Cancer Drug Safety and Public Health Policy: A Changing Landscape (Cancer Treatment and Research, 184)

This book offers a wide-ranging description and analysis of recent developments and current trends in health policy with regard to cancer drug safety. The book opens with an overview of pharmacovigilance for cancer blockbuster drugs, covering both general considerations and efforts to develop a structured framework for the identification and reporting of adverse drug reactions (ADRs). A number of important examples of serious ADRs to hematology and oncology drugs are then reviewed, with evaluation of the lessons learned and the policy implications of the ensuing legal cases and their settlements. Further, the difficulty of reporting such blockbuster side effects in the medical literature is explored in an empirical study. Significant advances have been achieved in analytic methods for the identification of ADRs, and here there is a particular focus on the value of optimal discriminant analysis. Finally, the impacts on pharmacovigilance and drug safety of the huge fines paid under the U.S. False Claims Act relating to the defrauding of governmental programs also receive careful attention – these fines are playing an important role in changing the landscape for pharmaceutical safety. Preface 6 Contents 8 Editors and Contributors 10 1 Fluoroquinolone-Associated Disability and Other Fluoroquinolone-Associated Serious Adverse Events: Unexpected Toxicities Have Emerged in Recent Years 13 1.1 Introduction 13 1.1.1 FQ Adverse Event Drug Label Warnings 14 1.1.2 FQ Drug Label Changes (See Table 1.1 for Levofloxacin Label Changes) 15 1.1.3 FDA Reports of FQ Adverse Events 23 1.1.4 November 5, 2015, FDA Advisory Committee Meeting Identifies FQAD 24 1.1.5 November 5, 2015, FDA Advisory Committee Votes 25 1.1.6 Boxwell FDA FQ Data Compared with Social Media FQ Reports 25 1.1.7 Gender 27 1.1.8 Specific FQs 28 1.1.9 Duration of FQAD 28 1.1.10 FQAD: Reasons for Which FQ was Prescribed 29 1.1.11 FQAD Specific Events 29 1.1.12 Possible Mechanism of FQ Toxicities 30 1.1.13 Another Possible Pathophysiologic Mechanism: Matrix Metalloproteinase Toxicity 31 1.1.14 FQ-Associated Peripheral Neuropathy 32 1.1.15 Levaquin Clinical Trials Completed Prior to FDA Approval in 1997 32 1.1.16 2001 FDA FQ Review 32 1.1.17 2003 FDA FQ Review 33 1.1.18 2008 FDA Pediatric Levofloxacin Review 33 1.1.19 2010 Pfizer Report 33 1.1.20 2011 Levaquin Postmarketing Review 34 1.1.21 2013 FDA Review 34 1.1.22 2014—Present Media Reports Regarding FQs 36 1.1.23 2014 FDA Advisory Committee Comments 36 1.1.24 2014 FDA Dear Healthcare Professional Letters 37 1.1.25 2014 Citizen Petition 38 1.1.26 2014 Meeting with U.S. Senate Health Committee 38 1.1.27 2015 Meeting with FDA 38 1.1.28 2015 FQ Case Studies 38 1.1.29 2015 FDA Advisory Committee Meeting 39 1.1.30 2015 FDA Listening Session 40 1.1.31 2016 FQ Neuropsychiatric Study 41 1.1.32 2016 FQ Label Updates 41 1.1.33 2016 FDA Response to Citizen Petition 41 1.1.34 2018 FQ Nature Article 42 1.1.35 2019 Citizen Petition 42 1.1.36 2019 FQ Neuropsychiatric Toxicity Study 43 1.2 Discussion 43 1.3 Conclusions 43 1.3.1 Recommendations 44 1.3.2 Significance of This FQ Study 44 1.4 REMS Request 44 References 50 2 Biosimilar Epoetin in the United States: A View from the Southern Network on Adverse Reactions 52 2.1 Introduction 52 2.1.1 Regulatory Approval for Epoetin Biosimilar in the United States 53 2.1.2 Chemistry, Manufacturing, and Controls 53 2.1.3 Biological Activity 54 2.1.4 Pharmacology/Toxicology 55 2.1.5 Immunogenicity 55 2.1.6 Clinical Pharmacology 55 2.1.7 Clinical Efficacy and Safety 56 2.1.8 Risk Evaluation and Mitigations Strategy (REMS) 56 2.1.9 Extrapolation 56 2.1.10 Findings of the Oncology Drug Advisory Committee (ODAC) of the FDA 57 2.1.11 Patents and Litigation 57 2.1.12 Naming and Labeling 58 2.1.13 Interchangeability 58 2.1.14 Substitution 58 2.1.15 Pharmacovigilance and Immunogenicity 58 2.1.16 Lessons from the European Union (EU) Countries 59 2.1.17 Lessons from Japan 59 2.2 Conclusions 60 References 61 3 Policing of Drug Safety Information Dissemination Under the False Claims Act 63 3.1 Introduction 63 3.1.1 The Settlement 64 3.1.2 Lessons Learned and Legal Precedent 66 3.1.3 Future of Policing Drug Safety Efforts 67 3.2 Conclusion 68 References 69 4 Translating Research into Health Policy: The Citizen Petition Experience with the Food and Drug Administration 70 4.1 Introduction 70 4.1.1 The Citizen Petitions 72 4.2 Conclusions 73 4.2.1 Policy Implications 76 References 81 5 Systemic Barriers and Potential Concerns from Reporting Serious Adverse Drug Reactions 83 5.1 Introduction 83 5.2 Findings of Litigation Risks 85 5.2.1 Fear of Being Included in a Lawsuit Against the Manufacturer 85 5.2.2 Fear of Being Sued for Libel 85 5.2.3 Fear of Personally Being Sued for Malpractice 86 5.2.4 Fear of Physician Partners Being Sued for Malpractice 86 5.3 Professional Retaliation 87 5.3.1 Fear of Exclusion from Cooperative Industry-Sponsored Clinical Trials 87 5.3.2 Fear of Jeopardizing Existing Academic Collaborations 87 5.3.3 Fear of Being Excluded from a Pharmaceutical Corporation’s Speaker’s Bureau 88 5.4 Regulatory Considerations 88 5.4.1 Concern that no Response from the FDA Was Likely 88 5.4.2 Concern that no Response from the FDA Was Needed 88 5.5 Discussion 89 References 91 6 Was There Something Rotten in Denmark: Nephrogenic System Fibrosis Cases Occurring in Copenhagen 94 6.1 Introduction 94 6.1.1 European Actions 102 6.1.2 Actions of the Manufacturer of Gadodiamide 103 6.2 Basic Science Considerations 103 6.3 Explanations for the Danish Findings 104 6.4 International Considerations 104 6.5 Summary 105 References 107 7 Rituximab-Associated Progressive Multifocal Leukoencephalopathy: A Twenty-Year Update 110 7.1 Introduction 110 7.2 Methods 111 7.3 Results 111 7.4 Case Series 111 7.4.1 Periodic Safety Update Report, Global Safety Database, EudraViglinance Database, and FAERS Database 113 7.5 Epidemiologic Studies 114 7.5.1 PML-Related Safety Notifications from Market Authorization Holders for Rituximab in the US and Europe 115 7.6 Discussion 116 References 117 8 Maximum Accuracy Machine Learning Statistical Analysis—A Novel Approach 119 8.1 Introduction 119 8.1.1 Data Analysis in Practice 120 8.1.2 Logistic Regression (MELR) Analysis 121 8.1.3 Using ODA to Maximize the Accuracy of the MELR Model 123 8.1.4 Novometric CTA Models Explicitly Maximizing ESS 125 8.2 Conclusion 130 References 131 9 Investigating Severe Adverse Reactions: Examples of the ANTICIPATE Methodology at Work 134 9.1 Introduction 134 9.1.1 The Toxicities 135 9.1.2 HX575-Associated PRCA 136 9.1.3 Gadodiamide-Induced Nephrogenic Systemic Fibrosis 136 9.1.4 Peginesatide-Associated Anaphylaxis 137 9.2 The ANTICIPATE Evaluation 137 9.2.1 Signal Detection 137 9.3 sADR Data Analysis 139 9.3.1 Root Cause Analyses/Toxicity Eradication 140 9.4 Conclusion 141 References 142 10 Consequences to Patients, Clinicians, and Manufacturers When Very Serious Adverse Drug Reactions Are Identified (1997–2019): A Qualitative Analysis from the Southern Network on Adverse Reactions (SONAR) 146 10.1 Introduction 146 10.2 Methods 147 10.3 Results 148 10.4 Clinical and Economic Impact 149 10.5 Harms to Clinicians 150 10.6 Harms to Manufacturers, Actions by Regulatory Agencies, Financial Payments, and Attempts to Discredit Physicians 150 10.7 Discussion 151 References 153 11 Moderna, Pfizer-BioNTech, and Johnson & Johnson/Janssen Post-Covid Vaccine Hematological Adverse Events Including Cerebral Venous Sinus Thrombosis (CVST), Thrombotic Thrombocytopenia (VITT), Blood Clots, Increased Vaginal/Menstrual Bleeding and/or Miscarriage, Stillbirth Delivery, or Premature Birth 155 11.1 Introduction 155 11.1.1 Study Implementation 156 11.2 Methods 156 11.3 Results 157 11.3.1 Blood Clot Related Events 158 11.3.2 Vaginal/Menstrual Bleeding AEs 161 11.3.3 Miscarriage, Stillbirth Delivery, or Premature Birth AEs 162 11.4 Conclusions 162 12 Investigating Novel Genetic Markers for Fluoroquinolone Associated Disorders 165 12.1 Introduction 165 12.1.1 Timeline of Events 166 12.1.2 Background of CYP2D6 168 12.2 Conclusion 169 References 169 Index 171