GE Healthcare Omniscan™ (Gadodiamide)
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OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 GE Healthcare Omniscan™ (gadodiamide) Injection NDA 20-123 Briefing Document for MIDAC August 1, 2017 GE Healthcare Inc. 100 Results Way Marlborough, MA 01752 USA ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Page 1 of 91 OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 Table of Contents 1 INTRODUCTION .......................................................................................................... 6 2 BACKGROUND ............................................................................................................ 7 2.1 Brain Gd Retention ............................................................................................. 8 2.2 MRI and GBCAs .............................................................................................. 10 2.3 Safety of GBCAs .............................................................................................. 12 3 CLINICAL DATA ON GADOLINIUM RETENTION .............................................. 13 3.1 MRI Evidence of Gd Retention in Brain .......................................................... 14 3.1.1 Other Possible Causes of T1 Hyperintensity .................................. 15 3.1.2 Direct Sensitive Detection of Gd in Brain Tissue .......................... 16 3.1.3 Mechanism of Gd Distribution to Brain with Normal BBB ........... 19 3.1.4 Detection of Gd in Non-Brain Tissues ........................................... 20 3.1.5 Clinical Significance of Gd Retention ............................................ 22 3.1.6 Overall Clinical Conclusions .......................................................... 27 3.2 NONCLINICAL DATA ON GADOLINIUM RETENTION .......................... 27 3.2.1 Gd in Brain Recent Nonclinical Publications ................................. 28 3.2.2 Relevant GEHC Nonclinical Studies and Supplementary Publications ........................................................................................................ 34 3.2.3 Potential Route of Uptake into the Brain ........................................ 40 3.2.4 GEHC Study B041015 ................................................................... 40 3.2.5 Future Nonclinical Research .......................................................... 44 3.2.6 Overall Nonclinical Conclusions .................................................... 44 3.3 PHARMACOVIGILANCE .............................................................................. 45 3.3.1 Summary of Events in Safety Database ......................................... 45 3.3.2 Summary of Current Knowledge on Gd Presence in Brain ............ 48 3.3.3 GEHC Position ............................................................................... 51 4 SERIOUS IDENTIFIED RISKS OF GBCA ................................................................ 52 4.1 Acute Hypersensitivity Reactions .................................................................... 52 4.1.1 Overview of Hypersensitivity Risk with GBCA Use ..................... 52 4.1.2 Omniscan's Low Rate of Hypersensivity Reactions ....................... 54 4.1.3 Implications of Differences Among GBCAs in Rates of Acute Hypersensitivity Reaction ............................................................... 59 4.2 Nephrogenic Systemic Fibrosis ........................................................................ 60 5 POTENTIAL MEASURES TO MINIMIZE RISK...................................................... 60 6 GEHC SCIENTIFIC RESEARCH PROGRAM ON GADOLINIUM RETENTION . 61 7 CONCLUSION ............................................................................................................ 62 8 APPENDICES .............................................................................................................. 63 8.1 Study Synopses of Gd Retention in Brain [Appendix A] ................................. 63 Page 2 of 91 OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 9 REFERENCES ............................................................................................................. 72 Page 3 of 91 OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 List of Abbreviations Abbreviation Meaning ACR American College of Radiology (ACR) ADR Adverse Drug Reaction AE Adverse Event BBB Blood-brain Barrier BG Basal Ganglia CE Contrast-enhanced CI Confidence Interval CLD Chronic Liver Disease CNS Central Nervous System CSF Cerebrospinal Fluid DCN Deep Cerebellar Nuclei DMIP Division of Medicinal Imaging Products DN Dentate Nucleus DTPA-BMA Diethylenetriamine Pentaacetic Acid Bis(methylamide) EBGM Empiric Bayes Geometric Mean EDS Energy Dispersive X-ray Spectroscopy eGFR Estimated Glomerular Filtration Rate EMA European Medicines Agency EU European Union FAERS Food and Drug Administration Adverse Event Reporting System FDA Food and Drug Administration FLAIR Fluid-attenuated Inversion Recovery GAED Global Adverse Events Database GBCA Gadolinium-based Contrast Agent Gd Gadolinium Gd+3 Gadolinium (III) Ion GDD Gadolinium Deposition Disease GEHC GE Healthcare GFR Glomerular Filtration Rate GP Globus Pallidus H&E Hematoxylin and Eosin HILIC Hydrophilic Interaction Liquid Chromatography HSR Hypersensitivity Reactions ICP-AES Inductively Coupled Plasma-atomic Emission Spectroscopy ICP-MS Inductively Coupled Plasma Mass Spectrometry ICP-SF-MS Inductively Coupled Plasma-sector Field Mass Spectrometry ICSR Individual Case Safety Report IND Investigational New Drug ISMRM International Society for Magnetic Resonance in Medicine Page 4 of 91 OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 Abbreviation Meaning IV Intravenous MCDA Multi-criteria Decision Analysis MCI Mild Cognitive Impairment MCSA Mayo Clinic Study of Aging MPRAGE Magnetization-prepared Rapid Acquisition of Gradient Echo MR Magnetic Resonance MRI Magnetic Resonance Imaging MS Multiple Sclerosis NMOsd Neuromyelitis Optica Spectrum Disorder NSF Nephrogenic Systemic Fibrosis nSI Native T1 Signal Intensity PRR Proportional Reporting Ratio PV Pharmacovigilance PVS Perivascular Space qT1 Quantitative T1 Value RITA Registry of Industrial Toxicology Animal-data RMP Risk Management Plan SE Spin Echo SI Signal Intensity SIR Signal Intensity-Ratio T1w T1-weighted TSI Tracked Safety Issue US United States Page 5 of 91 OMNISCAN™ (gadodiamide) Injection Advisory Committee Briefing Materials: Briefing Document Available for Public Release MIDAC Meeting: 8 September 2017 1 INTRODUCTION Gadolinium-based contrast agents (GBCAs) are intravenously administered drugs that help radiologists interpret magnetic resonance imaging (MRI) examinations by enhancing contrast in body tissues where the GBCA is located. Based on chemical characteristics, a GBCA can be classified as linear or macrocyclic, as ionic or non-ionic, and as protein-binding or non-protein- binding. OMNISCAN™ (gadodiamide) is a linear, non-ionic, non-protein binding GBCA indicated for diagnostic magnetic resonance imaging to visualize lesions with abnormal vascularity in the brain, spine and associated tissues and to facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities and the retroperitoneal space. Since commercial launch in 1993, Omniscan has been administered to an estimated 80,000,000 patients and is marketed in over 100 countries worldwide, including the United States. Numerous clinical studies and decades of clinical use support the efficacy and safety of Omniscan for its intended uses. These uses are similar to those across the class of GBCAs. GEHC acknowledges that recent publications on brain gadolinium (Gd) have identified a potential risk that requires further evaluation and applauds the Food and Drug Administration’s (FDA’s) efforts to do so. GEHC has already undertaken additional research to better understand the issue and is fully committed to undertake further nonclinical and clinical research to evaluate if there is any short, medium, or long-term risk to patients. Our understanding in this matter today is consistent with the FDA’s safety communication briefing on this matter and communication from the American College of Radiology (ACR) and the ISMRM. While we believe that there are trace amounts of Gd retained in the brain, there are no harmful effects to date with brain Gd retention. GBCA’s are used in clinical practice because of their utility. All GBCAs result in Gd detectable in the brain as well as other parts of the body; thus, the differences are currently quantitative rather than qualitative. • Whilst acknowledging the well-known limitations of AE reporting, it remains a fact that after hundreds of millions of Gd-enhanced imaging procedures over many years of use, we are not aware of any established clinical consequences of brain Gd. • Without clinical consequences (and a correlation with brain Gd) it is impossible to establish a level of brain Gd that could trigger a safety concern. • Given the state of knowledge, labelling changes can be made for the entire class of GBCAs highlighting the current observations,