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212155Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212155Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 212155 18F-Fluoroestradiol Multi-disciplinary Review and Evaluation NDA/BLA Multi-Disciplinary Review and Evaluation Application Type 505(b)(2) Application Number NDA 212155 Priority or Standard Standard Submit Date February 27, 2019 Received Date February 27, 2019 PDUFA Goal Date May 27, 2020 Division/Office Division of Imaging and Radiation Medicine (DIRM) / Office of Specialty Medicine (OSM) Review Completion Date May 20, 2020 Established/Proper Name Fluoroestradiol F 18 (Proposed) Trade Name Cerianna Pharmacologic Class Radioactive Diagnostic Agent for Positron Emission Tomography Applicant Zionexa Dosage form Injection Applicant Proposed Dosing 222 MBq with an allowable range from 111 MBq to 222 MBq (3 mCi Regimen to 6 mCi) Applicant Proposed For use with positron emission tomography (PET imaging) for (b) (4) Indication(s)/Population(s) characterization of estrogen receptor (ER) status breast cancer. Applicant Proposed SNOMED CT Indication Disease Term 363678002 |Positron emission tomographic imaging - action for each Proposed Indication Recommendation on Approval Regulatory Action Recommended For use with positron emission tomography (PET) imaging for Indication(s)/Population(s) detection of estrogen receptor (ER)-positive lesions as an adjunct to (if applicable) biopsy in patients with recurrent or metastatic breast cancer. Limitations of Use: Tissue biopsy should be used to confirm recurrence of breast cancer and to verify ER status by pathology. Cerianna is not useful for imaging other receptors, such as human epidermal growth factor receptor 2 (HER2) and the progesterone receptor (PR). Recommended SNOMED CT Indication Disease Term for 315004001 |Metastasis from malignant tumor of breast (disorder) each Indication (if applicable) Recommended Dosing 222 MBq (6 mCi), with a range of 111 MBq to 222 MBq (3 mCi to 6 Regimen mCi), administered as a single intravenous injection of 10 mL or less over 1 to 2 minutes 1 Version date: October 12, 2018 Reference ID: 4610895 NDA 212155 18F-Fluoroestradiol Multi-disciplinary Review and Evaluation Table of Contents Table of Contents ................................................................................................................ 2 Table of Tables .................................................................................................................... 5 Table of Figures ................................................................................................................... 6 Reviewers of Multi-Disciplinary Review and Evaluation .................................................... 7 Glossary ............................................................................................................................... 8 1. Executive Summary ......................................................................................................... 9 Product Introduction ................................................................................................ 9 Conclusions on the Substantial Evidence of Effectiveness ...................................... 9 Benefit-Risk Assessment ........................................................................................ 10 Patient Experience Data ......................................................................................... 13 2. Therapeutic Context ..................................................................................................... 14 Analysis of Condition .............................................................................................. 14 3. Regulatory Background ................................................................................................. 15 U.S. Regulatory Actions and Marketing History ..................................................... 15 Summary of Presubmission/Submission Regulatory Activity ................................ 15 Foreign Regulatory Actions and Marketing History ............................................... 16 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 16 Office of Scientific Investigations (OSI) .................................................................. 16 Product Quality ....................................................................................................... 16 Clinical Microbiology .............................................................................................. 17 Devices and Companion Diagnostic Issues ............................................................ 17 Office of Oncologic Disease (OOD) ......................................................................... 17 5. Nonclinical Pharmacology/Toxicology .......................................................................... 18 Executive Summary ................................................................................................ 18 Referenced NDAs, BLAs, DMFs ............................................................................... 20 Pharmacology ......................................................................................................... 20 ADME/PK ................................................................................................................ 21 Toxicology ............................................................................................................... 22 General Toxicology .......................................................................................... 22 Genetic Toxicology ........................................................................................... 24 Carcinogenicity ................................................................................................ 25 Reproductive and Developmental Toxicology ................................................. 25 Other Toxicology Studies ................................................................................. 25 2 Version date: October 12, 2018 Reference ID: 4610895 NDA 212155 18F-Fluoroestradiol Multi-disciplinary Review and Evaluation 6. Clinical Pharmacology ................................................................................................... 25 Executive Summary ................................................................................................ 25 Summary of Clinical Pharmacology Assessment .................................................... 26 General Dosing and Therapeutic Individualization ......................................... 26 Comprehensive Clinical Pharmacology Review ..................................................... 26 General Pharmacology and Pharmacokinetic Characteristics ......................... 26 Clinical Pharmacology Questions .................................................................... 27 7. Sources of Clinical Data and Review Strategy ............................................................... 29 Table of Clinical Studies .......................................................................................... 29 Review Strategy ...................................................................................................... 31 8. Statistical and Clinical and Evaluation .......................................................................... 31 Review of Relevant Individual Trials Used to Support Efficacy .............................. 31 Study 1 (Chae et al. 2019) ................................................................................ 31 Study Results .................................................................................................... 35 Assessment of Efficacy Across Trials ............................................................... 38 Review of Safety ..................................................................................................... 42 Review of the Safety Database ........................................................................ 42 Adequacy of Applicant’s Clinical Safety Assessments ..................................... 42 Safety Results ................................................................................................... 43 Analysis of Submission-Specific Safety Issues ................................................. 45 Clinical Outcome Assessment Analyses Informing Safety/Tolerability ........... 45 Safety Analyses by Demographic Subgroups................................................... 45 Specific Safety Studies/Clinical Trials............................................................... 46 Additional Safety Explorations ........................................................................ 46 Safety in the Postmarket Setting ..................................................................... 46 Integrated Assessment of Safety ................................................................... 46 Statistical Issues ...................................................................................................... 46 Conclusions and Recommendations ...................................................................... 48 9. Advisory Committee Meeting and Other External Consultations ................................ 49 10. Pediatrics ....................................................................................................................
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