, when appropriate, begin planning for these studies. The FDA	377
guidance entitled Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric	378
Study Plans and Amended Pediatric Study Plans (July 2020) discusses the content of and process	379
for submitting initial and amended PSPs and states that Section 10.1 (Pediatric Pharmacokinetic	380
or Pharmacokinetic/Pharmacodynamic Studies) should include:	381
382
36 Benjamin, DK, Jr, PB Smith, P Jadhav, JV Gobburu, MD Murphy, V Hasselblad, C Baker-Smith, RM Califf, and
JS Li, 2008, Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose Range, Hypertension,
51(4):834-840.
37 See the FDA guidance entitled E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (March
2018).
38 This issue is also discussed in the American Academy of Pediatrics Guidelines for the Ethical Conduct of Studies
to Evaluate Drugs in Pediatric Populations. See Shaddy, R and SC Denne, 2010, Clinical Report-Guidelines for the
Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, Pediatrics,125(4):850-860.
39 See section 505B(e)(1) of the FD&C Act; 21 U.S.C. 355c(e)(1); and section 505B(a)(1)(A) of the FD&C Act; 21
U.S.C. 355c(a)(1)(A).
40 See section 505B(k)(1) of the FD&C Act; 21 U.S.C. 355c(k)(1).
41 See section 505B(e)(1) of the FD&C Act; 21 U.S.C. 355c(e)(1); and section 505B(a)(1)(B) of the FD&C Act; 21
U.S.C. 355c(a)(1)(B).
42 See section 505B(k)(2) of the FD&C Act; 21 U.S.C. 355c(k)(2).
43 See section 505B(l) of the FD&C Act; 21 U.S.C. 355c(l).

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• 	The type of study/study design	383
384
• 	The objectives of the study	385
386
• 	The age group and population in which the study will be conducted	387
388
• 	The pediatric formulation(s) to be used in the study	389
390
• 	The dose ranges to be used in the PK studies	391
392
• 	The endpoints and justification (PK parameters; PD parameters)	393
394
• 	The existing or planned modeling and simulation to support dose selection and/or study	395
design, data analysis, and interpretation for planned pediatric studies	396
397
• 	Any planned pharmacogenomic analyses	398
399
• 	A justification for the sample size	400
401
When designing pediatric clinical studies, sponsors should be mindful that modeling and	402
simulation and pharmacologic considerations are often critical for the successful completion of a	403
study. Modeling and simulation (e.g., PK, PD, and trial simulations) should use all of the	404
information available and be an integral part of all pediatric development programs followed by	405
verification using results from pediatric clinical studies. The following sections are critically	406
important when developing the clinical pharmacology components of a pediatric study plan.	407
408
A. 	Approaches to Pediatric Studies	409
410
There are several recognized approaches to providing substantial evidence to support the safe	411
and effective use of drugs in pediatric populations.44 In some cases, previous data in adults and	412
other pediatric indications can be leveraged to provide this substantial evidence. This concept is	413
often referred to as pediatric extrapolation.	414
415
Pediatric extrapolation of efficacy is defined as an approach to providing evidence in support of	416
effectiveness of drugs in the pediatric population when it can be assumed that the course of the	417
disease and the expected response to a medicinal product would be sufficiently similar in the	418
pediatric and reference (adult or other pediatric) populations.45 Determination of the extent of	419
pediatric extrapolation is predicated on the understanding of the disease and drug effect in the	420
reference (adult or other pediatric) population and their similarity to the target pediatric	421
44 For more information, see the FDA draft guidance entitled Demonstrating Substantial Evidence of Effectiveness
for Human Drug and Biological Products (December 2019). When final, this guidance will represent the Agency’s
current thinking on this topic.
45 See the FDA guidance entitled E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric
Population (April 2018). See also 21 CFR 314.55(a).

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population. The data necessary to support efficacy when pediatric extrapolation is considered	422
will depend upon the existing data and the gaps in knowledge that should be addressed.46	423
Examples of potential approaches based on the availability and confidence in existing data are	424
discussed in sections 1 through 3 below.	425
426
While it is helpful and provides additional evidence to support extrapolation, formally	427
establishing and documenting similarity in exposure-response in adults and target pediatric	428
population is not a requirement in order to consider some degree of extrapolation. Exposure-	429
response assessments are, however being conducted more frequently in both adult and pediatric	430
patients. Knowledge of exposure-response, when available, can play a critical role in informing	431
the assessment of drug effect similarity between adults and pediatric patients and the	432
acceptability of an exposure-matching approach. In addition, exposure-response information can	433
serve a crucial role in supporting pediatric dose selection, dose optimization and formulation	434
development. When applicable, similarity in exposure-response relationships on a clinically	435
relevant biomarker or an appropriate clinical endpoint can contribute to an assessment of the	436
appropriateness of efficacy extrapolation from adults to pediatric patients.	437
438
Additionally, the extent of the required pediatric safety data can take into consideration prior	439
experience with similar drugs in pediatric populations and the seriousness of the adverse events	440
in adults or in pediatric populations. Usually, additional safety data in the indicated pediatric	441
indication will be needed. See the FDA guidance entitled E11(R1) Addendum: Clinical	442
Investigation of Medicinal Products in the Pediatric Population (April 2018) for more	443
information. The potential for pediatric patients to have a significantly different incidence,	444
severity, and types of adverse events compared to adults should always be considered.47,48	445
446
1. 	PK, Safety, and Efficacy Approach	447
448
If the disease or disease progression is unique to pediatric patients or its progression and/or	449
response to intervention is undefined or dissimilar to that in adults, then the pediatric	450
development program should use a PK, safety, and efficacy approach. The objectives of the	451
studies in the pediatric program would be to characterize the PK and exposure-response	452
relationships to help optimize pediatric dosing strategies and to provide evidence of effectiveness	453
and safety. A population PK analysis can be conducted using PK data from the efficacy study to	454
confirm PK estimates in the age subgroups.	455
456
46 See the FDA guidance entitled E11 Clinical Investigation of Medicinal Products in the Pediatric Population
(December 2000) for more information.
47 Liu XI, P Schuette, GJ Burckart, DJ Green, J La, JM Burnham, N Rakhmanina, A Robb, SM Huang, and JN van
den Anker, 2019, A Comparison of Pediatric and Adult Safety Studies for Antipsychotic and Antidepressant Drugs
Submitted to the US FDA, J Pediatrics, doi: 10.1016/j.jpeds.2018.12.033.
48 Momper JD, Y Chang, M Jackson, P Schuette, S Seo, I Younis, DR Abernethy, L Yao, EV Capparelli, and GJ
Burckart, 2015, Adverse Event Detection and Labeling in Pediatric Drug Development: Antiretroviral Drugs, Ther
Inn Reg Sci, 49(2):302-309.

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2. 	PK, Safety, and PD/Efficacy Approach	457
458
This approach should be considered when the disease and intervention are believed to behave	459
similarly in pediatrics and adults, but the exposure-response relationship in pediatrics is either	460
inadequately documented or assumed to not be sufficiently similar to adults. A clinically	461
relevant PD biomarker may be appropriate for purposes of evaluating the evidence of	462
effectiveness and to select pediatric doses. In the absence of a clinically relevant PD biomarker,	463
clinical measures (e.g., symptoms, signs, outcomes) may be appropriate. The number, type, and	464
size of pediatric studies to support a pediatric program depends on the residual uncertainty	465
associated with understanding of similarity of the disease and drug effect.	466
467
For the two approaches described above, response data in pediatric studies should be collected	468
and analyzed. Response or PD data can include biomarkers or clinical endpoints for both safety	469
and effectiveness. The specific endpoints, including those for an exposure-response evaluation,	470
for each drug should be discussed with the Agency. Appropriate endpoint selection and	471
enrichment strategies for the pediatric population in a trial are important. Of note, endpoints that	472
are unique to pediatric participants have been previously associated with failed pediatric trials	473
and should be carefully considered.49	474
475
3. 	PK and Safety Approach	476
477
The PK and safety approach should be considered when there is evidence that adults and	478
pediatrics share a sufficiently similar disease course and response to intervention to allow for	479
exposure matching to establish efficacy.	480
481
A PK study should be performed to identify the pediatric dose that will provide an exposure	482
similar to that found to be effective in adults. The antibacterial therapeutic area is a good	483
example of this approach, where the organism is expected to respond to similar systemic	484
concentrations in adults and pediatrics. In this example, the study should focus on identifying	485
the doses in the pediatric setting that would result in exposures similar to those attained in adults.	486
The criteria for determining exposure matching should be prospectively agreed upon with the	487
Agency before initiating these studies.50	488
489
Before conducting a PK study in any of these approaches, simulations should be performed to	490
identify initial dosing regimens. Clinical trial simulations may be performed to determine a trial	491
design, sample size, and the appropriateness of an endpoint for the pediatric study. Refining	492
models with available data can help verify assumptions made during the design of the study.	493
494
49 Green DJ, J Burnham, P Schuette, XI Liu, BM Maas, L Yao, SK McCune, J Chen, JN van den Anker, and GJ
Burckart, 2018, Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA, J Clin Pharmacol,
58(7):885-890.
50 Mulugeta, Y, JS Barrett, R Nelson, AT Eshete, A Mushtaq, L Yao, N Glasgow, AE Mulberg, D Gonzalez, D
Green, J Florian, K Krudys, S Seo, I Kim, D Chilukuri, and GJ Burckart, 2016, Exposure Matching for
Extrapolation of Efficacy in Pediatric Drug Development, J Clin Pharmacol, 56(11):1326-1334.

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B. 	Alternative Approaches to Conventional PK Studies	495
496
A dedicated PK study with intensive PK sampling may not be necessary in every age group. For	497
example, prior experience with dosing in adolescent participants has demonstrated that	498
knowledge of adult dosing and appropriate dose scaling can be sufficient for some drugs with	499
adequate justification. When a dedicated PK study is not considered essential or cannot be	500
conducted, it may be appropriate to use sparse PK sampling in the safety and/or efficacy studies	501
to confirm dose predictions. Modeling and simulation can also be used, when appropriate, to	502
help to fill these gaps in knowledge. See the FDA guidance entitled Considerations for the	503
Inclusion of Adolescent Patients in Adult Oncology Clinical Trials (March 2019) for more	504
information.	505
506
Other approaches beyond the use of conventional PK studies with intensive blood sampling may	507
be appropriate in pediatric participants to obtain useful drug exposure information, including:	508
509
• 	Sparse PK sampling with the use of modeling and simulation	510
511
• 	Opportunistic approaches that use excess blood collected for laboratory studies51	512
513
• 	Use of alternative specimens:	514
515
o 	Urine and saliva collection are noninvasive. However, the interpretation of drug	516
analyses of either source is complicated and requires careful consideration before	517
use.	518
519
o 	Likewise, tissue or cerebrospinal fluid collected for clinical purposes present both	520
an opportunity and a challenge for the appropriate interpretation of these results	521
in understanding the pharmacokinetics of the drug.	522
523
Modeling and simulation can help reduce the uncertainty about drug dosing in pediatric	524
populations. Model-informed drug development has been applied in regulatory applications for	525
pediatric drug development.52 Population PK approaches are commonly used, and	526
physiologically based PK (PBPK) approaches are increasingly applied in pediatric drug	527
development. In addition, quantitative systems pharmacology (QSP) models can help	528
51 For more information, see the FDA guidance entitled General Clinical Pharmacology Considerations for
Neonatal Studies for Drugs and Biological Products (July 2022).
52 Bi, Y, J Liu, L Li, J Yu, A Bhattaram, M Bewernitz, R Li, C Liu, J Earp, L Ma, L Zhuang, Y Yang, X Zhang, H
Zhu, and Y Wang, 2019, Role of Model-Informed Drug Development in Pediatric Drug Development, Regulatory
Evaluation, and Labeling, J Clin Pharmacol, 59(S1):S104-S111.

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16
incorporate disease processes.53,54 As science and technology continue to advance, in silico and	529
other alternative modeling study methods can provide preliminary data to inform the design and	530
conduct of PK-PD studies for investigational drugs in pediatric populations. For example, the	531
development of a PBPK in silico model that integrates drug-dependent parameters (e.g.,	532
physicochemical properties, hepatic intrinsic clearance, affinities to metabolic enzymes,	533
transporters, and proteins) and system- and age-dependent parameters (e.g., blood flow rate,	534
protein contents, tissue and organ size and composition, and enzyme and transporter abundances	535
and activities) is one possible approach.	536
537
Various modeling approaches have been used in pediatric drug development programs for a	538
variety of purposes, including:	539
540
• 	Planning for a first-in-pediatric PK study	541
542
• 	Optimizing the study design	543
544
• 	Verifying the model in specific age groups	545
546
• 	Recommending starting doses	547
548
• 	Informing enzyme ontogeny using a benchmark drug	549
550
• 	Facilitating covariate analysis for the effects of organ dysfunction or drug interactions in	551
pediatric participants55	552
553
The model selected should incorporate in vivo PK-PD data obtained in other groups of pediatric	554
and adult participants as well as human volunteer studies, as appropriate. To account for growth	555
across the pediatric population for modeling purposes, refer to standardized growth charts. The	556
Centers for Disease Control and Prevention (CDC) growth charts provide a preliminary	557
assessment of the weight ranges that can be anticipated within specific age groups.56 For	558
example, weights can vary 2.5- to 3-fold in healthy children between the 10 th percentile at 2	559
years and 90th percentile at age 6 (10.6 kg to 25.3 kg for males) and between the 10th percentile at	560
53 Momper, JD, GJ Burckart, and P Jadhav, 2013, Applications of Population Pharmacokinetics for Pediatric Drug
Development, Pediatric Drug Development: Concepts and Applications, AE Mulberg, D Murphy and LL Mathis,
Chichester, UK, John Wiley & Sons Ltd.
54 Wang, J, AN Edginton, D Avant, and GJ Burckart, 2015, Predicting Neonatal Pharmacokinetics From Prior Data
Using Population Pharmacokinetic Modeling, J Clin Pharmacol, 55(10):1175-1183.
55 Leong, R, MLT Vieira, P Zhao, Y Mulugeta, CS Lee, SM Huang, and GJ Burckart, 2012, Regulatory Experience
With Physiologically Based Pharmacokinetic Modeling for Pediatric Drug Trials, Clin Pharmacol Ther, 91(5):926-
931.
56 Centers for Disease Control and Prevention, National Center for Health Statistics, 2000 CDC Growth Charts for
the United States: Methods and Development (May 2002), available at:
http://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf (Accessed September 17th, 2019).

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6 years and the 90th percentile at 12 years (17.7 kg to 54 kg in males). Caution should be taken	561
in the use of standardized growth charts as they do not always represent the target pediatric	562
patient population.	563
564
C. 	Pediatric Dose Selection	565
566
Selecting a dose(s) and an age range should consider the overall benefit/risk profile of the drug.	567
When possible, a range of doses should be studied in the pediatric population.	568
569
Factors for consideration in dose selection include:	570
571
• 	The similarity of the disease and exposure-response in pediatric and adult groups	572
573
• 	The relative bioavailability of the new formulation compared to the previous	574
formulations	575
576
• 	The age and developmental stage of the pediatric population	577
578
• 	Any pharmacogenomic characteristics of the drug	579
580
• 	The toxicity of the drug	581
582
• 	Any PK data from other pediatric populations	583
584
Because there can be limited information on the safety of the dose to be administered to a	585
neonate or infant, the dose range used in initial studies requires careful consideration.57 When	586
developmental maturation and body size changes impact dosing, modeling and simulation can	587
help define an initial pediatric dosing in order to adequately minimize the risk for specific age	588
groups. Initial doses within a pediatric age group are typically normalized to body size (e.g.,	589
mg/kg), but developmental maturation can be an additional critical factor to be considered in	590
establishing initial doses in some age groups. In some pediatric participants such as adolescents,	591
body weight or surface area-based dosing are not always necessary. In some cases, final dosing	592
recommendations can include tiered dosing based on weight bands.	593
594
There are situations in which interpolation or scaling can reduce the uncertainty regarding initial	595
pediatric dosing. PK or PD information in certain pediatric age groups can be gained by	596
interpolating or bridging from existing data in adults, pediatric participants in other age groups,	597
or both. However, bridging of data to younger pediatric age groups, particularly neonates,	598
should be done cautiously and confirmed. Significant developmental differences that can exist	599
between young pediatric age groups and older pediatric age groups or adults are associated with	600
considerable differences in metabolism and drug disposition. This difference can lead to an	601
altered dose-exposure relationship and therefore the dose-response relationships.	602
603
57 For more information, see the FDA guidance entitled General Clinical Pharmacology Considerations for
Neonatal Studies for Drugs and Biological Products (July 2022).

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When initial PK studies are not feasible (see section IV), an adaptive design to selecting a dose	604
can be practical for the pediatric clinical studies. Adaptive designs should be prospectively	605
determined. See the FDA guidance entitled E11(R1) Addendum: Clinical Investigation of	606
Medicinal Products in the Pediatric Population (April 2018) for more information.	607
608
When separate efficacy studies in pediatrics are not conducted (i.e., for the PK and safety only	609
approach described in section V.A above), in general, PK studies in the pediatric population	610
should determine how the dosage regimen should be adjusted to achieve the same level of	611
systemic exposure in adults. Differences in intersubject variability in these PK measures and/or	612
parameters between age groups or between pediatric and adult populations should be interpreted	613
with regard to their impact on dosing, safety, and/or efficacy. In these instances, the sponsor	614
should pre-specify the criteria by which exposure matching is acceptable. For example, one	615
approach is to select the appropriate dosing strategy through simulations which result in pediatric	616
exposures within the 5th to 95th percentile shown to be safe and effective in adults.	617
618
Estimating the exposure-response relationship across a range of body-size doses (dose/kg or	619
dose/m 2) can be important. For the PK and PD/efficacy approaches discussed in section V.A2	620
above, investigating a range of doses and exposures allows for an assessment of those	621
relationships and the development of rational dosing instructions. The sponsor should also	622
consider determining the variability in achieved systemic exposures in the pediatric population in	623
the context of the exposure-response relationships for pharmacodynamics or efficacy.	624
625
When PK-PD data are available, the dose range should account for observed differences in	626
response between adults and the pediatric population, both in terms of exposure and response.	627
For example, there is evidence that pediatric populations are on average less sensitive to	628
antihypertensive drugs than the adult population.58 Therefore, pediatric studies could include	629
exposures greater than the highest drug exposure associated with the approved adult dose,	630
provided that prior data about the exposure-response relationship and safety information justify	631
such an exposure. Studies of distinctly different ranges of exposure are desirable to provide	632
sufficient information for the calculation of an optimal dose.	633
634
D. 	Pediatric Dosage Formulation	635
636
Pediatric formulations that permit accurate dosing and enhance adherence (e.g., palatability) are	637
an important part of pediatric drug development.59 See the FDA guidance entitled E11 Clinical	638
58 Benjamin, DK, Jr, PB Smith, P Jadhav, JV Gobburu, MD Murphy, V Hasselblad, C Baker-Smith, RM Califf, and
JS Li, 2008, Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose Range, Hypertension,
51(4):834-840.
59 Refer to the FDA draft guidance entitled Use of Liquids and/or Soft Foods as Vehicles for Drug Administration:
General Considerations for Selection and In Vitro Methods for Product Quality Assessments (July 2018) for
information on the use of liquids and/or soft foods for drug administration. When final, this guidance will represent
the Agency’s current thinking on this topic. In addition, refer to the following FDA guidances for more information
on assessing the bioavailability and effect of food on a new formulation: Assessing the Effects of Food on Drugs in
INDs and NDAs - Clinical Pharmacology Considerations (June 2022) and Bioavailability Studies Submitted in
NDAs or INDs - General Considerations (April 2022).

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Investigation of Medicinal Products in the Pediatric Population (December 2000) for more	639
information. If there is a pediatric indication, an age-appropriate dosage formulation must be	640
made available for pediatric patients in all relevant age groups.60 One way to fulfill this	641
requirement, when the adult formulation is not acceptable for the planned pediatric age range, is	642
to develop and test a pediatric formulation and seek approval for that formulation. To the extent	643
practicable, sponsors should include information in the iPSP regarding planned excipients that	644
will be contained in a pediatric formulation.	645
646
The bioavailability of any formulation used in pediatric studies should be characterized in	647
relation to the adult formulation. In some circumstances, a relative bioavailability study	648
comparing the age-appropriate formulation to the approved drug may be required.61 These	649
studies are generally performed in adults due to ethical reasons. Potential drug-food or vehicle	650
interactions should be considered, such as those that have been reported with apple juice.62	651
652
E. 	Sample Size	653
654
1. 	Number of Pediatric Participants	655
656
Prior knowledge of the disease, exposure, and response from adult and other relevant pediatric	657
data, such as that related to variability, can be used to derive a sample size for ensuring precise	658
parameter estimation. The sponsor should account for all potential sources of variability,	659
including inter-subject and intra-subject variability as well as differences between the adult and	660
pediatric populations when making the final selection of the sample size for each age group.	661
662
The distinct age groups to be studied should be chosen based upon what is known about potential	663
changes in drug response with age, the development of the drug-metabolizing enzymes and	664
excretory mechanisms, as well as safety considerations. Pediatric studies in all age groups	665
should be initiated as early as possible in drug development. The sequential study of age	666
cohorts, starting with the oldest pediatric age group, may be appropriate when there is a clear	667
rationale for doing so. If the drug is intended to be used in newborn infants, the iPSP should	668
specify how premature infants will be considered in the study population.	669
670
Because the selected age groups (strata) will be drug product-specific, the sponsor should discuss	671
the stratification plan, the distribution of the number of pediatric participants within each	672
stratum, and the appropriateness of these strata with the Agency.63 Justification should be	673
provided for the sample size selected. For example, one approach would be to prospectively	674
60 See section 505B(a)(2) of the FD&C Act, 21 U.S.C. 355c(a)(2).
61 21 CFR 320.21.
62 Abdel-Rahman, SM, MD Reed, TG Wells, and GL Kearns, 2007, Considerations in the Rational Design and
Conduct of Phase I/II Pediatric Clinical Trials: Avoiding the Problems and Pitfalls, Clin Pharmacol Ther, 81(4):483-
494.
63 McMahon, AW, K Watt, J Wang, D Green, R Tiwari, and GJ Burckart, 2016, Stratification, Hyopthesis Testing,
and Clinical Trial Simulation in Pediatric Drug Development, Ther Inn Regu Sci, doi: 10.1177/2168479016651661.

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target a 95 percent confidence interval within 60 percent and 140 percent of the geometric mean	675
estimates of clearance and volume of distribution for the drug in each pediatric stratum with at	676
least 80 percent power. Noncompartmental analysis (NCA) based on rich PK sampling,	677
population PK modeling analysis based on sparse PK sampling, or other scientifically justified	678
methods can be applied as appropriate to achieve this precision standard.64	679
680
Conceivably, certain disease states might not allow for the recruitment of an adequate number of	681
participants to meet the above standard, and as such, practical considerations should be taken	682
into account in determining the sample size.	683
684
2. 	Number of Samples Per Participant	685
686
In addition to the number of participants, the number of blood samples collected in the clinical	687
pharmacology study to estimate PK measures and parameters for each individual in the study	688
should be carefully considered. The amount of blood or number of samples possible is very	689
limited in some pediatric participants such as neonates (for more on collection of blood or	690
plasma samples, see section F below). Clinical trial simulations and optimal sampling strategies	691
are recommended to justify the proposed sampling scheme.	692
693
F. 	Sample Collection	694
695
The volume and frequency of blood sampling are often of concern in pediatric studies. Blood	696
samples can be obtained by direct venipuncture, through the use of an indwelling intravascular	697
catheter, or when appropriate, by capillary sampling. Because repeated venipuncture can cause	698
discomfort and bruising at the puncture site, an indwelling intravascular catheter should be used	699
when possible. The volume and frequency of blood sampling may be minimized by using micro-	700
volume drug assays, dried blood spots, and sparse-sampling techniques. See the FDA guidance	701
entitled Bioanalytical Method Validation (May 2018) for more information. These types of	702
assays and analysis are especially relevant when studying neonates.65 Modern assay techniques	703
allow small sample volumes to be used to determine drug concentrations, but data quality can be	704
affected if the sample volume is insufficient to allow for reanalysis when necessary. Blood	705
samples for analysis should be collected from the circulating blood volume and not from	706
reservoir dead space created by catheters or other devices. Sampling technique is critical when	707
using the available pediatric indwelling intravenous catheters. The time of sample collection,	708
proper sample transportation and storage, and sample handling techniques should be	709
documented. The collection of fluids such as cerebral spinal fluid (CSF) or bronchial fluids can	710
be beneficial when samples are being obtained for clinical purposes. Noninvasive sampling	711
procedures, such as urine and saliva collection, may be sufficient if correlated with outcomes or	712
if the correlation with blood, serum or plasma levels has been documented.	713
714
64 Wang, Y, PR Jadhav, M Lala, and JV Gobburu, 2012, Clarification on Precision Criteria to Derive Sample Size
When Designing Pediatric Pharmacokinetic Studies, J Clin Pharmacol, 52:1601-1606.
65 Long, D, G Koren, and A James, 1987, Ethics of Drug Studies in Infants: How Many Samples are Required for
Accurate Estimation of Pharmacokinetic Parameters in Neonates?, J Pediatrics, 111(6Pt1):918-921.

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21
Samples for DNA should be collected when appropriate, as discussed in section III of this	715
guidance. See also the FDA guidance entitled Clinical Pharmacogenomics: Premarket	716
Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling (January 2013)	717
for more information.	718
719
G. 	Covariates and Phenotype Data	720
721
Growth and developmental changes in the pediatric population create substantial changes in the	722
ADME characteristics of a drug. PK measures and parameters for a drug should be described as	723
a function of age and be related to some measure of body size, such as height, weight, or body	724
surface area (BSA). The maturational changes in systems affecting ADME, such as membrane	725
transporters and metabolizing enzymes, should be considered when choosing age groups and	726
doses to study in the pediatric population (see section III).	727
728
The sponsor should, at a minimum, obtain the following covariates for each pediatric participant:	729
730
• 	Age	731
• 	Body weight	732
• 	Height	733
• 	Calculated BMI	734
• 	Gestational age	735
• 	Post-menstrual and postnatal age for neonates66	736
• 	Race and ethnicity	737
• 	Sex	738
• 	Laboratory tests reflecting the function of organs responsible for drug elimination	739
• 	Concomitant and recent drug therapy	740
741
The impact of the disease state and obesity upon drug disposition and response should be	742
considered.67 Sponsors are encouraged to collect DNA samples in pediatric PK studies under the	743
circumstances described in section III, along with appropriate phenotype information to optimize	744
the interpretation of pharmacogenomics findings. For example, when genotype information is	745
obtained for a cytochrome P450 enzyme, the sponsor should investigate the influence of genetic	746
mutations on pharmacokinetics, pharmacodynamics, and/or dose-response to determine whether	747
genetically defined subsets of patients need special dosing considerations.	748
749
The sponsor should examine the relationship between the covariates and the pharmacokinetics of	750
the drug of interest. The contribution of weight or BSA and age to PK variability should be	751
assessed. Examples of practices for assessing the effect of age on pediatric pharmacokinetics	752
could include:	753
66 See the FDA guidance entitled General Clinical Pharmacology Considerations for Neonatal Studies for Drugs
and Biological Products (July 2022) for more information.
67 Vaughns JD, LS Conklin, Y Long, P Zheng, F Faruque, D Green, J van den Anker, and GJ Burckart, 2018,
Obesity and Pediatric Drug Development, J Clin Pharmacol, doi:10.1002/jcph.1054.

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22
754
• 	Identifying the accurate relationship between a drug’s pharmacokinetics and body weight	755
or BSA using allometric scaling	756
757
• 	Analyzing the residuals versus age, after accounting for body weight or the BSA effect	758
on CL, followed by a more formal analysis exploiting the physiological understanding	759
underlying CL, if appropriate. Testing for other biologically relevant predictive factors	760
for determining the pharmacokinetics of a drug in pediatrics can be important. The	761
covariate analysis may be performed on pooled data sets to allow for comparisons	762
between adults and/or different pediatric subgroups.	763
764
1. 	Immunogenicity	765
766
The pharmacokinetics of a drug such as therapeutic proteins can be affected by immunogenicity	767
to the drug. Immunogenicity to the administered product can negatively impact the safety and/or	768
efficacy of the drug. Therefore, assessing the immunogenicity of the relevant drugs and	769
determining its impact on pharmacokinetics, safety, and efficacy are critical components of drug	770
development and post-marketing surveillance. See the following FDA guidances for more	771
information:	772
773
• 	Immunogenicity Assessment for Therapeutic Protein Products (August 2014)	774
775
• 	Immunogenicity Testing of Therapeutic Protein Products - Developing and Validating	776
Assays for Anti-Drug Antibody Detection (January 2019)	777
778
In general, it is not appropriate to apply findings of the immunogenicity potential of a drug from	779
adult populations to pediatric populations; therefore, evaluation of the immunogenicity potential	780
of a drug should be conducted in pediatric trials regardless of the knowledge gained from adult	781
trials.	782
783
2. 	Renal Function	784
785
For drugs that are renally cleared, exposures can be impacted by both the maturation of kidney	786
function and renal impairment due to kidney disease. For this reason, pediatric patients with	787
impaired renal function should be recruited for clinical study when it is possible and ethically	788
justifiable to do so. One commonly used equation for the estimation of renal function is the	789
bedside Schwartz equation;68 however, in general any widely accepted measurement method	790
(where necessary) or equation for the estimation of renal function in pediatric PK studies is	791
acceptable69 and should be described in the protocol and labeling when relevant dose	792
68 Schwartz, GJ, A Munoz, MF Schneider, RH Mak, F Kaskel, BA Warady, and SL Furth, 2009, New Equations to
Estimate GFR in Children with CKD, J Amer Soc Nephrol 20(3):629-637.
69 Muhari-Stark E and GJ Burckart, 2018, Glomerular Filtration Rate Estimation Formulas for Pediatric and
Neonatal Use, J Pediatr Pharmacol Ther, 23(6):424–431.

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23
adjustments are derived. Sponsors should be aware of the laboratory methods used for the	793
measurement of creatinine, as this can influence which equation is useful.	794
795
Data from adults are generally used to complement the information obtained in pediatrics to	796
characterize the relationship between renal function and pharmacokinetics. Modeling and	797
simulation approaches should be applied to derive dosing recommendations for the entire	798
pediatric age range in which the product will be used.70 Generally, for children over the age of 2	799
years, where kidney function maturation is considered complete, the need for dose adjustment	800
should be evaluated and derived based on information evaluated in adults. For children less than	801
2 years of age, the additional impact of renal function ontogeny should be considered.71	802
Quantitative approaches such as PBPK analysis can also be explored to address dosing needs in	803
these situations. Of note, the application of modeling is limited by current understanding of	804
ontogeny and is particularly challenging in neonates. However, modeling approaches should use	805
all of the clinical information available.	806
807
H. 	Drug-Drug Interactions	808
809
In general, evaluations of drug-drug interactions (DDIs) are performed in adults. In some cases,	810
however, the potential or magnitude of a DDI in pediatrics can differ from that observed in	811
adults. Such differences in DDIs in pediatrics compared to adults can potentially be attributed to	812
the ontogeny of metabolizing enzymes and transporters as well as differences in intragastric pH,	813
gastric emptying, intestinal motility, or protein binding. Differences in diet, concomitant	814
medications, drug formulation, and dosing regimen could also contribute to differences in DDIs	815
between adults and pediatrics.72	816
817
Considering potential ethical concerns for standalone DDI studies in pediatrics, quantitative	818
approaches such as PBPK analyses should be explored to address pediatric DDIs during drug	819
development when differences in DDI are expected. Refer to the following FDA guidances for	820
more information:	821
822
• 	Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-	823
Mediated Drug Interactions (January 2020)	824
825
• 	Physiologically Based Pharmacokinetic Analyses — Format and Content (September	826
2018)	827
828
70 For information on studying trial participants with impaired renal function, see the FDA draft guidance entitled
Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing
(September 2020) for general concepts of study design. When final, this guidance will represent FDA’s current
thinking on the topic.
71 Zhang Y, N Mehta, E Muhari-Stark, GJ Burckart, J van den Anker, L Yao, and J Wang, 2019, Pediatric Renal
Ontogeny and Applications in Drug Development, J Clin Pharmacol, 59(S1):S9-S20.
72 Salerno, SN, GJ Burckart, SM Huang, and D Gonzalez, 2019, Pediatric Drug-Drug Interaction Studies: Barriers
and Opportunities, Clin Pharmacol Ther 105(5):1067-1070.

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24
Planning for DDI evaluations should be included as a section of the iPSP under Pediatric	829
Pharmacokinetic Studies and should address the impact of DDIs on drug dosing in specific age	830
groups. See the FDA guidance entitled Pediatric Study Plans: Content of and Process for	831
Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans (July 2020) for	832
more information.	833
834
I. 	Sample Analysis	835
836
An accurate, precise, sensitive, specific, and reproducible analytical method to quantify the drug	837
and metabolites in the biological fluids of interest is essential. See the FDA guidance entitled	838
Bioanalytical Method Validation (May 2018) for more information. The sponsor should choose	839
a method that is readily adaptable and uses only minimum sample volumes.	840
841
J. 	Data Analysis	842
843
The development of PK models should occur throughout the pediatric development program.	844
All prior knowledge, including adult data, should be used to develop initial models which can be	845
adapted as new data become available in pediatric subgroups. There are several basic	846
approaches for performing PK analysis in pediatrics. Population PK and noncompartmental PK	847
approaches are two of the most commonly used; however, novel approaches may be acceptable as	848
justified by the sponsor.	849
850
1. 	Population Analysis	851
852
A common approach for analyzing data from pediatric clinical pharmacology studies is the	853
population approach to PK analysis. Population PK accommodates rich (intensive) and	854
infrequent (sparse) sampling of blood, serum, or plasma from a larger population than in a	855
compartmental or noncompartmental analysis PK approach to determine the PK parameters.	856
Sparse sampling is generally considered more acceptable for pediatric studies because the total	857
volume of blood sampled in an individual can be minimized. Sampling can even be performed	858
concurrently with clinically necessary blood or urine sampling (e.g., opportunistic PK studies).	859
Because relatively large numbers of pediatric participants are studied, and samples can be	860
collected at various times of the day and repeated over time in a given participant, estimates of	861
both population and individual means, as well as estimates of intra- and inter-subject variability,	862
can be obtained if the population PK study is properly designed. See the FDA guidance entitled	863
Population Pharmacokinetics (February 2022) for more information.	864
865
Exposure-response analyses predominantly employ a population analysis approach. Individual	866
analysis is generally not recommended unless responses from a wide range of doses from each	867
participant are available. Modeling of data across all study participants typically provides the	868
best opportunity to describe the exposure-response relationship. See the FDA guidance entitled	869
Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications	870
for more information (May 2003).	871
872
2. 	Noncompartmental Analysis	873
874

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25
If consistent with relevant ethical considerations (see Section IV: Ethical Considerations), it may	875
be possible to utilize intensive PK sampling with relatively frequent blood and urine sample	876
collection, when administering either single or multiple doses of a drug to a relatively small	877
group of study participants. Samples are collected over specified time intervals chosen on the	878
basis of absorption and disposition half-lives, and subsequently assayed for either total or	879
unbound concentrations of drug and relevant metabolites. Noncompartmental analysis is a	880
general approach to establish PK statistics and parameters such as AUC, C max, CL, volume of	881
distribution, and half-life, which are descriptive of the concentration of drug or metabolite over	882
time. Data are usually expressed as the means of the relevant measure or parameter and inter-	883
individual variances. In this approach, including a sufficient number of study participants to give	884
a precise estimate of the mean is essential, as discussed in section V.E. If drug administration	885
and sampling are repeated in a participant in the PK study, some understanding of intra-	886
individual variability in PK parameters can be obtained.	887
888
K. 	Clinical Study Report	889
890
The clinical study report should follow the FDA guidance entitled E3 Structure and Content of	891
Clinical Study Reports (January 2013) for the general content and the format of the pediatric	892
clinical study report. The evaluation of exposure-response relationships and the population PK	893
analyses should be included as stipulated in the following FDA guidances:	894
895
• 	Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory	896
Applications (May 2003)	897
898
• 	Population Pharmacokinetics (February 2022)	899
900
When submitting PK information, the sponsor should submit data that illustrate the relationship	901
between the relevant PK parameters (e.g., CL unadjusted and adjusted for body size in the	902
manner described in section VI.G) and important covariates (e.g., age, renal function) in addition	903
to the results of noncompartmental analysis.	904
905
L. 	Data Submission	906
907
The preferred submission standard for clinical data is the Clinical Data Interchanges Standards	908
Consortium (CDISC) Study Data Tabulation Model (SDTM) standard. Please see the FDA Data	909
Standards Advisory Board73 and the CDER Study Data Standards web sites for more	910
information.74 The sponsor should also submit PK and exposure-response data used for	911
modeling and simulation in an SAS.XPT-compatible format.	912
73 See the FDA Data Standards Advisory Board, available at: https://www.fda.gov/industry/fda-resources-data-
standards.
74 See the FDA Study Data Standards for Submission to CDER, available at: https://www.fda.gov/industry/study-
data-standards-resources/study-data-submission-cder-and-cber.