Pediatric 

Gastroesophageal Reflux 

Disease:  Developing 

Drugs for Treatment 
 
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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 CDR Stacy Barley at 301-796-2137.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2017 

Clinical/Medical 

 
1152011dft.doc  
09/29/17    
Pediatric 

Gastroesophageal Reflux 

Disease:  Developing 

Drugs for Treatment 

Guidance for Industry 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
 
Silver Spring, MD  20993-0002  

Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353;  Email: druginfo@fda.hhs.gov 
 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2017 

Clinical/Medical 

   
TABLE OF CONTENTS 
 
 
I.	   INTRODUCTION............................................................................................................. 1
  
II.	   BACKGROUND OF PEDIATRIC GERD ..................................................................... 2 
 
A. 	  Physiology, Natural History, and Definitions of Gastroesophageal Reflux and 

Gastroesophageal Reflux Disease in Pediatric Patients .............................................................. 2
  
B. 	  Clinical Features of GER and GERD .......................................................................................... 3 
 
1.  Neonates (Birth to 1 Month) ............................................................................................................ 3
  
2.  Infants (1 Month to Younger Than 1 Year) ...................................................................................... 4 
 
3.  Children (1 Year to Younger Than 12 Years) .................................................................................. 4 
 
4.  Adolescents (12 Years to 17 Years) ................................................................................................. 4 
 
III. 	  DRUG DEVELOPMENT STRATEGY:  PARADIGMS AND REGULATORY 

CONSIDERATIONS ........................................................................................................ 5 
 
A.   Establishing Efficacy-Regulatory Requirements in Different Age Cohorts ............................. 5
  
1.  Age Cohorts ..................................................................................................................................... 5
  
2.  Pediatric Extrapolation ................................................................................................................... 5
  
B.   Dose Finding................................................................................................................................... 7
  
C.   Establishing Safety-Regulatory Requirements ........................................................................... 8 
 
1.  Nonclinical ....................................................................................................................................... 8
  
2.  Clinical............................................................................................................................................. 8
  
IV.   CLINICAL TRIAL DESIGN CONSIDERATIONS ..................................................... 9 
 
A.   Erosive GERD ................................................................................................................................ 9
  
B.   Symptomatic GERD .................................................................................................................... 10 
 
1.  Adolescents (12 Years to Younger Than 18 Years) ........................................................................ 11 
 
2.  Children (6 Years to 11 Years) ...................................................................................................... 11 
 
3.  Children (1 Year to 5 Years) .......................................................................................................... 11 
 
4.  Infants (1 Month to Younger Than 1 Year) .................................................................................... 11 
 
REFERENCES............................................................................................................................ 13 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Pediatric Gastroesophageal Reflux Disease:  
1 
Developing Drugs for Treatment 
2 
1 
Guidance for Industry  
3 
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  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
20  treatment of gastroesophageal reflux disease (GERD) in the pediatric population, encompassing 
21  infants, children, and adolescents. Specifically, this guidance addresses the Food and Drug 
22  Administrations (FDAs) current thinking regarding clinical presentation by age and disease, 
23  study populations, endpoints, and clinical pharmacology issues affecting dosing.  This draft 
24  guidance is intended to serve as a focus for continued discussions among the Division of 
25  Gastroenterology and Inborn Errors Products, pharmaceutical sponsors, the academic 
26  community, and the public.2    
27   
28  This guidance does not contain discussion of the general issues of statistical analysis. That topic 
29  is addressed in the ICH guidance for industry E9  Statistical Principles for Clinical Trials.3   
30   
                                                 
1  This guidance has been prepared  by  the Division  of Gastroenterology  and Inborn  Errors Products in  the Center for 
Drug Evaluation and Research at the Food and Drug Administration.   
 
2 In addition to consulting  guidances, sponsors are encouraged to contact the division to  discuss specific issues that 
arise during the development of drugs to treat pediatric GERD.  
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance web page  at  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  1
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
31  Sponsors are encouraged to discuss the specifics of pediatric programs as early as is feasible with 
32  the division on a case-by-case basis because sponsors are required to submit pediatric study plans 
33  under the Pediatric Research Equity Act no later than 60 days after an end-of-phase 2 meeting.4    
34   
35  The following guidances for industry provide additional information: 
36   
37     Draft guidance for industry General Clinical Pharmacology Considerations for Pediatric 
38  Studies for Drugs and Biological Products5  
39   
40     Draft guidance for industry Pediatric Study Plans: Content of and Process for 
41  Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans6  
42   
43     Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, 
44  and Regulatory Applications  
45   
46     Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
47  Development to Support Labeling Claims  
48   
49  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
50  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
51  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
52  the word should in Agency guidances means that something is suggested or recommended, but 
53  not required. 
54   
55   
56  II.  BACKGROUND OF PEDIATRIC GERD 
57   
58  A.  Physiology, Natural History, and Definitions of Gastroesophageal Reflux and 
59  Gastroesophageal Reflux Disease in Pediatric Patients  
60   
61  There are several anatomical structures that protect a patient against the development of reflux of 
62  acidic contents of the stomach (i.e., gastroesophageal reflux (GER)).  This antireflux barrier  
63  consists of the lower esophageal sphincter (LES), the crural diaphragm, and the 
64  phrenoesophageal ligament.  Non-erosive reflux disease (i.e., GER disease, or GERD) in the 
65  pediatric patient is defined by the presence of troublesome symptoms caused by the reflux of 
66  gastric contents and by the absence of mucosal breaks observed during endoscopy.  It is also 
67  referred to as symptomatic GERD.  Some of the pathogenic factors that can lead to the 
                                                 
4 Or such other time as may be agreed upon between FDA and the sponsor  (section 505B(e)(2)(A)  of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act); 21 U.S.C. 355c(e)(2)(A)).  For further information, FDA recommends 
sponsors refer to section  505B of the FD&C Act, and to the draft guidance for industry Pediatric Study Plans:   
Content of  and Process for Submitting Initial Pediatric Study Plans and  Amended  Initial Pediatric Study Plans. 
When  final, this guidance will represent the FDAs current  thinking on this topic. 
 
5  When final, this guidance will represent the FDAs current  thinking on this topic. 
 
6 Ibid. 
  2
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
68  development of GERD include transient LES relaxation, impaired esophageal clearance, delayed 
69  gastric emptying, and increased gastric volume  or pressure.  GERD may progress to erosive 
70  disease (eGERD, including erosive esophagitis).  Endoscopic classifications are used to grade the 
71  severity of erosive disease, by the presence and extent of mucosal breaks or erosions (Sherman, 
72  Hassall, et al. 2009). 
73   
74  As children grow older, they appear to naturally regurgitate less of their feedings.  When one 
75  examines the prevalence of regurgitation by quartiles of a year, infants at 4 to 6 months of age 
76  have the highest rates of regurgitation (67 percent at least once per day; 23 percent at least four 
77  times per day).  For 0- to 3-month olds, 51 percent regurgitate at least once per day and 17 
78  percent regurgitate at least four times per day.  In 7- to 9-month olds, the prevalence drops to 21 
79  percent of children regurgitating at least once per day and 7 percent of children regurgitating at 
80  least four times per day.  At 10 to 12 months old the prevalence drops further to 5 percent at least 
81  once per day and 3 percent at least four times per day (Nelson, Chen, et al. 1997).  By 2 years of 
82  age, this percentage drops to less than 1 percent (Martin, Pratt, et al. 2002).  When one examines 
83  the incidence rates in children ages 1 to 17, there is a U-shaped curve with the nadir at ages 8 to 
84  9 (approximately 0.6 per 1,000 patient years).  The incidence is highest at ages 16 to 17 
85  (approximately 2 per 1,000 patient years), closer to that of adults, and second highest at age 1 
86  (approximately 1.5 per 1,000 patient years) (Ruigomez, Wallander, et al. 2010). 
87   
88  B.  Clinical Features of GER and GERD 
89   
90  Practitioners must distinguish between GER and GERD.  GERD is GER with pathological signs 
91  and symptoms and/or complications, including the development of erosive esophagitis as a 
92  sequelae of GERD.  The clinical features of GERD vary with age and include regurgitation, 
93  vomiting, food refusal, growth effects, and, in patients able to complain, epigastric discomfort, 
94  acidic taste, heartburn, and abdominal pain.  Diagnosis based on signs and symptoms is more 
95  difficult in the younger age groups, while in adolescence, symptoms alone may be sufficient to 
96  make the initial diagnosis of GERD.  In patients who can accurately communicate these typical 
97  signs and symptoms (without pathological features (e.g., weight loss, failure to thrive)), currently 
98  the standard of care in a community setting would be an empiric trial of medication.  However, 
99  to confirm the existence of erosions, endoscopy would be required to diagnose eGERD, even in 
100  adolescents. 
101   
102  1.  Neonates (Birth to 1 Month) 
103   
104  Nonspecific signs and symptoms of GER can occur within the neonatal period.  GER may be a 
105  normal phenomenon in neonates and infants because of their age-specific body position and high 
106  fluid intake (Poets, Brockman, et al. 2011).  Clinical signs presumed to be associated, without 
107  confirmation of pathobiology, with GERD in the neonatal period include apnea, failure to thrive, 
108  and pulmonary complications, particularly in preterm infants.  Whether or not these clinical signs 
109  and symptoms indicate a diagnosis of GERD is unclear (Abu Jawdeh and Martin 2013).   
110   
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111  Signs and symptoms of GERD may be acid-mediated or non-acid-mediated.  Acid-mediated 
112  GERD is similar to GERD seen in older infants and other pediatric age groups.  Non-acid
113  mediated GERD symptoms may be because of poor motility of gastric contents and is not 
114  improved by acid-limiting drugs.  The pathogenic role of non-acid regurgitation requires further 
115  study before a relationship, if any, can be established with neonatal presentations of GERD and 
116  its complications.   
117   
118  2.  Infants (1 Month to Younger Than 1 Year) 
119   
120  GER is common in infants. Up to 67 percent of 4-month-old infants have regurgitation more 
121  than once a day (Campanozzi, Boccia, et al. 2009).  Regurgitation will resolve in most infants by 
122  10 to 12 months of age and can be treated effectively with lifestyle changes alone (e.g., 
123  thickening feeds), without the need for pharmacologic therapy (Campanozzi, Boccia, et al. 
124  2009). Infants with GERD will demonstrate regurgitation, poor weight gain, and refusal to feed.  
125  The presentation of erosive esophagitis in this population is rare, based on epidemiological 
126  studies, and, where it exists, it is potentially related to pathogenic causes such as viral and 
127  bacterial infections, instead of GER. The signs and symptoms of GERD in infants can be caused 
128  by the effect of acid and non-acid reflux on the esophagus.  Because GERD in infants has many 
129  etiologies and presents diagnostic difficulties, sponsors who wish to develop drugs for this 
130  indication should request a meeting with FDA to discuss clinical trial designs.  
131   
132  3.  Children (1 Year to Younger Than 12 Years) 
133   
134  GERD may present as eGERD in this age cohort.  Eliciting accurate histories of pain and 
135  location of pain may be difficult in children younger than 8 to 12 years of age (Vandenplas, 
136  Rudolph, et al. 2009). In contrast to infants, toddlers and school age children may complain of 
137  abdominal pain, heartburn, respiratory problems including cough, feeding problems including 
138  odynophagia, dysphagia, weight loss, regurgitation, vomiting, and food refusal.  In children aged 
139  1 year to 5 years, cough, food refusal, and regurgitation/vomiting are more common than in older 
140  children.  Older children are more likely to complain of epigastric pain or heartburn and 
141  regurgitation (Sherman, Hassall, et al. 2009).  Signs and symptoms of eGERD are similar to 
142  those described for GERD, but also include endoscopic findings of esophageal erosions 
143   
144  4.  Adolescents (12 Years to 17 Years) 
145   
146  The clinical features of GERD are similar to those seen in adults.  The otherwise healthy 
147  adolescent should be able to describe symptoms  of heartburn and the location of abdominal pain.  
148  Thus, a diagnosis of GERD can be made when substernal, burning chest pain with or without 
149  regurgitation presents as primary symptoms.  Signs and symptoms of eGERD are similar to those 
150  described for GERD, but also include endoscopic findings of esophageal erosions, in addition to 
151  possible vomiting, hematemesis, and weight loss. 
152   
153   
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  Contains Nonbinding Recommendations 
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154  III.  DRUG DEVELOPMENT STRATEGY:  PARADIGMS AND REGULATORY 
155  CONSIDERATIONS  
156   
157  A.  Establishing  Efficacy-Regulatory Requirements in Different Age Cohorts 
158   
159  1.  Age Cohorts 
160   
161  Sponsors should address the entire pediatric age range (birth through 16 years).  If physiologic 
162  categories or groupings based upon systems ontogeny are used, they should be supported with 
163  scientific and developmental data.  Age cohort determination should be based on clinical and 
164  biological factors and drug characteristics. For example, healing of erosive esophagitis should 
165  be studied in pediatric patients 1 month to 17 years of age (as the disease is rare in neonates).7    
166   
167  To ensure adequate characterization of pharmacokinetics, pharmacodynamics, safety, and/or 
168  effectiveness for dosing recommendations in pediatric patients, age cohorts should be defined 
169  before a pediatric study is conducted so that a sufficient number of patients representing each age 
170  cohort will be enrolled in the study. For example, for development of proton pump inhibitors 
171  (PPIs) for healing of erosive esophagitis, patients generally should be stratified into four age 
172  cohorts:  1 to 11 months, 1 to 5 years, 6 to 11 years, and 12 to 17 years.  For patients aged 1 to 11 
173  months, the ontogeny of both metabolic enzymes (e.g., CYP2C19, a primary metabolic enzyme  
174  for most PPIs) and the proton pump should be considered to determine the appropriate 
175  stratification.  Because age stratification takes into consideration both the developmental biology 
176  and pharmacology, age cohorts can differ for drugs with a different mechanism of action even 
177  though they may be for the same indication.  
178   
179  2.  Pediatric Extrapolation 
180   
181  Extrapolation of efficacy from adult populations to pediatric populations may be appropriate if 
182  the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric 
183  patients.8  Extrapolation of efficacy from one pediatric age group to another pediatric age group 
184  also may be appropriate.9  Although efficacy can be extrapolated, additional safety and dosing 
185  information generally will need to be collected.10  
186   
                                                 
7 Because erosive esophagitis is rare in neonates, the requirement of studies for the treatment of erosive esophagitis 
would be waived in the neonatal age cohort.  
 
8  See section 505B(a)(2)(B)(i) of  the FD&C Act; 21 U.S.C. 355c(a)(2)(B(i). 
 
9 See section 505B(a)(2)(B)(ii) of the FD&C Act; 21  U.S.C. 355c(a)(2)(B(ii).   
 
10 See 21 CFR 201.80(f)(9)(iv).  See Dunne, Rodriguez, et al. 2011 and the draft guidance for industry  General 
Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological  Products for information on  
extrapolation in  pediatric settings in  general.  
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187  If a sponsor proposes to rely upon pediatric extrapolation, a scientific rationale, including 
188  sufficient justification and supporting data, should be submitted to the Agency and, when one is 
189  required under section 505B of the Federal Food, Drug, and Cosmetic Act, should also be 
190  included in a pediatric study plan.11  Represented in Table 1 are examples of GERD-related 
191  indications and the Agencys current thinking on the potential appropriateness of pediatric 
192  extrapolation in those cases.  
193   
194  Table 1: Potential for Pediatric Extrapolation 
Proposed  Patient Age  Potential for Pediatric Extrapolation 
Indication   Group 
Healing of  Birth to < 1  Pediatric extrapolation not likely relevant for this age group, as  this 
erosive  month of age  disease is rare in the neonatal age group. 
esophagitis  1 month to 17  Pediatric extrapolation may be acceptable depending on the totality  
years of age   of available information on the specific drug and the class.  
Maintenance  Birth to < 1  Pediatric extrapolation not likely relevant for this age group, as  this 
of healing of  month of age  disease is rare in the neonatal age group. 
erosive  1 month to 17  The Agency  is currently unlikely to accept pediatric extrapolation 
esophagitis  years of age   for this indication because it is uncertain whether pediatric patients 
require a maintenance period after healing of erosive esophagitis is 
established. Furthermore, if maintenance treatment is required, the 
duration required for such treatment is unclear.   
GERD  Birth to 11  The Agency  currently does not consider pediatric extrapolation 
months of age  appropriate for drugs that are targeted at acid blockage, such as 
PPIs, in patients < 1 year of age.  Trials in this age group for PPIs 
have not demonstrated efficacy and the signs and symptoms of  
GERD in patients < 1 year of age may  not be solely due to 
increased acid. Extrapolation may be considered for drugs with a 
different mode of action, taking into consideration its effect on the 
presentation of signs and symptoms in this age group. 
1 year to 17  Whether the Agency  would accept pediatric extrapolation for this 
years of age   indication depends in part on whether the mechanism of action of  
the specific drug will support that the response to treatment will be 
the same between the populations involved in potential 
extrapolation. Furthermore,  the ability of the patient or the 
observer/caregiver (for children who are too young to self-report) 
to reliably recognize, report, and measure heartburn and related 
symptoms or behaviors thought to be associated with those 
symptoms in young children, would affect the appropriateness of 
pediatric extrapolation. 
195   
                                                 
11 For additional information, see the draft guidance for industry Pediatric Study Plans:  Content  of and Process for 
Submitting Initial Pediatric Study  Plans and Amended Initial Pediatric Study Plans. 
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196  B.  Dose Finding 
197   
198  Adequate evaluation of an appropriate dose range is an integral part of developing scientifically 
199  sound and rational dosing recommendations in pediatrics.  In general, it is important to study a 
200  wide range of doses to establish dose/exposure-response over a wide range and at the same time  
201  gather safety data at higher doses.  As appropriate, the use of modeling and simulation and/or 
202  clinical trial simulation is recommended for designing pediatric clinical trials and for selecting 
203  dose. It is also possible to use adaptive study designs for dose selection.12  Depending on the 
204  level of extrapolation, there are in general three different approaches for obtaining the data that 
205  are needed to support dose selection in pediatric patients:  
206   
207  (1)  Pharmacokinetic (PK) and efficacy approach.  If neither disease progression nor 
208  response to intervention is expected to be similar in pediatrics and adults, then 
209  extrapolation of efficacy from adults to pediatric population is not possible.  In such a 
210  case, adequate dose-ranging studies should be conducted in pediatric patients to establish 
211  dosing, followed by conducting efficacy and safety trials at the identified doses.13  It is 
212  recommended to collect PK data in these trials to establish the exposure-response 
213  relationship to aid in dose optimization in pediatric patients.  
214   
215  (2)  PK and pharmacodynamic approach.  This approach of dose finding is applicable 
216  when disease progression and response to intervention are similar in pediatrics and 
217  adults, yet it is not known whether the exposure-response relationship between adults and 
218  pediatric patients is similar.  In such a case, the exposure-response relationship in adults 
219  should be well-characterized and accepted by the Agency.  Note that the response may be 
220  measured by an appropriate clinical measure or a biomarker (e.g., percent time pH greater 
221  than 4 in 24 hours). An adequate dose-ranging study is then conducted in pediatric 
222  patients to select doses in children that achieve the target effect.  In this regard, the dose 
223  range to be covered should take into consideration the potential or observed differences 
224  in both exposure and response.14 It is recommended to collect PK data in these trials to  
225  establish the exposure-response relationship to aid in dose optimization in pediatric 
226  patients.  
227   
228  (3)  PK-only approach.  This dose-selection approach is applicable when disease 
229  progression and response to intervention as well as the exposure-response are similar in 
230  pediatrics and adults (full extrapolation).  In such a case, dose-ranging studies in 
231  pediatrics are not needed. Adequate PK studies in pediatrics are conducted to select a 
232  dose in pediatric patients that provides exposures similar to that of the approved doses in 
                                                 
12 See the draft guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics.  When final, this 
guidance will represent the FDAs current thinking  on this topic. 
 
13 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies for 
Drugs and Biological Products.  When final, this guidance will represent the FDAs current thinking on this topic. 
 
14 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies for 
Drugs and Biological Products. 
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233  adults. PK simulations should be performed to identify the pediatric dose that is expected 
234  to produce exposures similar to adults. 
235   
236  The precision of the PK parameters is critical when designing the pediatric PK studies.  For 
237  pediatric studies that are vital for dose selection, sponsors are recommended to prospectively 
238  design the pediatric studies with an adequate sample size to obtain precise estimates of PK 
239  parameters (Wang, Jadhav, et al. 2012).  Prior knowledge of disease, exposure from adults, and 
240  other relevant pediatric data can be used to derive the sample size for pediatric studies.  See the 
241  draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies 
242  for Drugs and Biological Products for more details.  
243   
244  C.  Establishing Safety-Regulatory Requirements 
245   
246  1.  Nonclinical 
247   
248  The nonclinical safety assessment to support marketing approval should comply with 
249  recommendations outlined in the ICH guidance for industry M3(R2) Nonclinical Safety Studies 
250  for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. 
251  Additional information on the timing and role of nonclinical studies to support the safety 
252  evaluation of pharmaceuticals for the pediatric population is available in the guidance for 
253  industry Nonclinical Safety Evaluation of Pediatric Drug Products. Attention should be paid to 
254  providing sufficient nonclinical data to support the youngest age group and maximum doses and 
255  duration of treatment for patients expected to be enrolled in pediatric studies.  
256   
257  2.  Clinical  
258   
259  There must be adequate safety data for all claimed indications in all relevant patient ages for 
260  which the drug would be approved for use.15    
261   
262  Although the total safety database contributes to the safety database, there should be sufficient 
263  data at the highest dose to support approval of that dose.   
264   
265  Ideally, safety data should be collected for all indications.  Although additional safety 
266  information should be collected even when pediatric extrapolation of efficacy is appropriate, 
267  safety data obtained for one indication may support safety in another indication if the patient 
268  populations are sufficiently similar, and if the doses and duration of treatment studied are 
269  comparable.  For example, the safety data obtained in patients 12 years of age and older for the 
270  maintenance of healing of erosive esophagitis may be able to support the safety profile for the 
271  acute treatment of erosive esophagitis in patients 12 years of age and older, provided that the 
272  patient populations were sufficiently similar, that the dose and frequency in the maintenance of 
273  healing of erosive esophagitis safety database were at least as high and as frequent as would be 
274  in the acute treatment of erosive esophagitis indication, and that the duration of use in the 
275  maintenance of healing of erosive esophagitis safety database was at least as long as would be 
276  needed for the acute treatment of erosive esophagitis indication.   
                                                 
15  See section 505B(a)(2)(A)(i) of  the FD&C Act; 21 U.S.C.  355c(a)(2)(A)(i).  
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277   
278   
279  IV.  CLINICAL TRIAL DESIGN CONSIDERATIONS 
280   
281  This section presents issues for sponsors to consider in their drug development programs to 
282  establish efficacy of a new drug for the treatment of pediatric GERD.  An overview of efficacy 
283  and the need for pediatric efficacy trials is first presented, followed by details specific to 
284  pediatric GERD.   
285   
286  Establishing efficacy for a drug requires substantial evidence, consisting of adequate and 
287  well-controlled investigations.16  The details are not discussed here, and additional detailed 
288  guidances on clinical trials should be consulted when designing a pediatric drug development 
289  program.  In cases where FDA determines that extrapolation of efficacy is acceptable (see 
290  section III.A.2., Pediatric Extrapolation), a fully powered trial, designed with efficacy endpoints 
291  for all pediatric age groups, may not be needed.  This section provides guidance for when 
292  extrapolation cannot be used and a phase 3 trial is needed.  For further guidance on use of 
293  extrapolation and the approach to pediatric studies, see the draft guidance for industry General 
294  Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products. 
295   
296  A.  Erosive GERD 
297   
298  For an indication in treatment of eGERD, such as healing of erosions, the study population 
299  should consist entirely of patients with esophageal erosions secondary to GERD.  Because 
300  eGERD in infants is rare and potentially related to pathogenic causes such as viral and bacterial 
301  infections, and because of the inability to accurately establish  a diagnosis in neonates, neonates 
302  generally should be excluded from clinical trials for an eGERD indication.  The diagnosis of 
303  eGERD should be established through direct visualization of one or more esophageal erosions on 
304  upper endoscopy. Endoscopic classifications are used to grade the severity of erosive disease by 
305  the presence and extent of mucosal breaks (erosions).  Other etiologies that can cause erosions  
306  should be excluded, including Crohns esophagitis, eosinophilic esophagitis, and esophagitis 
307  secondary to infection, toxins, and caustics.  In children with severe neurodevelopmental delay, 
308  there may be other etiologies for presumed GERD-related signs and symptoms.  Endoscopic 
309  biopsy procedures should be described in the protocol as to biopsy location, number, method, 
310  and adjudication (ideally a panel of independent experts to adjudicate the diagnosis).   
311   
312  For an indication of treatment of eGERD or erosions, the primary endpoint should be healing of 
313  erosions, which should be assessed at 8 to 12 weeks using the same diagnostic procedure(s) used 
314  to establish the diagnosis at baseline. A primary endpoint of symptom improvement alone is not 
315  acceptable, because there is a weak relationship between the existence of erosions and the 
316  presence of symptoms.  However, it may be possible to obtain an additional indication of 
317  symptom improvement if the symptom assessment instrument is included as a primary or key 
318  secondary endpoint in conjunction with endoscopic and histologic healing.  
319   
                                                 
16 For establishing efficacy of a drug, see 21 CFR 314.126.  See also generally the guidance for industry Providing 
Clinical Evidence of Effectiveness for Human Drug  and Biological Products. 
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320  As a general matter, a patient-reported outcome (PRO) symptom assessment instrument 
321  measures the core symptoms of GERD in children who are old enough to reliably self-report 
322  their symptoms.  An observer-reported outcome  (ObsRO) assessment will be needed to assess  
323  efficacy for children who are unable to self-report.17   
324   
325  B.  Symptomatic GERD 
326   
327  Obtaining an indication for GERD in children is potentially problematic because of the variety of 
328  working definitions of GERD, which include the following:  (1) suspected (symptoms without 
329  performing endoscopy); (2) signs and symptoms without erosions seen on endoscopy; and (3) 
330  signs and symptoms without inflammation seen on endoscopy.  The Agency prefers the 
331  documented non-erosion definition (number 2, above) because this allows the potential 
332  extrapolation from adult data unless the sponsor can adequately justify not using it.  Currently, 
333  biopsy evidence of inflammation is assessed as part of an endoscopy (in clinical practice) but 
334  used to differentiate between GERD and other diseases that have mucosal characteristics (i.e., 
335  eosinophilic esophagitis) that also can be responsive to PPI therapy.  Therefore, the protocol 
336  should define GERD for the purposes of the trial.  Children with other etiologies of GERD 
337  (Helicobacter pylori, Crohns, eosinophilic esophagitis, and others that may require biopsy) 
338  should be excluded from the trial population to exclude any potential for bias in the 
339  interpretation of the study results. 
340   
341  For an indication of treatment of GERD, a treatment duration of 8 to 12 weeks is acceptable.   
342   
343  Given the central role of symptoms in GERD, the ability of a drug to improve symptoms is 
344  critical to its approval. Consequently, the primary endpoint should include a PRO measure that 
345  measures signs and symptoms for older children and an ObsRO measure in infants and younger 
346  children. If an alternative endpoint, such as weight gain, is considered appropriate for the 
347  population selected for study, these PRO and ObsRO measures should be included as important 
348  secondary endpoints. 
349   
350  There are unique considerations when developing instruments to measure signs and symptoms in 
351  children ranging in age from infants to adolescents; further information can be found in the 
352  guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
353  Development to Support Labeling Claims. A childs self-report of symptoms using a PRO 
354  instrument is preferred at the age when children can provide valid and reliable self-report.  
355  However, the minimum age of self-report also depends, in part, on the complexity of what is 
356  being measured (e.g., comprehension of the concept) and how it is being measured (e.g., 
357  vocabulary being used, duration of recall required).  Children as young as 6 to 7 years of age 
358  may be able to respond reliably to PRO instruments that ask simple questions using age
359  appropriate language (Matza, Patrick, et al. 2013).   
360   
361  It is important to note that some children may be able to read but not understand concepts, while 
362  others may be able to understand concepts but not read on their own.  Interviewer (e.g., parent, 
                                                 
17 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims. 
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363  computer-assisted) administration of the instrument may be considered for young children who 
364  cannot yet read. Although the measure can be developed as an interviewer-administered 
365  instrument, the administration should be standardized to minimize variation across interviewers, 
366  and any influence on the childs response or alteration of the childs response by the interviewer 
367  should be avoided. Childrens understanding and interest in completion of the instrument may 
368  be enhanced by using illustrations and/or platforms for administration that children may already 
369  be familiar with.  Daily diaries or current state assessments of symptoms in children are 
370  generally preferred over instruments with longer recall periods. 
371   
372  As previously stated, an ObsRO measure will be needed to evaluate infants and young children 
373  who are not able to report for themselves.  Observers (e.g., parents, caregivers) can only validly 
374  report on signs and behaviors that they can directly observe and should not be asked to rate an 
375  unobservable concept (e.g., abdominal pain) or influence the childs responses in any way.  
376  Therefore, ObsRO instruments should only include questions related to signs and behaviors (e.g., 
377  crying, vomiting) rather than symptoms (e.g., pain).  
378   
379  1.  Adolescents (12 Years to Younger Than 18 Years) 
380   
381  The primary endpoint in adolescents with GERD should be symptom-based using a PRO 
382  instrument.  In this case, an acceptable primary endpoint could be an evaluation of symptom-free 
383  days of heartburn, which has been used as the basis of approval for drugs to treat GERD in 
384  adults. 
385   
386  2.  Children (6 Years to 11 Years) 
387   
388  Children with GERD in this age group may be able to reliably report their symptoms, but the 
389  extent to which they can do so reliably may vary across this age range such that the minimum 
390  age of reliable self-report should be evaluated and discussed with the Agency.  Children with 
391  GERD in this age group may also present differently than older children with the condition.  The 
392  preferred primary endpoint is a measure of symptoms using a PRO, if appropriate, or a measure 
393  of observable signs and behaviors using an ObsRO.  The primary endpoint should be assessed in 
394  the same way at enrollment and end of treatment.     
395   
396  3.  Children (1 Year to 5 Years) 
397   
398  In this age group, the main issue is limited communicative ability and a different clinical 
399  presentation compared to older children, adolescents, and adults.  The primary endpoint should 
400  be assessed using an ObsRO instrument that asks the observer (e.g., parent or caregiver) only 
401  about observable signs and behaviors.  A well-defined and reliable ObsRO instrument for this 
402  age group would be useful for efficacy determination.  The primary endpoint should be assessed 
403  in the same way at enrollment and end of treatment.     
404   
405  4.  Infants (1 Month to Younger Than 1 Year) 
406   
407  Diagnosing and treating GERD in infants is challenging.  Infant GERD is not well-characterized, 
408  and diagnostic problems create issues with identifying an appropriate target population for 
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409  clinical trials.  Because of the inability to accurately establish  a diagnosis in neonates, this age 
410  group should be excluded from clinical trials.  The natural history of GERD in infants is not 
411  well-understood, such as the effect of normal maturation on GERD resolution.  Symptoms of 
412  GERD are difficult to measure in infants and nonspecific.  In infants, GERD signs and symptoms  
413  overlap with other conditions such as colic or food allergy, and this presents a unique challenge 
414  in the setting of a clinical trial.  Sponsors planning to conduct clinical trials of GERD in infants 
415  should first reach agreement with FDA on an acceptable disease definition and outcome  
416  measures.  Primary outcome measures related to the drugs specific mechanism of action may be 
417  acceptable if adequately justified and supported with data.   
418   
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419  REFERENCES  
420   
421  Literature 
422   
423  Abu Jawdeh E and Martin R, 2013, Neonatal Apnea and Gastroesophageal Reflux (GER):  Is 
424  There a Problem? Early Human Development, 89S1:S14-S16. 
425   
426  Benjamin DK Jr, Smith PB, Jadhav P, Gobburu JV, Murphy MD, Hasselblad V, Baker-Smith C, 
427  Califf RM, and Li JS, 2008, Hypertension, 51(4), 834-40. 
428   
429  Campanozzi A, Boccia G, Pensabene L et.al., 2009, Prevalence and Natural History of 
430  Gastroesophageal Reflux: Pediatric Prospective Survey, Pediatrics, 123:779-783. 
431   
432  Dunne J, Rodriguez WJ, Murphy MD et al., 2011, Extrapolation of Adult Data and Other Data in 
433  Pediatric Drug-Development Programs, Pediatrics, 128(5):e1242-9. 
434   
435  Martin AJ, Pratt N, Kennedy JD, et al., 2002, Natural History and Familial Relationships of 
436  Infant Spilling to 9 Years of Age, Pediatrics, Jun;109(6):1061-67. 
437   
438  Matza LS, Patrick DL, Riley AW, et al., 2013, Pediatric Patient-Reported Outcome Instruments 
439  for Research to Support Medical Product Labeling:  Report of the ISPOR PRO Good Research 
440  Practices for the Assessment of Children and Adolescent Task Force, Value in Health, 16:461
441  479. 
442   
443  Nelson SP, Chen EH, Syniar GM, et al., 1997, Prevalence of Symptoms  of Gastroesophageal 
444  Reflux During Infancy, Arch Pediatr Adolesc Med, 151:569-72. 
445   
446  Poets C and Brockman P, 2011, Myth:  Gastroesophageal Reflux Is a Pathological Entity in the 
447  Preterm Infant, Seminars in Fetal &Neonatal Medicine, 16:259-263. 
448   
449  Ruigomez A, Wallander MA, Lundborg P, et al., 2010, Gastroesophageal Reflux Disease in 
450  Children and Adolescents in Primary Care, Scand J Gastroenterol, 45(2):139-46. 
451   
452  Sherman P, Hassall E, Fagundes-Neto U et al., 2009, A Global, Evidence-Based Consensus on 
453  the Definition of Gastroesophageal Reflux Disease in the Pediatric Population, Am J 
454  Gastroenterol, 104:1278-1295. 
455   
456  Vandenplas Y, Rudolph C et al., 2009, Pediatric Gastroesophageal Reflux Clinical Practice 
457  Guidelines:  Joint Recommendations of the North American Society for Pediatric 
458  Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for 
459  Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), Journal of Pediatric 
460  Gastroenterology and Nutrition, 49:498547 by European Society for Pediatric 
461  Gastroenterology, Hepatology. 
462   
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463  Wang Y, Jadhav PR, Lala M, and Gobburu JV, 2012, Clarification on Precision Criteria to 
464  Derive Sample Size When Designing Pediatric Pharmacokinetic Studies, Journal of Clinical 
465  Pharmacology, (52)10, 1601-1606. 
466   
467  Guidances18  
468   
469  Draft guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics  
470   
471  Draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies 
472  for Drugs and Biological Products   
473   
474  Draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial 
475  Pediatric Study Plans and Amended Initial Pediatric Study Plans  
476   
477  Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
478  Regulatory Applications  
479   
480  Guidance for industry Nonclinical Safety Evaluation of Pediatric Drug Products  
481   
482  Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
483  Development to Support Labeling Claims   
484   
485  Guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
486  Biological Products  
487   
488  ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Human Clinical Trials and 
489  Marketing Authorization for Pharmaceuticals  
490   
                                                 
18 Guidances can be  found  on the FDA  Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
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