What are the patients' and health care professionals' understanding and behaviors towards adverse drug reaction reporting and additional monitoring?

Abstract Background The additional monitoring (AM)/black triangle concept is aimed to enhance ADR reporting for certain types of medicinal products for which the safety profile is less well established. Purpose The objective of this survey was to assess (a) attitudes towards ADR reporting and reasons for not reporting an ADR and (b) awareness of AM among HCPs, patients or their careers in EU countries. Methods An online questionnaire which was available in all EU languages was completed by 2918 responders coming from all EEA countries. Results The main factors motivating to report an ADR were severity or novelty of the reaction or novelty of the medicine. The main factors for not reporting an ADR was the fact that the ADR is already known (35%), the ADR was not serious (18%) or reporter was not sure if the ADR was related to the medicine (15%). Half of the respondents indicated that they have seen AM statement before. Thirty percent of the responders had correct understanding of the AM concept while 20 % misunderstood the concept. Conclusion Underreporting occurs but it seems this is because of reporter's prioritisation towards certain type of ADRs. AM aims to increase reporting for certain medicines, however, approximately half of responders have seen the AM symbol before and 20% of all responders (independent of their previous awareness) misunderstood the concept.


| INTRODUCTION
The EU system of pharmacovigilance was significantly strengthened in 2012 with the introduction of new legislation delivering new processes, responsibilities and tools. 1 Adverse drug reaction (ADR) reporting is an essential part of the surveillance after introducing new medicines to the market. Underreporting is well recognised and is reported to be as high as 94%. 2 Increasing ADR reporting aims to improve detection of new safety issues. Various legislative changes have been introduced to increase ADR reporting. 1,3,4 One of these changes was the additional monitoring (AM) system, which was introduced by the 2010 pharmacovigilance legislation to enhance ADR reporting for certain types of medicinal products for which the safety profile is less well established and by so doing, to increase detection of safety issues. 3,4 Figure 1 shows which medicinal products fall under the mandatory scope of AM. Since April 2013 every medicine subject to AM must display an inverted black triangle and accompanying statement in product information, as shown in Figure 2.
Since 2013 various activities have been undertaken by national competent authorities (NCA) and by the European Medicines Agency (EMA) to increase the awareness of additional monitoring. NCAs' web-sites, publications and Health Care Professional (HCP) conferences were the most frequent activities. 5 Our study aimed to better understand patients' and healthcare professionals' awareness of ADRs reporting in general and in particular their understanding of the AM concept and reporting of ADRs for medicinal products under AM. While there are many studies investigating the patterns in ADR reporting (or underreporting) overall, much less is known about the impact of AM. 2,6,7 Therefore our survey was among the first investigations into HCPs' and patients' understanding of the AM concept. 6,8 This research was mandated by the Pharmacovigilance Risk Assessment Committee (PRAC) impact strategy group 9 and was conducted to support the EMA and NCA contribution for the European Commission (EC) report on the experience with the list of products subject to additional monitoring 1

KEY POINTS
• Pan European survey investigated attitudes and awareness of adverse drug reaction (ADR) reporting and additional monitoring (AM).
• Reporters were most likely to reports ADRs that were fatal, serious, novel or were associated with a new medicine, and not report the ADRs that are already known, not serious, or if reporter was not sure if the ADR was related to the medicine.
• Awareness of AM varies between different respondent groups, the greatest being among pharmacists, and one in five respondents misunderstood the concept of AM.

| Analysis of responses
Responses to open-ended question on AM understanding ("In your opinion, what does the black triangle and the accompanying statement mean?") were translated to English (if needed) and assessed by two independent evaluators. In case of disagreement between the two evaluators, the open question response was sent to the third evaluator. The incidence of such disagreement was very low (<1%). All responses were classified into five categories of understanding, see Table 1 below. These five categories were created by analysing the sample of 100 responses. The structured responses were described using counts and frequencies and compared using non-parametric tests for independent grouped categorical data (chi-square tests and P-value). MS Excel software was used.

| RESULTS
In total 2918 responses were received, 2862 of them being from EEA countries (median: 40 per country, range: 4-569) and 56 from non- The 2230 responders that had observed or experienced an ADR, were asked, how many times they reported an ADR. 76% of HCPs and 73% non-HCPs indicated that they reported at least once (n = 1668 in total). Figure 4 shows the proportion of responders who reported an ADR at least once, when the number of observed/experienced ADRs was 1 or more. This suggests underreporting of ADRs varied by responder type and ranged between at least 19% and 42%.
Among ADR reporters (n = 1668), 14% (n = 227) reported an ADR for a product identified with a black triangle (this question was populated only if the responder did not select "none" in the question on how many ADRs they had ever reported). Those who responded positively to this question (n = 227) were asked if the black triangle influenced their decision to report the ADR. Thirty seven percentage of this group indicated that the black triangle was an influencing factor.
The main reasons to for not reporting an ADR were investigated.
The results are shown in Figure 5 below. Our results indicate that the main reasons for lack of ADR reporting is the fact that the ADR is already known (35%), the ADR is not serious (18%) or the reporter is not sure if the ADR was related to the medicine (15%). Six Hundred and thirty eight responders indicated that they reported all reactions that they have observed/experienced.  HCPs the most frequent response (n = 44) was unsupportive physician (physician who did not believe the patient when told about an ADR or refused to report it). Six responses stated that they did not know that they can report ADRs and six reported that they expected HCPs to report their ADRs.
The respondents' attitudes were then investigated with the question "How likely are you to report the following types of reactions" with a matrix table listing various types of ADRs. As presented in Figure 6, the main factors motivating to report an ADR were severity or novelty of the reaction or novelty of the medicine. Fifty seven percentage of HCPs would probably or definitely report any ADR; this percentage was over 70% for vaccines and biological products.
A total of 88% indicated that they would definitely or probably report an ADR for a medicine identified with a black triangle which mirrors the answers to the question on new medicines (also 88%).
Serious reactions (leading to hospitalisation or fatal outcomes) were overall the most likely to be reported (93% and 95%, respectively).
Reporting attitudes were different among different respondent types (P < .001). Physicians and pharmacists are less likely than patients and members of the public to report "any ADR" but more likely to report fatal and serious ADRs (over 97% and 93%, respectively) and for new medicines and those with a black triangle (93% and 90%, respectively).
With regards to the AM symbol (black triangle), 51% of the 2918 responders indicated that they had seen the black triangle and the accompanying statement before. Awareness varied between different respondents, the lowest was among patients (30% reported that they had seen it before) and the highest among pharmacists (83%). Among responses classified as "misunderstanding", the most prevalent themes were perceived safety concerns (eg, "drug is toxic", "drug causes more side effects than other drugs"), lack of safety data (eg, "trial drug", "drug marketed without clinical trial", "unknown safety profile") and a combination of other themes ("narrow therapeutic index drug", "a need of patient monitoring", "keep out of reach of children", "careful driving"), or other ("washing instruction", "drop down list"). The themes in the responses were also similar between HCPs and non-HCPs.

| DISCUSSION
To our knowledge, this study is the first to measure the understanding of the concept of additional monitoring and its impact on ADR reporting across Europe. One of the main limitations of this study is may also be subject to response bias, 10 with responders presenting a more favourable responses, likely inflating the proportion of responders who responded that they would report various ADRs/ report all ADRs Also, responders were asked to choose in which role they prefer to respond (HCP or non-HCP) however, we have no data on whether HCPs chose to respond to the survey as non-HCP or vice versa. Another limitation is that three countries (Portugal, Germany, and Italy) accounted for the 49% of the responses. Awareness of AM in these countries was better than the survey average, with 43% of responders from Germany and 33% in both Portugal and Italy having a good understanding of AM. In the UK, the black triangle concept existed before the AM was introduced in the EU. Awareness of AM in the UK was not better than the average for our survey (37% had correct understanding of AM and 23% misunderstood the concept).
However, it is acknowledged that the criteria for AM are different from the ones that were used in the UK black triangle scheme.
The main reasons for not reporting an ADR were based on a lack of certainty, namely not being sure if an ADR is previously known or if it is related to the medicine. Our results show that HCPs and non-HCPs are likely to report an ADR if the reaction is serious and not previously known and these findings are in line with previous research. 6,7,8 Only 8% of non-HCPs indicated that they have not reported an ADR because they did not know how to do so (see Figure 5). This is an interesting finding which is not in line with previ- Therefore targeted awareness campaigns to HCPs might improve reporting practice, especially for AM products. This in turn allows the reporting of suspected reactions, detection and assessment of potential risks related to the use of medicines and thus optimising the benefit-risk balance for patients.
It is difficult to conclude whether AM/black triangle had an effect on actual ADR reporting behaviour, as a very limited number of responders replied that they reported an ADR for an AM medicine.
Another study conducted in the United Kingdom on the impact of the black triangle label on prescribing of new drugs concluded that AM was unlikely to change prescribing practice. 12 The survey was available in all EU countries, and to our knowledge, this is the largest one on the topic to date. A wider-reaching survey, not only online, but also paper-based for those unable to use digital media and reaching a wider range of patients might give more representative estimates on AM awareness by reflecting a less specialised profile of responder.