Analyses of Spontaneous Adverse Drug Reaction Databases Using Descriptive and Inferential Statistics Dissertation zur Erlangung des Doktorgrades (PhD) der Medizinischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn Diana Ivonne Dubrall aus Heidenheim an der Brenz 2020 Angefertigt mit der Genehmigung der Medizinischen Fakultät der Universität Bonn 1. Gutachter: Prof. Dr. rer. nat. Matthias Schmid 2. Gutachter: Prof. Dr. med. Bernhardt Sachs Tag der mündlichen Prüfung: 04.09.2020 Aus dem Institut für Medizinische Biometrie, Informatik und Epidemiologie Direktor: Prof. Dr. rer. nat. Matthias Schmid 3 Table of content Table of content ........................................................................................................ 3 List of abbreviations ................................................................................................. 4 1. Summary ............................................................................................................... 5 2. Introduction ........................................................................................................... 5 3. Objectives ............................................................................................................. 8 4. Methods ................................................................................................................. 8 4.1 BfArM’s ADR database ...................................................................................... 8 4.2 EudraVigilance .................................................................................................. 8 4.3 Descriptive analysis of all ADR reports .............................................................. 9 4.4 Adverse drug reactions in older adults .............................................................. 9 4.5 Drug-induced anaphylactic reactions in children ............................................... 9 4.6 Comparative analysis of ACEi, ARBs and aliskiren angioedema reports .......... 9 4.7 Statistical analysis ............................................................................................ 10 4.7.1 Odds Ratios ............................................................................................... 10 4.7.2 ADR reports per 100,000 inhabitants/assumed drug-exposed inhabitants 10 5. Results .................................................................................................................. 11 5.1 Descriptive analysis of all ADR reports ............................................................. 11 5.2 Adverse drug reactions in older adults ............................................................. 11 5.3 Drug-induced anaphylactic reactions in children .............................................. 12 5.4 Comparative analysis of ACEi, ARBs, and aliskiren angioedema reports ........ 12 6. Discussion ........................................................................................................... 12 7. Acknowledgement ............................................................................................... 15 8. References ........................................................................................................... 16 Appendix A ............................................................................................................... 24 Appendix B ...............................................................................................................45 Appendix C ...............................................................................................................84 Appendix D ...............................................................................................................97 Appendix E .............................................................................................................150 4 List of abbreviations ACEi Angiotensin-Converting Enzyme Inhibitor ADR Adverse Drug Reaction ARB Angiotensin-Receptor Blocker BfArM Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinpodukte) EMA European Medicines Agency EudraVigilance European Adverse Drug Reaction Database CI Confidence Intervals DEGS1 German Health Interview and Examination Survey for Adults EEA European Economic Area HCP Health Care Professionals IMBIE Institute for Medical Biometry, Informatics and Epidemiology Non-HCP Non-Health Care Professionals NSAID Non-Steroidal Anti-Inflammatory Drugs OR Odds Ratios OTC Over the Counter Drugs RAS Renin-Angiotensin System SMQ Standardised MedDRA Query USA United States of America 5 1. Summary The presented cumulative dissertation summarizes four scientific research papers of anal- yses assessing data of the adverse drug reaction (ADR) database of the Federal Institute for Drugs and Medical Devices (BfArM) and the European ADR database (EudraVigi- lance) of the European Medicines Agency (EMA). The objective was to analyse all ADR reports contained in BfArM’s ADR database descriptively for the first time and subse- quently with regard to three relevant pharmacovigilance questions. Therefore, research strategies for the identification of the cases depending on the research question were established and different statistical methods were used. Two of the known limitations of analysis performed in ADR databases are the lack of matching control groups and exact exposure data. To overcome these issues, we generated control groups within the ADR database and used external data sources to set the number of ADR reports in relation to the number of inhabitants and assumed drug-exposed inhabitants. All research articles have been published in international peer-reviewed journals (see Appendix A-D). 2. Introduction Prior to the approval of a drug, its safety and efficacy have to be investigated in clinical trials. In these only a limited number of patients are included, which are often selected according to strictly pre-defined inclusion and exclusion criteria (EMA, 2020). Especially vulnerable patients such as very old as well as very young patients or patients with comor- bidities are often not involved. Thus, the complete extent of ADRs is unknown when a drug is released to the market. Therefore, post-authorisation monitoring of the approved drugs remains crucial. Among others, ADR databases are one of the suitable tools to monitor drug safety. In the past, ADR reports served as one of the sources of evidence in 94.4 % of all regulatory actions due to safety issues in Europe (Lane et al., 2018). In Germany, ADRs are reported by Health Care Professionals (HCP) e.g. physicians and non-Health Care Professionals (non-HCP) e.g. consumers (Kommas et al., 2019). A de- tailed description about reporting channels and reporting obligations can be found else- where (Kommas et al., 2019). In brevity, all ADR reports of chemical defined drugs were stored in BfArM’s ADR database until November 22, 2017 (BfArM, 2013 a). Since then all ADR reports are being sent to the European ADR database (EudraVigilance). 6 The first study of this cumulative dissertation represents a descriptive analysis of all ADR reports contained in BfArM’s ADR database (Appendix A). Descriptive analyses of ADR databases were also published for other countries (Ozcan et al., 2016; Thiessard et al, 2005). However, the results from other countries cannot be transferred to Germany, since these may vary significantly due to different prescribing behaviours and differences be- tween the patient populations involved (e.g. genetic differences). In Germany, nearly 2.4 % - 6.4 % of all hospital admissions were ADR related and in- creased with rising age (Schneeweiss et al., 2002; Schurig et al., 2018). Likewise, the number of ADR reports per inhabitants referring to older adults (> 65 years) compared to younger adults was higher in other ADR database analysis (Aagaard et al., 2012). With regard to drug therapy in older adults, information on safety and efficacy are contained in less than half of initial drug approval documents (Ruiter at al., 2019). However, older adults are more prone to develop ADRs, since they exhibit numerous risk factors such as multi- morbidity, polypharmacy, as well as changes in pharmacokinetics, due to reduced kidney and liver function (Davies and O'Mahony, 2015). Additionally, the forthcoming demo- graphic change will shift the proportion of older adults in the German population. An in- crease up to 24-30 % until the year 2060 (2018: ~ 19 %) is expected (Destatis, 2019). Hence, the impact and significance of ADRs in older adults is supposed to gain further medical and economic relevance in the future. In our second study we analysed, whether an increase in the number of ADR reports referring to older adults in relation to the number of inhabitants and assumed drug-exposed inhabitants could already be observed in the past. Further on, we investigated whether there are differences in the reported character- istics in ADR reports of older and younger adults, which may highlight ADRs of particular importance for older adults (Appendix B). Opposed to older adults, ADR related hospital admissions are reported to be less common in children (Impicciatore et al., 2001). Based on emergency department records the inci- dence of drug-induced anaphylaxis for children (< 19 years) was estimated to be 0.5/100,000 person-years (West et al., 2007). Anaphylaxis is defined as a potentially se- vere generalized or systemic hypersensitivity reaction, in which the skin (e.g. urticaria, angioedema), the respiratory tract (e.g. dyspnea),