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

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

2. 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

3. 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)”

4. 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]

5. 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)

6. < 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.

7. >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.

8. Requested Studies by Age Group

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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)

19. 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

20. 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

21. 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.

22. 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.