Adverse Drug Reaction Reporting by Patients: Experience of 12 European Countries

Spontaneous reporting of suspected adverse drug reactions (ADRs) by a patient is an important method in minimizing safety risks related to medicine use. Patients as reporters of suspected ADRs are valuable participants of pharmacovigilance system. The aim of this study to examine the contribution of the patients to pharmacovigilance in European countries that started patient reporting schemes in 2012-2013 and to compare different tools used by their authorities to promote patients’ reporting. A web-based questionnaire was sent to the NCAs of the Europe countries. The received answers were systematized and compared with each other through meta-analysis. Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated in a random or fixed-effects model. Heterogeneity was determined using the Cochrane Q-Test.

minimal experience in pharmacovigilance systems with direct patient reporting schemes to organize comprehensive campaigns on ADR reporting. However, some countries do not promote the patient's reporting schemes actively, which implies that the patient reporting is considered as mandatory and not as a supporting tool for safer medicines to consumers.

BACKGROUND
The primary source of information about medicines safety is health care professionals.
However, the studies have shown that the doctors provide incomplete ADR reports or do not provide at all (1). The failure to provide adequate ADR reports by the doctors is attributed to a lack of time on their side. Additionally, it was shown that the direct patient reporting of ADR could provide information about ADRs from other perspectives. The combined information about ADRs from healthcare professionals and the first-hand source has a significant impact on signal detection of new, rear, or serious ADRs (2). The amendments to the European Parliament Directive 2001/83/EC on the Community code relating to medicinal products for human use (Directive 2010/84/EU) obligate the Member States to take all necessary measures to encourage all parties within the health care system including patients to report suspected adverse drug reactions. The Member States should develop and provide the reporting formats for direct patient reporting (3). The significance of adopting such an improved reporting system is that patients can actively participate in critical health care decisions.
In several countries, the direct consumers' ADRs reporting schemes are promoted since the beginning of pharmacovigilance systems or shortly after the start. For instance, the practice has been carried out in the US, New Zealand, the Netherlands, Denmark, Sweden.
After the introduction of new European pharmacovigilance legislation in 2012-2013, 15 countries in Europe started the direct patient reporting to the competent authorities (4).
Some studies have investigated the motives of patients to report ADRs, patient reporting schemes within and outside of Europe. In addition, the investigations have also focused on the methods used to promote ADRs reporting and sociodemographic and economic features as explanatory factors for population ADRs reporting (2,5,6,7). However, little insight has been undertaken of relatively newly developed patient reporting schemes.
The aim of this study is to review and to compare different aspects of the experiences of ADRs reporting in European countries with newly implemented ADR reporting by patients' schemes. The study is also aiming to examine the specific methods and tools used by competent authorities to promote patients' direct reporting. In addition, it seeks statistically to evaluate the ADR reports received by the responsible authority of each country.

METHODS
This was a descriptive questionnaire-based study conducted among 15 countries that initiated the implementation of the direct patient reporting of adverse drug reactions in 2012-2013 together with new European pharmacovigilance legislation: Latvia, Estonia, Austria, Finland, Ireland, Belgium, Portugal, Slovakia, Spain, Lithuania, Germany, Greece, Luxembourg, Poland, and Bulgaria. A questionnaire was sent by email to the NCA of each surveyed country. The questionnaire was designed to collect statistical data, methods for patients to report ADR, tools in use to promote patient reporting, and if personalized feedback about the reported ADR is given to the patient. Meta-analysis was performed using a random-effects model and fixed-effects model to evaluate the changes in the number of received ADR reports over the analyzed period in interviewed countries.
Confidence intervals (95%) for each data set were calculated. MedCalc software version 12 was used for data analysis. Heterogeneity was explored using Cochrane's Q test of heterogeneity.

RESULTS
Out of 15 countries that were actively involved in the study survey, 12 countries remitted their responses through the questionnaires that were issued to them. The follow-up emails were sent out to the nonresponsive NCAs. However, the responses from Luxembourg, Poland, and Bulgaria were not received. The answers from 12 countries were representative of 80% of all study participants, which is a substantial portion for conducting a comprehensive study.
The main reporting methods used in the countries include post, e-mail, phone call, fax, and online internet-based methods ( Table 1). Table 1 The countries, NCA websites selected for the survey, presence of specific patient reporting form, methods of ADR report collection, and personalized feedback to the reporter. limited to the information provided on the NCA webpages. Germany did not name the promotion tools, though the information could be found on the NCA webpage. Table 2 The feedback, tools, and methods, used to promote direct ADR reporting for the 12 countries. In Table 2 actively to contribute to medicine safety (8)(9)(10)(11)(12)(13). The present study has reviewed the first years of experience of consumer reporting schemes in 12 European countries. In addition, the tools that are in use to promote patient ADR reporting have also been explored.
Based on the numbers of received ADR reports for the 12 countries considered in the study, the problem of under-reporting ADRs is seemingly present in the countries reviewed. However, it is not easy to establish an accurate measure of the level of underreporting in these countries. Based on the statistics of the study and existing research, it can, however, be deduced that the levels of under-reporting could reach 90% and more (14). Though the reasons for under-reporting by health-care professionals, pharmacists, and consumers were not analyzed in the present study, several surveys and research have documented potential causes. Some of the common reasons include lack of time, other priorities, and lack of awareness (15)(16)(17)(18). Differently, from health-care professionals, the main barriers to consumers to report ADR are poor awareness, lack of knowledge about who should report and whom, difficulties with reporting procedures, high costs involved, and lack of feedback (19). reporting is considered as a regulatory mandate and not as a supporting tool for safer medicines (2,19,20). The results of this study propose that the methods and their variety used to employ the patients actively to report ADR have an essential impact. Despite the meta-analysis results were the significant increase of ADR reports in each country was observed, the highest growth of direct patient reports over the analyzed time interval is found in Ireland, as well as the diversity of tools used to promote ADR reporting.
The main goal of the EU pharmacovigilance system is to enhance better and faster decisions in medicine and health care matters. A systematic review had shown that the median interval between the first reported adverse reaction and withdrawal of the medicine launched after 1960 is three years, which is two times shorter than for medicines launched before 1960 (22). The shortened period indicates that ADR signal detection and regulations of new medicines improved, however, insufficient. ADRs remain a significant health issue worldwide. Spontaneous ADR reporting by patients was shown to be a valuable tool for early safety signal detection (23,24). NCAs need to focus on enhancing the patient to become an active figure in pharmacovigilance management. In CONCLUSIONS This is the first study that summaries the ADR reporting by patients in European countries that recently started patient reporting schemes. The number of ADR reports received from patients by regulatory agencies and the variety of methods used to promote direct patient reporting indicates the lack of adequate knowledge on the pharmacovigilance system and the insufficient level of health education. Going forward, it would be critical for health care practitioners in collaboration with health care agencies to establish concrete and reliable systems that can be used to tap information on the ADR of patients. One formidable means of achieving this noble objective is to maximize awareness to many people on the need to report ADR to health care providers. In carrying out the awareness campaigns, it would be essential to enlighten people on the significance of ADR reporting and its positive potential for improving the overall well-being of society. Not applicable.

Consent for publication
Not applicable.

Availability of data and materials
The datasets analyzed during the current study are available from the corresponding author on reasonable request to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality and study ethical approval conditions.

Figure 1
The changes in the number of ADR reports received individually by each country