Guidance for Industry
 
Orally Inhaled and Intranasal 
Corticosteroids:  Evaluation of the 
Effects on Growth in Children 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
   March 2007 
Clinical/Medical 
 
 
   
Guidance for Industry 
Orally Inhaled and Intranasal 
Corticosteroids:  Evaluation of the 
Effects on Growth in Children 
 
 
 
Additional copies are available from: 
 
Office of Training and Communications 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD  20857 
(Tel) 301-827-4573 
http://www.fda.gov/cder/guidance/index.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
   March 2007 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  OVERVIEW OF RECOMMENDATIONS FOR GROWTH STUDIES....................3 
IV.  GENERAL GROWTH STUDY DESIGN RECOMMENDATIONS..........................4 
V.  PROTOCOL DESIGN.....................................................................................................6 
A.  Inclusion Criteria...........................................................................................................................6 
B.  Exclusion Criteria..........................................................................................................................7 
C.  Dose and Dosage Regimens...........................................................................................................8 
D.  Action Plan for Worsening Symptoms.........................................................................................8 
E.  Methodology to Ensure Adequacy of Interpretability................................................................9 
1. Treatment Controls..........................................................................................................................9 
2. Assessment of Patient Adherence...................................................................................................10 
3. Assessment of Data Points.............................................................................................................10 
F.  Sample Size...................................................................................................................................10 
VI.  DATA ANALYSIS..........................................................................................................11 
A.  Primary Analysis..........................................................................................................................11 
B.  Secondary Analyses.....................................................................................................................11 
C.  Other Safety Endpoints and Analyses........................................................................................12 
D.  Efficacy Endpoints and Analyses...............................................................................................12 
REFERENCES............................................................................................................................14 
  Contains Nonbinding Recommendations 
1
Guidance for Industry
Orally Inhaled and Intranasal Corticosteroids:   
Evaluation of the Effects on Growth in Children 
 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations for sponsors of orally inhaled and intranasal 
corticosteroids regarding the design, conduct, and evaluation of clinical studies to assess the 
effects of these drug products on growth.  The recommendations comprise study design and 
efficacy and safety issues for: 1) approved drug products whose treatment effect on 
prepubescent growth has not been adequately characterized, and 2) potential new drug products 
that could be used in the treatment of allergic rhinitis and/or asthma in children.  Although the 
recommendations in this guidance specifically apply to intranasal and orally inhaled 
corticosteroids, many of the recommendations can be extended to include evaluation of possible 
growth effects with other therapies for asthma and allergic rhinitis. 
 
This guidance does not address study designs for comparison of two different products 
containing the same active moiety.  This guidance also does not address study designs for the 
effects of orally inhaled and intranasal corticosteroids on final adult height.  The study design 
considerations suggested in this guidance are not intended to reproduce actual clinical practice.  
Rather, this guidance outlines characteristics of study designs that can reduce the variability 
and/or potential bias of the estimates of differences in growth velocity between treatment groups. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
                                                 
1 This guidance has been prepared by the Division of Pulmonary and Allergy Products in consultation with the 
Division of Metabolism and Endocrinology Products and the Office of Biostatistics in the Center for Drug 
Evaluation and Research (CDER) at the Food and Drug Administration. 
1  Contains Nonbinding Recommendations 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
Information regarding the potential adverse effects of orally inhaled and intranasal 
corticosteroids on growth rates in children first became available in the mid-1990s.  Studies 
submitted to the FDA with several different active corticosteroid moieties demonstrated reduced 
growth velocities over a 1-year time period of approximately 1 centimeter (cm) per year among 
active treatment groups exposed to orally inhaled or intranasal corticosteroids as compared to 
control groups (placebo or noncorticosteroid asthma treatments such as beta-agonists).   
 
After the FDA received the results of several growth studies with intranasal and orally inhaled 
corticosteroids in 1996-7, the FDA convened a joint meeting between the Pulmonary Allergy 
Drugs Advisory Committee and the Endocrine and Metabolic Drugs Advisory Committee in 
1998 to discuss the implications for the labeling of these drug products.  Results from the 
available growth studies were presented.  The joint Advisory Committee recommended the 
addition of labeling for orally inhaled and intranasal corticosteroids to the Precautions/General, 
Precautions/Pediatric Use, and Adverse Reactions sections.  The recommended labeling 
presumes that all corticosteroids administered by all routes can potentially have systemic effects, 
including effects on growth.  This finding is considered to be a class effect, the result of a 
presumed direct effect on bone osteoclast-osteoblast activity as well as indirect hormonal effects. 
Based on the joint Advisory Committee recommendation, the FDA sent a letter to the holders of 
new drug applications for all orally inhaled and intranasal corticosteroids on file as of November 
1998, requesting the addition of standardized language to the labeling regarding the potential for 
effects on growth.2  Labeling changes were implemented in 1998-9.   
 
 
                                                 
2 The language shown below is what was requested in 1998, with currently recommended modifications.  Some of the wording is 
no longer applicable, or has since been modified for clarity.  Language in square brackets (e.g., [orally inhaled/intranasal]) is to 
be inserted as appropriate.  The product name is to be inserted by the sponsor.  Language in curly brackets {} can be omitted.  
Some labels have minor variations of the wording. 
PRECAUTIONS, General: [Orally inhaled/intranasal] corticosteroids may cause a reduction in growth velocity when 
administered to pediatric patients (see PRECAUTIONS, Pediatric Use section). 
PRECAUTIONS, Pediatric Use: Controlled clinical studies have shown that [orally inhaled/intranasal] corticosteroids may 
cause a reduction in growth velocity in pediatric patients.  {In these studies, the mean reduction in growth velocity was 
approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of 
exposure.}  This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) 
axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in 
pediatric patients than some commonly used tests of HPA axis function.  The long-term effects of this reduction in growth 
velocity associated with [orally inhaled/intranasal] corticosteroids, including the impact on final adult height, are unknown. 
The potential for catch-up growth following discontinuation of treatment with [orally inhaled/intranasal] corticosteroids 
has not been adequately studied.  The growth of pediatric patients receiving [orally inhaled/intranasal] corticosteroids, 
including (product name), should be monitored routinely (e.g., via stadiometry).  The potential growth effects of prolonged 
treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives.  To 
minimize the systemic effects of [orally inhaled/intranasal] corticosteroids, including (product name), each patient should 
be titrated to {his/her lowest effective dose} [the lowest dose that effectively controls his or her symptoms]. 
ADVERSE REACTIONS: Cases of growth suppression have been reported for [orally inhaled/intranasal] corticosteroids 
[including (product name), if appropriate] (see PRECAUTIONS, Pediatric Use section).  
  2 Contains Nonbinding Recommendations 
III.  OVERVIEW OF RECOMMENDATIONS FOR GROWTH STUDIES 
 
Many long-term adverse consequences of the systemic activity of corticosteroids are difficult to 
measure.  Our experience has been that growth studies have yielded positive results even when 
carefully performed hypothalamic-pituitary-adrenal axis studies have not.  Therefore, we believe 
that well-conducted growth assessments represent one of the most sensitive indicators of 
systemic effects of corticosteroids, and should be considered an important sentinel of 
unmeasured systemic effects.  For this reason, the FDA considers growth information important 
additional safety information for orally inhaled and intranasal corticosteroid drug products, and 
we encourage sponsors to perform growth studies as part of their development program.  
Sponsors should discuss with the review division the timing of submission of the results of a 
growth study with respect to their overall development program. 
 
The growth studies that the FDA has reviewed have varied greatly in their designs.  Although 
some studies focused on the question of potential differences in growth rates between treatment 
regimens that represent how children are actually treated in clinical practice, this approach has 
led to the introduction of confounders that limited the interpretation of the studies results.  
Specifically, some studies allowed for one or more of the following practices: titration of 
corticosteroid dose, generous use of oral corticosteroids as rescue medication, and inclusion of 
older children who could potentially enter the pubertal growth spurt during the trial.  
Measurement error and missing data further complicated the analyses and results.  The 
recommendations provided in this guidance are based on an in-depth review of the issues raised 
by these types of pediatric growth studies.  Sponsors are strongly encouraged to discuss details 
of study design and specific issues relating to individual drug products with the review division 
before conducting clinical trials that estimate growth effects. 
 
It should be noted that the recommendations for pediatric growth studies contained in this 
guidance reflect normative growth data gathered from healthy children in a U.S. population.  
Sponsors planning to conduct international studies should take this observation into 
consideration and are strongly encouraged to contact the Division of Pulmonary and Allergy 
Products for further guidance before the initiation of such trials.   
 
The growth study recommendations described in this guidance do not fit into the usual 
framework of a superiority, inferiority, or equivalence study, and we discourage growth studies 
from being designed and interpreted in this manner.  Rather, the objective of a growth study 
should be to characterize, as accurately as possible, the estimate of the difference in 
prepubescent growth velocities between treatment with an active moiety and a control group.  
The reasoning for not using an hypothesis testing design (e.g., superiority, inferiority, or 
equivalence study) is because systemically administered corticosteroids are known to affect 
growth.  Since there is a presumption of a growth effect, the studies should be designed to 
characterize that effect as fully as feasible. 
 
The goal of growth studies characterized in this guidance is, in many respects, pharmacodynamic 
in nature.  The safety information from such studies is considered a stand-alone measure of the 
potential of a corticosteroid to cause systemic effect.  To detect a deceleration in growth velocity 
over the approximate 1-year study course, the expected growth velocity should be relatively 
  3 Contains Nonbinding Recommendations 
constant.  For this reason, we recommend that growth studies be conducted during a narrow 
window of age ranges during the so-called growth hormone dependent phase between the 
infant/toddler and pubescent growth periods, when the growth velocity is relatively linear.  This 
age range is the only one with relatively constant background growth velocity, providing 
accurate measurement and a less confounded comparison of active and control treatments over 
time.  Although the growth effect is measured in children, the pharmacodynamic effect is not 
age-limited and is applicable to patients of all ages. 
 
The clinical relevance of the differences in prepubescent growth velocities on final adult height 
as estimated by 1-year trials is yet unknown.  Several studies have evaluated effects on longer-
term growth, but the growth studies recommended in this guidance are relatively short, and not 
designed to determine effects on longer-term growth.  These studies are not designed to 
determine whether the changes are transient or permanent, or whether catch-up growth occurs 
with continued use.  Because the clinical relevance of the differences in prepubescent growth 
velocities on final adult height is unknown, a clinically meaningful difference of 1-year growth 
velocities between treatment groups can be difficult to define.  Therefore, the sample size of the 
study should be based on the desired precision (width of a 95 percent confidence interval) for the 
treatment effect and not on a clinically meaningful difference between treatments (see section 
V.F., Sample Size). 
 
In general, an evaluation of growth should be performed separately for both orally inhaled and 
intranasal formulations containing the same active moiety of a corticosteroid where products 
given by both routes of administration are proposed for marketing.  Separate evaluations are 
preferred because of substantial differences in the bioavailability of the two routes of 
administration for a corticosteroid and because of differences in the risk-to-benefit ratios for 
intranasal and orally inhaled indications.  However, in certain circumstances, sponsors of both 
orally inhaled and intranasal corticosteroid products that contain the same active moiety can use 
pharmacokinetic data to bridge the growth findings associated with one formulation to a second 
formulation.  Systemic exposure from an orally inhaled formulation may be adequate to support 
an intranasal formulation provided that the systemic exposure is higher with the orally inhaled 
formulation and a well-conducted growth study with the orally inhaled formulation shows no 
growth effect.  Consultation with the review division is recommended before and during the 
design of a bridging program. 
 
 
IV.  GENERAL GROWTH STUDY DESIGN RECOMMENDATIONS  
 
General recommendations for designing growth studies in children with asthma and/or allergic 
rhinitis are described in the following bulleted list.  Adherence to these recommendations can 
help minimize variability in results and improve interpretability of findings.   
 
  For both the orally inhaled and the intranasal corticosteroids, assessment of growth 
effects should be based on adequate and well-controlled phase 3 or phase 4, double-blind, 
randomized, parallel group clinical trials.  There should be a single-blind (patient-
blinded) baseline period to assess baseline growth velocity.  There also should be a 
follow-up period (preferably using a single-blind placebo or noncorticosteroid 
  4 Contains Nonbinding Recommendations 
medication, as described earlier) to assess potential short-term catch-up growth and to 
assess Tanner stage.  The duration of the baseline period should be at least 16 weeks, the 
treatment period should be at least 48 weeks, and the follow-up period should be at least 
8 weeks.  Use of stadiometer data from office visits before randomization as baseline data 
in lieu of the baseline period may be appropriate under some circumstances.  However, 
the sponsor is encouraged to consult with the review division concerning this approach 
because of the potential to introduce variability into baseline growth velocity estimates.   
 
  Measurements should be made using stadiometry and recorded to the nearest 10th of a 
centimeter.  If the stadiometer has not been calibrated in the previous 4 hours, it should 
be calibrated immediately before use.  The stadiometric measurement protocol should be 
specific (e.g., no socks, shoes, or hats; three reproducible measurements; calibration 
frequency). 
 
  The study design should incorporate practices that reduce measurement error.  The 
investigators or examiners should be trained in stadiometry and calibration procedures.  
Ideally, the same person should measure the patients at every visit and should be blinded 
to the patients status in the study (e.g., on-study, receiving double-blind treatment, 
discontinued, receiving open-label treatment).  Visits should be scheduled so that 
measurements can be taken at approximately the same time of day throughout the study.  
 
  The sponsor should make every effort to obtain growth measurements as planned, 
irrespective of whether patients discontinue the study medication.  Although patients who 
discontinue study treatment may be administered other medications that affect growth, 
measurements obtained after discontinuation are useful for assessing the sensitivity of the 
analyses and results (see section VI.B., Secondary Analyses). 
 
  The investigator, examiner, patient, caregiver, and study personnel should remain blinded 
to the study treatment for patients who discontinue, unless unblinding is important for 
safety or treatment decisions. 
 
  To minimize the confounding effects of nonlinear growth rates and inaccuracies inherent 
in measurement of recumbent length, we recommend avoiding enrollment of children 
younger than 3 years of age.  Likewise, we recommend not recruiting children near the 
time of puberty because of the rapid increase in growth velocity that can occur over a 
relatively brief period (Tanner and Davies 1985).  Although information concerning 
growth suppression during the pubertal growth spurt has clinical relevance, the 
interpretation of resultant data is confounded when a childs growth velocity undergoes 
normal physiological acceleration associated with puberty.  For this reason, prepubertal 
children are preferred, and the study design should minimize the likelihood of patients 
entering puberty during the study.   
 
  Tanner staging at baseline and during the treatment and follow-up periods is intended to 
help identify patients entering puberty.  However, such assessments may not identify all 
patients experiencing a pubertal growth spurt.  The first measurable sign of puberty in 
girls can be the beginning of the growth spurt, and it can precede the onset of secondary 
  5 Contains Nonbinding Recommendations 
sexual characteristics by as much as 1 year (Kaplan and Love 2001; Kulin 1996).  There 
are conflicting statements in the literature about the timing of the growth spurt in boys 
relative to the onset of secondary sexual characteristics.3  Nevertheless, we recommend 
Tanner staging.  In addition, stratified randomization based on age and sex is 
recommended to help balance the percentage of patients whose pubertal growth spurt 
may have already begun during the baseline period or will begin during the treatment 
period. 
 
 
V.  PROTOCOL DESIGN 
 
A.  Inclusion Criteria 
 
For reasons stated earlier, the lower age limit for enrollment should be patients 3 years of age.  
To minimize the potential for patients to reach the onset of puberty during the trial, the inclusion 
criteria should limit the maximal age of the male subjects to those who will be 10.5 years and the 
maximal age of the female subjects to those who will be 9.5 years at the end of the follow-up 
period.  The sponsor is encouraged to set the upper age limit inclusion criteria as low as feasible 
to minimize the likelihood of recruiting pubertal children, based on prior recruitment experiences 
and available normative data for the population under study.  The sponsor should choose an age 
range that is appropriate to the drug product, indication, and good clinical practices (i.e., 
stadiometry and FEV/Peak Flow measurements, ability to coordinate use of an inhaler).   
 
The patient population for intranasal products should have a history of perennial allergic rhinitis 
with persistent symptoms for a minimum of 2 years before study entry.4
 
                                                 
3 Adolescent Medicine, 3rd Edition (1997), states that, The growth spurt [in males] usually begins at stage 3, 
reaches a peak during stage 4 and is all but complete by stage 5 (p. 13).  Rudolphs Pediatrics, 20th Edition (1996), 
section 22.9.1 states that, the initiation of the adolescent growth spurt precedes the onset of secondary sex 
characteristics by approximately 1 year in boys and girls.  
 
4 For recommended inclusion and exclusion criteria for patients with perennial allergic rhinitis, see the draft 
guidance for industry Allergic Rhinitis:  Clinical Development Programs for Drug Products.  When final, this 
guidance will represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check 
the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 
  6 Contains Nonbinding Recommendations 
For orally inhaled corticosteroids, patients with mild persistent asthma (National Heart, Lung, 
and Blood Institute 1997 and 2002) are the preferred population for a number of ethical and 
clinical design reasons.5,6  The population of children with mild persistent asthma is likely to be 
less subject to confounding variables than populations encompassing more severe disease (e.g., 
need for oral corticosteroid bursts).  This population should yield a more informative estimate of 
the growth effect compared to a more severely affected population, in whom both efficacy and 
growth effects can be confounded.  Children with mild persistent asthma are unlikely to suffer 
serious consequences if randomized to noncorticosteroid maintenance therapy but are 
sufficiently ill to justify potential randomization to corticosteroid therapy that may suppress 
growth.  Children with mild persistent asthma are expected to have limited, if any, need for oral 
corticosteroids during the 1-year treatment period; therefore, the effect of oral corticosteroid use 
on analyses of growth velocity will be minimized. 
 
Patients should have a history of mild persistent asthma for a minimum of 6 months before study 
entry.  Screening and first baseline visit qualification criteria should be set consistent with this 
diagnostic grouping.  Qualification should be performed after withholding beta-agonists for 6 or 
more hours.  Inclusion criteria can warrant modification if the sponsor is conducting a study of 
the growth effects of noncorticosteroid drug products to be used in the treatment of asthma. 
 
Since the intent of such studies is to characterize the formulation and not the molecules effect, 
we specifically discourage the use of a spacer for orally inhaled drug products.  Use of a spacer 
device creates an extemporaneous formulation that can result in different local effects and 
systemic bioavailability than that achieved by the drug product without the spacer device.  In 
vitro data show that a spacer used with certain orally inhaled corticosteroid metered dose 
inhalers can significantly reduce the amount of active drug inhaled if there is any delay between 
actuation and inhalation, potentially confounding the measurement of the growth effect of the 
drug product.  For this reason, we encourage inclusion of patients who are able to adequately 
coordinate use of the device without the addition of a spacer. 
 
B.  Exclusion Criteria 
 
Tanner staging should be performed at the end of each period (baseline, treatment, and follow-
up) to help identify pubescent patients.  Patients with Tanner stage greater than 1 during the 
baseline period should be excluded from entering the treatment period.  (Note that if patients 
become pubescent during the treatment or follow-up periods, they should remain in the trial, 
performing all visit procedures.)  Other exclusion criteria include:   
 
                                                 
5 Based on the consensus recommendations of the FDA Pediatric Subcommittee of the Anti-Infective Drugs 
Advisory Committee of November 15, 1999 (http://www.fda.gov/cder/pediatric/ethics-statement.htm), pediatric 
studies should be conducted in subjects who can benefit from participation in the trial.  Usually this implies the 
subject has or is susceptible to the disease under study.  The Advisory Subcommittee used a broad definition of 
potential benefit.  Since patients with mild intermittent disease by definition might not benefit from daily controller 
therapy, a population of mild persistent asthmatics is the preferred population. 
 
6 Investigational Review Board duties and criteria for pediatric studies fall under the jurisdiction of 21 CFR part 50, 
subpart D, Additional Safeguards for Children in Clinical Investigations. 
  7 Contains Nonbinding Recommendations 
  Baseline growth velocity less than the 3rd or greater than the 97th percentile.7 
 
  Weight and body mass index less than the 3rd or greater than the 97th percentiles.8 
 
  Bone age greater than 1 year different from the patients chronological age.  It is strongly 
recommended that the bone age be determined by a central reader for all study patients.9 
 
  Use of inhaled, intranasal, or high potency topical corticosteroids within 6 weeks and 
systemic corticosteroids within 3 months of the first baseline visit. 
 
  Use of corticosteroids by any route of administration likely to have a systemic effect 
during the baseline period. 
 
  Treatment at any time before screening that might influence growth, including, but not 
limited to, methylphenidate hydrochloride, thyroid hormone, growth hormone, anabolic 
steroids, calcitonin, estrogens, progestins, biphosphonates, anticonvulsants, or phosphate-
binding antacids. 
 
C.  Dose and Dosage Regimens 
 
For intranasal corticosteroids, sponsors are encouraged to study the highest dose proposed for 
the pediatric age range.  For orally inhaled corticosteroids, sponsors are encouraged to study the 
highest dose proposed for the pediatric age range, although a sponsor can consider a lower dose 
or range of doses in consultation with the division. 
 
D.  Action Plan for Worsening Symptoms 
 
The study protocol should specify the course of action to be taken in the event of worsening 
asthma or allergic rhinitis and should include the types and doses of allowed rescue medication.  
                                                 
7 The purpose of this criterion is to exclude patients with growth disorders from studies in which they may receive a 
growth-inhibiting drug.  Historical data can be used to determine historical growth velocity as an exclusionary 
criterion. 
 
8 If the study is to be performed in the United States, current standard growth charts for height, weight, and body 
mass index percentiles for age from the Centers for Disease Control and Prevention should be used 
(http://www.cdc.gov/growthcharts). 
 
9 Children whose bone age is greater than or equal to 2 years different from their chronological age are considered to 
be outside of the normal range for this parameter.  On this basis, it can be argued that a 1-year upper limit is unduly 
restrictive and that an upper limit of less than 2 years would be more appropriate.  Sponsors considering 
modification of their protocols based on this exclusion criterion are strongly urged to contact the review division for 
advice.  In particular, the importance of a 2-year difference between bone age and chronological age increases at the 
extremes of the prepubertal age range.  A 4-year-old child who has the bone age of a 2-year old is of greater concern 
than an 8-year old with a bone age of 6 years and is more likely to have baseline growth abnormalities.  Similarly, a 
9-year-old child with a bone age of 11 years may be close to entering his or her pubertal growth spurt and ideally 
should not be recruited into a growth study.  The importance of a close correlation between bone age and 
chronological age also increases if a non-U.S. study is contemplated, since normative data based on U.S. children 
may not apply (see section III, Overview of Recommendations for Growth Studies). 
  8 Contains Nonbinding Recommendations 
For worsening allergic rhinitis, an oral decongestant or antihistamine can be considered.  For 
safety reasons, standard-of-care guidelines should be followed in the management of all acute 
asthma exacerbations.  Asthma management can include repeat doses of beta-agonists and 
systemic corticosteroids, administered orally or parenterally, at the discretion of the primary 
investigator.  Worsening asthma control that is asymptomatic (e.g., when a patient is found to 
have a decline from baseline in peak expiratory flow rate or FEV ) can be managed less 
1
intensively.  Continued observation with no immediate change in therapy or the addition of (or 
increase in) an inhaled corticosteroid can be considered reasonable options.  In each of these 
cases, patients should be continued in the study, and the protocol should specify how rescue 
medication use will be analyzed between the treatment groups.  Analyses of outcomes under the 
various conditions of rescue medication use (dose and duration) should be provided in the 
clinical trial report (see section VI.B., Secondary Analyses). 
 
E.  Methodology to Ensure Adequacy of Interpretability 
 
In addition to the aforementioned general and specific recommendations regarding conduct of 
growth studies, the following recommendations can help ensure adequacy of interpretability of 
the findings. 
 
1.  Treatment Controls 
 
The choice of the comparator or control group selected for allergic rhinitis and asthma 
indications is critical to interpretability.  In addition, use of placebo control in studies involving 
children invokes ethical concerns.  The combination of both ethical and methodological issues 
makes careful selection of control and population studied essential to the adequate performance 
and evaluation of such studies. 
 
It is generally accepted that placebo-controlled studies can be ethically performed for the 
indication of allergic rhinitis.10  For these studies, use of a placebo is recommended because the 
risk-to-benefit ratio precludes use of a positive control. 
 
Choice of the control arm or arms is more complex in asthma studies.  We have found that 
placebo-controlled studies in pediatric patients with asthma can be performed ethically as long as 
the study population (mild persistent asthma) and action plans for worsening symptoms are 
clearly and specifically defined, as previously outlined (see section V.A., Inclusion Criteria, and 
section V.D., Action Plan for Worsening Symptoms).  One alternative methodology has been to 
include as a control arm a clinically appropriate, noncorticosteroid medication consistent with 
published guidelines (National Heart, Lung, and Blood Institute 1997 and 2002).  This 
methodology is acceptable, as long as the on-treatment growth effect for that drug product has 
already been well characterized.  One issue with the use of a placebo or an active comparator 
that is not expected to cause a growth effect is that if the study results show no growth effect for 
both the test treatment and the comparator, issues of interpretability may arise (e.g., low 
                                                 
10 See the consensus recommendations of the FDA Pediatric Subcommittee of the Anti-Infective Drugs Advisory 
Committee of September 11, 2000 (http://www.fda.gov/cder/pediatric/ethics-statement-2000.htm) for a discussion of 
the use of a placebo control group in pediatric studies. 
  9 Contains Nonbinding Recommendations 
adherence may have impaired an ability to show a growth effect in the test treatment).  For this 
reason, an ideal design might include three treatment arms: 1) test drug product; 2) a placebo or 
active comparator with a known lack of growth effects; and 3) use of an active control arm with 
a known growth effect (i.e., a positive control).  The positive control group would allow for an 
assessment of the studys ability to show a growth effect of the test drug product, were one to 
exist.  Since the choice of a comparator raises complex issues, the choice of the comparator or 
comparators for growth studies in asthma should be discussed with the review division. 
 
2.  Assessment of Patient Adherence 
 
Since lack of compliance with use of study drugs is a potential major source of false-negative 
findings in long-term studies, every effort should be made to maximize and document patient 
adherence to use of study drug.  The study protocol should specify how adherence to medication 
use will be determined and documented throughout the trial.  Possibilities include but are not 
limited to the use of patient diaries, weighing (for inhalers) or counting (for tablets) returned 
study drug, and efficacy assessments (see section VI.D., Efficacy Endpoints and Analyses). 
 
3.  Assessment of Data Points 
 
The protocol or prospective statistical analysis plan should specify the manner in which 
physiologically improbable data points or sequences of data points will be assessed (i.e., data 
points that demonstrate a large increase or decrease in height between visits, or a sequence of 
data points that show a pattern of linear growth for a time, then a sharp increase in height, 
followed by a decrease and the original linear pattern). 
 
F.  Sample Size 
 
As discussed in section III, Overview of Recommendations for Growth Studies, the growth 
effect seen in such a trial should be regarded as a pharmacodynamic surrogate of the potential for 
a corticosteroid drug to cause systemic effects.  Although there is general agreement that a 
decrement in growth velocity over a 1-year period can have clinical relevance, there remains 
some disagreement about how much change is clinically relevant.  Since a clinically meaningful 
difference in growth velocities between treatment groups has not been determined and can be 
difficult to accurately define, interpreting inferential statistical testing also can be difficult.  
Therefore, a stand-alone approach is highly recommended, with the objective of the study to 
yield an estimation of the growth rate and the surrounding confidence interval with a high level 
of precision.  If the sponsor plans to perform statistical tests comparing treatments, the study 
protocol or prospective statistical analysis plan should specify provisions for the statistical 
analyses and adjustments for multiple comparisons. 
 
Since the objective of a growth study is to quantify any effect on growth as a measure of the 
potential to cause systemic effects, powering need not rely on an estimation of a clinically 
meaningful difference in growth velocities between treatment groups.  Therefore, sample size 
estimations should be based on the desired precision (width of a 95 percent confidence interval) 
of the estimate of the difference in mean growth velocities between active and control 
treatments.  A high level of precision should be obtainable with a carefully controlled study (e.g., 
  10 Contains Nonbinding Recommendations 
few dropouts, complete follow-up on all patients, small measurement error), and a sample size of 
approximately 150 to 200 patients per arm.  Sponsors should perform their own sample size 
calculations based on the expected standard deviation using their planned study design, patient 
population, and active moiety.  Studies with 95 percent confidence intervals considerably wider 
than 0.5 cm likely will not be interpretable because of the lack of precision in the estimate of 
treatment effect.  Similarly, studies with high numbers of dropouts, incomplete data on many 
patients, or obvious problems with measurement error might not be reliable enough to be 
interpreted. 
 
 
VI.  DATA ANALYSIS 
 
A.  Primary Analysis 
 
The preferred measure of growth effects is the difference in growth velocity during the treatment 
period between active and placebo (or other noncorticosteroid) treatments.  Individual patient 
growth velocities during the baseline, treatment, and follow-up periods should be calculated.11  
A linear regression model is the preferred methodology to estimate growth velocity, since it 
takes into account all height measurements during the treatment period, whereas change from 
baseline in height does not.  An ANCOVA model involving all randomized patients with at least 
three recorded height measurements during the double-blind treatment period is recommended to 
estimate the mean difference between treatment groups in growth velocity over the treatment 
period.  Appropriate predefined factors and covariates should be used in the model as 
explanatory variables.  Factors that should be considered include baseline height, age, and sex.  
A 95 percent confidence interval around the mean difference in growth velocities between the 
control group and the active treatment group should be constructed.  No interim analyses should 
be performed.  
 
B.  Secondary Analyses 
 
The sponsor should perform the following secondary analyses: 
 
  Subset analyses excluding:  
  Any patient who exhibits greater than or equal to Tanner Stage 2 characteristics at 
any point during the treatment or follow-up period 
 
  Questionable height measurements 
 
  Measurements taken after children received rescue systemic corticosteroids during 
the double-blind treatment period 
 
                                                 
11 The last day of the baseline period is usually the first day of the treatment period.  The measurement on that day 
should be used in both the baseline growth velocity calculation and the treatment period growth velocity calculation. 
  11 Contains Nonbinding Recommendations 
  Analysis of the percent of children who are below a certain percentile of growth velocity 
(e.g., 3rd, 10th, 25th percentile) or percent of children whose percentile for height 
decreases during the treatment period 
 
  Categorical or shift analysis showing change in growth velocity percentile for each child 
from baseline to endpoint (e.g., by quartiles) 
 
  Analysis of the first 3 months of data 
 
  Summary of growth velocities during the pretreatment and follow-up periods 
 
  Descriptive comparison of the growth velocities based on sex and ethnicity 
 
The sponsor also should consider performing the following secondary analyses: 
 
  Analysis of efficacy (see section VI.D., Efficacy Endpoints and Analyses) 
 
  Analysis of standard deviation scores, using currently published standards12 
 
  Random coefficients analysis 
 
C.  Other Safety Endpoints and Analyses 
 
All routine laboratory tests (chemistry, hematology, liver function, and urinalysis) should be 
obtained in study patients at least four times: at screening and at the last visit of each phase of 
the study (baseline, treatment, and follow-up).  Also, assessment of adrenal response using a 
sensitive test (e.g., through 24-hour urinary-free cortisol level measurements or 24-hour plasma 
cortisol area under the curve, at pretreatment, study endpoint, and 6 weeks post-study) should be 
conducted in studies of corticosteroids.  The sponsor can choose to include evaluations of other 
safety endpoints.  The sponsor should summarize these data for each phase of the study 
(baseline, treatment, and follow-up periods) for each treatment group, as appropriate. 
 
D.  Efficacy Endpoints and Analyses 
 
Assessment of efficacy endpoints in these studies can help identify nonadherence and/or poorly 
controlled asthma or allergic rhinitis.  Therefore, for the asthma studies, pulmonary function tests 
should be performed at every office visit (FEV  in patients who are able to perform this test, or 
1
peak flow rates in patients who are unable to perform an FEV  maneuver because of age).  Peak 
1
flow rates, asthma symptom scores, and use of rescue medication should be recorded in daily 
diaries.  For allergic rhinitis studies, efficacy assessments should include nasal symptom scores 
                                                 
12 The current equation used for calculation of standard deviation scores is:  
(Observed height)-(NCHS Std Median HT for age at baseline)
(NCHS Standard 95 percentile HT 5 percentile HT)
2 X 1.645
 
  12 Contains Nonbinding Recommendations 
and use of rescue medication recorded in patient diaries.13  The sponsor should summarize these 
data for each study phase (baseline, treatment, and follow-up periods) for each treatment group. 
 
 
                                                 
13 We suggest evaluation of the following instantaneous and/or reflective symptom scores: rhinorrhea, nasal 
congestion, nasal itching, and sneezing, rated on a 0-3 scale of severity before dosing.   
  13 Contains Nonbinding Recommendations 
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Berkey, CS, 1993, Longitudinal Height Velocity Standards for U.S. Adolescents, Statistics in 
Medicine, 12:403-414. 
 
Herman-Giddens, ME, EJ Slora, RC Wasserman, CJ Bourdony, MV Bhapkar et al., 1997, 
Secondary Sexual Characteristics and Menses in Young Girls Seen in Office Practice:  A Study 
from the Pediatric Research in Office Settings Network, Pediatrics, 4:505-512. 
 
Hoffmann, AD and DE Greydanus, 1997, Adolescent Medicine, 3rd Edition, Appleton and 
Lange. 
 
Kaplan, DW and KA Love, 2001, Adolescence, Chapter 4 in Current Pediatric Diagnosis and 
Treatment, 15th Edition, Lange Medical Books/McGraw-Hill. 
 
Kulin, HE, 1996, Normal Pubertal Development, Section 22.9 in Rudolphs Pediatrics, 20th 
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National Heart, Lung, and Blood Institute, National Institutes of Health, Pub No 97-4051, 
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National Heart, Lung, and Blood Institute, National Institutes of Health, Pub No 02-5075, 
NAEPP Guidelines for the Diagnosis and Management of Asthma  Update on Selected Topics 
2002. 
 
Tanner, JM and PS Davies, 1985, Clinical Longitudinal Standards for Height and Height 
Velocity for North American Children, Journal of Pediatrics, 107:317-329. 
 
Voss, LD, BJ Bailey, K Cumming, TJ Wilkin, and PR Betts, 1990, The Reliability of Height 
Measurement (The Wessex Growth Study), Archives of Disease in Childhood, 65:1340-1344. 
 
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