Active involvement of the general public in pharmacovigilance

Active involvement of the general public in pharmacovigilance 5 immediate family, and show some differences with health professionals in the assessment of these adverse reactions and also the type of reactions.[28] Patient reporting has already led to important contributions in valuable information on drug safety, for example increasing the number of spontaneous reports collected, contributing with a large proportion of reports on drug-ADR pairs that eventually became signals,[28,49] or even contributing to the detection of known and unknown ADRs, symptoms or signs earlier than HCPs[21,29,43,48]. Avery et al. [29] have shown the differences between patients and HCPs concerning to the type of drugs and events they report, and how signals of some drug-related reactions might not emerge unless evidence from patients is integrated with that from professionals. lives, that leads to better information collection on the adverse effects of drugs and giving useful details about other problems with treatments, such as inadequate prescriptions or incorrect use of drugs, which would be very difficult to obtain otherwise.[28,32] Patients could identify different ADRs from those reported by HCPs or those which are not featured in existing product information, contributing to a different view of ADR reporting, a better knowledge of the nature and incidence of ADRs, and an increase in generated potential signals, than HCPs reports alone. As an example, patients reported a higher percentage of known and non-serious reactions than HCPs. Drugs widely used in the community setting, and over-the-counter (OTC) products, were the drugs most frequently reported by patients. In contrast, few reports involving reactions to antineoplastic agents or contrast media drugs mostly used in a hospital setting were sent by patients.[28] There have been worries in the past that patient reporting could create additional noise . However, experiences with patient reporting in countries such as the UK showed that more signals were detected when reports of suspected adverse reactions from both consumers and health professionals were collected.[32] Additionally, patients often supply more detail on how unwanted reactions actually affect their lives.[29,36] physiological effect of ADRs, patient reporting presents variable experiences of emotional impact: disbelief, anger, fear, frustration and isolation are common among patients that suffered an ADR.[52] A study from the Netherlands characterized patient motivation to report an ADR, mainly in two major groups: altruistic and personal reasons. Altruistic motives concerned preventing harm to other patients, making the ADR publicly known, increasing medical knowledge, and wanting to improve the patient information leaflet. Personal motives for 14 reporting an ADR included wanting more information about the ADR, indicating that the ADR was too severe not to report, being angry, or wanting confirmation about the ADR, or when they consider that an HCP has not paid attention to their concerns.[47,56] The introduction and active participation of patients in the reporting schemes can make the public aware of possible ADRs and add value to pharmacovigilance.[34] The access to the leaflet information on adverse reactions [43] patients to make informed choices about whether or not to use medicines and to recognize ADRs when they are experiencing them.[34] The potential benefits of patient reporting include the promotion of consumer rights and equity, increasing the knowledge of consumers concerning medicines utilization and safety, and the opportunity to have unique perspectives and experiences. Patients input to regulatory benefit-risk assessments through public hearings and consultations, including patient engagement, risk communication and patient preference assessment are seen as important actions to empower patients in pharmacovigilance, giving them the opportunity to share their perspectives and preferences in drug related issues.[54] Recent patient-centric regulatory and related initiatives are transforming pharmacovigilance, both to regulatory authorities and industry, giving patients the opportunity to participate in decision-making processes, as development of new medicinal products and devices, or intervening in benefitrisk assessment or in risk management, risk minimization and risk communication projects.[54,55] Healthcare and patient organizations would also benefit from consumer involvement.[29,34] Greater understanding of the reasons for reporting could be beneficial in marketing strategies aiming to increase the number and quality of reports. The findings described above suggest that further promotion of patient reporting schemes are justified, along with improvements in existing reporting systems.[29] Different countries performed studies in knowledge of patients about pharmacovigilance and results point out to a general low level of knowledge between patients.[57 60] The awareness that patients can report ADRs is still thought to be low in most countries. organizations are lacking resources to organize large publicity campaigns and/or to handle a large number of reports in addition to HCP In order to achieve a more patient-centered culture, pharmacovigilance centers could use a framework-driven approach to patient engagement, and become proficient in a range of patient-centered competencies.[54,61] Almost 15 all countries have patient and consumer organizations that are dedicated to healthcare and welfare issues.[62] Patient organizations have a privileged position to be active agents in promoting pharmacovigilance and patient engagement, educating patients on pharmacovigilance topics, improving the awareness of pharmacovigilance, and encouraging direct patient reporting, which facilitates patient reporting of ADRs to National Competent Authorities (NCAs).[63,64]. In addition, greater publicity and promotion of the reporting scheme by HCPs, plus wider availability and accessibility of the reporting forms were required, since these factors could be directly related with patient participation in pharmacovigilance.[8,65,66] A recent study from Inácio et al. shows that sociodemographic and economic factors could have an impact on ADRs reporting by patients, as healthcare investment; however, countries views on patient reporting, attitude of pharmacovigilance centers or pharmacovigilance awareness among HCPs and patients can potentially help explain why countries with similar society and economic characteristics have different participation in pharmacovigilance.[66,67] Furthermore, in some countries, experiences with media attention about safety issues had increased reporting in a positive way, increasing awareness of the reporting scheme to the public.[8,68] In conclusion, a better understanding of patient reasons and opinions regarding spontaneous reporting will improve the robustness and ability of the pharmacovigilance system relating to the reduction of under-reporting, covering blind spots of pharmacovigilance systems, like herbal drugs or OTC medication and improving faster signal detection. High quality information for patients is crucial, as good information on medicines and ADRs can empower patients to participate more actively in healthcare-related decisions, together with health professionals.[21 23,54,55] Nowadays, there are numerous initiatives undertaken to promote patient involvement along the life cycle of medicines together with regulatory authorities, patient organizations, interdisciplinary initiatives, professional societies and health technology assessment bodies, including initiatives as CIOMS Working Group (WG) XI, focused on Patient involvement in the development and safe use of medicines. In the next years, it is expected to drive to a more patient-centered approach in pharmacovigilance and decision making.[54,55] If patient reporting is recognized as beneficial for pharmacovigilance and further optimized, methodology and best practice must be internationally shared and promoted.[7] 16 REFERENCES 1. World Health Organization. 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Drug Saf. 2011;34(3):187 97. 26. Van Grootheest K, de Graaf L, others. Consumer adverse drug reaction reporting. Drug Saf. 2003;26(4):211 7. 27. EC. Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance. Directive 2001/83/EC on the Community code relating to medicinalproducts for human us [online]. Available from URL: http://eur-lex. europa. eu/LexUriServ/LexUriServ. douri= OJ: L: 2010: 348: 0074: 0099: EN: PDF [Accessed 2011 May 30]; 2010. 28. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf. 2013;36(4):267 76. 29. Avery AJ, Anderson C, Bond CM, Fortnum H, Gifford A, Hannaford PC, et al. Evaluation of descriptive and qualitative analyses, and questionnaire surveys. Health Technol Assess (Rockv). 2011; 30. van Hunsel FPAM. The contribution of direct patient reporting to pharmacovigilance. [S; 2011. 31. 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Patient Prefer Adherence. 2016;10:631. 39. Lloyd K, White J. Democratizing clinical research. Nature. 2011;474(7351):277. 40. Sox HC, Greenfield S. Comparative effectiveness research: a report from the Institute of 18 Medicine. Ann Intern Med. 2009;151(3):203 5. 41. patient-reported measures. Heal Expect. 2016;19(5):993 1001. 42. direct patient reporting of adverse drug reactions and their prospects of future development in the European Union. Public Health. 2018;155:119 28. 43. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362(10):865 9. 44. Pakhomov S, Jacobsen SJ, Chute CG, Roger VL. Agreement between patient-reported symptoms and their documentation in the medical record. Am J Manag Care. 2008;14(8):530. 45. Rolfes L, van Hunsel F, Taxis K, van Puijenbroek E. The impact of experiencing adverse drug -sectional study in the Netherlands. Drug Saf. 2016;39(8):769 76. 46. Rolfes L, Wilkes S, van Hunsel F, van Puijenbroek E, van Grootheest K. Important information regarding reporting of adverse drug reactions: a qualitative study. Int J Pharm Pract. 2014;22(3):231 3. 47. van Hunsel F, van der Welle C, Passier A, van Puijenbroek E, van Grootheest K. Motives for reporting adverse drug reactions by patient-reporters in the Netherlands. Eur J Clin Pharmacol. 2010;66(11):1143 50. 48. Egberts TCG, Smulders M, De Koning FHP, Meyboom RHB, Leufkens HGM. Can adverse drug reactions be detected earlier? A comparison of reports by patients and professionals. BMJ. 1996;313(7056):530 1. 49. Rolfes L, van Hunsel F, Caster O, Taavola H, Taxis K, van Puijenbroek E. Does patient reporting lead to earlier detection of drug safety signals? A retrospective comparison of time to reporting between patients and healthcare professionals in a global database. Br J Clin Pharmacol. 2018;84(7):1514 24. 50. Inácio P, Cavaco A, Airaksinen M. Current trends in pharmacovigilance: value and gaps of patient reporting. Int J Clin Pharm. 2018;40(4):754 7. 51. Rolfes L. Patient participation in pharmacovigilance. Groningen Rijksuniv Groningen. 2018; 52. patients and their views on reporting. J Clin Pharm Ther. 2012;37(2):148 52. 53. Vilhelmsson A, Svensson T, Meeuwisse A, Carlsten A. What can we learn from consumer reports on psychiatric adverse drug reactions with antidepressant medication? Experiences from reports to a consumer association. BMC Clin Pharmacol. 2011;11(1):16. 54. Building a Patient-Centric Drug Safety Organization. Drug Saf. 2016;39(9):779 85. 55. CIOMS. CIOMS - Working Group XI Patient Involvement [Internet]. Available from: https://cioms.ch/working_groups/working-group-xi-patient-involvement/ 56. van Hunsel FPAM, ten Berge EAAM, Borgsteede SD, van Grootheest K. What motivates patients to report an adverse drug reaction? Ann Pharmacother. 2010;44(5):936 7. 57. Reis CD, Veiga CE, Martins JJ. Pharmacovigilance in Cabo Verde: measuring the awareness and knowledge of consumers. J Pharmacovigil. 2016; 58. erspectives on adverse drug reaction reporting in a developing country: a case study from Ghana. Drug Saf. 2017;40(10):911 21. 19 59. Jacobs TG, Ampadu HH, Hoekman J, Dodoo ANO, Mantel-Teeuwisse AK. The contribution of Ghanaian patients to the reporting of adverse drug reactions: a quantitative and qualitative study. BMC Public Health. 2018;18(1):1384. 60. Aslani P, Hamrosi K, Tong V, Chen TF, Cook J, Fois R, et al. Consumer opinions on adverse events associated with medicines and vaccines. Patient Prefer Adherence. 2018;12:1383. 61. Bahk CY, Goshgarian M, Donahue K, Freifeld CC, Menone CM, Pierce CE, et al. Increasing patient engagement in pharmacovigilance through online community outreach and mobile reporting applications: an analysis of adverse event reporting for the Essure device in the US. Pharmaceut Med. 2015;29(6):331 40. 62. World Health Organization. Reporting and learning systems for medication errors: the role of pharmacovigilance centres. 2014; 63. Härmark L, van Hunsel F, Grundmark B. ADR Reporting by the General Public: Lessons Learnt from the Dutch and Swedish Systems. Drug Saf. 2015;38(4):337 47. 64. Härmark L, Raine J, Leufkens H, Edwards IR, Moretti U, Sarinic VM, et al. Patient-Reported Safety Information: A Renaissance of Pharmacovigilance? Drug Saf. 2016;1 8. 65. McLernon DJ, Bond CM, Lee AJ, Watson MC, Hannaford PC, Fortnum H, et al. Patient views and experiences of making adverse drug reaction reports to the Yellow Card Scheme in the UK. Pharmacoepidemiol Drug Saf. 2011;20(5):523 31. 66. Inácio P, Gomes JJ, Airaksinen M, Cavaco A. Exploring sociodemographic and economic factors that promote adverse drug reactions reporting by patients. Health Policy (New York). 2018;122(3):263 8. 67. Inácio P, Cavaco A, Airaksinen M. The value of patient reporting to the pharmacovigilance system: a systematic review. Br J Clin Pharmacol. 2017;83(2):227 46. 68. van Hunsel F, van Puijenbroek E, de Jong-van den Berg L, van Grootheest K. Media attention and the influence on the reporting odds ratio in disproportionality analysis: an example of patient reporting of statins. Pharmacoepidemiol Drug Saf. 2010;19(1):26 32. 20 AIM OF THE THESIS The aim of this thesis is to explore the role of general public in pharmacovigilance. SPECIFIC OBJECTIVES The thesis included six studies divided over four chapters, followed by a general discussion on the implications of this research. The specific objectives of thesis are described below, explaining the content of each chapter. i. To describe the attitudes and knowledge of the general public regarding spontaneous reporting and the reasons and opinions that ca adverse drug reaction underreporting; ii. To describe attitudes toward patient reporting systems, and progress toward implementing such systems among national competent authorities participating in the World Health Organization Programme for International Drug Monitoring; iii. To understand the role of European patient organizations as stakeholders to optimize patient involvement in pharmacovigilance; iv. To assess risk perception of developing adverse drug reactions and knowledge, attitudes and opinions regarding pharmacovigilance in patients with diabetes and to investigate whether being a member of a patient organization for diabetes had an effect on these factors; v. To describe the attitudes and knowledge of different community pharmacy professional groups regarding the spontaneous reporting of adverse drug reactions to identify the factors that can influence adverse drug reaction under-reporting; vi. To evaluate community pharmacy professionals as role players in improving to reactions. 21 30 31 32 33 34 39 46 47 48 49 50 53 WHO Collaborating Centre for Pharmacovigilance in Education and Patient reporting As a collaborating Centre for patient reporting we want to support countries who are members of the WHO Programme for international drug monitoring in setting up, running and analyzing data from patient reports. In order to be able to support these countries, we would first like to know what their needs are concerning patient reporting. In order to identify these needs, we suggest to conduct qualitative interviews during the Meyler course and Lareb conference on patient reporting. Based on these interviews a questionnaire will be designed and distributed to all countries who are participating in the WHO Programme for International Drug Monitoring. The interviews would be conducted with persons from various geographical regions and with persons representing organizations who are in different stages of their implementation of patient reporting. Interview guide Since what time have patients been able to report in your country? Or How are you planning to introduce patient reporting in your country? How would your describe your organization s work with patient reporting? How is patient reporting implemented in your country? How well known is your organization to the general public? How do you promote reporting in the general public? How to you cooperate with patient organisations? What are your experiences with: Means of reporting (forms, telephone etc?) Coding Is it more difficult to code patient reports than HP reports? Does it take more time to code? Severity/Quality of Life- Do you use the information about severity/QOL in patient reports? And if so, in what way? Feedback Do you sent feedback to patients and in what form? Signal detection have patient reports contributed to signal detection in your country? Or do you think they will contribute in the future? What do you think is the contribution of patient reports to pharmacovigilance in your country? What do you think the contribution of patient reporting in your country could be in the future? What are your plans for the future? Are you acquainted with Lareb as the WHO Collaborating Centre for Pharmacovigilance in Education and patient reporting? What support do you need in the starting up phase? What support do you need when you have implemented patient reporting? What services could we provide as the WHO Collaborating Centre for Pharmacovigilance in Education and patient reporting? (for instance cources, literature on website, possibility for training visits etc, webinars) 54 55 62 63 64 65 66 67 68 69 70 71 81 82 83 84 85 86 87 95 - Question 7, 8 and 10 are equal, respectively to 11, 12 and 13. DECISION TREE The questionnaire below is the original document from Surveymonkey®, without any changes. The entire questionnaire is not applicable to the respondents: Answers to questions 7 to 13 depends on the answer on Question 4 and respondents were questioned in accordance with the following decision tree: Question 1 to 6 - To all respondents Depending on the answer to Question 4: Answer -european organizations of specific diseases - we represent - Questions 7 to 10 Answer organizations - we represent several national Questions 7 to 10 Answer - Questions 11 to 13 Answer - we represent Questions 7 to 10 Answer - Questions 7 to 10 Questions 14 to 27 - To all respondents 96 97 98 99 100 101 102 103 111 112 Diabetes pharmacovigilance knowledge and risk perception The influence of being part of a patient organization (Submitted to Therapeutic Advances in Drug Safety In press) ABSTRACT Objective: To assess risk perception for developing adverse drug reactions (ADRs) and knowledge, attitudes and opinions regarding pharmacovigilance in patients with diabetes and to investigate whether being a member of a patient organization for diabetes have an effect on these factors, in comparison with other patients, both with or without diabetes. Methods: A cross-sectional study experiencing ADRs, through a face-to-face questionnaire. Diabetes patients followed at the Portuguese Diabetes Association - APDP Diabetes Portugal were included, together with two comparison groups (one with and one without diabetes patients). An overview of the patient characteristics was performed using descriptive analyses. Kruskal-Wallis tests were used to compare the three pat ed by a post-hoc Dunn Visual Analogue Scales (VAS) were used to assess risk perception scores. Results: 314 patients participated in the survey, including 104 followed at APDP, 106 with diabetes not followed at the patient organization, and 104 without diabetes diagnosis. APDP patients presented higher risk perception scores for medicines related to their disease. Those patients affirmed that their doctor explained the possible ADRs of their medication and showed higher intention to report ADRs in the future if they are serious or unexpected. Conclusions: Patients with diabetes showed more positive opinions related to pharmacovigilance. They would like to have more information about general ADRs related to anti-diabetes medication and present higher intention to acquire information on how to report when compared to non-diabetic patients. Patients followed in a diabetes patient association presented higher score of risk perception, which could be influenced by the presence of the diabetes disease in a p also by information received from the patient organization. Hence, patient organizations are well positioned to be a source where patients can obtain reliable information, changing their attitudes and perceptions about the disease and drug treatments. Keywords organization; diabetes; risk perception; adverse drug reactions 1. INTRODUCTION Risk perception can be defined as the belief (whether rational or irrational) held by an individual, group, or society about the chance of occurrence of a risk or about the extent, magnitude, and timing of its effect(s). [1] Several factors could influence the general risk perception, such as cognitive and emotional state of the perceiver, subconscious and socio-cultural, economic and individual factors. [2,3] Several studies have tried to identify the risk perception for adverse drug reactions (ADRs) in different healthcare professionals (HCP) and patients. [4 7] Major differences were found in risk perception of ADRs between those groups; [8] revealing the importance of adequate communication on drugs for the general population. [4,5] Different experiences from patients and HCP related to the use of medicines and their positive or negative views about its safety enrich the knowledge of drugs. Personal experiences with ADRs have shown to increase the 115 risk perceived, in the future, that a specific reaction is occurring. [9] Moreover, there is a close relationship between the intensity of potential ADRs related to medicines and a higher risk perception for a reaction to that medicine. A significant underestimation of risks of medicines most commonly used, such as non-steroidal anti-inflammatory drugs (NSAIDS), antihypertensive drugs and oral contraceptives, has been described for both patients and HCPs. [10,11] Previous studies have investigated general risk perception in random groups of patients, [12,13] or evaluated risk perception for specific drug classes such as NSAIDs or paracetamol. [14 16] Recently, risk perception in diabetes patients who have experienced adverse reactions was also studied. [9] Risk perception and knowledge on ADRs are closely tied to pharmacovigilance, which highly depends on the adequate reporting of ADRs in a post-marketing setting. [17] However, since underreporting of ADRs is still evident, creating awareness and promote ADRs reporting for both HCP and patients is needed.[18] One of the reasons for the lack of reporting by HCPs and patients is the shared uncertainty in evaluating and recognizing an ADR. [19,20] A low and weak risk perception, together with insufficient attention given in the training of HCP regarding practical approaches of pharmacology, pharmacovigilance and drug safety-related issues are given as underlying reasons. [6,8,21] From the point of view, underreporting can be attributed to patient-related factors like failure to recognize ADRs, inability to link the ADR to a drug, low or inexistent risk perception about newly marketed drugs or to insufficient knowledge to identify ADRs. [22,23] Furthermore, for pharmacovigilance centers, it is important to investigate how risks are perceived and how patients could be optimally informed about drug safety issues and, subsequently, how to create a reporting culture among patients where they share their experiences with ADRs. From the literature, it is known that patients usually underrate the risk of adverse reactions of their medications. (20) Therefore, they should receive enough information regarding the medicines they use, including benefits and risks, as well as the correct way of administering them. However, studies have shown that this communication is virtually inexistent or very limited. [24] Obstacles in communication to patients could influence risk perception. [8,23,25 27] Patients desire to be informed of ADRs related to their medication, regardless of how uncommon they are. [5] HCPs have an important role in giving this information and to create awareness of potential ADRs, since they might be prevented if patients are better informed and attentive to their risks. [28 30] Despite this, drug risk perception is complex, and it depends on the personal impression of drug users. [8] Quantifying risk perception, knowledge on pharmacovigilance, and describe patients attitudes could identify several factors to be optimized through educational interventions, to improve their knowledge about drug safety issues and, in addition, increase the ADRs reporting for different groups of patients. [31] Recently, there has been a lot of attention to patient-reported outcomes and initiatives to involve patients. [32 34] Patient reporting is seen as a useful source of information in addition to HCP reporting, not just in gaining more reports, but in receiving the [35 38] Collaboration between patient organizations and national competent authorities is important to raise awareness about pharmacovigilance among the general public [39] and can play a role in educating patients on Patient organizations may be pivotal in the education of patients, and their members may be better informed on the risks related to drug use. [32,40] Members of patient organizations are usually better informed about their health and are potentially more likely to report ADRs. Patient organizations offer easy access to target groups to spread information, in an easy way, to a specific group of consumers [38,41]. Accordingly to the European Medicines Agency (EMA), organizations are defined as not-for-profit organizations which are patient-focused, 116 and whereby patients and/or carers (the latter when patients are unable to represent [42] Besides, these organizations could contribute to the reporting of ADRs to pharmacovigilance centers. [37,43 45] The roles that patient organizations have played in supporting research and raising public awareness were highlighted in several publications. [46 51] A recent study reveals that there is a wide range of interest in drug safety issues among patient organizations. Many organizations thought that patients could contribute to pharmacovigilance in different ways, including providing different information to that given by HCPs; aiding detection of new ADRs, their severity, and their impact on quality of life; and reporting information that was useful and based on their experience with medicines, even without medical confirmation. [39] An important number of organizations doesn´t appear to have activities or involvement on pharmacovigilance. Bringing pharmacovigilance stakeholders and patient organizations together could create a more optimal patient reporting culture. [39] The importance of the perspective of patients on public health and the impact of regulatory decisions is clear and national competent authorities have made an effort in recent years to involve patient organizations in decision making. [52] A study investigating the risk perception of medicines in general, found that patients have a lesser risk perception for medicines used in diabetes (as oral antidiabetics and/or insulin), in relation to other medicines groups, such as sleeping pills, tranquillisers or antidepressants. [5] A recent study suggests that the personal experience of diabetes patients with adverse reactions should be considered when authorities seek to include patients in developing regulatory decisions. [9] Although risk perception in people with diabetes has previously been studied, the role that patient organizations can play in risk perception for medicines used in diabetes remains unexplored. The objective of this study was to assess the risk perception for developing ADRs and knowledge, attitudes and opinions regarding pharmacovigilance in patients with diabetes and to investigate whether being a member of a patient organization for diabetes have an effect on their risk perception, knowledge, attitudes and opinions, in comparison with other patients, both with and without diabetes. 2. METHODS A cross-sectional study was conducted to investigate patients risk perception of experience adverse reactions related to their medication and to assess their knowledge, attitudes and opinions regarding pharmacovigilance, using face-to-face questionnaires. Respondents were recruited based on a cross-sectional design, comparing patients from a patient organization for diabetes Portuguese Diabetes Association APDP - Diabetes Portugal, followed in their clinic, with other two groups of patients, one constituted by people with diabetes not followed in the organization and other group of patients without diabetes. APDP is a patient organization recognized by the International Diabetes Federation as a reference center for diabetes and receives the most serious cases in Portugal, with 40% of patients being treated with insulin. APDP provides medical support to its members through medical follow-up, counselling and care (nursing, nutrition, among others).[53] 2.1. Study Population First group was recruited at the outpatient clinic of APDP, using convenience sampling during May 2018; patients were included if they had a diabetes diagnosis and were over 18 years old. Only type 1 and type 2 patients were invited to participate in the study, in the days of their medical appointments, by personal interview while waiting for consultation. No gestational diabetes patients were surveyed. 117 Two comparison groups were recruited in a community pharmacy in Coimbra, Portugal, during June and July 2018. Comparison groups included a group of patients with diabetes not being followed at APDP and a group of patients without a diabetes diagnosis. Patients for the comparison groups were invited to participate from community pharmacy visitors. To improve the comparability between groups, age and level of education distribution of the first group were taken into consideration to recruiting comparison groups. In order to enhance the participation in the study, a point-of-care blood glucose test was offered to all patients that accepted to participate in the survey the study aimed to obtain a similar group size for comparison groups. Written informed consent was obtained from each participant. The Ethics Committee of APDP- Diabetes Portugal approved this study, and no financial benefits were given to the participants. The individual questionnaire was anonymous, and the data were intended only for scientific purposes of this study and were stored in agreement with privacy regulations. 2.2. Questionnaire Design A questionnaire for the assessment of the ADR risk perception was developed by the authors in collaboration with HCPs of APDP clinical research team. The questionnaire was pre-tested for content validity by several volunteers (n=16), not included in the sample, in order to improve the understanding of the questionnaire. The content validity was assessed and discussed in section 4.3 Strengths and Limitations of the study. The final questionnaire included four major sections: Section I - characteristics (gender, age, education, time since diagnosis and diabetes type). In Section II, twelve sentences were used to assess the attitudes and opinions about spontaneous reporting of ADRs, based on previous studies. [18,43,54] Likert Scales were used, and responses were coded as an ordinal scale: 1, 2, 3, 4 and 5 (representing strongly disagree, disagree, neutral, agree and strongly agree, respectively). This section also contained questions regarding experiences and knowledge on pharmacovigilance. In Section III, participants were asked to assess their perception of the risk of occurrence of any ADRs related with pre-specified drug classes, using visual analogue scales (VAS). In Section IV, only patients with diabetes were asked about the risk for ADRs associated with diabetes drugs used by them. In the as used to assess risk perception scores. Respondents were asked to evaluate their perception of risk of having an ADR for each drug class, and the perceived risk of ADRs was assessed by measuring the distance by the mark made by the participant in the 10 cm visual scale and transforming this to a score ranging between 0 and 10. A final question was added to classify the perception of the likelihood of potential ADRs for antidiabetic drugs. The selection of these ADRs was based on bibliographic research and included hypoglycaemia, [55 64] loss of appetite, [61,62,65,66] increase of appetite, [55] diarrhea, [55,61,62,67] nausea, [55,56,61 63,67] cutaneous reactions, [60,61,63,67] urinary tract infection [60,68] and allergic reactions. [55,61,62,64] The questionnaire was constructed using layman language, everyday wording to define medicines and drug classes and examples of medicines, in order to facilitate its comprehension. [69] 118 2.3. Data Analysis Descriptive analyses were used to provide an overview of the patient characteristics. For the comparison of age, educational level and the onset of diabetes of the two groups of people with diabetes, Pearson chiwas used. This test was also used for the comparison of attitudes and knowledge regarding pharmacovigilance in Portugal, among the groups. For the comparison of opinions and experiences about ADRs and perceived risk for the prespecified different drug classes, the Kruskal-Wallis test was used. When the test provided strong evidence of a difference (p<0.05) between the mean ranks of at least one pair of groups, a post-hoc test using multiple comparison test was carried out for the three pairs of groups, to check evidence of a difference between the two groups (p value was set as <0.05). All p-values were two-tailed with statistical significance set as p<0.05. In order to analyse the risk perception for a different type of diabetes patients related to antidiabetic drugs, a Pearson chi- For all Pearson chi-square ignificance was based on a twop<0.05. If the expected counts in the contingency table are less than 5, the results from the chi-square test are not statistically valid, The results between type 1 and type 2 diabetes patients were separately assessed and results were presented in Table 5 and Table 6. Data were analyzed using the statistical SPSS® Statistics Version 22.0 software (IBM Corporation, Armonk, NY, USA). 119 groups, which could alter their perception of risk regarding their medicines. On the other hand, the fact that they are involved with a patient organization may influence a higher risk perception of these patients compared with other groups, making them better informed about the risks of medicines due to the fact they were receiving information from APDP and/or from their practitioners during their visits to the diabetes clinic. Compared with other studies conducted in general patients regarding their risk perception of having ADRs, using the same method of assessment (VAS), patients with diabetes surveyed in this study showed a higher risk perception score for medicines they potentially use in their disease (oral antidiabetics and insulin) than patients included in other studies. [5] From the perception of the relationship between drugs for diabetes and adverse reactions presented in Table 5, we conclude that patients usually underrate the risk of ADRs of their medications, which is also in accordance with previous studies, which assess knowledge of ADRs in a group of patients. [7] In another study conducted in Thailand, perception and knowledge concerning medicines risks is generally low, but higher in those who had received side effect information. [16] In accordance with this, patients with diabetes potentially received information related to their medicines during medical appointments, which could explain the higher risk perception in medicines used in diabetes. No studies were found comparing different groups of patients with or without disease and/or being members organization. As far as the authors know, this is the first study conducted to assess the impact of the disease on risk perception, as well as the impact of being a member of a patient organization. In the comparison between type of diabetes, results mostly seem to reflect the knowledge patients have regarding the medicines they use, which are different for type 1 and type 2 diabetes patients. (Table 5 and 6) Comparison between patients with the same type of diabetes was performed between the two groups of patients; however, since the sample size was too small, it was not possible to obtain reliable results. Also, as expected, differences were found when comparing patients with diabetes vs patients without diabetes. Results show significant differences between groups for most of the specific ADRs surveyed, except nausea and allergic reactions. (Table 6) For hypoglycaemia, patients followed at the patient organization had a significantly higher score of their risk perception compared with patients not followed at APDP. However, this is explained by the pattern of use of antidiabetic medicines by the two groups. Patients followed at APDP represent mostly type 1 patients, which are treated with insulin and hypoglycaemia can be related to its use. In the other group, more type 2 patients are present, who have a higher score of risk perception for most used medicines (metformin, metformin + DPP-IV inhibitors and sulfonylureas), compared with type 1 patients of the same group. Although these results may indicate that a patient organization seems to have an important role in increasing patients' risk perception, positive attitudes towards pharmacovigilance and that the organization changes the attitudes and perceptions about the disease and treatment, further studies would be needed to assess the causality of this relation. In addition to the possible difference in perception related to diabetes type, it could be that particularly those patients with positive attitudes and higher risk perceptions would become a member of a patient organization. In the future, more qualitative research could be done to investigate this. The authors not considered that the findings are restricted to diabetes patients, so alignment to other disease groups should be investigated. 4.3. Strengths and Limitations of the study 126 One of the strengths of this study is related to the questionnaire construction, which was developed by authors together with a clinical research team associated with a diabetes patient organization and their inputs were taken in account to construct the final questionnaire. To construct content validity, volunteers were asked whether topics/questions were missing and to provide comments regarding the format and comprehension of each item. The involvement of the patient organization in the construction of the questionnaire improved the understanding of the questionnaire by people with diabetes. The questionnaire was field tested by several volunteers (n = 16), not included in the sample, before its implementation. Volunteers were asked whether topics/questions were missing and to provide comments regarding the format and comprehension of each item. Following the review of the comments, items within each construct were amended. During pre-testing, respondents mentioned that a few statements were confusing and these were rewritten to provide an easier understanding of the questionnaire. The amendments mostly represented changing words or revising sentence structure to increase item comprehension. Despite this, in the data analysis, the authors could observe that the wording of the questionnaire was still not optimal, as certain participants were confused by the answer options. The similarity between groups in educational level and age improves the comparability of the results. However, there is a difference in diabetes type and the time since diagnosis between groups. We were not able to exactly match patients on these aspects, during the sampling phase. This fact is reflected in some of the answers given by both groups, including the risk perception for adverse reactions, that are related to drugs used more in a specific type of diabetes (for example: hypoglycaemia related with insulin use in type 1 patients, with patients with type 1 diabetes having an higher risk perception score for hypoglycaemia related with insulin than type 2 patients). In addition, patients weren't surveyed about concomitant diseases or the participation in other patient organizations not related with diabetes. Concerning to the previous experience with ADRs, the results showed that more patients followed at ADPD had experienced an ADR in the past. It is possible that these differences across the groups influence their risk perception, with patients that experienced ADRs in the past having higher risk perception scores than the others. The study also has some other drawbacks: the use of face-to-face survey could lead to social desirability bias, leading to biased answers. [71] The wording of questions may also influence the way patients responded, causing response bias due to misinterpretation of questions. Selection bias could also be present, since proper randomization was not used in selecting respondents, mainly due to the selection method of sampling (convenience sample), but also because comparison groups were collected from a different setting than the APDP group, so validity of the results might be threatened and lead to inconclusive and non-comparable results. [72][73] a result of the sampling method since the interpretation is potentially impacted by self-selection and non-randomization. [74,75] 5. CONCLUSIONS Patients with diabetes showed more positive opinions related to pharmacovigilance. They would like to obtain more information about ADRs related to their medication and a higher intention to acquire information on how to report when compared to non-diabetic patients. Patients followed in a diabetes patient association presented a higher score of risk perception, which could be influenced by the presence of the diabetes disease in the as by their previous experiences using the medicines, but also by the information received from the patient organization. Being a member of a patient organization seems to play an important role in 127 increasing risk perception since they presented the highest risk perception scores for medicines related to their disease. Those patients affirmed that their doctor explained the possible ADRs of their medication and they have higher intention to report ADRs in the future, if they are serious or unexpected. Hence, patient organizations are well positioned to be a source where patients can obtain reliable information, changing their attitudes and perceptions about the disease and drug treatments. Acknowledgements The authors would like to thank the respondents who participated in the survey. Further, we would like to express our gratitude to APDP- Diabetes - Portugal for the collaboration in the study, their acceptance and the help in the recruitment of the participants in APDP Clinic. Compliance with Ethical Standards The Ethics Committee of APDP - Diabetes, Portugal approved this study, and no financial benefits were given to the participants. The individual questionnaire was anonymous, and the data were intended only for scientific purposes of this study and stored in agreement with privacy regulations. Funding No funding sources were used to assist in the preparation of this article. Rogério Ribeiro is a recipient of an FCT post-doctoral fellowship from Portugal (SFRH/BPD/110426/2015). Conflicts of interest Cristiano Matos, Florence van Hunsel, Rogério Ribeiro, Dulce Nascimento do Ó and João Filipe Raposo have no conflicts of interest that are directly relevant to the content of this study. ontribution All authors contributed to the design and conception of the work. C.M. collected the data. C.M and F.H contributed to data analysis and interpretation. C.M and F.H contributed to the drafting the article. F.H., R.R., D.Ó and J.R contributed to the critical revision of the article. All authors contributed to the final approval of the version to be published. 6. BIBLIOGRAPHY 1. Sjöberg L, Moen B-E, Rundmo T. Explaining risk perception. An evaluation of the psychometric paradigm in risk perception research. Trondheim, Norw Rotunde. 2004; 2. van der Linden S. The social-psychological determinants of climate change risk perceptions: Towards a comprehensive model. 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