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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

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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

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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)”

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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]

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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)

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< 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.

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>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.

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Requested Studies by Age Group

Neonates andPre-Term

Infants

1 month to11 months

1 year to 11years

12 years to 16years

PK - single dose - repeated dose

PD

Exposure/Response

Efficacy

Safety

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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.

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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.