Measuring Growth and 
Evaluating Pubertal 
Development in 
Pediatric Clinical Trials 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) the Division of Pediatric and 
Maternal Health at 301-796-2200 or (CBER) the Office of Communication, Outreach, and 
Development at 800-835-4709 or 240-402-8010. 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
November 2022 
Clinical/Medical 
 
35593015dft.docx 
10/27/22   
Measuring Growth and 
Evaluating Pubertal 
Development in 
Pediatric Clinical Trials 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
and/or 
 
Office of Communication, Outreach, and Development  
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Food and Drug Administration 
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Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances  
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
November 2022 
Clinical/Medical 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  MEASUREMENTS OF GROWTH AND PUBERTAL DEVELOPMENT ............... 2 
A.  Growth Measurements .................................................................................................................. 2 
1. General Considerations ................................................................................................................... 2 
a.  Reducing measurement error .................................................................................................... 2 
b.  Determining age ........................................................................................................................ 3 
c.  Using standardized charts ......................................................................................................... 4 
2. Weight Assessment ........................................................................................................................... 5 
3. Linear Growth (Length and Height) Assessment ............................................................................. 6 
4. Head Circumference Assessment ..................................................................................................... 7 
5. Other Considerations ....................................................................................................................... 8 
B.  Pubertal Development ................................................................................................................... 8 
C.  Other Measurements ..................................................................................................................... 9 
1. Skeletal Age ...................................................................................................................................... 9 
2. Dual-Energy X-ray Absorptiometry Scan ...................................................................................... 10 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Measuring Growth and Evaluating  
2  Pubertal Development in Pediatric Clinical Trials 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  This guidance is intended to assist sponsors in monitoring growth and, when appropriate, 
20  pubertal development in clinical trials that enroll pediatric participants with rare and common 
21  diseases.  This guidance provides recommendations for the most appropriate methods for 
22  measuring and recording growth and evaluating pubertal development for evaluation of safety. 
23   
24  This guidance does not address use of growth or pubertal development data to support primary 
25  evidence of efficacy in growth disorders (e.g., primary growth deficiency, disorders of pubertal 
26  development such as precocious puberty or delayed puberty).  Sponsors should further discuss 
27  with the appropriate review division how to establish efficacy for such drugs.2 
28   
29  This guidance does not address evaluation of nutritional status.  This guidance does not address 
30  statistical methods for analyzing growth or pubertal developmental data.  
31   
32  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
33  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
34  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
35  the word should in Agency guidances means that something is suggested or recommended, but 
36  not required. 
37   
38   
 
1 This guidance has been prepared by the Division of Diabetes Lipid Disorders and Obesity, the Division of 
Pediatrics and Maternal Health, and the Division of Rare Diseases and Medical Genetics in the Office of New Drugs 
in the Center for Drug Evaluation and Research, the Office of Pediatric Therapeutics, and the Center for Biologics 
Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
39  II.  BACKGROUND 
40   
41  In general, pediatric clinical trials should include accurate, serial measurements and recordings 
42  of growth parameters if an investigational drug has the potential to affect growth or pubertal 
43  development.  Typically, growth is assessed using measurements of weight and linear growth 
44  (length and height), and when appropriate, head circumference.  Additional measurements and 
45  calculations may be needed in certain pediatric age groups and disease populations, as discussed 
46  further in section III., Measurements of Growth and Pubertal Development.  Typically, pubertal 
47  development is assessed using clinical phenotyping.  Accurately identifying the onset and 
48  progression of puberty is essential for accurate interpretation of growth data.  
49   
50   
51  III.  MEASUREMENTS OF GROWTH AND PUBERTAL DEVELOPMENT 
52   
53  A.  Growth Measurements 
54   
55  1.  General Considerations 
56   
57  Sponsors should consider the following for measuring growth in pediatric participants enrolled in 
58  clinical trials: 
59   
60    Develop a protocol for training investigators and trial site personnel responsible for 
61  collecting growth parameters and conducting physical examinations and include 
62  procedures for determining a trial participants age, obtaining growth measurements, 
63  instrument calibration, and evaluation of pubertal development.   
64   
65    Avoid self-reported growth measurements because they may not be sufficiently accurate, 
66  consistent, and reliable for data collection.  Growth measurements assessed outside of 
67  established trial sites may be acceptable if the measurements are taken by a trained health 
68  care professional using appropriate and calibrated instruments. 
69   
70    In general, collect and record growth measurements for a minimum trial duration of 12 
71  months.  Sponsors should discuss alternative trial durations with the appropriate review 
72  division and consider any potential safety concerns related to the drug for the intended 
73  patient population. 
74   
75    Keep pediatric participants who discontinue the study treatment in the trial to continue to 
76  obtain their growth measurements.  Measurements obtained after treatment 
77  discontinuation may be useful for ensuring the reliability and interpretability of analyses 
78  and results. 
79   
80  a.  Reducing measurement error 
81   
82  To reduce measurement error, the sponsor should include procedures and practices in the 
83  protocol, such as the following:  
84   
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
85    Outline procedures for calibration of measuring instruments (e.g., calibration timing 
86  relative to measurement, calibration frequency). 
87   
88    Document how measurements are obtained (e.g., for weight, use of tared weight, 
89  documenting type of scale, clothing; for height, use of recumbent or standing methods of 
90  measurement) and how to address challenges in obtaining measurements (e.g., 
91  uncooperative child, assistive technology). 
92   
93    For trials involving multiple treatment arms, blind trial site personnel to each trial arm.  
94  For single-arm trials, the sponsor should discuss with the appropriate review division 
95  how the trial could be designed to avoid biased measurement of growth parameters. 
96   
97    Because of diurnal variations in height and weight, schedule study visits and/or perform 
98  growth measurements at the same time of day unless justification is provided. 
99   
100  b.  Determining age 
101   
102  Appropriately determining a participants age is important for accurate and consistent 
103  documentation of growth.  Sponsors should consider the following when determining age: 
104   
105    For participants 3 years of age and older, calculate and use the chronological age to the 
106  nearest month and year. 
107   
108    For participants younger than 3 years of age, consider whether the participant was born at 
109  term (37 weeks gestation or later) or preterm (before 37 weeks gestation).  
110   
111  For participants born at term, sponsors should consider the following calculations for age:   
112   
113  i.  For participants older than 12 months of age, calculate age to the nearest month. 
114   
115  ii.  For participants from three to 12 months of age, calculate age in completed weeks 
116  or months.  
117   
118  iii.  For participants less than 3 months of age, calculate age in completed weeks. 
119   
120  For participants born preterm, sponsors should consider the following for calculating age:  
121   
122  i.  Determine the gestational age (GA) at birth (e.g., based on the first day of 
123  mothers last menstrual period (LMP), prenatal ultrasonography, history of 
124  assisted reproduction, postnatal physical exam), and document the method for 
125  determining GA. 
126   
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Draft  Not for Implementation 
127  ii.  Document both the chronological and corrected age3 for each growth assessment 
128  until participants have transitioned from corrected to chronological age.  Given a 
129  lack of consensus about thresholds of transition from corrected to chronological 
130  age, sponsors should provide data to support or justify the selected age correction 
131  strategy. 
132   
133  c.  Using standardized charts 
134   
135  Sponsors should plot anthropometric measurements based on age and sex using the appropriate 
136  standardized charts for the trial population. 
137   
138  Unless justification is provided to support using an alternative approach for growth 
139  measurement, sponsors should consider the following for pediatric participants enrolled in U.S. 
140  trial sites: 
141   
142    For participants born at term (37 weeks gestation or later):  
143   
144  i.  Two years of age and older, use the Centers for Disease Control and Prevention 
145  (CDC) growth charts.4 
146   
147  ii.  Birth to younger than 2 years of age, use the World Health Organization (WHO) 
148  growth charts.5 
149   
150    For participants born prematurely (before 37 weeks gestation): 
151   
152  i.  Born at 22 to 36 6/7 weeks GA, use the Fenton6,7 preterm infant growth chart. 
153   
 
3 Definitions of terms for corrected age include gestational age (GA; completed weeks) that means time elapsed 
between the first day of the last menstrual period and the day of delivery; chronological age (days, weeks, months, 
or years) that means time elapsed from birth; postmenstrual age (PMA; weeks) that means GA plus chronological 
age; and corrected age (CA; weeks or months) that means chronological age reduced by the number of weeks born 
before 40 weeks of gestation. 
 
4 See the CDCs Clinical Growth Charts web page available at 
https://www.cdc.gov/growthcharts/clinical_charts.htm. 
 
5 See Department of Health and Human Services, CDC, 2010, Use of World Health Organization and CDC Growth 
Charts for Children Aged 059 Months in the United States, MMWR, 59 (No. RR-9):115, available at 
https://www.cdc.gov/mmwr/PDF/rr/rr5909.pdf. 
 
6 See Fenton TR and Kim JH, 2013, A Systematic Review and MetaAnalysis to Revise the Fenton Growth Chart 
for Preterm Infants, BMC Pediatr, 13:59. 
 
7 See Olsen IE, Groveman SA, Lawson ML, Clark RH, and Zemel BS, 2010, New Intrauterine Growth Curves 
Based on United States Data, Pediatrics, 125(2):e214e224. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
154  ii.  Born at 28 weeks to 36 6/7 weeks GA, use the International Fetal and Newborn 
155  Growth Consortium for the 21st Century (INTERGROWTH-21st) preterm 
156  postnatal growth standards as an alternative to Fenton.8,9 
157   
158  iii.  Once a child reaches the term equivalent (40 weeks or later) postmenstrual age, 
159  transition to use of the WHO growth charts. 
160   
161  For trials conducted outside the United States, sponsors should use growth charts based on 
162  normative data for the trial population, when available. 
163   
164  When disease-specific growth charts (e.g., for Down syndrome, achondroplasia) are available, 
165  sponsors should use both standardized and disease-specific growth charts. 
166   
167  2.  Weight Assessment 
168   
169  Sponsors enrolling pediatric participants in clinical trials should consider incorporating the 
170  following considerations in the trial protocol regarding weight assessment: 
171   
172    Use a scale with an electronic (i.e., digital) reading that allows for adjusting the scale to 
173  zero prior to weighing the pediatric participant.  
174   
175    Place the scale on a flat, hard, and even surface. 
176   
177    Calibrate all scales used during trials at a standardized time before each study visit. 
178   
179    Record weight for participants weighing more than or equal to 5 kilograms (kg) to the 
180  nearest 0.1 kg; for neonates weighing less than 5 kg, recording weight to the nearest 10 
181  grams. 
182   
183    Address in the protocol how weight will be assessed in participants who are technology-
184  dependent (e.g., ventilator-dependent), device-dependent (e.g., gastrostomy tube), or 
185  require assistive technology (e.g., orthotics, prostheses, wheelchairs).  Techniques to 
186  consider include the following: 
187   
188   If the technology can be safely removed10, weigh the participant without the 
189  technology. 
190   
 
8 See the Global Health Network International Fetal and Newborn Growth Consortium for the 21st Centurys 
Postnatal Growth of Preterm Infants on the INTERGROWTH-21st website available at 
https://intergrowth21.tghn.org/standards-tools/. 
 
9 See Villar J, Giuliani F, Barros F, Roggero P, et al., 2018, Monitoring the Postnatal Growth of Preterm Infants: A 
Paradigm Change, Pediatrics, 141(2):e20172467. 
 
10 Risk(s) associated with these measurements in participants who require a supportive device may need to be 
considered by institutional review boards in their subpart D determinations (21 CFR part 50, subpart D, Additional 
Safeguards for Children in Clinical Investigations). 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
191   If the technology cannot be safely removed, measure the weight of the participant 
192  with the technology and subtracting its estimated weight (based on device 
193  specifications).  Include a source document that captures the weight of the technology 
194  and the scale weight, which would be the first recording of the data value.  Record 
195  this calculated weight (i.e., the weight of the participant minus the weight of the 
196  technology) as the participants weight.  In addition, document the weight of the 
197  participant with the technology and the estimated weight of the technology. 
198   
199    Weigh the participant in an examination gown and underwear, and remove all other 
200  clothing including shoes and socks.  Sponsors should have trial site personnel document 
201  the clothing worn when weight is measured and consider the following:  
202   
203   When a participant uses diapers, weigh the participant in a freshly changed diaper. 
204   
205   In preterm neonates, weigh the participant without a diaper or adjust the scale to zero 
206  to account for the diaper weight, prior to weighing the pediatric participant.  
207   
208    Weigh participants using a standing scale once they are able to independently stand still. 
209   
210    Consider the following techniques to measure weight in participants 2 years of age and 
211  older who cannot stand independently:  
212   
213   When the pediatric participant must be held by an adult, set the scale to zero to 
214  account for the adults weight, weigh the adult holding the pediatric participant and 
215  record the weight. 
216   
217   Use chair scales, bucket scales, wheelchair scales, or bed scales as appropriate for the 
218  intended patient population. 
219   
220    In participants with conditions that may result in fluid retention, document edema 
221  describing the location and degree of edema, using objective descriptors when possible 
222  (e.g., grade 1 to 3 ascites; 1+ to 4+ pretibial, pedal, presacral peripheral edema), that are 
223  based on definitions agreed upon with the appropriate review division and specified in 
224  the protocol. 
225   
226    Weigh dialysis-dependent participants after dialysis. 
227   
228  3.  Linear Growth (Length and Height) Assessment 
229   
230  Sponsors should consider the following for measuring length and height in pediatric participants 
231  enrolled in clinical trials: 
232   
233    Measure recumbent length in participants from birth to less than 2 years of age using a 
234  length board (or infantometer) with a fixed head piece, horizontal backboard, and an 
235  adjustable foot piece.  The length board should be placed on a flat, stable surface. 
236   
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Draft  Not for Implementation 
237    Measure standing height in participants 2 years of age and older using a stadiometer 
238  mounted at a right angle between a level floor and against a straight, vertical surface.    
239   
240    When transitioning from recumbent length to standing height measurements in 
241  participants between 2 to 3 years of age, measure both length and height.  
242   
243    Measure linear growth to the nearest 0.1 centimeter (cm). 
244   
245    Before measuring linear growth, remove shoes, hats, hair ornaments, and braids 
246  whenever possible because these items will interfere with accurate linear growth 
247  measurement. 
248   
249    Measure linear growth three times at each study visit to improve accuracy and consider 
250  the following:  
251   
252   Repeat measurements that are not clinically plausible (e.g., height measurement that 
253  is lower than the height measured at the previous or prior study visits).  
254   
255   Calculate the mean of the three linear growth measurements.  
256   
257   Record individual growth measurements and the mean of the measurements. 
258   
259   Use the mean value in linear growth analyses. 
260   
261    Provide details in the protocol on any alternative strategies that will be used for 
262  evaluating linear growth in trials enrolling pediatric participants with conditions that may 
263  affect measurement of linear growth (e.g., contractures, genetic syndromes including 
264  skeletal dysplasia, scoliosis).  For participants who are not cooperative with linear growth 
265  measurements, sponsors should consider an adjustment strategy based on 
266  recommendations by WHO11 or other professional health organizations.  
267   
268  4.  Head Circumference Assessment 
269   
270  Sponsors should consider the following for measuring head circumference in pediatric 
271  participants enrolled in clinical trials: 
272   
273    Measure head circumference (HC) using a nonelastic tape measure. 
274   
275    Measure HC in all participants younger than 2 years of age or until sutures are fused.  
276   
277    Measure HC in participants 2 years of age and older in some clinical situations (e.g., 
278  neurocognitive impairment, microcephaly, macrocephaly, diseases that affect 
279  neurodevelopment) and in trials investigating therapeutics that may cause neurotoxicity. 
 
11 See the Child Growth Standards web page on the WHO website at https://www.who.int/tools/child-growth-
standards/standards. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
280   
281    Measure HC at the maximum diameter of the head (the glabella to the occiput) and to the 
282  nearest 0.1 cm.  Abnormal head shape (e.g. craniosynostosis, positional plagiocephaly, 
283  microcephaly) should be documented. 
284   
285    Measure HC three times at each study visit to improve accuracy and also consider the 
286  following:  
287   
288   Repeat measurements that are not clinically plausible.  
289   Calculate the mean of the three HC measurements.  
290   Record individual HC measurements and the mean of the measurements. 
291   Use the mean value in HC analyses. 
292   
293  5.  Other Considerations 
294   
295  Sponsors should also consider the following when enrolling pediatric participants in clinical 
296  trials: 
297   
298    Confirm diagnoses for genetic disorders affecting growth with molecular or cytogenetic 
299  testing to ensure use of appropriate growth charts and accurate interpretation of 
300  anthropometric data.  
301   
302    Discuss collection of relevant family history data (e.g., growth and puberty patterns) with 
303  the appropriate review division. 
304   
305  Note that FDA currently does not recognize biomarkers as validated assessments of growth.   
306   
307  B.  Pubertal Development 
308   
309  Sponsors enrolling pediatric participants in clinical trials should use a sexual maturity rating 
310  (e.g., Tanner Staging) to evaluate and document pubertal development at baseline (i.e., trial 
311  entry) and at regular intervals based on the potential safety concerns associated with the drug and 
312  the pubertal development stage of the pediatric participant.  Sponsors should also consider the 
313  following: 
314   
315    Discuss with the appropriate review division the appropriate intervals for evaluation of 
316  pubertal development. 
317   
318    Sexual maturity ratings should be based on both breast and pubic hair changes in females 
319  and on both genital and pubic hair changes in males.  Evaluation of genital changes in 
320  males should include an assessment of testicular volume using an orchidometer. 
321   
322    Discontinue or do not initiate pubertal development assessments when the participant has 
323  completed puberty (i.e., Tanner 5).  FDA also recommends the following: 
324   
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Draft  Not for Implementation 
325   Train investigators and examiners on how to conduct sexual maturity ratings.  
326  Whenever possible, the same trial health care professional should evaluate pubertal 
327  development. 
328   
329   Identify and record the age at menarche for female participants. 
330   
331  C.  Other Measurements 
332   
333  1.  Skeletal Age 
334   
335  Sponsors should consider the following recommendations when assessing skeletal age in 
336  pediatric participants enrolled in clinical trials:  
337   
338    Evaluate skeletal maturation by validated assessments and tools to provide information 
339  about skeletal maturity compared to chronological age.  Potential bone age assessments 
340  include imaging of the following: 
341   
342   For hand and wrist bones, using the following: 
343   
344    X-ray (Greulich and Pyle method, Tanner-Whitehouse method, Gilsanz and 
345  Ratibin atlas, or computer-assisted skeletal bone age systems) 
346   
347    Ultrasound 
348   
349    Magnetic resonance imaging 
350   
351   For knee joints, using X-ray (OConnor knee scale) 
352   
353    Discuss the appropriate bone age assessments for the trial participant population with the 
354  appropriate review division. 
355   
356    Use the same validated methodology or instrument for all participants throughout the trial 
357  to improve consistency and accuracy.  Sponsors can consider alternative methods if 
358  adequate validation is demonstrated.  
359   
360    For consistency, reassess all readings with a blinded, single central reader, when using 
361  reader dependent methods, to limit interreader reliability issues intrinsic to these 
362  methods.  Sponsors should use the results from the single central reading as the primary 
363  data source for analyses. 
364   
365    For body proportions, discuss with the appropriate review division the need for additional 
366  measurements in pediatric participants with specific diseases known to be associated with 
367  disproportionate growth (e.g., Marfan syndrome, skeletal dysplasia).  
368   
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369  2.  Dual-Energy X-ray Absorptiometry Scan 
370   
371  Depending on the study population, sponsors that enroll pediatric participants in clinical trials 
372  can use dual-energy X-ray absorptiometry (DXA) scans to monitor bone mineral density, bone 
373  mineral content, and body composition.  Sponsors should discuss the conduct of DXA scans with 
374  the appropriate review division. 
  10