# Presentation: 396657

## Proton-Pump Inhibitor (PPI) Template for Pediatric Written Requests

**Pediatric Advisory Subcommittee of the Anti-Infective Drug Advisory Committee**
**Hugo E. Gallo-Torres, M.D., Ph.D.**
**Medical Team Leader**
**Division of Gastrointestinal & Coagulation Drug Products**
**June 11, 2001**

## Outline 

- 1.	 Introduction
- 2.  Rationale
- 3. Extrapolation of Efficacy Data
- 4. Table of Requested Studies
- 5.  Description of Each Study
- Age 12 years to 16 years
- Age 1 year to 11 years
- Age 1 month to 11 months
- Neonate and Preterm infants with a corrected age <44 weeks
- 6.  Overall Summary

## Introduction

- The pediatric Written Request (WR) is part of a voluntary program that provides financial incentives to companies for conducting needed studies of drugs that may produce a health benefit in the pediatric population.
- Proton-pump inhibitor (PPI) template:  “Template for Written Requests (WRs) for PPIs used in the treatment of gastroesophageal reflux disease (GERD)”

## Rationale

- Information relating to the use of PPIs may produce a meaningful health benefit in  the treatment of GERD in the pediatric population.
- PPIs widely used in pediatrics
- Published treatment algorithms for pediatric patients with GERD
- usage data [IMS Health]

## Extrapolation of Efficacy Data

- FDA regulations permit extrapolation of adult efficacy data to pediatric patients when there is:
- similar course of the disease
- similar drug effects (both beneficial and adverse)
- Other information supporting pediatric use also is needed (e.g., safety data and PK data to support dose selection)

## < 1 year of age

- Course of GERD in adults is not sufficiently similar to the course of pathological GER in this group to permit extrapolation of the adult efficacy data.
- Therefore, PPI template ***does*** request efficacy studies in this pediatric age group.

## >1 year of age

- Course of GERD is sufficiently similar to the course of GERD in adults to permit extrapolation of efficacy.
- Effects of PPIs both beneficial and adverse are expected to be similar in these patients as in adults.
- Therefore, PPI template ***does not*** request efficacy studies in this pediatric age group.

## Requested Studies by Age Group

## 12 Years to 16 Years of Age(Study 6)

**PK and Safety**
- Clinical diagnosis of suspected GERD
- PK Component
- Randomized, PK and safety of at least 2 dose levels of PPI     for single and repeated dose
- Either traditional or population PK
- Repeated dose PPI levels selected based on results of Part 1
-  Eight-week Safety Component       [n=100]
- Multicenter, open-label, non-randomized, _>_ 8 weeks treatment
- Doses based on PK component
- Clinical outcome measures assessed weekly

## 1 Year to 11 Years of Age(Study 5)

**PK, Exposure/Response and Safety**
- Patients with endoscopically proven GERD
- PK Component
- Exposure/Response and Safety Component    [n=80]
- Age 1 to 5 years, n=40;   Age 6 to 11 years, n=40
- Randomized, double-blind, dose-ranging (_>_3 dose levels) with _>_ 8 weeks treatment
- Dose levels based on PK component plus other trials
- Clinical outcome measures assessed weekly

## 1 Month to 11 Months of Age (Study 3)

**PK, PD and Safety**
- Hospitalized patients candidates for acid suppressive therapy because  of a presumptive diagnosis of GERD
- PK Component
- PD and Safety Component                     [n=12 / treatment group]
- Randomized, at least 2 dose levels of PPI
- Change in gastric and/or esophageal pH
- Dose levels and frequency of dosing based on results from single dose PK
- PD assessments in patients that require tube placement or pH monitoring for clinical management
- Safety:  physical examination, clinical laboratories, adverse events

## 1 Month to 11 Months of Age (Study 4) 

**Efficacy and Safety**
- Patient characteristics:
- Clinical diagnosis of suspected GERD
- Term or post-term infant <12 months of age or pre-term infant with a corrected age of at least 44 weeks but <12 months
- Acute life-threatening events due to GERD excluded
- Results of tests used to establish the diagnosis will be provided

## 1 Month to 11 Months of Age (Study 4) (cont’d)

- Design
- Multicenter, double-blind, placebo-controlled, randomized, treatment-withdrawal design
- Provision for independent data monitoring committee (DMC)
- Patients randomly assigned in a double-blind fashion to continue receiving either PPI (from the run-in phase) or placebo
- Patients monitored closely and promptly discontinued from randomized test medication if clinically appropriate
- Clinical outcome measures assessed weekly

## 1 Month to 11 Months of Age (Study 4) (cont’d)

- Design (cont’d)
- Endpoints:  supraesophageal and airway complications associated with GERD;  GERD signs and symptoms, growth parameters; frequency, severity and duration of aspiration and wheezing; compliance
- Powered for efficacy:  Clinically meaningful treatment effect at conventional statistical significance
- Safety:  Physical examination, clinical laboratory studies, adverse events
- Long-term safety: follow-up developmental growth and safety assessment 6 and 12 months after enrollment

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 1) 

**PK, PD and Safety**
- Patients
- Monitored patients admitted to NICU or special care nursery;
-  Evidence of obstructive apnea;
- Candidates for acid suppressive therapy to treat a presumptive diagnosis of GERD;
- Body weight of at least 800 grams
- PK Component

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 1) (cont’d)

- PD and Safety Component
- Dose level(s) and frequency of dosing selected based on results from single dose PK
- PD assessments of intragastric and/or intraesophageal pH performed in at least 6 of these (or other) patients that require tube placement or pH monitoring for clinical management
- Safety:  Apnea and bradycardia assessed concurrent to pHmetry

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 2) 

**Efficacy and Safety**
- Patient characteristics same as for Study 1
- Design
- Multicenter, double-blind, placebo-controlled, randomized, treatment-withdrawal design
- Provision for independent data monitoring committee (DMC)
- Patients randomly assigned in a double-blind fashion to continue receiving either PPI (from the run-in phase) or placebo
- Patients monitored closely and promptly discontinued from randomized test medication if clinically appropriate

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 2) (cont’d)

- Design (cont’d)
- Stratified by:   a) methylxanthine and b) corrected age
- Consider whether patient is receiving concomitant prokinetic agent
- Patient enrollment and efficacy measured by obstructive apnea as assessed by pneumograms
- Additional outcome measures:  Patient discontinuations due to ineffective treatment, apnea as assessed by conventional cardio-respiratory monitoring and nursing observations, severity of apneic episodes (e.g., as manifested by drop in O2 saturation, cyanosis, bradycardia and/or need for positive pressure ventilation)

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 2) (cont’d)

- Design (cont’d)
- Powered for efficacy:  Clinically meaningful treatment effect at conventional statistical significance
- Safety measures:  Overall mortality; adverse events including co-morbidities of prematurity (acquired sepsis/pneumonia, necrotizing enterocolitis, bronchopulmonary dysplasia); growth (weight, length and head circumference); significant clinical laboratory changes, and trough blood levels determined in a subset of at least 24 patients

## Neonates and Preterm Infants with a Corrected Age <44 Weeks(Study 2) (cont’d)

- Withdrawal Phase
- The protocol will define discontinuation criteria due to adverse events or therapeutic failure.
- Therapy for central apnea tracked
- Caregivers that will be making observational assessments of apnea and bradycardia will be trained appropriately in these monitoring procedures
- Cardiorespiratory monitors used to assess apnea and bradycardia will be capable of recording and storing each patient’s data for the duration of the trial
- Long-term safety: follow-up developmental growth and safety assessment 6 and 12 months after enrollment

## Overall Summary 

- 1.	Adult efficacy data cannot be extrapolated to pediatric patients <1 year of age.
- 2.	Efficacy of PPIs in treatment of GERD in pediatric patients  < 1 year of age must be established in adequate and well-controlled clinical studies.
- 3.	The randomized withdrawal design can minimize prolonged exposure to placebo in situations where inclusion of a placebo arm may be felt to be undesirable or not feasible.

## Overall Summary (cont’d)

- 4.	The WR has provisions for prompt discontinuation from randomized study therapy when discontinuation is felt to be clinically appropriate.
- 5.	For pediatric patients  >1 year of age, efficacy of PPIs in treatment of GERD may be extrapolated from efficacy studies in adults.
- 6.	For all pediatric populations, adequate PK and safety information is needed.