Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on Growth in Children

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

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
Guidance for Industry1
Orally Inhaled and Intranasal Corticosteroids:
Evaluation of the Effects on Growth in Children
This guidance represents the Food and Drug Administration’s (FDA’s) 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.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s 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 child’s 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). Rudolph’s 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 FDA’s 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 molecule’s 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 patient’s 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 FEV1 ) can be managed less
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 study’s 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 (FEV1 in patients who are able to perform this test, or
peak flow rates in patients who are unable to perform an FEV1 maneuver because of age). Peak
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
REFERENCES
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 Rudolph’s Pediatrics, 20th
Edition, Appleton and Lange.
National Heart, Lung, and Blood Institute, National Institutes of Health, Pub No 97-4051,
NAEPP Guidelines for the Diagnosis and Management of Asthma 1997.
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.
14