Diagnostic Cardiac Biomarkers for Acute Coronary Syndromes

Diagnostic Cardiac Biomarkers for Acute Coronary Syndromes EU Analysis and Market Forecasts GDME1026CFR / Published April 2013

Executive Summary Diagnostic Cardiac Biomarkers for Acute Coronary Syndromes: Key Metrics in EU Device Markets Number of suspected acute coronary syndromes cases (2012) Number of acute coronary syndromes cases (2012) 2012 Reagents Market Sales EU Pipeline Assessment 1.48 million 0.49 million $23.9m Acute coronary syndromes risk prediction tests 40% Acute coronary syndromes diagnostic tests 60% Key events (2012 2018) 2015: Major European uptake of Thermo Scientific s copeptin biomarker tests 2015: Major European uptake of heart-type fatty acid binding protein biomarker tests 2018 Reagents Market Sales EU Source: GlobalData. Note: EU = France, Germany, Italy, Spain, and the UK Level of Impact $32.8m Sales for Acute Coronary Syndromes In Vitro Diagnostic Testing Reagents GlobalData estimates the 2012 sales of ACS in vitro diagnostic testing reagents to be just under $24m across the five regions covered in this study, which are France, Germany, Italy, Spain, and the UK. By 2018, the end of the forecast period, the ACS in vitro diagnostic testing reagents market will grow to $33m, corresponding to a Compound Annual Growth Rate (CAGR) of 5.4%. The key drivers for the market in the forecast are: Uptake of pipeline biomarker tests such as copeptin and heart-type fatty acid binding protein (H-FABP) Increasing adoption of premium-priced point-of-care testing (POC) as POC troponin tests become more sensitive The key barriers for the market in the forecast are as follows. The decreasing number of cases of ACS in the UK, and steady rates in the other countries covered in the report is an overall constrainer to the market. Cardiac troponin testing, the major in vitro test carried out for the diagnosis of ACS, has reached saturation and therefore further growth is constrained in Europe. Creatine kinase-mb isoenzyme (CK-MB) and myoglobin in vitro diagnostic testing volumes are on the decline across the European markets and this will have a negative impact on the market for the first half of the study period as clinicians are not replacing these tests. Page 2 GDME1026CFR / Published APR 2013

Executive Summary ACS In Vitro Diagnostic Testing Reagents Revenue by European Market, 2012 and 2018 Spain 27% Spain 28% UK 17% UK 16% Source: GlobalData. France 14% Italy 21% Italy 20% France 14% Germany 21% Germany 22% 2012 Total: $23.9m 2018 Total: $32.8m A Market Dominated by Cardiac Troponin Testing Cardiac troponins, namely troponin I and T, are the goldstandard biomarkers for the diagnosis of ACS and myocardial infarction (MI). Interviewed key opinion leaders in Europe all report that the vast majority of their suspected ACS patients will receive a troponin biomarker test. The only situation when a patient might not get a test immediately is that if they are having an obvious and severe MI, and even in these cases a test will often be ordered as a matter of course. Interviewed experts also note that the tests are relatively inexpensive and the results are available in a short time frame. The advent of high-sensitivity troponin testing will provide emergency physicians with a diagnostic tool that can potentially shorten the time to diagnosis of ACS; however, interviewed cardiologists are concerned about the potential increase in false positives, and how that will impact the management of their patients. GlobalData expects the troponins to maintain a dominant position across the European markets, and based on key opinion leader insight, expects pipeline tests such as copeptin and H-FABP to be supplementary to the troponins rather than replacements. Unmet Need Remains a Challenge While the cardiac troponins have transformed the landscape for ACS in vitro diagnostic testing, there still remain several areas of unmet need. Some of the major unmet needs reported by key opinion leaders interviewed by GlobalData are listed below. Tests that can rule in or rule out ACS earlier in suspected ACS patients are a major need. Emergency room overcrowding is a significant problem in Europe, and this invokes both a health and economic cost to already overburdened healthcare systems. Due to the issue of false-positive results, particularly with the high-sensitivity troponin assays, cardiologists interviewed by GlobalData report a need for more specific diagnostic tests that can identify ACS patients with accuracy. Some interviewed experts call for markers that can detect myocardial ischemia, a major event in the pathway towards MI and ACS. A reliable biochemical marker for myocardial ischemia could have a major impact, especially as it would negate the need to utilize relatively expensive imaging tests. Page 3 GDME1026CFR / Published APR 2013

Executive Summary Remaining Opportunities for New and Existing Manufacturers Significant market opportunities still exist for developers of high-sensitivity troponin assays. Interviewed experts report the screening assessment of the normal, healthy population with high-sensitivity troponin could be the future model for these tests. In this situation patients would be monitored much like the current situation with cholesterol tests, with the aim of limiting cardiac injury. Furthermore, there remains market potential for developers of new tests for the early rule-in and rule-out of ACS, especially as this will reduce the requirement for serial troponin testing. Copeptin and H-FABP have the potential to address this opportunity to some degree; however, experts report that the utility of these tests is in early rule-out of ACS and neither of these tests provides any advantages over troponin for early rule-in of the disease. Also, GlobalData anticipates that developers of POC tests with enhanced troponin sensitivity will have an opportunity for market penetration as hospitals continue to covet time-saving measures in their emergency rooms. What do Physicians Think? Physicians support cardiac troponin as the gold standard for the diagnosis of ACS and MI, and do not differentiate between the two subtypes, I and T: Troponin is the preferred biomarker for the investigation of MI, as the diagnosis is defined now on the basis of troponin elevation in the new universal definition. Troponin I or T doesn t matter; the choice of this is hospital-dependent. In the global market place troponin I tests have the lion s share and they are more useful in patients with renal impairment. So, troponin I is a good test. Physicians expect laboratories to move to high-sensitivity troponin assays when they become available: There are still some hospitals using the previousgeneration tests, but the high-sensitivity tests will become a majority, particularly as the vendors will phase out the previous-generation assays and move entirely over to high-sensitivity. The biochemists have defined what they want in terms [of] sensitivity, and only the high-sensitivity assays meet those criteria. So, the old ones will have to be phased out, and I think in the next year or so, in the UK there will be nobody on the previous generation of troponin assays. European Key Opinion Leader, January, 2013 Physicians report that hospitals are removing CK-MB and myoglobin from their ACS in vitro diagnostic testing panels: The argument for measurement of CK-MB and myoglobin was on the basis that these would show an earlier rise than cardiac troponin. But the sensitivity of troponin assays has proved this not to be the case in a series of studies now. It has been shown quite clearly that the diagnostic performance of CK-MB and myoglobin is inferior to that of a troponin assay. They only remain in place in some of the POC testing panels and that s because the troponin assay being used there is not up to scratch. European Key Opinion Leader, February, 2013 European Key Opinion Leader, January, 2013 Page 4 GDME1026CFR / Published APR 2013

Executive Summary Physicians believe that hospitals will switch to POC if these troponin assays have sufficient sensitivity: As the POC assays get better there will be less of any issue [of repeating tests in the laboratory]. You know, POC lives and dies, and grows and shrinks and even though we were not true believers in POC, the crowding problems that US hospitals are having in the ER is a real public health problem. So, accepting a less-than-perfect assay and dispositioning patients faster has been a necessary move on our part, and [while] there is no solution in sight for ER overcrowding, this is where POC can really help, by moving patients expeditiously. US Key Opinion Leader, January, 2013 Physicians call for new tests that can diagnose ACS earlier: From the clinical point of view the greatest unmet need is for more rapid diagnosis, both for the rule-out and the rule-in of MI We are wasting time in providing this diagnosis, and the more rapid diagnosis the more benefit from the therapy. So this is our challenge. There are some recommendations saying that if you are unable to produce a result within 60 minutes of arrival, you should consider point-of-care systems. The World Health Organization guidelines say that we need to get an answer before 60 minutes to get the best outcome, so the laboratories have to reduce the turnaround time, and [this should] obviously reduce the time from onset to clinical diagnosis of the patient. Physicians are cautiously optimistic about the impact the pipeline biomarkers copeptin and H-FABP will have on the diagnosis of ACS: The biomarker of interest for me in the area of ACS is copeptin, [which is] a very early marker of myocardial disease. Most importantly it is a marker that can potentially rule-out earlier than troponin. Troponin requires three to six hours of negative results before you can confidently say that a person is not suffering a heart attack; on the other hand, with copeptin, in theory, the decision could be made in one to two hours. If true, and if adopted, this will accelerate the rule-out process. The majority of patients that present to the hospital with chest pain, 85% 90% do not have MI and do not need to be there for the six hours that are necessary with troponin. So copeptin may be able to accelerate that decision. US Key Opinion Leader, January, 2013 I would say H-FABP is interesting, again, it was a formerly an assay that was not appropriate for the STAT department. [However,] we need to check whether it has any complementary role with troponin. European Key Opinion Leader, January, 2013 European Key Opinion Leader, January, 2013 Page 5 GDME1026CFR / Published APR 2013

1 Table of Contents 1 Table of Contents... 6 1.1 List of Tables... 12 1.2 List of Figures... 15 2 Introduction... 16 2.1 Catalyst... 16 2.2 Related Reports... 16 2.3 Upcoming Related Reports... 16 3 Disease Overview... 17 3.1 Acute Coronary Syndromes... 17 3.2 Anatomy and Physiology... 18 3.3 Pathophysiology... 19 3.4 Clinical Presentation... 20 3.4.1 Symptoms... 20 3.4.2 Diagnosis... 20 3.5 Clinical Outcomes... 25 3.5.1 Treatment Options... 25 3.5.2 Treatment Paradigm... 28 3.6 Epidemiology... 29 3.7 Economic Impact... 30 4 Competitive Assessment... 32 4.1 Overview... 32 4.2 Cardiac Troponins... 33 4.2.1 Overview... 33 4.2.2 Clinical Application and Utility... 34 4.2.3 Market Penetration... 38 4.2.4 SWOT Analysis... 39 4.3 Creatine Kinase-MB... 39 Page 6 GDME1026CFR / Published APR 2013

4.3.1 Overview... 39 4.3.2 Clinical Application and Utility... 40 4.3.3 Market Penetration... 42 4.3.4 SWOT Analysis... 42 4.4 Myoglobin... 42 4.4.1 Overview... 42 4.4.2 Clinical Application and Utility... 43 4.4.3 Market Penetration... 45 4.4.4 SWOT Analysis... 45 4.5 Point-of-Care... 45 4.5.1 Overview... 45 4.5.2 Clinical Application and Utility... 47 4.5.3 Market Penetration... 50 4.5.4 SWOT Analysis... 51 5 Unmet Needs... 52 5.1 Overview... 52 5.2 Earlier Diagnosis... 53 5.3 Specificity and False Positives... 55 5.4 Interpretation of Biochemical Assay Results... 56 5.5 Markers for Myocardial Ischemia... 58 6 Pipeline Products... 59 6.1 Overview... 59 6.2 BAG3 (Biouniversia)... 60 6.2.1 Overview... 60 6.2.2 SWOT Analysis... 60 6.3 CAVARISK (Cavadis)... 60 6.3.1 Overview... 60 6.3.2 SWOT Analysis... 60 Page 7 GDME1026CFR / Published APR 2013

6.4 CardioScore (BG Medicine)... 61 6.4.1 Overview... 61 6.4.2 SWOT Analysis... 61 6.5 Circulating Endothelial Cells... 62 6.5.1 Overview... 62 6.5.2 SWOT Analysis... 63 6.6 Copeptin (Thermo Scientific)... 63 6.6.1 Overview... 63 6.6.2 SWOT Analysis... 66 6.7 Heart-Type Fatty Acid Binding Protein... 66 6.7.1 Overview... 66 6.7.2 SWOT Analysis... 68 6.8 MIRISK VP Assessment (Aviir)... 69 6.8.1 Overview... 69 6.8.2 SWOT Analysis... 69 6.9 Early Emerging Tests... 70 6.9.1 Heart Diagnostic Assay (Prevencio/University of Pittsburgh)... 70 6.9.2 Sentinel CVD (GeneNews)... 70 6.9.3 SomaScan Cardiovascular Assay (SomaLogic)... 70 7 Industry Overview... 71 7.1 ACS Diagnostic Biomarker Testing Trends... 71 7.2 Market Access... 73 7.3 Reimbursement Trends... 75 7.4 Regulatory Environment... 78 7.4.1 Approval of New Tests... 78 7.4.2 Product Recalls... 79 8 Current and Future Players... 81 8.1 Overview... 81 Page 8 GDME1026CFR / Published APR 2013

8.2 Trends in Corporate Strategy... 81 8.3 Abbott Diagnostics... 82 8.3.1 Overview... 82 8.3.2 Portfolio Assessment... 82 8.4 Alere... 84 8.4.1 Overview... 84 8.4.2 Portfolio Assessment... 85 8.5 Beckman Coulter... 86 8.5.1 Overview... 86 8.5.2 Portfolio Assessment... 87 8.6 biomérieux... 88 8.6.1 Overview... 88 8.6.2 Portfolio Assessment... 89 8.7 Mitsubishi Chemical Medience Corporation... 90 8.7.1 Overview... 90 8.7.2 Portfolio Assessment... 91 8.8 Ortho-Clinical Diagnostics... 92 8.8.1 Overview... 92 8.8.2 Portfolio Assessment... 93 8.9 Radiometer Medical... 94 8.9.1 Overview... 94 8.9.2 Portfolio Assessment... 95 8.10 Randox Laboratories... 96 8.10.1 Overview... 96 8.10.2 Portfolio Assessment... 97 8.11 Response Biomedical... 98 8.11.1 Overview... 98 8.11.2 Portfolio Assessment... 99 Page 9 GDME1026CFR / Published APR 2013

8.12 Roche Diagnostics... 100 8.12.1 Overview... 100 8.12.2 Portfolio Assessment... 101 8.13 Siemens Healthcare... 102 8.13.1 Overview... 102 8.13.2 Portfolio Assessment... 103 8.14 Thermo Scientific... 104 8.14.1 Overview... 104 8.14.2 Portfolio Assessment... 105 9 Market Drivers and Opportunities and Barriers... 106 9.1 Market Drivers... 106 9.1.1 Uptake of Pipeline Biomarker Tests... 106 9.1.2 Increasing Adoption of POC Testing... 107 9.2 Market Opportunities... 108 9.2.1 High-Sensitivity Troponin Assays... 108 9.2.2 Enhancement in Sensitivity of Troponin POC Assays... 110 9.2.3 New Pipeline Tests for Early Diagnosis of ACS... 110 9.3 Market Barriers... 111 9.3.1 Saturation of Troponin Testing in the European Markets... 111 9.3.2 Removal of CK-MB and Myoglobin from Testing Panels... 111 9.3.3 Reimbursement... 111 10 Country Outlooks and Forecasts... 112 10.1 European Markets Overview... 112 10.2 France... 114 10.3 Germany... 117 10.4 Italy... 118 10.5 Spain... 119 10.6 UK... 122 Page 10 GDME1026CFR / Published APR 2013

11 Appendix... 125 11.1 Bibliography... 125 11.2 Abbreviations... 137 11.3 Research Methodology... 139 11.3.1 Overview... 139 11.3.2 Coverage... 139 11.3.3 Secondary Research... 139 11.3.4 Forecast Methodology... 140 11.4 Primary Research... 141 11.5 Physicians and Specialists Included in this Study... 142 11.6 About the Authors... 144 11.6.1 Analysts... 144 11.6.2 Global Head of Healthcare... 145 11.7 About MediPoint... 146 11.8 About GlobalData... 146 11.9 Contact Us... 146 11.10 Disclaimer... 147 Page 11 GDME1026CFR / Published APR 2013

1.1 List of Tables Table 1: Risk Factors Associated with ACS... 21 Table 2: Properties of Common ACS and MI Diagnostic Biomarkers... 24 Table 3: Diagnosis and Risk Stratification of ACS... 24 Table 4: Common PCI Periprocedural Antithrombotic Drugs... 25 Table 5: Common Drugs for Fibrinolysis... 26 Table 6: Common Drugs for the Treatment of NSTEMI and UA... 27 Table 7: Description of Direct and Indirect Economic Costs... 30 Table 8: Economic Impact ($bn) of CAD in Europe, 2009 to 2018... 30 Table 9: Product Profile Cardiac Troponins... 34 Table 10: Cardiac Troponin Concentrations of Selected Current Troponin Assays... 35 Table 11: Cardiac Troponin Concentrations of Selected High-Sensitivity Troponin Assays.. 36 Table 12: Cardiac Troponins SWOT Analysis... 39 Table 13: Product Profile Creatine Kinase-MB... 40 Table 14: Creatine Kinase-MB SWOT Analysis... 42 Table 15: Product Profile Myoglobin... 43 Table 16: Myoglobin SWOT Analysis... 45 Table 17: Product Profile Point-of-Care Testing... 46 Table 18: Cardiac Troponin Concentrations of POC Troponin Assays... 48 Table 19: Point-of-Care Cardiac Panel SWOT Analysis... 51 Table 20: ACS Cardiac Biomarker Product Pipeline... 59 Table 21: BAG3 SWOT Analysis... 60 Table 22: CAVARISK SWOT Analysis... 60 Table 23: CardioScore SWOT Analysis... 61 Table 24: Circulating Endothelial Cells SWOT Analysis... 63 Table 25: Copeptin SWOT Analysis... 66 Table 26: Heart-Type Fatty Acid Binding Protein SWOT Analysis... 68 Table 27: MIRISK VP SWOT Analysis... 69 Page 12 GDME1026CFR / Published APR 2013

Table 28: Company Profile Abbott Diagnostics... 82 Table 29: Abbott Diagnostics SWOT Analysis, 2013... 83 Table 30: Company Profile Alere... 84 Table 31: Alere SWOT Analysis, 2013... 85 Table 32: Company Profile Beckman Coulter... 86 Table 33: Beckman Coulter SWOT Analysis, 2013... 87 Table 34: Company Profile biomérieux... 88 Table 35: biomérieux SWOT Analysis, 2013... 89 Table 36: Company Profile Mitsubishi Chemical Medience Corporation... 90 Table 37: Mitsubishi Chemical Medience Corporation SWOT Analysis, 2013... 91 Table 38: Company Profile Ortho-Clinical Diagnostics... 92 Table 39: Ortho-Clinical Diagnostics SWOT Analysis, 2013... 93 Table 40: Company Profile Radiometer Medical... 94 Table 41: Radiometer Medical SWOT Analysis, 2013... 95 Table 42: Company Profile Randox Laboratories... 96 Table 43: Randox Laboratories SWOT Analysis, 2013... 97 Table 44: Company Profile Response Biomedical... 98 Table 45: Response Biomedical SWOT Analysis, 2013... 99 Table 46: Company Profile Roche Diagnostics... 100 Table 47: Roche Diagnostics SWOT Analysis, 2013... 102 Table 48: Company Profile Siemens Healthcare... 103 Table 49: Siemens Healthcare SWOT Analysis, 2013... 103 Table 50: Company Profile Thermo Scientific... 104 Table 51: Thermo Scientific SWOT Analysis, 2013... 105 Table 52: Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in the European Markets, ($m), 2009 2018... 112 Table 53: Major Events Affecting the European ACS In Vitro Diagnostics Market... 113 Table 54: Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in France, ($m), 2009 2018... 114 Page 13 GDME1026CFR / Published APR 2013

Table 55: Table 56: Table 57: Table 58: Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in Germany, ($m), 2009 2018... 117 Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in Italy, ($m), 2009 2018... 118 Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in Spain, ($m), 2009 2018... 119 Sales Forecasts for ACS In Vitro Diagnostic Testing Reagents in the UK, ($m) 2009 2018... 122 Page 14 GDME1026CFR / Published APR 2013

1.2 List of Figures Figure 1: Anatomy of the Human Heart... 18 Figure 2: Heart Muscle Damage, Atherosclerosis and Thrombosis... 19 Figure 3: Strategy for Evaluating ACS... 21 Figure 4: Treatment and Management of ACS... 28 Figure 5: Annual Number of ACS Cases Across Europe, 2009 2018... 29 Figure 6: Direct and Indirect Costs ($bn) of CAD in Europe, 2011 to 2018... 31 Figure 7: Europe Market Share by Test Type for ACS In Vitro Diagnostic Testing Reagents, 2012... 32 Figure 8: Estimated European ACS Diagnostic Biomarker Testing Volumes, 2009 to 2018... 72 Figure 9: Figure 10: Figure 11: Figure 12: Figure 13: Figure 14: Figure 15: Figure 16: Figure 17: Figure 18: European Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m), 2009 2018... 112 European Market Share for ACS In Vitro Diagnostic Testing Reagents, 2012 and 2018... 113 France Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m), 2009 2018... 114 France Market Share by Test Type for ACS In Vitro Diagnostic Testing Reagents, 2012 and 2018... 116 Germany Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m), 2009 2018... 117 Italy Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m), 2009 2018... 118 Spain Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m), 2009 2018... 119 Spain Market Share by Test Type for ACS In Vitro Diagnostic Testing Reagents, 2012 and 2018... 121 UK Sales Forecast for ACS In Vitro Diagnostic Testing Reagents, ($m) 2009 2018... 122 UK Market Share by Test Type for ACS In Vitro Diagnostic Testing Reagents, 2012 and 2018... 124 Page 15 GDME1026CFR / Published APR 2013

Introduction 2 Introduction Acute Coronary Syndromes (ACS) encompasses an array of clinical symptoms (most commonly chest discomfort) manifesting from acute myocardial ischemia, and consists of two major diseases: myocardial infarction and unstable angina, with the former being one of the major killers in Europe. Though the incidence of ACS is either in decline or constant across the European countries, hundreds of thousands of ACS and suspected ACS patients still visit emergency rooms every year with symptoms such as chest pain. These patients are typically assessed with in vitro diagnostic biomarker tests, and in particular these tests are essential in accurately diagnosing patients with non-st-segment elevation myocardial infarction. Early diagnosis of ACS can result in prompt treatment and management of symptoms and improve outcomes substantially. This report focuses on the ACS in vitro diagnostic testing reagents markets in Europe (France, Germany, Italy, Spain, and the UK), and identifies unmet needs in the market, physician attitudes towards current ACS diagnostic biomarker testing, and whether pipeline biomarkers have the potential to meet these unmet needs. 2.1 Catalyst In Europe, the ACS in vitro diagnostics market is dominated by a single biomarker test, cardiac troponins. However, this market remains of high interest due to advancements in assay sensitivity both on laboratory and point-of-care platforms. GlobalData expects these advancements to have an impact on other diagnostic tests such as creatine kinase-mb isoenzyme and myoglobin. Furthermore, the emergence of pipeline biomarker tests will change the landscape of ACS in vitro diagnostic testing and is expected to provide enhancements in the early diagnosis of the disease. This report will provide in-depth coverage of these dynamics with underpinning insight from key opinion leaders of varying disciplines, including laboratory managers, biochemists, emergency physicians, and cardiologists. The report also incorporates recommendations on how companies in the market or companies interested in entering can best navigate it. Furthermore, in-depth analysis of current products and upcoming pipeline tests is offered, as well as country-specific forecasting of the ACS in vitro diagnostic testing reagents market. Page 16 GDME1026CFR / Published APR 2013

Appendix 11.7 About MediPoint MediPoint is the flagship product for GlobalData s Medical team. Each MediPoint report is built from the ground-up by our team of healthcare analysts in the US and UK. Each report includes input from experienced physicians and leading Key Opinion Leaders (KOL). Running throughout each report in the series, What Physicians Think quotes provide a unique insight into how healthcare professionals are reacting to events within the industry, and what their responses could mean for industry strategists. 11.8 About GlobalData GlobalData is a leading global provider of business intelligence in the Healthcare industry. GlobalData provides its clients with up-to-date information and analysis on the latest developments in drug research, disease analysis, and clinical research and development. Our integrated business intelligence solutions include a range of interactive online databases, analytical tools, reports and forecasts. Our analysis is supported by a 24/7 client support and analyst team. GlobalData has offices in New York, Boston, London, India and Singapore. Page 146 GDME1026CFR / Published APR 2013

Appendix 11.10 Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GlobalData. Page 147 GDME1026CFR / Published APR 2013