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

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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
  lt44 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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lt 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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gt1 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
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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 n100
• Multicenter, open-label, non-randomized, gt 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 n80
• Age 1 to 5 years, n40 Age 6 to 11 years, n40
  
• Randomized, double-blind, dose-ranging (gt3 dose
  levels) with gt 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 n12
  / 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 lt12 months of age or
  pre-term infant with a corrected age of at least
  44 weeks but lt12 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) (contd)

• 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) (contd)

• Design (contd)
• 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
lt44 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
lt44 Weeks(Study 1) (contd)

• 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
lt44 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
lt44 Weeks(Study 2) (contd)

• Design (contd)
• 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
lt44 Weeks(Study 2) (contd)

• Design (contd)
• 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
lt44 Weeks(Study 2) (contd)

• 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 patients 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 lt1 year of age.
• 2. Efficacy of PPIs in treatment of GERD in
  pediatric patients lt 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 (contd)

• 4. The WR has provisions for prompt
  discontinuation from randomized study therapy
  when discontinuation is felt to be clinically
  appropriate.
• 5. For pediatric patients gt1 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.