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Application Type sNDA
Application Number(s) 22056/S-
Priority or Standard Standard
Received Date(s) April 3, 2015
PDUFA Goal Date February 3, 2016
Division / Office CDER/ODE III/DGIEP
Reviewer Name(s) Marjorie F. Dannis, MD,
through
Anil Rajpal, MD
Review Completion Date December 23, 2015
Established Name Omeprazole Magnesium
(Proposed) Trade Name Prilosec
Therapeutic Class Proton Pump Inhibitor (PPI)
Applicant AstraZeneca
Formulation(s) Delayed-Release Oral
Suspension
Dosing Regimen Once daily
Indication(s) Treatment of erosive
esophagitis (EE) due to acid-
mediated gastroesophageal
reflux disease (GERD)
Intended Population(s) 1-11 month olds, inclusive
Marjorie F. Dannis, M.D.
Prilosec (omeprazole)
- NDA 22056/S-
- 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT Table of Contents
- 1.1 Recommendation on Regulatory Action
- 1.2 Risk Benefit Assessment
- 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
- 1.4 Recommendations for Postmarket Requirements and Commitments
- 2 INTRODUCTION AND REGULATORY BACKGROUND
- 2.1 Product Information
- 2.2 Tables of Currently Available Treatments for Proposed Indications
- 2.3 Availability of Proposed Active Ingredient in the United States
- 2.4 Important Safety Issues With Consideration to Related Drugs............................
- 2.5 Summary of Presubmission Regulatory Activity Related to Submission
- 3 ETHICS AND GOOD CLINICAL PRACTICES
- 3.1 Submission Quality and Integrity
- 3.2 Compliance with Good Clinical Practices
- 3.3 Financial Disclosures
- DISCIPLINES........................................................................................................... 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
- 4.1 Chemistry Manufacturing and Controls
- 4.2 Clinical Microbiology
- 4.3 Preclinical Pharmacology/Toxicology
- 4.4 Clinical Pharmacology - 4.4.1 Mechanism of Action - 4.4.2 Pharmacodynamics..................................................................................... - 4.4.3 Pharmacokinetics
- 5 SOURCES OF CLINICAL DATA.............................................................................
- 5.1 Tables of Studies/Clinical Trials.........................................................................
- 5.2 Review Strategy.................................................................................................
- 6 REVIEW OF EFFICACY
- 7 REVIEW OF SAFETY
- 8 POSTMARKET EXPERIENCE
- 9 APPENDICES
- 9.1 Literature Review/References
- 9.2 Labeling Recommendations
- 9.3 Advisory Committee Meeting
Marjorie F. Dannis, M.D.
NDA 22056/S-
Prilosec (omeprazole)
1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
Strategies
None
1.4 Recommendations for Postmarket Requirements and Commitments
None
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
2 Introduction and Regulatory Background
The clinical manifestations of gastroesophageal reflux disease (GERD) range from minor symptoms, such as heartburn or regurgitation, to more complicated disease, such as erosive esophagitis, esophageal stricture, or Barrett’s esophagus.^4 Erosive esophagitis (EE) is defined as the presence of endoscopically visible esophageal injury.^5 Although exact prevalence is unknown, a retrospective cross-sectional study of 12 children’s hospitals in the U.S. using the Pediatric Endoscopy Database System-Clinical Outcomes Research Initiative (PEDS-CORI) determined that 29 of 531 (5.5%) children ages 0 to 1 year who underwent endoscopy had erosive esophagitis.^6
2.1 Product Information
Prilosec is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. Prilosec is currently available in delayed-release capsules (10 mg, 20 mg and 40 mg) and in a delayed-release oral suspension (2.5 mg and 10 mg).
2.2 Tables of Currently Available Treatments for Proposed Indications
Currently, Nexium (esomeprazole magnesium) is approved for the treatment of EE due to acid- mediated GERD in pediatric patients one month to less than one year of age. In addition, two histamine-2 receptor antagonists (H 2 RA), Zantac (ranitidine) and Pepcid (famotidine) are approved in this age group for the proposed indication.
2.3 Availability of Proposed Active Ingredient in the United States
Prilosec is available in the U.S. as a prescription drug for the treatment of several indications in adults and pediatric patients ages 1 year and older. Table 1 below outlines Prilosec’s specific indications and usage at the current time.
(^4) Shepard RW, Evans JWS, Lander M, et al. Gastroesophageal reflux disease in children. Clin Pediatr 1987;26:55-60. (^5) Armstrong D, Marshal JK, Chiba N, et al. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults – update 2004. Can J Gastroenterol 2005;19:15-35. (^6) Gilger MA, El-Serag HB, Gold BDm et al. Prevalence of endoscopic findings of erosive esophagitis in children: a population-based study. J Pediatr Gastroenterol Nutr 2008;47:141-6.
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
New PMR 2062-1: Deferred study under PREA to evaluate the pharmacokinetics, pharmacodynamics, and safety of omeprazole in patients 1 month to 11 months of age with EE. The new dates were as listed below: . Final Protocol Submission: March 2014 Study/Trial Completion: March 2016 Final Report Submission: September 2016
The June 20, 2013 e-mail from Astra Zeneca (AZ) noted that the Sponsor still had concerns about potential recruitment difficulty for this EE study. They stated that they planned to request FDA’s feedback regarding the proposed study once they had completed the feasibility analysis.
In December 2013, AZ completed the feasibility analysis and submitted a report to the FDA wherein they concluded that the new PMR required study would be impossible or highly impracticable to conduct. Further, they questioned whether it would be ethical to justify the risks of such an invasive study in small children as the studied therapy would not represent a meaningful benefit over already existing therapies.
On February 20, 2014, FDA stated that AZ’s proposal to use available PK/PD and safety data from previous studies with Prilosec in children to fulfill a bridging strategy may be an acceptable option to fulfill the current PREA PMR.^8
AstraZeneca had previously conducted several pediatric studies with Prilosec which included some infants aged 1-11 months.
In the current submission, AZ claims that they provided the data to support the statements below.
- PK/PD relationship is similar in children and in adults:
- PK modeling demonstrating a dose/PK relationship in small children
- Suggestion for doses in children giving an exposure in children similar to the exposure in adults given the EE dose
(^8) From February 20, 2014 written responses provided to AZ in lieu of a meeting.
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
4 Significant Efficacy/Safety Issues Related to Other Review
Disciplines
4.1 Chemistry Manufacturing and Controls
No additional information was submitted. Clinical studies previously submitted in support of this application used Prilosec 2.5 mg/10 mg as Delayed-Release Oral Suspension. According to the Sponsor, this is the same formulation that is currently marketed in the U.S. As a result, AZ did not submit new CMC information.
4.2 Clinical Microbiology
No additional information was submitted.
4.3 Preclinical Pharmacology/Toxicology
No additional information was submitted.
4.4 Clinical Pharmacology
4.4.1 Mechanism of Action
Prilosec is a proton pump inhibitor that inhibits gastric acid secretion through irreversible inhibition of the H+/K+^ ATPase in the gastric parietal cell.
4.4.2 Pharmacodynamics
Please refer to the Clinical Pharmacology and Pharmacometrics reviews by Drs. Justin Earp, Nitin Mehrotra, Dilara Jappar and Sue Chih Lee for complete details.
The Sponsor submitted results from prior PK/PD studies to describe the exposure- response relationship in patients less than 1 year of age and adults.
4.4.3 Pharmacokinetics
Please refer to the Clinical Pharmacology and Pharmacometrics reviews by Drs. Justin Earp, Nitin Mehrotra, Dilara Jappar and Sue Chih Lee for complete details.
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
5 Sources of Clinical Data
5.1 Tables of Studies/Clinical Trials
No new clinical data were submitted.
5.2 Review Strategy
No new clinical efficacy data were submitted during this review cycle. There have not been any clinical trials specifically designed to establish the efficacy of Prilosec in treating erosive esophagitis in children ages 1-11 months. Instead, the majority of the enrolled pediatric patients in prior clinical trials consisted of those with suspected or symptomatic GERD^9. Safety data from previous clinical trials which included pediatric patients ages 1- months was reviewed. In addition, post marketing data in this pediatric age subgroup was reviewed.
(^9) This was also the situation for the approval of Nexium for treatment of EE due to acid-mediated GERD in pediatric patients ages 1-11 months in which extrapolation and PK/PD modeling were used.
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
7 Review of Safety
Prilosec is approved for use in children in the EU, the US and many other international markets. In the US, Prilosec is approved for treatment of GERD and treatment/maintenance of healing of erosive esophagitis in children from 1 year and older. In the EU, it is approved in children over 1 year of age with a body weight of ≥ 10 kg for the indications of: reflux esophagitis, symptomatic treatment of heartburn and acid regurgitation in GERD, and for H. pylori eradication in combination with antibiotics in treatment of duodenal ulcer caused by H. pylori in children over 4 years.
In the current submission, the Sponsor resubmitted safety data for the relevant pediatric age subgroup (1-11 month) from two previous clinical studies (Studies 251 and 250 done in 2000 ) as well as from a compilation of post- marketing data. The safety review will focus only on the relevant population.
Study 251 Study 251 was a randomized, single-blind, 56 day, safety/efficacy study in pediatric GERD patients 0 - 24 months^10. This study included patients with a 2-month history of clinically diagnosed GERD-related symptoms. Of the 115 patients randomized, 102 were < 1yr. Patients were randomized to a Prilosec dose of 0.5 mg/kg, 1.0 mg/kg, or 1. mg/kg. There were a total of 215 adverse events in any category and 2 serious adverse events^11 .Table 2 below describes the particular adverse events (≥ 2 events) which occurred during the study. These events were similar to typical symptoms observed in a general population of pediatric patients.
Table 2: Study 251: Number of patients with reported adverse events ≥ 2 (preferred term) sorted by decreasing frequency in all randomized patients (safety population)
(^10) The primary objective was to investigate whether once-daily treatment with Prilosec safely and effectively reduced the number of regurgitation episodes (^11) Events are counted by preferred term, ie, for patients with multiple events falling under the same preferred term, only 1 occurrence of the event was counted
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
8 Postmarket Experience
A 2010 FDA review of the PPI utilization in the US showed that between 2002 - more than (b) (4)Prilosec prescriptions were dispensed to children in the age group <1 year.^13
Adverse event data were collected from Prilosec marketed use (medically confirmed reports) up to Oct 15, 2013.^14 In total, since the first approval in 1987, the Sponsor received information regarding more than 800 medically confirmed case reports in the age group 0-17. Except for classically neonatal diseases, there were no major differences in AEs between pediatric age groups, also when compared with adult AEs.
In the relevant pediatric age subgroup, Table 4 below lists the most commonly reported AEs (≥ 5 patients). With the exception of “Off label Use”, this reviewer concludes that most of these common AEs would be most likely related to the natural history and/or disease-related events in a neonatal patient population.
Table 4: Post Marketing: Most frequently Reported Adverse Events in Children Age ≤ 1 year
Adapted from Appendix B of Population PKPD Modeling Report dated February 24, 2014
(^13) FDA briefing information for the November 5, 2010 meeting of the Gastrointestinal Drug Advisory Committee. (^14) The Sponsor did not provide updated data as they stated they had no new data to report (although requested in the safety update)
Marjorie F. Dannis, M.D. NDA 22056/S- Prilosec (omeprazole)
9 Appendices
9.1 Literature Review/References
None
9.2 Labeling Recommendations
At the current time, labeling negotiations are taking place with the Sponsor, thus the final labeling recommendations are unavailable.
9.3 Advisory Committee Meeting
No advisory committee meeting is planned regarding this submission.
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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
/s/
MARJORIE F DANNIS
ANIL K RAJPAL
I concur with Dr. Dannis.
