1 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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1 Proton-Pump Inhibitor (PPI) Template for Pediatric Written Requests Pediatric Advisory Subcommittee of the Anti- Infective Drug Advisory Committee Hugo.
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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
– 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
– 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.