Preface

Pharmacoepidemiology is a relevant emerging field that applies epidemiological methodologies to study the interactions between health products and large human populations in real-life settings, namely the effects, benefits, and risks of drug use, with the goal of endorsing/optimizing their rational use to improve health outcomes. Pharmacovigilance, or drug safety, is a significant area within pharmacoepidemiology, and addresses the assessment, detection, monitoring, and prevention of adverse drug reactions, thus being fundamental for recognizing the safety of medicines and, at the same time, preventing patients from potential harms.

*New Insights into the Future of Pharmacoepidemiology and Drug Safety* provides scientific information on important subjects within the fields of pharmacoepidemiology, pharmacovigilance, and drug safety, aiming to improve public health surveillance and shed light on some critical unexplored concepts. Furthermore, it allows readers to acquire an in-depth understanding of the main roles, key principles, developments, and practices adopted in these disciplines while also highlighting their latest advances. This book is for students and those working in pharmacology, epidemiology, drug safety, clinical research, regulatory affairs, pharmacovigilance, and risk management, including researchers, health professionals, and employees from clinical research organizations.

The book contains ten chapters divided into four sections. The introductory chapter "Pharmacovigilance and Public Health Safety" offers a comprehensive overview of the key features of pharmacovigilance and its high importance in preserving public health by enhancing patient safety and quality of life. The remaining nine chapters are included in the following sections.

Section 2, "Recent Findings and New Advances of Adverse Drug Reactions," includes the following five chapters: "Adverse Drug Reactions and Pharmacovigilance," "Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy," "Prevalence and Significance of Antibiotic-Associated Adverse Reactions," "Evaluation of the Medication Safety of Chemotherapy Drugs," and "Small Molecule/HLA Complexes Alter the Cellular Proteomic Content." These chapters explore the significant benefits of monitoring and reporting adverse drug reactions while a drug is in clinical trials as well as after its market authorization. Drugs examined include those used for anti-tuberculosis therapy and chemotherapy as well as antibiotics. Furthermore, this section also reviews the epidemiological data related to antibiotic-associated adverse reactions and analyzes drug–protein interactions within the human leukocyte antigen (HLA) system and its association with adverse drug reactions and disease.

Section 3, "Drug Safety among Older People," includes the two chapters: "Pharmacovigilance in Older Adults" and "Drug-Induced Delirium among Older People." These chapters study the interactions between polypharmacy and adverse drug effects in older adults, such as delirium, namely through the prescription of inappropriate medication, thus highlighting the importance of encouraging pharmacovigilance practices among this special population.

Section 4, "Scientific Methods and Tools for Safety Surveillance" includes two chapters: "Computer-Aided Pharmacoepidemiology in Drug Use and Safety: Examining the Intersection between Data Science and Medicines Research" and "Basics and Essentials of Medical Devices Safety Surveillance." These chapters explore the increasing use of real-world data in pharmacoepidemiologic research and medication safety, while at the same time assessing the main strengths and limitations of relevant healthcare tools such as electronic databases and medical devices.

In sum, this book provides a general overview of past and new scientific research developments in pharmacoepidemiology and drug safety, as well as reinforces the main goals, strengths, and limitations of the most critical concepts within these fields.

#### **Maria Teresa Herdeiro and Tânia Magalhães Silva**

iBiMED – Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

#### **Fátima Roque**

Research Unit for Inland Development – Guarda Polytechnic Institute (UDI-IPG), Guarda, Portugal

> Health Sciences Research Centre, University of Beira Interior (CICS-UBI), Covilhã, Portugal

#### **Adolfo Figueiras**

Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain

Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiology and Public Health - CIBERESP), Madrid, Spain

Section 1 Introduction

#### **Chapter 1**

## Introductory Chapter: Pharmacovigilance and Public Health Safety

*Maria Teresa Herdeiro, Tânia Magalhães Silva, Inês Ribeiro-Vaz, Eva Rebelo Gomes, Adolfo Figueiras and Fátima Roque*

#### **1. Introduction to pharmacovigilance**

Worldwide, pharmacovigilance is one of the most important scientific disciplines within public health [1]. According to the World Health Organization (WHO), pharmacovigilance is described as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem" [2]. The implementation of pharmacovigilance activities was essential to globally promote and protect public health, particularly by reducing the significant burden of morbidity, mortality and associated increased healthcare costs, triggered by the occurrence of adverse reactions to medicines [3]. The Memo/08/782, released in 2008 by the European Commission, highlights the importance of pharmacovigilance, namely for saving lives, by revealing estimates of about 197 thousand deaths per year and total costs to society of 79 billion euros in the European Union (EU), due to adverse reactions [4].

The fundamental goals of pharmacovigilance are [5–7]:


In sum, the golden objective of pharmacovigilance process is to enhance patient's safety and quality of life, and strictly preserve public health by identifying, preventing or decreasing the harmful effects and risks related to the use of health products in humans. Therefore, the science that assesses drug's safety and efficacy profiles stands as highly important throughout the entire drug development lifecycle, from preclinical development until post-market surveillance, as it promotes the continuous vigilance of the drug effects. It plays a crucial role within pharmaceuticals, not only for the prevention of drug-related risks in humans, as well as for the reduction of the financial expenses linked to the occurrence of unexpected adverse effects [5–8].

#### **2. Pharmacovigilance history**

Pharmacovigilance has a long history. Although the first findings were dated from 172 years ago, when a patient died after being anesthetized with chloroform, followed by 107 deaths in the United States of America in 1937, due to the high toxicity caused by diethyleneglycol, a sulfanilamide elixir-containing solvent, its official inception to address drug safety problems was only heralded after the thalidomide tragedy, in 1961 [1, 8]. This drug was commonly used in Europe by pregnant women as a nonaddictive, nonbarbiturate sedative for nausea treatment, and resulted into a devasting 10 thousand birth abnormalities, namely phocomelia, and increased miscarriage rates [9]. At that time, Dr. McBride highlighted the link between the consumption of thalidomide in pregnancy and the prevalence of fetal congenital malformations, by writing a letter to The Lancet journal editor and reporting an increase of 20% in these cases. In response to the thalidomide disaster, it became evident the urgency in requiring the rigorous safety and efficacy testing of drugs before their market authorization, as well as a global awareness concerning the need for creating pharmacovigilance systems [8].

The pharmacovigilance system suffered many alterations since then and, due to a collaborative effort of many stakeholders, such as physicians, pharmacists, other healthcare professionals, patients, regulatory health authorities, academia and industry, in 1968 the WHO Pilot Research Programme for International Drug Monitoring was instituted. This program intended to establish an active, systematic, organized and regulated network at an international level, mainly for uncovering formerly unknown or poorly recognized drug's adverse effects, leading to the formal adoption of the pharmacovigilance term in the 1970s [7, 8]. In early 1980s, the Council for International Organizations of Medical Sciences (CIOMS) introduced its programme on drug development and usage, together with WHO. In the 1990s, a remarkable impact on international drug regulatory activity was observed, specifically after the implementation of various of the recommendations provided by CIOMS by the formerly International Conference on Harmonization (ICH), currently known as International Council for Harmonization [1, 7, 8]. The ICH helped to harmonize the regulatory infrastructures of the regulatory agencies and pharmaceutical companies from Europe, Japan and the United States [1]. Thereafter, a positive development was observed in several countries, concerning the organization and associated regulations of drug safety, ultimately resulting in the creation of the European Society of Pharmacovigilance (ESOP) in 1992, posteriorly renamed to International Society of Pharmacovigilance (ISoP). Finally, in 1995 the European Medicines Agency (EMA) was founded, followed by the Eudravigilance launch in 2001 [7, 8].

Besides thalidomide disaster, another significant landmark in the history of pharmacovigilance was the market authorization of rofecoxib, a cyclooxigenase-2 *Introductory Chapter: Pharmacovigilance and Public Health Safety DOI: http://dx.doi.org/10.5772/intechopen.95293*

inhibitor. In the end of 2000, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study revealed an association between rofecoxib consumption and myocardial infections in patients with chronic pain [10–12]. By this time, this risk became a critical public health issue as rofecoxib was prescribed to tens of millions of people in more than 80 countries. This was one of the most highly publicized drug withdrawals ever reported and, together with other subsequent related episodes, raised some concerns regarding public trust on the role of pre- and postmarketing surveillance [10–13]. Due to the public's lack of confidence on pharmacovigilance, more robust regulations had to be adopted [12, 14]. These include, for instance, the EU risk management plan, implemented in 2005, which became a mandatory document for marketing authorization applications to evaluate the information on drug toxicology, the request for a pharmacovigilance plan as well as for epidemiological information on the population receiving the drug therapy, and the submission of protocols to the regulatory authorities prior to the study start for a proper safety assessment [12]. Other important measures implemented were the education of physicians and medical students, active participation of other health professionals (pharmacists, nurses) in adverse drug reaction (ADR) reporting, feedback transmission and improvements on ADR reporting [14]. The introduction of all these approaches were essential to safeguard public health, with the particularity of primarily assessing the effects on the population, especially on the patient, rather than over the drug under study [6, 12].

#### **3. Pharmacovigilance systems**

Given the high importance of pharmacovigilance, currently, countless countries around the world already have well-established, active and robust national pharmacovigilance systems to safeguard patient's wellbeing.

Pharmacovigilance activities of these systems can also involve the [1]:


Therefore, it is not surprising that the WHO programme, responsible to aid in the design, development and assistance of the pharmacovigilance systems, has already 170 countries as partnership members [15].

#### **3.1 WHO collaborating Center for International Drug Monitoring: the Uppsala monitoring Center**

As previously referred, the WHO Programme for International Drug Monitoring started, in 1968, to systematically collect all available information on drug's adverse effects, as a worldwide response to the thalidomide disaster. Ten years later, in 1978, with the intuit to support this programme, the Uppsala Monitoring Center (UMC) was set up. The UMC is an international, independent and non-profit center in

Uppsala, Sweden, devoted to investigating the harms and benefits of medicines, to ensure a safe and efficient consumption of these drugs by patients [5, 7].

The key mission of UCM, on behalf of the WHO, is to protect patients through an effective and global pharmacovigilance practice, namely the management of the international database of ADR reports received from each country national center, within the WHO's global pharmacovigilance network [5, 7]. This distinctive WHO data repository, known as VigiBase, is the world's single largest database system of individual case safety reports (ICSR), which are solely submitted by members of the WHO programme [16]. The ICSR, also commonly recognized as "spontaneous" or voluntary ADR report, is a safety document that includes the information needed to support the reporting of adverse events, as well as of products-related problems and consumer complaints generated during the drug post-marketing phase. An ICSR can be filled either in paper or electronically and, to be considered as valid, has to include at least the following four elements: an identifiable patient, one identifiable reporter, one suspected medicinal product and one suspected adverse event [17, 18].

In sum, firstly the national pharmacovigilance system of each country receives the spontaneous ADR reports from health professionals, consumers and pharmaceutical companies. Afterwards, the ICSR are locally validated and evaluated, and a regulatory action can be potentially initiated, if needed. Finally, all the member countries are committed to disclose the on-time reports comprising complete postmarketing data into VigiBase, therefore enabling the uncovering of ADR-associated signs between different countries.

Until May 2019, VigiBase has held over 20 million of ICSR associated with medicines [16]. VigiBase collects the reports sent by the member countries of the WHO program, including 140 full member countries and 30 associate members [19]. The majority of the national joining centers have a straightforward electronic access to these standardized and structured reports, which contain a specific hierarchical code for the particular ADR registered, aiming to help in the fast identification of signals by any country member [5, 7]. The terminologies established for coding adverse reaction terms within the WHO programme, such as the WHO – Adverse Reaction Terminology (WHO-ART), afterwards replaced by the Medical Dictionary for Regulatory Activities (MedDRA), have been broadly embraced by national centers, manufacturers and medicinal product regulators [5, 7].

Spontaneous reporting systems are indispensable to post-marketing surveillance, and have shown to be effective in detecting various types of ADR, especially rare ones. Moreover, the ADR report method also evaluates the need to pursuit further investigations to check if exists an association with the medicine and can hence trigger alarm signals [20]. However, the search for complements to the existing pharmacovigilance systems has shown to be extremely important, mainly due to the significant delays encountered on the detection of more common types of ADR, in addition to the persisting high amount of unreported ADR [20].

#### **3.2 European Medicines Agency**

Globally, it is possible to find a selection of regulatory authorities whose main function is to regulate and support pharmacovigilance. For instance, while in the United States, the responsible structure is the Food and Drug Administration (FDA), in the EU is the EMA [21].

Briefly, EMA's gold mission relies on the promotion of scientific merit pertaining to medicine's evaluation and oversight, for the benefit of public and animal health in the EU. In compliance with the EU legislation requirements, EMA's main responsibilities are related to the:


The legal pharmacovigilance framework for human medicines marketed within the EU/European Economic Area (EEA) is given in Regulation (EC) No 726/2004, with regard to the EU authorized medicinal products, and Directive 2001/83/ EC, concerning the nationally authorized medicinal products, together with the Commission Implementing Regulation (EU) No 520/2012, which summarizes the practical aspects and obligations to be respected and followed by marketing authorization holders and regulatory authorities. Posteriorly, the Directive 2010/84/EC was introduced to substitute the previous directive, with minor amendments being performed in 2012. The EU law requires marketing authorization holders, national competent authorities and EMA to operate services and processes in line with EU legislation, aiming to support a quality assured EU regulatory pharmacovigilance system and to reduce the number of ADR in EU [21–23]. The EU pharmacovigilance system is one of the most sophisticated and comprehensive in the world and allows monitoring the safety of medicines on the European market through prevention, detection and assessment of adverse reactions to drugs, leading to an increased level of public health protection throughout the EU. This system operates through a robust and close collaboration between the competent regulatory authorities from the EU member states, EMA (system coordinator responsible for centrally authorized drugs) and the European Commission (competent authority for drugs centrally authorized in the EU), to rapidly manage and act against an emerging problem, unceasingly prioritizing a safer and more efficacious access of patients to medicinal products. The Pharmacovigilance Risk Assessment Committee (PRAC) was formed in response to this need in July 2012, thus being responsible to provide recommendations on all aspects related to human drugs risk management [21–23].

The European pharmacovigilance network not only successfully collaborates at the European level with high transparency, but also coordinates the necessary regulatory actions, hence producing efficient and accurate safety results able to be transmitted to the EU public in a timely manner. Some of the regulatory tools accessible after the implementation of the revised legislation involve risk management planning, signal detection and management at EU level, periodic safety update reports assessment, drug reviews through referrals post-authorization safety and efficacy studies, communication and training [23].

Within EU, the implementation of the different national pharmacovigilance systems occurred at distinct times. In 1963, The Netherlands became the first EU country to launch their own pharmacovigilance system for spontaneous ADR reporting, followed by the United Kingdom, in 1964, via the Yellow Card Scheme [24].

To achieve a consistent pharmacovigilance system, it is imperative that guidelines and standards are established as they clarify the practical details of the intended information flow, thus being very valuable, for instance, for health professionals training [5]. Thereby, the pharmacovigilance legislation in force in EU since

#### *New Insights into the Future of Pharmacoepidemiology and Drug Safety*

July 2012 led to the development of an important set of principles and measures on Good Pharmacovigilance Practices (GVP), to conduct the safety monitoring of medicines in EU [25]. One of the EMA's advisors on the development of these guidelines and standards on operational features of the EU pharmacovigilance is PRAC [22]. The GVP guidelines, covering medicinal products authorized in the EU either centrally via EMA or nationally, apply to EU marketing authorization holders, EMA and the competent authorities from each member state. The GVP can slightly differ between countries, thus being established by each country regulatory authorities. Moreover, the guidelines set is divided into two chapter types [25]:


Although EMA is known to support several pharmacovigilance databases, the network system used for collecting, managing and analyzing suspected ADR related to authorized medicines within EEA is EudraVigilance. This electronic reporting database system allows the early detection of potential safety signals of post-marketed drugs by effectively analyzing the spontaneous reports previously submitted by marketing authorization holders and member states [26].

The **Figure 1** below synthesizes the key features of pharmacovigilance for the global protection of the public health.

**Figure 1.**

*Pharmacovigilance (PV) highlights in public health safety.*

#### **Appendices and nomenclature**


*Introductory Chapter: Pharmacovigilance and Public Health Safety DOI: http://dx.doi.org/10.5772/intechopen.95293*


### **Author details**

Maria Teresa Herdeiro1 \*, Tânia Magalhães Silva1 , Inês Ribeiro-Vaz2,3, Eva Rebelo Gomes4 , Adolfo Figueiras5,6 and Fátima Roque7,8

1 iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

2 Porto Pharmacovigilance Center, Faculty of Medicine of University of Porto, Porto, Portugal

3 Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine of University of Porto, Porto, Portugal

4 Allergy and Clinical Immunology Service, University Hospital Center of Porto, Porto, Portugal

5 Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Santiago de Compostela, Spain

6 Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

7 Research Unit for Inland Development, Guarda Polytechnic Institute (UDI-IPG), Guarda, Portugal

8 Health Sciences Research Center, University of Beira Interior (CICS-UBI), Covilhã, Portugal

\*Address all correspondence to: teresaherdeiro@ua.pt

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Beninger P. Pharmacovigilance: An Overview. Clin Ther [Internet]. 2018 Dec;40(12):1991-2004. Available from: https://linkinghub.elsevier.com/ retrieve/pii/S0149291818303175

[2] World Health Organization. Pharmacovigilance: Ensuring the Safe Use of Medicines. [Internet]. Geneva, WHO; 2004 [cited 2020 Nov 7]. Available from: www.who. int/medicines/areas/quality\_safety/ safety\_efficacy/pharmvigi/en/

[3] Santoro A, Genov G, Spooner A, Raine J, Arlett P. Promoting and Protecting Public Health: How the European Union Pharmacovigilance System Works. Drug Saf [Internet]. 2017 Oct 22;40(10):855-69. Available from: http://link.springer.com/10.1007/ s40264-017-0572-8

[4] European Commission. MEMO/08/782: Strengthening pharmacovigilance to reduce adverse effects of medicines. [Internet]. Brussels; 2008. Available from: https:// ec.europa.eu/commission/presscorner/ detail/en/MEMO\_08\_782

[5] WHO. The Safety of Medicines in Public Health Programmes: Pharmacovigilance an essential tool [Internet]. WHO Collaborating Centre for International Drug Monitoring; 2006. Available from: https://www.who.int/ hiv/pub/pharmacovigilance/safety/en/

[6] Pitts PJ, Louet H Le, Moride Y, Conti RM. 21st century pharmacovigilance: efforts, roles, and responsibilities. Lancet Oncol [Internet]. 2016 Nov;17(11):e486-92. Available from: https://linkinghub. elsevier.com/retrieve/pii/ S1470204516303126

[7] WHO. The Importance of Pharmacovigilance: Safety Monitoring of medicinal products [Internet]. WHO Collaborating Centre for International Drug Monitoring; 2002. Available from: https://apps.who.int/iris/ handle/10665/42493

[8] Fornasier G, Francescon S, Leone R, Baldo P. An historical overview over Pharmacovigilance. Int J Clin Pharm [Internet]. 2018 Aug 15;40(4):744-7. Available from: http://link.springer. com/10.1007/s11096-018-0657-1

[9] Kim JH, Scialli AR. Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease. Toxicol Sci [Internet]. 2011 Jul;122(1):1-6. Available from: https://academic. oup.com/toxsci/article/1672454/ Thalidomide:

[10] Waxman HA. The Lessons of Vioxx — Drug Safety and Sales. N Engl J Med [Internet]. 2005 Jun 23;352(25):2576-8. Available from: http://www.nejm.org/ doi/abs/10.1056/NEJMp058136

[11] Barry AR, Koshman SL, Pearson GJ. Adverse drug reactions: The importance of maintaining pharmacovigilance. Can Pharm J / Rev des Pharm du Canada [Internet]. 2014 Jul 2;147(4):233-8. Available from: http://journals.sagepub. com/doi/10.1177/1715163514536523

[12] Greener M. First do no harm. EMBO Rep [Internet]. 2008 Mar 8;9(3):221-4. Available from: https://onlinelibrary. wiley.com/doi/abs/10.1038/ embor.2008.17

[13] Huybrechts KF, Desai RJ, Park M, Gagne JJ, Najafzadeh M, Avorn J. The Potential Return on Public Investment in Detecting Adverse Drug Effects. Med Care [Internet]. 2017 Jun;55(6):545-51. Available from: http://journals.lww. com/00005650-201706000-00002

[14] Dainesi SM. Pharmacovigilance: more than ever, an overall responsibility. Clinics [Internet].

*Introductory Chapter: Pharmacovigilance and Public Health Safety DOI: http://dx.doi.org/10.5772/intechopen.95293*

2005 Aug;60(4). Available from: http://www.scielo.br/scielo. php?script=sci\_arttext&pid=S180- 59322005000400002&lng=en&nrm=is o&tlng=en

[15] Uppsala Monitoring Center [Internet]. [cited 2020 Nov 9]. Available from: https://www.who-umc.org/ about-us/who-we-are/

[16] Uppsala Monitoring Centre. VigiBase [Internet]. [cited 2020 Nov 9]. Available from: https://www.who-umc. org/vigibase/vigibase/

[17] Jalali RK. Individual Case Safety Reports. In: Pharmaceutical Medicine and Translational Clinical Research [Internet]. Elsevier; 2018. p. 413-8. Available from: https:// linkinghub.elsevier.com/retrieve/pii/ B9780128021033000298

[18] European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products [Internet]. 2017. Available from: https://www. ema.europa.eu/en/documents/ regulatory-procedural-guideline/ guideline-good-pharmacovigilancepractices-gvp-module-vi-collectionmanagement-submission-reports\_en.pdf

[19] Uppsala Monitoring Center. WHO Programme Members for International Drug Monitoring [Internet]. Available from: https://www.who-umc.org/globalpharmacovigilance/who-programmefor-international-drug-monitoring/ who-programme-members/

[20] Baldo P, Francescon S, Fornasier G. Pharmacovigilance workflow in Europe and Italy and pharmacovigilance terminology. Int J Clin Pharm [Internet]. 2018 Aug 9;40(4):748-53. Available from: http://link.springer. com/10.1007/s11096-018-0711-z

[21] Felix T, Jordan JB, Akers C, Patel B, Drago D. Current state of biologic pharmacovigilance in the European Union: improvements are needed. Expert Opin Drug Saf [Internet]. 2019 Mar 4;18(3):231- 40. Available from: https://www. tandfonline.com/doi/full/10.1080/14740 338.2019.1577818

[22] European Medicines Agency. EMA pharmacovigilance system manual, version 1.2. [Internet]. 2016. Available from: https://www.ema.europa.eu/en/ documents/other/european-medicinesagency-pharmacovigilance-systemmanual\_en.pdf

[23] European Commission. Monitoring safety of medicines for patients. Pharmacovigilance activities related to medicines for human use in the EU [Internet]. 2017. Available from: https://ec.europa.eu/health/sites/ health/files/files/pharmacovigilance/ pharmacovigilance-report-2012-2014.pdf

[24] Rabbur RSM, Emmerton L. An introduction to adverse drug reaction reporting systems in different countries. Int J Pharm Pract [Internet]. 2005 Mar 1;13(1):91-100. Available from: http:// doi.wiley.com/10.1211/0022357055821

[25] European Medicines Agency. Guidelines on good pharmacovigilance practices (GVP) - Introductory cover note [Internet]. 2020. Available from: https://www. ema.europa.eu/en/documents/ regulatory-procedural-guideline/ guidelines-good-pharmacovigilancepractices-gvp-introductory-cover-notelast-updated-revision-3\_en.pdf

[26] Postigo R, Brosch S, Slattery J, van Haren A, Dogné J-M, Kurz X, et al. EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection. Drug Saf [Internet]. 2018 Jul 9;41(7):665-75. Available from: http://link.springer.com/10.1007/ s40264-018-0647-1

## Section 2
