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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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Draft  Not for Implementation 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 
Draft  Not for Implementation 
1  General Clinical Pharmacology Considerations for Pediatric Studies 
2  of Drugs, Including Biological Products 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance assists sponsors of investigational new drug applications (INDs) and applicants of 
18  new drug applications (NDAs) under section 505 of the Federal Food, Drug, and Cosmetic Act 
19  (the FD&C Act), biologics license applications (BLAs) under section 351(a) of the Public Health 
20  Service Act (PHS Act), and supplements to such applications who are planning to conduct 
21  clinical studies in pediatric populations.2,3,4  In addition, this guidance assists clinical 
22  investigators in the design and planning of, and Institutional Review Boards (IRBs) in the 
23  assessment of, clinical studies in pediatric populations.   
24   
25  Effectiveness, safety, or dose-finding studies in pediatric populations involve gathering clinical 
26  pharmacology information, such as information regarding a products pharmacokinetics and 
27  pharmacodynamics, to inform dose selection and individualization.  This guidance addresses 
28  general clinical pharmacology considerations for conducting studies so that the dosing and safety 
 
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 Agencys 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).   
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
29  information for drugs in pediatric populations can be sufficiently characterized, leading to well-
30  designed trials to evaluate effectiveness. 
31   
32  In general, this guidance focuses on the clinical pharmacology information (e.g., exposure-
33  response, pharmacokinetics, and pharmacodynamics) that supports findings of effectiveness and 
34  safety and helps identify appropriate doses in pediatric populations.  This guidance also describes 
35  how quantitative approaches (i.e., pharmacometrics) can use disease and exposure-response 
36  knowledge from relevant prior clinical studies to help design and evaluate future pediatric 
37  studies.   
38   
39  This guidance does not describe:  (1) the standards for the approval of drugs in the pediatric 
40  population; (2) the determination that the course of a disease is the same in adults and pediatric 
41  populations; or (3) the clinical pharmacology studies for the development of vaccine therapies, 
42  blood products, or other products not regulated by the Center for Drug Evaluation and Research.  
43   
44  In general, FDAs guidance documents do not establish legally enforceable 
45  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and 
46  should be viewed only as recommendations, unless specific regulatory or statutory 
47  requirements are cited.  The use of the word should in Agency guidance means that 
48  something is suggested or recommended, but not required. 
49   
50   
51  II.  BACKGROUND 
52   
53  Over the past several decades, the FDA has tackled the problem of inadequate testing of drugs in 
54  pediatric patients and inadequate pediatric use information in drug labeling.  The Food and Drug 
55  Administration Modernization Act of 1997 (FDAMA) addressed the need for improved 
56  information about the use of drugs in the pediatric population by establishing incentives for 
57  conducting pediatric studies on drugs for which exclusivity or patent protection exists.5  
58  Congress subsequently passed the Best Pharmaceuticals for Children Act (BPCA)6 in 2002 and 
59  the Pediatric Research Equity Act (PREA) in 2003.7  Both BPCA and PREA were reauthorized 
60  in 2007.8  In 2010, the Biologics Price Competition and Innovation Act extended certain 
61  provisions of the BPCA to biological products.9  In 2012, BPCA and PREA were made 
62  permanent under Title V of the FDA Safety and Innovation Act (FDASIA).10 
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).   
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
64  Under BPCA, sponsors of certain applications and supplements filed under section 505 of the 
65  FD&C Act and under section 351(a) of the PHS Act can obtain an additional six months of 
66  exclusivity if, in accordance with the requirements of the statute, the sponsor submits 
67  information responding to a Written Request from the Secretary relating to the use of a drug in 
68  the pediatric population.11   
69   
70  Under PREA, sponsors of certain applications and supplements filed under section 505 of the 
71  FD&C Act or section 351(a) of the Public Health Service Act are required to submit pediatric 
72  assessments, unless they receive an applicable waiver or deferral of this requirement.12,13  If 
73  applicable, sponsors must submit a request for a deferral or waiver as part of an initial pediatric 
74  study plan (iPSP)14 (see section V of this guidance).   
75   
76  The FD&C Act requires a description of pediatric study data in labeling arising from study data 
77  submitted in response to a Written Request under BPCA and/or data from studies required under 
78  PREA, whether the findings are positive, negative, or inconclusive.15  The PREA requirements 
79  are triggered by the submission of an application or supplement for a drug under section 505 of 
80  the FD&C Act or section 351 of the PHS Act for a new active ingredient, new indication, new 
81  dosage form, new dosing regimen, or new route of administration.16  If a full or partial waiver is 
82  granted under PREA because there is evidence that the drug would be ineffective or unsafe in 
83  some or all pediatric populations, the information must be included in the products labeling.17  
84   
85  This guidance addresses the clinical pharmacology considerations of any planned pediatric study, 
86  whether or not it is conducted pursuant to BPCA or PREA.18  
87   
88   
89  III.  CLINICAL PHARMACOLOGY CONSIDERATIONS 
90   
91  Clinical pharmacology studies in the pediatric population should be conducted in individuals 
92  with the disease which the drug is intended to treat, or in rare instances, in those who are at risk 
93  of this disease.  Identifying the appropriate pediatric population to study should take into 
 
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 Agencys 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). 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
94  consideration:  1) the disease; 2) the profile of the drug under study; 3) scientific and ethical 
95  justifications; and 4) developmental changes in the pediatric population. 
96   
97  Sponsors should address the entire pediatric age range (birth to <17 years of age19) in their iPSP 
98  (waivers and deferrals of the requirements under PREA may be appropriate for specific age 
99  ranges).  The pharmacokinetics of a drug is typically evaluated over the entire pediatric age 
100  range in which the agent will be used.  See the FDA guidance entitled E11 Clinical Investigation 
101  of Medicinal Products in the Pediatric Population (December 2000) for more information.  The 
102  Center for Drug Evaluation and Research generally divides the pediatric population into the 
103  following groups:20 
104   
105    Neonates:  Birth up to 1 month21,22 
106    Infants:  1 month up to 2 years 
107    Children:  2 years up to 12 years 
108    Adolescents:  12 years up to younger than 17 years 
109   
110  If other categorizations such as physiologic categories based upon systems ontogeny or disease 
111  pathophysiology are used, they should be supported with scientific and developmental data. 
112  These categories should not be arbitrarily applied for trial enrollment but can help ensure 
113  adequate inclusion of participants across the pediatric age range. 
114    
115  The measurement or prediction of a drugs pharmacokinetics (exposure) and pharmacodynamics 
116  (response) is essential to the clinical pharmacology assessment.  It is important to describe the 
117  exposure-response relationship of a drug in the pediatric population when possible to enhance 
118  the understanding of effective dose ranges or support the ability to extrapolate information from 
119  older pediatric participants.  A pediatric drug development program should consider the time 
120  course of development of the drug metabolizing enzymes, drug excretory systems, transporters 
121  and drug target/receptors relevant (if known) to the drug being studied.  This can be addressed by 
122  characterizing the pharmacokinetics and/or pharmacodynamics of the drug across the appropriate 
123  pediatric age range. 
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 Agencys 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). 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
125  A.  Pharmacokinetics 
126   
127  Pharmacokinetic (PK) measures, such as area under the curve (AUC) and maximum 
128  concentration (C ), and parameters such as clearance (CL), half-life, and volume of 
max
129  distribution, reflect the absorption (A), distribution (D), and excretion (E) of a drug from the 
130  body.  Drugs can be eliminated in the unchanged (parent) form or undergo metabolism (M) to 
131  one or more active and inactive metabolites.  This overall set of processes is often referred to as 
132  ADME, which ultimately determines the systemic exposure to a drug and its metabolites after 
133  drug administration.  This systemic exposure, reflected as drug or metabolite concentrations or 
134  both, is generally correlated with both beneficial and adverse drug effects.  All drugs show inter- 
135  and intra-individual variability in PK measures and parameters. 
136   
137  In the pediatric population, growth and developmental changes in the factors that influence 
138  ADME can lead to changes in PK parameters which can lead to changes in drug 
139  response/adverse effects.  Specifically, the ontogeny of drug metabolizing enzymes, transporters, 
140  and receptors should be taken into account when planning and analyzing data from pediatric PK 
141  studies.   
142   
143  The methodological issues in designing pediatric PK studies have been reviewed previously.23 
144  Special areas of importance in planning pediatric PK studies are discussed in the following 
145  paragraphs. 
146   
147  1.  Absorption 
148   
149  Developmental changes in the pediatric population that can affect absorption include effects on 
150  gastric acidity, rates of gastric and intestinal emptying, surface area of the absorption site, 
151  gastrointestinal drug-metabolizing enzyme systems, gastrointestinal permeability, biliary 
152  function, and transporter expression.  Similarly, developmental changes in skin, muscle, and fat, 
153  including changes in water content and degree of vascularization, can affect absorption patterns 
154  of drugs delivered by intramuscular, subcutaneous, or percutaneous absorption.24  See section 
155  V.D for a discussion on the effect of the formulation on drug absorption. 
156   
157  2.  Distribution 
158   
159  Distribution of a drug can be affected by changes in body composition, such as changes in total 
160  body water and adipose tissue, which are not necessarily proportional to changes in total body 
161  weight.  Plasma protein binding and tissue-binding changes arising from changes in body 
162  composition with growth and development can also influence distribution.  Differences between 
163  the pediatric and adult populations in blood flow to an organ, such as the brain, can also affect 
164  the distribution of a drug in the body.   
 
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. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
165   
166  3.  Metabolism 
167   
168  Drug metabolism commonly occurs in the liver, but can also occur in the blood, gastrointestinal 
169  wall, kidney, lung, and skin.  Developmental changes in metabolizing capacity can affect both 
170  bioavailability and elimination, depending on the degree to which intestinal and hepatic 
171  metabolic processes are involved.25  Developmental changes in drug metabolism are well 
172  recognized, and information on the ontogeny of drug metabolism in newborns, infants, and 
173  children is now included in modeling approaches to predicting drug elimination in these groups.  
174  Both the rates of metabolite formation and the principal metabolic pathway can be different in 
175  the pediatric population compared to adults and within the pediatric population.  In vitro studies 
176  performed early in drug development can be useful in identifying the metabolic pathways for a 
177  drug.  See the FDA guidance entitled In Vitro Drug Interaction Studies - Cytochrome P450 
178  Enzyme- and Transporter-Mediated Drug Interactions (January 2020) for more information. 
179   
180  4.  Excretion 
181   
182  Drug excretion by the kidney is the net result of glomerular filtration, tubular secretion, and 
183  tubular reabsorption.  Because these processes mature at different rates in the pediatric 
184  population, age can affect the systemic exposure of drugs when renal excretion is a dominant 
185  pathway of elimination.  The maturation of other excretory pathways, including biliary and 
186  pulmonary routes of excretion, is also important. 
187   
188  5.  Protein Binding 
189   
190  Protein binding to a drug or its metabolites can change with age and concomitant illness.  In 
191  certain circumstances, an understanding of protein binding is important to interpret the data from 
192  a blood level measurement and to determine appropriate dose adjustments.26  In vitro plasma 
193  protein binding studies can determine the extent of binding of the parent and the major active 
194  metabolite(s) and identify specific binding proteins, such as albumin and alpha-1 acid 
195  glycoprotein.  
196   
197  6.  Clearance 
198   
199  Clearance of drugs as a function of age and body weight is generally a valuable parameter for 
200  determining the dose in the pediatric population, and drug clearance has provided a valuable tool 
201  in the assessment of pediatric clinical pharmacology studies.  Scaling of drug clearance from one 
202  age group to another is a commonly used approach.    
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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204  B.  Pharmacodynamics 
205   
206  Sponsors should collect and analyze PK and, whenever possible, pharmacodynamic (PD) data in 
207  pediatric studies to determine how the two are linked (i.e., the PK-PD or exposure-response 
208  relationship).  PD data can include the effect of the drug on biomarkers or clinical endpoints for 
209  both effectiveness and safety.  These measurements can allow a better understanding of whether 
210  the PK-PD relationships of the drug in pediatrics are similar to those observed in adults and can 
211  help derive rational dosing strategies in pediatrics. 
212   
213  If the clinical endpoint cannot be measured directly because the effect is delayed or infrequent, 
214  then the selection of an appropriate biomarker to substitute for the clinical effectiveness or 
215  toxicity endpoint is essential.  Endpoint selection is a critical part of pediatric study design.27    
216   
217  C.  Pharmacogenomics 
218   
219  Documentation that genetic differences can impact drug exposure and response is increasing,28 
220  but the relationship between genomic profiles and developmentally regulated gene expression 
221  has not been extensively studied in pediatric populations.  Genotype-phenotype relationships 
222  observed in adults are not always representative of those observed in pediatric populations, 
223  particularly neonates and infants.29  Nevertheless, if drug exposure and/or response is dependent 
224  on a well-known pharmacogenomic biomarker (e.g., cytochrome P4502D6), collecting and 
225  analyzing pharmacogenetic samples in a pediatric clinical pharmacology study could provide 
226  additional information for the interpretation of the PK and PD results.  See the FDA guidance 
227  entitled Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-
228  Mediated Drug Interactions (January 2020) for more information. 
229   
230   
231  IV.  ETHICAL CONSIDERATIONS 
232   
233  FDA-regulated clinical investigations are governed, in part, by IRB regulations in 21 CFR Part 
234  56 and the human subject protection regulations in 21 CFR Part 50.  The requirements in 21 CFR 
235  Part 50, subpart D, Additional Safeguards for Children in Clinical Investigations, apply to FDA-
236  regulated clinical pharmacology studies that enroll pediatric participants.  If the proposed 
237  intervention or procedure does not offer a prospect of direct clinical benefit to the individual 
238  child, these safeguards restrict the allowable risk to which a pediatric participant can be exposed 
239  in a clinical investigation to minimal risk (21 CFR 50.51) or no more than a minor increase over 
 
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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240  minimal risk (21 CFR 50.53) unless the protocol is referred to the FDA by the IRB and allowed 
241  to proceed under 21 CFR 50.54 (see further description below).   
242   
243  Clinical pharmacology studies generally do not provide a direct clinical benefit to individual 
244  pediatric participants and must therefore present minimal risk (21 CFR 50.51) or no more than a 
245  minor increase over minimal risk (21 CFR 50.53) in order to be approved by an IRB under 21 
246  CFR Part 50, subpart D.  However, if a clinical pharmacology study offers the prospect of direct 
247  benefit to the participant, such as by ensuring that serum levels of a drug remain within the 
248  therapeutic range, then the study potentially could be approvable by an IRB under 21 CFR 50.52. 
249   
250  Before initiation of the clinical trial, an IRB must determine that the proposed trial is in 
251  compliance with the requirements of 21 CFR 50, subpart D.30  However, if FDA has concerns 
252  that the rights and safety of pediatric participants may not be adequately protected, such concerns 
253  could present sufficient grounds for the FDA to impose a clinical hold because the investigation 
254  could present an unreasonable and significant risk of illness or injury to the pediatric participants 
255  (21 CFR 312.42(b)).  
256   
257  The assessment of a clinical pharmacology protocol under 21 CFR part 50, subpart D depends on 
258  whether the investigational drug is being administered:  (1) solely for the purposes of obtaining 
259  PK data; or (2) in such a way that it offers the pediatric participant a prospect of direct clinical 
260  benefit.  The two scenarios are discussed further in the case studies below.  
261   
262  Regardless of the scenario, administration of an investigational drug would generally be 
263  considered to represent more than minimal risk and thus would not meet the requirements for 
264  approval by an IRB under 21 CFR 50.51 (clinical investigations not involving greater than 
265  minimal risk).  For IRB approval under 21 CFR 50.53, the pediatric participants must have a 
266  disorder or condition that is the focus of the clinical investigation, the investigational drug must 
267  present experiences to those subjects that are reasonably commensurate with those inherent in 
268  their actual or expected medical, dental, psychological, social, or educational situations, and the 
269  clinical investigation must be likely to yield generalizable knowledge about the disease or 
270  condition that is of vital importance for the understanding or amelioration of that disorder or 
271  condition.  For IRB approval of a clinical investigation under 21 CFR 50.52, the pediatric 
272  participants must have a prospect of direct clinical benefit from administration of the 
273  investigational product, the risk to the pediatric participants must be justified by the anticipated 
274  benefit, and the relation of the anticipated benefit to the risk must be at least as favorable to the 
275  pediatric participants as that presented by available alternative approaches.  Accordingly, healthy 
276  pediatric participants (i.e., without a disorder or condition which is the focus of the research) 
277  cannot be enrolled in FDA-regulated clinical pharmacology studies unless the Commissioner 
278  determines, after consultation with a panel of experts in pertinent disciplines and opportunity for 
279  public review and comment, that the conditions in 21 CFR 50.54 are met.31  That regulation 
280  applies to clinical investigations that are not approvable under 21 CFR 50.51, 50.52, or 50.53 but 
 
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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281  that present an opportunity to understand, prevent, or alleviate a serious problem affecting the 
282  health or welfare of children. 
283   
284  A.  Case 1:  IRB Review of a Clinical Pharmacology Study Involving Pediatric 
285  Participants Under 21 CFR 50.53 
286   
287  When the investigational drug is being administered to a pediatric participant with the disease or 
288  condition for which the drug is being developed, but the intent of the study is solely for the 
289  purpose of obtaining PK data, the risk(s) presented by the investigational drug, the route of 
290  administration, and the PK sampling schedule must represent no more than a minor increase over 
291  minimal risk (21 CFR 50.53(a)) in order to be approvable by the IRB.  Pediatric participants may 
292  be exposed to no more than a minor increase over minimal risk if, among other criteria, the 
293  intervention or procedure is likely to yield generalizable knowledge about the subjects disorder 
294  or condition that is of vital importance for the understanding or amelioration of that disorder or 
295  condition (21 CFR 50.53(c)).  Thus, for a clinical investigation to be approved by an IRB under 
296  this category, the enrolled pediatric participant must have a disorder or condition that meets these 
297  requirements.  The FDA interprets condition to include being at risk for the disease (disorder) 
298  based on, for example, epidemiologic, genetic, and other factors.   
299   
300  Furthermore, sufficient empirical data regarding the risks of the proposed interventions or 
301  procedures should be available to ascertain that the risks are no more than a minor increase over 
302  minimal risk (21 CFR 50.53(a)).  If available, adult data (including dose-response information) 
303  should be considered for this purpose.  When there are not enough human data to adequately 
304  characterize the risk, then the intervention or procedure generally would not be considered to 
305  present no more than a minor increase over minimal risk because the risks of the intervention or 
306  procedure would not be known with sufficient accuracy.   
307   
308  The risks of any blood and/or fluid sampling procedures also must represent no more than a 
309  minor increase over minimal risk (21 CFR 50.53(a)).  The limited venipunctures to obtain 
310  specimens for PK analyses would generally be considered either minimal risk or a minor 
311  increase over minimal risk, and therefore could be approvable by the IRB even without the 
312  prospect of direct benefit (see 21 CFR 50.51(a) and 50.53(a)).  This approach to the analysis of 
313  clinical trials is often called a component analysis of risk, whereby to determine the overall 
314  acceptability of the clinical investigation, the risks and anticipated direct clinical benefits of the 
315  interventions included in a protocol are analyzed individually as well as collectively.32,33,34   
316   
317  An example of a clinical pharmacology study that generally would fall under 21 CFR 50.53 is 
318  the pharmacokinetics of the oral administration of a single dose of an over-the-counter cough and 
319  cold product.  To be enrolled in such a study, a child would either be symptomatic from an upper 
 
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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320  respiratory infection (URI) or be at risk for a future URI based on the presence of criteria such as 
321  the frequency of past infections, number of people living in the home, or exposure to others in a 
322  preschool or school setting.  As stated above, the associated blood draws to collect PK samples 
323  would generally be considered to be minimal risk (21 CFR 50.51(a)) or no more than a minor 
324  increase over minimal risk (21 CFR 50.53(a)) and a single oral dose of the over-the-counter 
325  cough and cold product would generally be considered as no more than a minor increase over 
326  minimal risk (21 CFR 50.53(a)), thus allowing the study to proceed under 21 CFR 50.53. 
327   
328  If administration of a single dose of an investigational drug exceeds a minor increase over 
329  minimal risk (or there are insufficient data available to make that determination), the clinical 
330  pharmacology study either would be required to meet the requirements in 21 CFR 50.52 (as 
331  discussed below) or would require referral for review under 21 CFR 50.54 (assuming that the 
332  other requirements of that regulation were met).  
333   
334  B.  Case 2:  IRB Review of a Clinical Pharmacology Study Involving Pediatric 
335  Participants Under 21 CFR 50.52 
336   
337  The administration of an investigational drug with more than a minor increase over minimal risk 
338  could be approved by an IRB if the level of risk exposure is justified by a sufficient prospect of 
339  direct clinical benefit to the participants (21 CFR 50.52(a)).  For example, dose-monitoring 
340  studies that ensure serum levels of an investigational drug remain within a therapeutic range 
341  generally would fall under 21 CFR 50.52 when the investigational drug presents the prospect of 
342  direct benefit to the enrolled pediatric participants and the investigational drug is administered 
343  under the protocol using a dosing regimen (including duration) that offers a sufficient prospect of 
344  direct clinical benefit to justify the risks (21 CFR 50.52(a)).   
345   
346  Multiple-dose PK-PD studies can be designed to offer a prospect of direct benefit, but the dose 
347  and duration of exposure to the investigational product should be sufficient to result in potential 
348  changes in the clinical manifestations of the condition or in disease-specific biomarkers that 
349  reflect a clinical benefit.  For example, the duration of the PK-PD study could be extended, or 
350  perhaps combined as the lead-in phase to an efficacy trial, to provide a suitable duration of drug 
351  exposure that offers a sufficient prospect of direct clinical benefit to justify the risks.35   
352   
353  C.  Ethical Justification for Pediatric Pharmacology Studies 
354   
355  Adequate information from clinical pharmacology studies to support pediatric dosing is critical 
356  to the development of ethically sound confirmatory trials.  Inadequate pediatric dosing may lead 
 
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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357  to failed pediatric clinical trials.36  The FDA considers the public health need for adequate 
358  pediatric dosing in its assessment of the ethical propriety of proposed studies.37,38 
359     
360   
361  V.  THE PEDIATRIC STUDY PLAN DESIGN AND POINTS TO CONSIDER 
362   
363  A sponsor who is planning to submit a marketing application (or supplement to an application) 
364  for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route 
365  of administration is required to submit an iPSP39 unless the drug is for an indication for which 
366  orphan designation has been granted.40  In addition, a sponsor who is planning to submit, on or 
367  after August 20, 2020, an original application for a new active ingredient that is subject to the 
368  molecularly targeted cancer drug provision of PREA (i.e., the drug that is the subject of the 
369  application is intended for the treatment of an adult cancer and is directed at a molecular target 
370  that the FDA determines to be substantially relevant to the growth or progression of a pediatric 
371  cancer) is also required to submit an iPSP,41 regardless of whether the drug is for an indication 
372  for which orphan designation has been granted.42  By statute, a biosimilar product that has not 
373  been determined to be interchangeable with the reference product is considered to have a new 
374  active ingredient for purposes of PREA.43   
375   
376  The submission of the iPSP is intended to encourage sponsors to consider pediatric studies early 
377  in product development and, when appropriate, begin planning for these studies.  The FDA 
378  guidance entitled Pediatric Study Plans:  Content of and Process for Submitting Initial Pediatric 
379  Study Plans and Amended Pediatric Study Plans (July 2020) discusses the content of and process 
380  for submitting initial and amended PSPs and states that Section 10.1 (Pediatric Pharmacokinetic 
381  or Pharmacokinetic/Pharmacodynamic Studies) should include: 
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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383    The type of study/study design  
384   
385    The objectives of the study  
386   
387    The age group and population in which the study will be conducted  
388   
389    The pediatric formulation(s) to be used in the study  
390   
391    The dose ranges to be used in the PK studies  
392   
393    The endpoints and justification (PK parameters; PD parameters)  
394   
395    The existing or planned modeling and simulation to support dose selection and/or study 
396  design, data analysis, and interpretation for planned pediatric studies  
397   
398    Any planned pharmacogenomic analyses  
399   
400    A justification for the sample size 
401   
402  When designing pediatric clinical studies, sponsors should be mindful that modeling and 
403  simulation and pharmacologic considerations are often critical for the successful completion of a 
404  study.  Modeling and simulation (e.g., PK, PD, and trial simulations) should use all of the 
405  information available and be an integral part of all pediatric development programs followed by 
406  verification using results from pediatric clinical studies.  The following sections are critically 
407  important when developing the clinical pharmacology components of a pediatric study plan. 
408   
409  A.  Approaches to Pediatric Studies   
410   
411  There are several recognized approaches to providing substantial evidence to support the safe 
412  and effective use of drugs in pediatric populations.44  In some cases, previous data in adults and 
413  other pediatric indications can be leveraged to provide this substantial evidence.  This concept is 
414  often referred to as pediatric extrapolation.     
415   
416  Pediatric extrapolation of efficacy is defined as an approach to providing evidence in support of 
417  effectiveness of drugs in the pediatric population when it can be assumed that the course of the 
418  disease and the expected response to a medicinal product would be sufficiently similar in the 
419  pediatric and reference (adult or other pediatric) populations.45  Determination of the extent of 
420  pediatric extrapolation is predicated on the understanding of the disease and drug effect in the 
421  reference (adult or other pediatric) population and their similarity to the target pediatric 
 
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 Agencys 
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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422  population.  The data necessary to support efficacy when pediatric extrapolation is considered 
423  will depend upon the existing data and the gaps in knowledge that should be addressed.46  
424  Examples of potential approaches based on the availability and confidence in existing data are 
425  discussed in sections 1 through 3 below.   
426   
427  While it is helpful and provides additional evidence to support extrapolation, formally 
428  establishing and documenting similarity in exposure-response in adults and target pediatric 
429  population is not a requirement in order to consider some degree of extrapolation.  Exposure-
430  response assessments are, however being conducted more frequently in both adult and pediatric 
431  patients.  Knowledge of exposure-response, when available, can play a critical role in informing 
432  the assessment of drug effect similarity between adults and pediatric patients and the 
433  acceptability of an exposure-matching approach.  In addition, exposure-response information can 
434  serve a crucial role in supporting pediatric dose selection, dose optimization and formulation 
435  development.  When applicable, similarity in exposure-response relationships on a clinically 
436  relevant biomarker or an appropriate clinical endpoint can contribute to an assessment of the 
437  appropriateness of efficacy extrapolation from adults to pediatric patients. 
438   
439  Additionally, the extent of the required pediatric safety data can take into consideration prior 
440  experience with similar drugs in pediatric populations and the seriousness of the adverse events 
441  in adults or in pediatric populations.  Usually, additional safety data in the indicated pediatric 
442  indication will be needed.  See the FDA guidance entitled E11(R1) Addendum: Clinical 
443  Investigation of Medicinal Products in the Pediatric Population (April 2018) for more 
444  information.  The potential for pediatric patients to have a significantly different incidence, 
445  severity, and types of adverse events compared to adults should always be considered.47,48 
446   
447  1.  PK, Safety, and Efficacy Approach  
448   
449  If the disease or disease progression is unique to pediatric patients or its progression and/or 
450  response to intervention is undefined or dissimilar to that in adults, then the pediatric 
451  development program should use a PK, safety, and efficacy approach.  The objectives of the 
452  studies in the pediatric program would be to characterize the PK and exposure-response 
453  relationships to help optimize pediatric dosing strategies and to provide evidence of effectiveness 
454  and safety.  A population PK analysis can be conducted using PK data from the efficacy study to 
455  confirm PK estimates in the age subgroups.  
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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457  2.  PK, Safety, and PD/Efficacy Approach  
458   
459  This approach should be considered when the disease and intervention are believed to behave 
460  similarly in pediatrics and adults, but the exposure-response relationship in pediatrics is either 
461  inadequately documented or assumed to not be sufficiently similar to adults.  A clinically 
462  relevant PD biomarker may be appropriate for purposes of evaluating the evidence of 
463  effectiveness and to select pediatric doses.  In the absence of a clinically relevant PD biomarker, 
464  clinical measures (e.g., symptoms, signs, outcomes) may be appropriate.  The number, type, and 
465  size of pediatric studies to support a pediatric program depends on the residual uncertainty 
466  associated with understanding of similarity of the disease and drug effect.  
467     
468  For the two approaches described above, response data in pediatric studies should be collected 
469  and analyzed.  Response or PD data can include biomarkers or clinical endpoints for both safety 
470  and effectiveness.  The specific endpoints, including those for an exposure-response evaluation, 
471  for each drug should be discussed with the Agency.  Appropriate endpoint selection and 
472  enrichment strategies for the pediatric population in a trial are important.  Of note, endpoints that 
473  are unique to pediatric participants have been previously associated with failed pediatric trials 
474  and should be carefully considered.49 
475   
476  3.  PK and Safety Approach  
477   
478  The PK and safety approach should be considered when there is evidence that adults and 
479  pediatrics share a sufficiently similar disease course and response to intervention to allow for 
480  exposure matching to establish efficacy. 
481   
482  A PK study should be performed to identify the pediatric dose that will provide an exposure 
483  similar to that found to be effective in adults.  The antibacterial therapeutic area is a good 
484  example of this approach, where the organism is expected to respond to similar systemic 
485  concentrations in adults and pediatrics.  In this example, the study should focus on identifying 
486  the doses in the pediatric setting that would result in exposures similar to those attained in adults.  
487  The criteria for determining exposure matching should be prospectively agreed upon with the 
488  Agency before initiating these studies.50  
489   
490  Before conducting a PK study in any of these approaches, simulations should be performed to 
491  identify initial dosing regimens.  Clinical trial simulations may be performed to determine a trial 
492  design, sample size, and the appropriateness of an endpoint for the pediatric study.  Refining 
493  models with available data can help verify assumptions made during the design of the study. 
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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495  B.  Alternative Approaches to Conventional PK Studies 
496   
497  A dedicated PK study with intensive PK sampling may not be necessary in every age group.  For 
498  example, prior experience with dosing in adolescent participants has demonstrated that 
499  knowledge of adult dosing and appropriate dose scaling can be sufficient for some drugs with 
500  adequate justification.  When a dedicated PK study is not considered essential or cannot be 
501  conducted, it may be appropriate to use sparse PK sampling in the safety and/or efficacy studies 
502  to confirm dose predictions.  Modeling and simulation can also be used, when appropriate, to 
503  help to fill these gaps in knowledge.  See the FDA guidance entitled Considerations for the 
504  Inclusion of Adolescent Patients in Adult Oncology Clinical Trials (March 2019) for more 
505  information. 
506   
507  Other approaches beyond the use of conventional PK studies with intensive blood sampling may 
508  be appropriate in pediatric participants to obtain useful drug exposure information, including: 
509   
510    Sparse PK sampling with the use of modeling and simulation 
511   
512    Opportunistic approaches that use excess blood collected for laboratory studies51 
513   
514    Use of alternative specimens: 
515   
516    Urine and saliva collection are noninvasive.  However, the interpretation of drug 
o
517  analyses of either source is complicated and requires careful consideration before 
518  use.  
519   
520    Likewise, tissue or cerebrospinal fluid collected for clinical purposes present both 
o
521  an opportunity and a challenge for the appropriate interpretation of these results 
522  in understanding the pharmacokinetics of the drug. 
523   
524  Modeling and simulation can help reduce the uncertainty about drug dosing in pediatric 
525  populations.  Model-informed drug development has been applied in regulatory applications for 
526  pediatric drug development.52  Population PK approaches are commonly used, and 
527  physiologically based PK (PBPK) approaches are increasingly applied in pediatric drug 
528  development.  In addition, quantitative systems pharmacology (QSP) models can help 
 
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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529  incorporate disease processes.53,54  As science and technology continue to advance, in silico and 
530  other alternative modeling study methods can provide preliminary data to inform the design and 
531  conduct of PK-PD studies for investigational drugs in pediatric populations.  For example, the 
532  development of a PBPK in silico model that integrates drug-dependent parameters (e.g., 
533  physicochemical properties, hepatic intrinsic clearance, affinities to metabolic enzymes, 
534  transporters, and proteins) and system- and age-dependent parameters (e.g., blood flow rate, 
535  protein contents, tissue and organ size and composition, and enzyme and transporter abundances 
536  and activities) is one possible approach.   
537   
538  Various modeling approaches have been used in pediatric drug development programs for a 
539  variety of purposes, including: 
540   
541    Planning for a first-in-pediatric PK study 
542   
543    Optimizing the study design 
544   
545    Verifying the model in specific age groups 
546   
547    Recommending starting doses 
548   
549    Informing enzyme ontogeny using a benchmark drug 
550   
551    Facilitating covariate analysis for the effects of organ dysfunction or drug interactions in 
552  pediatric participants55 
553   
554  The model selected should incorporate in vivo PK-PD data obtained in other groups of pediatric 
555  and adult participants as well as human volunteer studies, as appropriate.  To account for growth 
556  across the pediatric population for modeling purposes, refer to standardized growth charts.  The 
557  Centers for Disease Control and Prevention (CDC) growth charts provide a preliminary 
558  assessment of the weight ranges that can be anticipated within specific age groups.56  For 
559  example, weights can vary 2.5- to 3-fold in healthy children between the 10th percentile at 2 
560  years and 90th percentile at age 6 (10.6 kg to 25.3 kg for males) and between the 10th percentile at 
 
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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561  6 years and the 90th percentile at 12 years (17.7 kg to 54 kg in males).  Caution should be taken 
562  in the use of standardized growth charts as they do not always represent the target pediatric 
563  patient population. 
564   
565  C.  Pediatric Dose Selection 
566   
567  Selecting a dose(s) and an age range should consider the overall benefit/risk profile of the drug.  
568  When possible, a range of doses should be studied in the pediatric population.   
569   
570  Factors for consideration in dose selection include:  
571   
572    The similarity of the disease and exposure-response in pediatric and adult groups 
573   
574    The relative bioavailability of the new formulation compared to the previous 
575  formulations 
576   
577    The age and developmental stage of the pediatric population 
578   
579    Any pharmacogenomic characteristics of the drug 
580   
581    The toxicity of the drug 
582   
583    Any PK data from other pediatric populations  
584   
585  Because there can be limited information on the safety of the dose to be administered to a 
586  neonate or infant, the dose range used in initial studies requires careful consideration.57  When 
587  developmental maturation and body size changes impact dosing, modeling and simulation can 
588  help define an initial pediatric dosing in order to adequately minimize the risk for specific age 
589  groups.  Initial doses within a pediatric age group are typically normalized to body size (e.g., 
590  mg/kg), but developmental maturation can be an additional critical factor to be considered in 
591  establishing initial doses in some age groups.  In some pediatric participants such as adolescents, 
592  body weight or surface area-based dosing are not always necessary.  In some cases, final dosing 
593  recommendations can include tiered dosing based on weight bands.      
594   
595  There are situations in which interpolation or scaling can reduce the uncertainty regarding initial 
596  pediatric dosing.  PK or PD information in certain pediatric age groups can be gained by 
597  interpolating or bridging from existing data in adults, pediatric participants in other age groups, 
598  or both.  However, bridging of data to younger pediatric age groups, particularly neonates, 
599  should be done cautiously and confirmed.  Significant developmental differences that can exist 
600  between young pediatric age groups and older pediatric age groups or adults are associated with 
601  considerable differences in metabolism and drug disposition.  This difference can lead to an 
602  altered dose-exposure relationship and therefore the dose-response relationships.   
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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604  When initial PK studies are not feasible (see section IV), an adaptive design to selecting a dose 
605  can be practical for the pediatric clinical studies.  Adaptive designs should be prospectively 
606  determined.  See the FDA guidance entitled E11(R1) Addendum: Clinical Investigation of 
607  Medicinal Products in the Pediatric Population (April 2018) for more information. 
608   
609  When separate efficacy studies in pediatrics are not conducted (i.e., for the PK and safety only 
610  approach described in section V.A above), in general, PK studies in the pediatric population 
611  should determine how the dosage regimen should be adjusted to achieve the same level of 
612  systemic exposure in adults.  Differences in intersubject variability in these PK measures and/or 
613  parameters between age groups or between pediatric and adult populations should be interpreted 
614  with regard to their impact on dosing, safety, and/or efficacy.  In these instances, the sponsor 
615  should pre-specify the criteria by which exposure matching is acceptable.  For example, one 
616  approach is to select the appropriate dosing strategy through simulations which result in pediatric 
617  exposures within the 5th to 95th percentile shown to be safe and effective in adults. 
618   
619  Estimating the exposure-response relationship across a range of body-size doses (dose/kg or 
620  dose/m2) can be important.  For the PK and PD/efficacy approaches discussed in section V.A2 
621  above, investigating a range of doses and exposures allows for an assessment of those 
622  relationships and the development of rational dosing instructions.  The sponsor should also 
623  consider determining the variability in achieved systemic exposures in the pediatric population in 
624  the context of the exposure-response relationships for pharmacodynamics or efficacy. 
625   
626  When PK-PD data are available, the dose range should account for observed differences in 
627  response between adults and the pediatric population, both in terms of exposure and response.  
628  For example, there is evidence that pediatric populations are on average less sensitive to 
629  antihypertensive drugs than the adult population.58  Therefore, pediatric studies could include 
630  exposures greater than the highest drug exposure associated with the approved adult dose, 
631  provided that prior data about the exposure-response relationship and safety information justify 
632  such an exposure.  Studies of distinctly different ranges of exposure are desirable to provide 
633  sufficient information for the calculation of an optimal dose. 
634   
635  D.   Pediatric Dosage Formulation 
636   
637  Pediatric formulations that permit accurate dosing and enhance adherence (e.g., palatability) are 
638  an important part of pediatric drug development.59  See the FDA guidance entitled E11 Clinical 
 
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 Agencys 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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639  Investigation of Medicinal Products in the Pediatric Population (December 2000) for more 
640  information.  If there is a pediatric indication, an age-appropriate dosage formulation must be 
641  made available for pediatric patients in all relevant age groups.60  One way to fulfill this 
642  requirement, when the adult formulation is not acceptable for the planned pediatric age range, is 
643  to develop and test a pediatric formulation and seek approval for that formulation.  To the extent 
644  practicable, sponsors should include information in the iPSP regarding planned excipients that 
645  will be contained in a pediatric formulation. 
646   
647  The bioavailability of any formulation used in pediatric studies should be characterized in 
648  relation to the adult formulation.  In some circumstances, a relative bioavailability study 
649  comparing the age-appropriate formulation to the approved drug may be required.61  These 
650  studies are generally performed in adults due to ethical reasons.  Potential drug-food or vehicle 
651  interactions should be considered, such as those that have been reported with apple juice.62  
652   
653  E.  Sample Size 
654   
655  1.  Number of Pediatric Participants  
656   
657  Prior knowledge of the disease, exposure, and response from adult and other relevant pediatric 
658  data, such as that related to variability, can be used to derive a sample size for ensuring precise 
659  parameter estimation.  The sponsor should account for all potential sources of variability, 
660  including inter-subject and intra-subject variability as well as differences between the adult and 
661  pediatric populations when making the final selection of the sample size for each age group. 
662   
663  The distinct age groups to be studied should be chosen based upon what is known about potential 
664  changes in drug response with age, the development of the drug-metabolizing enzymes and 
665  excretory mechanisms, as well as safety considerations.  Pediatric studies in all age groups 
666  should be initiated as early as possible in drug development.  The sequential study of age 
667  cohorts, starting with the oldest pediatric age group, may be appropriate when there is a clear 
668  rationale for doing so.  If the drug is intended to be used in newborn infants, the iPSP should 
669  specify how premature infants will be considered in the study population. 
670   
671  Because the selected age groups (strata) will be drug product-specific, the sponsor should discuss 
672  the stratification plan, the distribution of the number of pediatric participants within each 
673  stratum, and the appropriateness of these strata with the Agency.63  Justification should be 
674  provided for the sample size selected.  For example, one approach would be to prospectively 
 
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. 
  19  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
675  target a 95 percent confidence interval within 60 percent and 140 percent of the geometric mean 
676  estimates of clearance and volume of distribution for the drug in each pediatric stratum with at 
677  least 80 percent power.  Noncompartmental analysis (NCA) based on rich PK sampling, 
678  population PK modeling analysis based on sparse PK sampling, or other scientifically justified 
679  methods can be applied as appropriate to achieve this precision standard.64   
680   
681  Conceivably, certain disease states might not allow for the recruitment of an adequate number of 
682  participants to meet the above standard, and as such, practical considerations should be taken 
683  into account in determining the sample size. 
684   
685  2.  Number of Samples Per Participant 
686   
687  In addition to the number of participants, the number of blood samples collected in the clinical 
688  pharmacology study to estimate PK measures and parameters for each individual in the study 
689  should be carefully considered.  The amount of blood or number of samples possible is very 
690  limited in some pediatric participants such as neonates (for more on collection of blood or 
691  plasma samples, see section F below).  Clinical trial simulations and optimal sampling strategies 
692  are recommended to justify the proposed sampling scheme.   
693   
694  F.  Sample Collection 
695   
696  The volume and frequency of blood sampling are often of concern in pediatric studies.  Blood 
697  samples can be obtained by direct venipuncture, through the use of an indwelling intravascular 
698  catheter, or when appropriate, by capillary sampling.  Because repeated venipuncture can cause 
699  discomfort and bruising at the puncture site, an indwelling intravascular catheter should be used 
700  when possible.  The volume and frequency of blood sampling may be minimized by using micro-
701  volume drug assays, dried blood spots, and sparse-sampling techniques.  See the FDA guidance 
702  entitled Bioanalytical Method Validation (May 2018) for more information.  These types of 
703  assays and analysis are especially relevant when studying neonates.65  Modern assay techniques 
704  allow small sample volumes to be used to determine drug concentrations, but data quality can be 
705  affected if the sample volume is insufficient to allow for reanalysis when necessary.  Blood 
706  samples for analysis should be collected from the circulating blood volume and not from 
707  reservoir dead space created by catheters or other devices.  Sampling technique is critical when 
708  using the available pediatric indwelling intravenous catheters.  The time of sample collection, 
709  proper sample transportation and storage, and sample handling techniques should be 
710  documented.  The collection of fluids such as cerebral spinal fluid (CSF) or bronchial fluids can 
711  be beneficial when samples are being obtained for clinical purposes.  Noninvasive sampling 
712  procedures, such as urine and saliva collection, may be sufficient if correlated with outcomes or 
713  if the correlation with blood, serum or plasma levels has been documented. 
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. 
  20  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
715  Samples for DNA should be collected when appropriate, as discussed in section III of this 
716  guidance.  See also the FDA guidance entitled Clinical Pharmacogenomics: Premarket 
717  Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling (January 2013) 
718  for more information. 
719   
720  G.  Covariates and Phenotype Data 
721   
722  Growth and developmental changes in the pediatric population create substantial changes in the 
723  ADME characteristics of a drug.  PK measures and parameters for a drug should be described as 
724  a function of age and be related to some measure of body size, such as height, weight, or body 
725  surface area (BSA).  The maturational changes in systems affecting ADME, such as membrane 
726  transporters and metabolizing enzymes, should be considered when choosing age groups and 
727  doses to study in the pediatric population (see section III). 
728   
729  The sponsor should, at a minimum, obtain the following covariates for each pediatric participant:  
730   
731    Age 
732    Body weight 
733    Height 
734    Calculated BMI 
735    Gestational age 
736    Post-menstrual and postnatal age for neonates66 
737    Race and ethnicity 
738    Sex 
739    Laboratory tests reflecting the function of organs responsible for drug elimination 
740    Concomitant and recent drug therapy 
741   
742  The impact of the disease state and obesity upon drug disposition and response should be 
743  considered.67  Sponsors are encouraged to collect DNA samples in pediatric PK studies under the 
744  circumstances described in section III, along with appropriate phenotype information to optimize 
745  the interpretation of pharmacogenomics findings.  For example, when genotype information is 
746  obtained for a cytochrome P450 enzyme, the sponsor should investigate the influence of genetic 
747  mutations on pharmacokinetics, pharmacodynamics, and/or dose-response to determine whether 
748  genetically defined subsets of patients need special dosing considerations. 
749   
750  The sponsor should examine the relationship between the covariates and the pharmacokinetics of 
751  the drug of interest.  The contribution of weight or BSA and age to PK variability should be 
752  assessed.  Examples of practices for assessing the effect of age on pediatric pharmacokinetics 
753  could include:  
 
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. 
 
 
  21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
754   
755    Identifying the accurate relationship between a drugs pharmacokinetics and body weight 
756  or BSA using allometric scaling 
757   
758    Analyzing the residuals versus age, after accounting for body weight or the BSA effect 
759  on CL, followed by a more formal analysis exploiting the physiological understanding 
760  underlying CL, if appropriate.  Testing for other biologically relevant predictive factors 
761  for determining the pharmacokinetics of a drug in pediatrics can be important.  The 
762  covariate analysis may be performed on pooled data sets to allow for comparisons 
763  between adults and/or different pediatric subgroups. 
764   
765  1.  Immunogenicity 
766   
767  The pharmacokinetics of a drug such as therapeutic proteins can be affected by immunogenicity 
768  to the drug.  Immunogenicity to the administered product can negatively impact the safety and/or 
769  efficacy of the drug.  Therefore, assessing the immunogenicity of the relevant drugs and 
770  determining its impact on pharmacokinetics, safety, and efficacy are critical components of drug 
771  development and post-marketing surveillance.  See the following FDA guidances for more 
772  information: 
773   
774    Immunogenicity Assessment for Therapeutic Protein Products (August 2014) 
775   
776    Immunogenicity Testing of Therapeutic Protein Products - Developing and Validating 
777  Assays for Anti-Drug Antibody Detection (January 2019) 
778   
779  In general, it is not appropriate to apply findings of the immunogenicity potential of a drug from 
780  adult populations to pediatric populations; therefore, evaluation of the immunogenicity potential 
781  of a drug should be conducted in pediatric trials regardless of the knowledge gained from adult 
782  trials.   
783   
784  2.  Renal Function 
785   
786  For drugs that are renally cleared, exposures can be impacted by both the maturation of kidney 
787  function and renal impairment due to kidney disease.  For this reason, pediatric patients with 
788  impaired renal function should be recruited for clinical study when it is possible and ethically 
789  justifiable to do so.  One commonly used equation for the estimation of renal function is the 
790  bedside Schwartz equation;68 however, in general any widely accepted measurement method 
791  (where necessary) or equation for the estimation of renal function in pediatric PK studies is 
792  acceptable69 and should be described in the protocol and labeling when relevant dose 
 
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):424431. 
 
  22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
793  adjustments are derived.  Sponsors should be aware of the laboratory methods used for the 
794  measurement of creatinine, as this can influence which equation is useful.     
795   
796  Data from adults are generally used to complement the information obtained in pediatrics to 
797  characterize the relationship between renal function and pharmacokinetics.  Modeling and 
798  simulation approaches should be applied to derive dosing recommendations for the entire 
799  pediatric age range in which the product will be used.70  Generally, for children over the age of 2 
800  years, where kidney function maturation is considered complete, the need for dose adjustment 
801  should be evaluated and derived based on information evaluated in adults.  For children less than 
802  2 years of age, the additional impact of renal function ontogeny should be considered.71  
803  Quantitative approaches such as PBPK analysis can also be explored to address dosing needs in 
804  these situations.  Of note, the application of modeling is limited by current understanding of 
805  ontogeny and is particularly challenging in neonates.  However, modeling approaches should use 
806  all of the clinical information available.    
807   
808  H.  Drug-Drug Interactions 
809   
810  In general, evaluations of drug-drug interactions (DDIs) are performed in adults.  In some cases, 
811  however, the potential or magnitude of a DDI in pediatrics can differ from that observed in 
812  adults.  Such differences in DDIs in pediatrics compared to adults can potentially be attributed to 
813  the ontogeny of metabolizing enzymes and transporters as well as differences in intragastric pH, 
814  gastric emptying, intestinal motility, or protein binding.  Differences in diet, concomitant 
815  medications, drug formulation, and dosing regimen could also contribute to differences in DDIs 
816  between adults and pediatrics.72 
817   
818  Considering potential ethical concerns for standalone DDI studies in pediatrics, quantitative 
819  approaches such as PBPK analyses should be explored to address pediatric DDIs during drug 
820  development when differences in DDI are expected.  Refer to the following FDA guidances for 
821  more information: 
822   
823    Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-
824  Mediated Drug Interactions (January 2020) 
825   
826    Physiologically Based Pharmacokinetic Analyses  Format and Content (September 
827  2018) 
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 FDAs 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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Draft  Not for Implementation 
829  Planning for DDI evaluations should be included as a section of the iPSP under Pediatric 
830  Pharmacokinetic Studies and should address the impact of DDIs on drug dosing in specific age 
831  groups.  See the FDA guidance entitled Pediatric Study Plans:  Content of and Process for 
832  Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans (July 2020) for 
833  more information. 
834   
835  I.  Sample Analysis 
836   
837  An accurate, precise, sensitive, specific, and reproducible analytical method to quantify the drug 
838  and metabolites in the biological fluids of interest is essential.  See the FDA guidance entitled 
839  Bioanalytical Method Validation (May 2018) for more information.  The sponsor should choose 
840  a method that is readily adaptable and uses only minimum sample volumes. 
841   
842  J.   Data Analysis 
843   
844  The development of PK models should occur throughout the pediatric development program.  
845  All prior knowledge, including adult data, should be used to develop initial models which can be 
846  adapted as new data become available in pediatric subgroups.  There are several basic 
847  approaches for performing PK analysis in pediatrics.  Population PK and noncompartmental PK 
848  approaches are two of the most commonly used; however, novel approaches may be acceptable as 
849  justified by the sponsor.   
850   
851  1.     Population Analysis 
852   
853  A common approach for analyzing data from pediatric clinical pharmacology studies is the 
854  population approach to PK analysis.  Population PK accommodates rich (intensive) and 
855  infrequent (sparse) sampling of blood, serum, or plasma from a larger population than in a 
856  compartmental or noncompartmental analysis PK approach to determine the PK parameters.  
857  Sparse sampling is generally considered more acceptable for pediatric studies because the total 
858  volume of blood sampled in an individual can be minimized.  Sampling can even be performed 
859  concurrently with clinically necessary blood or urine sampling (e.g., opportunistic PK studies).  
860  Because relatively large numbers of pediatric participants are studied, and samples can be 
861  collected at various times of the day and repeated over time in a given participant, estimates of 
862  both population and individual means, as well as estimates of intra- and inter-subject variability, 
863  can be obtained if the population PK study is properly designed.  See the FDA guidance entitled 
864  Population Pharmacokinetics (February 2022) for more information. 
865   
866  Exposure-response analyses predominantly employ a population analysis approach.  Individual 
867  analysis is generally not recommended unless responses from a wide range of doses from each 
868  participant are available.  Modeling of data across all study participants typically provides the 
869  best opportunity to describe the exposure-response relationship.  See the FDA guidance entitled 
870  Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory Applications 
871  for more information (May 2003). 
872   
873  2.        Noncompartmental Analysis 
874   
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875  If consistent with relevant ethical considerations (see Section IV: Ethical Considerations), it may 
876  be possible to utilize intensive PK sampling with relatively frequent blood and urine sample 
877  collection, when administering either single or multiple doses of a drug to a relatively small 
878  group of study participants.  Samples are collected over specified time intervals chosen on the 
879  basis of absorption and disposition half-lives, and subsequently assayed for either total or 
880  unbound concentrations of drug and relevant metabolites.  Noncompartmental analysis is a 
881  general approach to establish PK statistics and parameters such as AUC, C , CL, volume of 
max
882  distribution, and half-life, which are descriptive of the concentration of drug or metabolite over 
883  time.  Data are usually expressed as the means of the relevant measure or parameter and inter-
884  individual variances.  In this approach, including a sufficient number of study participants to give 
885  a precise estimate of the mean is essential, as discussed in section V.E.  If drug administration 
886  and sampling are repeated in a participant in the PK study, some understanding of intra-
887  individual variability in PK parameters can be obtained. 
888   
889  K.   Clinical Study Report 
890   
891  The clinical study report should follow the FDA guidance entitled E3 Structure and Content of 
892  Clinical Study Reports (January 2013) for the general content and the format of the pediatric 
893  clinical study report.  The evaluation of exposure-response relationships and the population PK 
894  analyses should be included as stipulated in the following FDA guidances: 
895   
896    Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
897  Applications (May 2003) 
898   
899    Population Pharmacokinetics (February 2022) 
900   
901  When submitting PK information, the sponsor should submit data that illustrate the relationship 
902  between the relevant PK parameters (e.g., CL unadjusted and adjusted for body size in the 
903  manner described in section VI.G) and important covariates (e.g., age, renal function) in addition 
904  to the results of noncompartmental analysis. 
905   
906  L.  Data Submission 
907   
908  The preferred submission standard for clinical data is the Clinical Data Interchanges Standards 
909  Consortium (CDISC) Study Data Tabulation Model (SDTM) standard.  Please see the FDA Data 
910  Standards Advisory Board73 and the CDER Study Data Standards web sites for more 
911  information.74  The sponsor should also submit PK and exposure-response data used for 
912  modeling and simulation in an SAS.XPT-compatible format.  
 
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.  
 
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