Safety Communication Tools and Healthcare Professionals’ Awareness of Specific Drug Safety Issues in Europe: A Survey Study

Safety Communication Tools and Healthcare Professionals’ Awareness of Specific Drug Safety... Drug Saf (2018) 41:713–724 https://doi.org/10.1007/s40264-018-0643-5 OR IGINAL RESEARCH ARTIC L E Safety Communication Tools and Healthcare Professionals’ Awareness of Specific Drug Safety Issues in Europe: A Survey Study 1 1,2 3 • • • Sieta T. de Vries Maartje J. M. van der Sar Anna Marie Coleman 4 4 4 • • • Yvette Escudero Alfonso Rodr´ ıguez Pascual Miguel-Angel Macia ´ Martı ´nez 5 5 6 6 • • ´ • ´ • Amelia Cupelli Ilaria Baldelli Ivana Sipic Adriana Andric 7 1 1,2 • • • Line Michan Petra Denig Peter G. M. Mol on behalf of SCOPE work package 6 Published online: 2 March 2018 The Author(s) 2018. This article is an open access publication Abstract Methods GPs, cardiologists, and pharmacists from nine Introduction National competent authorities (NCAs) use European countries (Croatia, Denmark, Ireland, Italy, the Direct Healthcare Professional Communications (DHPCs) Netherlands, Norway, Spain, Sweden, and the UK) com- to communicate new drug safety issues to healthcare pro- pleted a web-based survey. The survey was conducted in fessionals (HCPs). More knowledge is needed about the the context of the Strengthening Collaboration for Oper- effectiveness of DHPCs and the extent to which they raise ating Pharmacovigilance in Europe (SCOPE) Joint Action. awareness of new safety issues among HCPs. Respondents were asked about their familiarity with Objective The objective was to assess and compare gen- DHPCs in general and their awareness of safety issues that eral practitioners’ (GPs’), cardiologists’, and pharmacists’ had recently been communicated and involved the fol- familiarity with DHPCs as communication tools, their lowing drugs: combined hormonal contraceptives, awareness of specific drug safety issues, and the sources diclofenac, valproate, and ivabradine. Those HCPs who through which they had become aware of the specific were aware of the specific safety issues were subsequently issues. asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a 2 2 The other members of SCOPE work package 6 are listed in Pearson v test per country and post hoc Pearson v tests in Acknowledgements. the case of statistically significant differences. Results Of the 3288 included respondents, 54% were GPs, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40264-018-0643-5) contains supple- 40% were pharmacists, and 7% were cardiologists. The mentary material, which is available to authorized users. number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with & Peter G. M. Mol DHPCs, with one significant difference between the pro- p.g.m.mol@umcg.nl fessions: pharmacists were more familiar than GPs in Italy Department of Clinical Pharmacy and Pharmacology, (99 vs 90%, P = 0.004). GPs’ awareness ranged from 96% University of Groningen, University Medical Center for the diclofenac issue to 70% for the ivabradine issue. A Groningen, Groningen, The Netherlands similar pattern was shown for pharmacists (91% aware of Dutch Medicines Evaluation Board, Utrecht, The Netherlands the diclofenac issue to 66% of the ivabradine issue). Car- Health Products Regulatory Authority (HPRA), Dublin, diologists’ awareness ranged from 91% for the ivabradine Ireland issue to 34% for the valproate issue. Overall, DHPCs were Spanish Agency for Medicines and Medical Devices a common source through which GPs (range: 45% of those (AEMPS), Madrid, Spain aware of the contraceptives issue to 60% of those aware of Italian Medicines Agency (AIFA), Rome, Italy the valproate issue), cardiologists (range: 33% for the Agency for Medicinal Products and Medical Devices of contraceptives issue to 61% for the valproate issue), and Croatia (HALMED), Zagreb, Croatia pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the Danish Medicines Agency (DKMA), Copenhagen, Denmark 714 S. T. de Vries et al. specific safety issues, followed by information on websites authorities (NCAs) inform HCPs about these risks and the or in newsletters. actions that they should take to minimise or manage them. Conclusions GPs, cardiologists, and pharmacists were to a Research, however, has shown that the safety advice in similar extent (highly) familiar with DHPCs, but they communications from regulators is not always followed differed in awareness levels of specific safety issues. Car- [3–5]. Before HCPs can act on a safety issue, they first diologists were less aware of safety issues associated with need to become aware of it. A study published in 2012 non-cardiology drugs even if these had cardiovascular among a sample of Dutch HCPs showed mixed awareness safety concerns. This implies that additional strategies may of drug safety issues, ranging from 56% of HCPs being be needed to reach specialists when communicating safety aware of new safety issues with etoricoxib up to 88% for issues regarding drugs outside their therapeutic area but clopidogrel [6]. Moreover, it was shown that awareness with risks related to their field of specialisation. DHPCs varied among professions, where pharmacists were gener- were an important source for the different professions to ally more aware of safety issues than general practitioners become aware of specific safety issues, but other sources (GPs) [6]. were also often used. NCAs should consider the use of a Direct Healthcare Professional Communications range of sources when communicating important safety (DHPCs) are an important tool that NCAs use to commu- issues to HCPs. nicate new drug safety information to HCPs [7]. DHPCs are letters predominantly distributed by pharmaceutical companies following content approval by the NCAs. Some research suggests that about one-fifth of HCPs are not Key Points familiar with these communications. Again, differences between professions were seen, with GPs being more Familiarity with Direct Healthcare Professional familiar with these communications than pharmacists [6]. Communications (DHPCs) was high among general Besides DHPCs, NCAs can use additional tools to raise practitioners (GPs), cardiologists, and pharmacists awareness of safety issues, such as the NCA’s own com- across Europe. munications (e.g. newsletters) [7]. Currently, it is not Cardiologists were more aware than GPs of the known how HCPs become aware of safety issues (i.e. via safety issue for a drug within their field of expertise DHPCs or other sources) and whether this differs between (ivabradine) and less aware than GPs and professions. A previous study showed that NCAs from pharmacists of safety issues of other drugs European countries generally use similar methods for (contraceptives, diclofenac, and valproate), despite safety communication, but that GPs’ awareness of safety some of these relating to cardiovascular risks. communication tools differ across countries [8]. The aim of this study was to expand the current knowledge DHPCs were an important source for GPs, about differences between professions in familiarity with cardiologists, and pharmacists to become aware of DHPCs and awareness of safety issues in various European specific safety issues, but other sources, such as countries. More specifically, our aims were to compare GPs, websites or newsletters and medical journals, were cardiologists, and pharmacists regarding their familiarity with also relevant. DHPCs, their awareness of specific recent drug safety issues, and the sources through which they have become aware of these issues. This knowledge is important for NCAs in the evaluation of their current safety communication strategies and to facilitate improvement in the future. Knowing how 1 Introduction different professions perceive current drug safety communi- cation tools and the sources they used most in informing There have been some high-profile drug safety issues in themselves of important updates can help NCAs to optimise recent years where re-evaluation of the risks associated their safety communication strategies. with drugs such as rosiglitazone and sibutramine led to their removal from the market by European regulators as the benefit–risk balance was judged to be negative [1, 2]. 2 Methods More often, however, important new safety issues emerge where the overall benefit–risk balance of the drug remains 2.1 Study Design and Data Collection positive provided healthcare professionals (HCPs) take into account certain warnings and precautions and the drug Cross-sectional data from a web-based survey about HCPs’ remains on the market. In these cases, national competent views and experiences regarding drug safety information Safety Communication Tools and Awareness of Drug Safety Issues 715 were used for this study. The data were collected in the in the period just prior to the survey being conducted year 2015 in the context of the Strengthening Collaboration [following review within safety referral procedures by the for Operating Pharmacovigilance in Europe (SCOPE) Joint Pharmacovigilance Risk Assessment Committee (PRAC)], Action Work Package 6 (http://www.scopejointaction.eu/). and to have a representative sample of drugs used in pri- The active partners in this work package developed the mary care (contraceptives and diclofenac) along with spe- survey in the English language (see Electronic Supple- cialised care (valproate and ivabradine). The safety issue mentary Material 1). This survey was translated by an for ivabradine was not included in the Norwegian survey official translation agency in the following languages: because this drug is not on the market in Norway. Croatian, Danish, Dutch, Italian, Norwegian, Spanish, and Finally, when respondents indicated that they were Swedish. Thereafter, the surveys were back-translated and aware of a certain safety issue, they were asked how they pilot tested to check whether the translations had the same had heard about it. The source options provided were as meaning as the English version and whether the survey was follows: via a DHPC, a website or newsletter, educational understandable for people not involved in the project. materials, a professional body, a colleague, a medical Unipark software (http://www.unipark.com/en/) was used journal, lay media (newspaper/television), or other source. to create the web-based format of the survey. Ethical The Norwegian survey included an additional answer approval was not considered necessary because of the option, i.e. through the national medicines agency. It was nature of the study, in which HCPs were asked to complete possible to provide multiple answers on how HCPs became a survey about safety communication strategies. aware of the safety issues. 2.2 Participants 2.4 Analyses The survey was distributed among HCPs in nine European Descriptive information about the included population is countries that were active partners in Work Package 6 of presented as frequencies with percentages for the total the Joint Action; i.e. Croatia, Denmark, Ireland, Italy, the population and per profession. Netherlands, Norway, Spain, Sweden, and the UK. HCPs HCPs’ familiarity with DHPCs and awareness of each of were recruited via a link to the survey on websites, in the four specific safety issues are presented as percentages newsletters, and/or in an email sent by the NCA, a pro- per profession within each country. Only HCPs who were fessional body, or a commercial organisation to all their familiar with DHPCs were included in the assessment of subscribers or members. HCPs that were actively targeted awareness of the safety issues. Differences in familiarity and included in this study were GPs, cardiologists, and with DHPCs and awareness between professions were tested using a Pearson v pharmacists. In Spain and Sweden, only GPs and cardiol- test per country. In the case of a ogists were actively targeted. statistically significant result (P value of\0.05), Pearson v tests were used to assess which professions differed 2.3 Outcome Assessment from each other. A Bonferroni adjustment to correct for multiple testing (N = 3) was used for these post hoc tests, To assess HCPs’ familiarity with DHPCs the survey con- implying that a P value of\0.016 was considered statis- tained a short introduction about DHPCs with two exam- tically significant. ples pictured, after which respondents were asked the Data from the sources through which the HCPs heard of following closed-ended question: ‘‘Are you familiar with the safety issues were analysed descriptively. The results of this type of safety communication?’’ Respondents these analyses are presented per profession using percentages answering ‘‘Yes’’ were considered familiar, whereas per safety issue and per country for those HCPs who were respondents answering ‘‘No, I have heard of DHPCs, but I aware of the safety issue. The additional answer option in the have never seen one’’ or ‘‘No, I have never heard of Norwegian survey was classified as ‘‘other’’ sources. DHPCs’’ were considered unfamiliar with DHPCs. All analyses were conducted using Stata version 13 (Stata HCPs’ awareness of specific safety issues was assessed Corp., College Station, TX, USA), and Microsoft Excel 2010 using the following question: ‘‘Are you aware of updates to was used for the graphical presentation of the results. the safety profiles of the following medicines?’’ The pre- sented drug safety issues were updates on the risk of thrombosis with combined hormonal contraceptives (con- 3 Results traceptives), cardiovascular harms with diclofenac, terato- genicity with valproate, and cardiovascular events with In total, 3625 HCPs completed the survey, of whom 337 ivabradine (Table 1). These safety issues were chosen as had a profession different than the target population of they had been the subject of NCA safety communications GPs, cardiologists, and pharmacists. Of the remaining 3288 716 S. T. de Vries et al. Table 1 Summary of the drugs for which the safety updates were assessed in this study Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Indicated for/ Contraception Relieving pain and Generalised, partial or other Symptomatic treatment of treatment of inflammation epilepsy; bipolar disorder chronic stable angina pectoris. Treatment of chronic heart failure Most common GPs GPs Neurologists, psychiatrists Cardiologists prescriber New safety Risk of VTE. Confirmation Risk of cardiovascular events. Risk of teratogenicity. Further Risk of cardiovascular events. information that the absolute risk of VTE The same cardiovascular characterisation of the A small but significant with all CHCs is small and precautions now apply for teratogenic effects: children increase of the combined ranges from 5 to 12 cases of diclofenac as for selective exposed in utero are at a risk of cardiovascular death, VTE per 10,000 women per COX-2 inhibitors, i.e. high risk of serious myocardial infarction, and year, but that differences ‘coxibs’ developmental disorders (in cardiac failure was seen in exist depending on the type up to 30–40% of cases) and/ patients with symptomatic of progestogen they contain or congenital malformations angina [9] and for a given dose of (in approximately 10% of oestrogen, with cases) levonorgestrel, norethisterone or norgestimate (so called second generation) having the lowest risk as per the available evidence Implications of Careful consideration to be Use contraindicated in Valproate should not be used Ivabradine is indicated only the new given to the new evidence ischaemic heart disease, in female children/ for symptomatic treatment safety when prescribing CHCs in peripheral arterial disease, adolescents of childbearing of chronic stable angina information addition to emphasising cerebrovascular disease, and potential or pregnant women pectoris because ivabradine existing contraindications congestive heart failure. unless other treatments are has no benefits on for use and evaluating the Careful consideration to be ineffective or not tolerated. cardiovascular outcomes individual woman’s current given to an individual’s risk It must be started and (e.g. myocardial infarction risk factors for VTE factors for cardiovascular supervised by a doctor or cardiovascular death) in events before prescribing experienced in managing patients with symptomatic (e.g. hypertension, diabetes, epilepsy or bipolar disorder. angina. Serial heart rate hyperlipidaemia, and All female patients must be measurements are required smoking) informed of and fully prior to initiation of therapy understand the risks of use or prior to dose titration. during pregnancy Concomitant use with verapamil or diltiazem is contraindicated. Treatment should only be initiated in patients with a resting heart rate of at least 70 bpm Year of DHPC 2014 2013 2014 2014 Distribution of DHPC per country Format Croatia Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts for HCPs at primary level, for HCPs at primary level, for HCPs at primary level, for HCPs at primary level, NCA website and newsletter NCA website and newsletter NCA website and newsletter NCA website and newsletter Denmark Electronic and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Ireland Hardcopy letter (also Hardcopy letter (also Hardcopy letter (also Hardcopy letter (also published on NCA website published on NCA website published on NCA website published on NCA website and article included in and article included in and article included in and article included in electronic NCA newsletter) electronic NCA newsletter) electronic NCA newsletter) electronic NCA newsletter) Italy Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Netherlands Hardcopy, NCA website and Hardcopy, NCA website and Hardcopy, NCA website and Hardcopy, NCA website and NCA newsletter NCA newsletter NCA newsletter NCA newsletter Norway Hardcopy and point-of-care- Hardcopy and point-of-care- Hardcopy and point-of-care- N/A alerts alerts alerts Safety Communication Tools and Awareness of Drug Safety Issues 717 Table 1 continued Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Spain Electronic and NCA website Electronic and NCA website Electronic and NCA website Electronic and NCA website Sweden Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website UK Electronic cascade Hardcopy letter and NCA Electronic cascade Hardcopy letter and NCA distribution and NCA website distribution and NCA website website website Targeted HCPs Croatia Gynaecologists, GPs, Internists, rheumatologists, Neurologists, psychiatrists, Cardiologists, internists, GPs, pharmacists, selected GPs, pharmacists gynaecologists, GPs, selected learned societies, learned societies, hospitals’ pharmacists, selected hospitals’ medicines medicines committees learned societies, hospitals’ committees medicines committees Denmark Danish medical societies, GPs GPs, pharmacists, internists, GPs, neurologists, GPs, cardiologists, internists association, Danish medical rheumatologists psychiatrists, paediatricians, in cardiology departments, association, medical society clinical pharmacologists, medical societies for for gynaecology and industrial medical officers, cardiology and GPs, Danish obstetrics medical societies for Heart Association neurology, psychiatry and clinical pharmacology, patient societies for epilepsia and psychiatry Ireland GPs, family planning clinics, GPs, all consultants Neurologists, psychiatrists, GPs, cardiologists, pharmacists, obstetricians, (specialists), pharmacists, GPs, obstetricians, geriatricians, general gynaecologists dentists gynaecologists, family medicine consultants, planning centres, pharmacists pharmacists, relevant HCP professional organisations Italy Gynaecologists, emergency GPs, internists, cardiologists, Neurologists, psychiatrists, Internists, cardiologists, GPs, room physicians, rheumatologists, GPs, obstetricians/ relevant learned societies pneumologists, orthopaedics, geriatrics, gynaecologists, family cardiologists, pharmacists planning centres, midwife, haematologists, hospital pharmacists (community and pharmacists, relevant hospital), relevant scientific scientific and HCP and HCP organisations/patient organisations/patient organisations organisations Netherlands GPs, gynaecologists, GPs, rheumatologists, Neurologists, psychiatrists, Cardiologists, GPs, hospital pharmacists, hospital internists, pharmacists, gynaecologists, pharmacists pharmacists hospital pharmacists, paediatricians and paediatric orthopaedics nurses, obstetricians, pharmacists Norway GPs, pharmacists, GPs, pharmacists, internists, GPs, pharmacists, N/A gynaecologists, midwifes, rheumatologists, surgeons, gynaecologists, neurologists, public health nurses, orthopaedists, emergency psychiatrists, midwifes, emergency medical services, medical services industrial medical officers hospital surgical and internal medicine wards Spain GPs, gynaecologists, clinical GPs, geriatricians, internal Psychiatrists, neurologists, Cardiologists, GPs, internal pharmacologists, medicine specialists, GPs, paediatricians, clinical medicine specialists, community pharmacists, rheumatologists, pharmacologists, geriatricians, clinical PhV centres traumatologists, pharmacists (community and pharmacologists, rehabilitation specialists, hospital), PhV centres pharmacists (community and pharmacists (community and hospital), PhV centres hospital), PhV centres 718 S. T. de Vries et al. Table 1 continued Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Sweden GPs, gynaecologists, midwifes GPs, specialists in internal Neurologists, psychiatrists, Cardiologists, specialists in medicine (including gynaecologists, specialists in internal medicine, GPs rheumatologists and internal medicine, learned cardiologists), orthopaedist, societies (neurology, pharmacies, county council epilepsy, psychiatry), county drug committees council drug committees UK GPs, family planning clinics, GPs, retail pharmacists, chief GPs, pharmacists (community GPs, internal medicine nurses, gynaecologists, all pharmacists in secondary and hospital), secondary specialists, cardiologists, pharmacists (community and care, dentists in practice, care chief pharmacists hospital), midwives dentists in mainstream hospitals, dental hospitals Sender of the DHPC Croatia MAH MAH MAH MAH Denmark NCA MAH MAH MAH Ireland MAH MAH MAH MAH Italy MAH MAH MAH MAH Netherlands MAH MAH MAH MAH Norway MAH MAH MAH N/A Spain Learned societies of targeted Learned societies of targeted Learned societies of targeted Learned societies of targeted HCPs HCPs HCPs HCPs Sweden MAH MAH MAH MAH UK NCA MAH NCA MAH CHCs combined hormonal contraceptives, COX cyclo-oxygenase, DHPC Direct Healthcare Professional Communication, GP general practitioner, HCP healthcare professional, MAH marketing authorisation holder, N/A not applicable, NCA national competent authority, PhV pharmacovigilance, VTE venous thromboembolism respondents, 54% were GPs, 40% were pharmacists, and GPs), Croatia (i.e. cardiologists), and Norway (i.e. 7% were cardiologists (Fig. 1). The number of respondents pharmacists). ranged from 67 in Denmark to 916 in Spain. Most of the GPs, cardiologists, and pharmacists were from, respec- 3.2 Awareness of the Four Specific Safety Issues tively, Spain (N = 847), Italy (N = 63), and Norway (N = 381) (Fig. 2). More than half of the respondents per Overall, GPs were most aware of the safety issue con- country were female, except for Italy (42% female) and the cerning diclofenac (96%), followed by contraceptives Netherlands (31% female) (see Electronic Supplementary (88%), valproate (76%), and ivabradine (70%). The same Material 2). pattern was shown for the pharmacists, with highest awareness of diclofenac (91%), followed by contraceptives 3.1 Familiarity with DHPCs (90%), valproate (80%), and ivabradine (66%). For the cardiologists, the pattern was different, with highest Most respondents (92%) were familiar with DHPCs, and in awareness of the ivabradine safety issue (91%), followed general there were only small differences between GPs, by diclofenac (79%), contraceptives (61%), and valproate cardiologists, and pharmacists in terms of their familiarity (34%). (Fig. 3). Only in Italy a significant difference between the Cardiologists were significantly less aware of the con- professions was shown (P = 0.016). More pharmacists traceptives safety issue than GPs and/or pharmacists in six were familiar with DHPCs than GPs (99 vs 90%, countries (i.e. Denmark, Italy, the Netherlands, Norway, P = 0.004). Familiarity was highest in Ireland, Italy, Spain, and the UK) (Fig. 4a). In three countries (i.e. Spain, Spain, and the UK, where more than 90% of the GPs, Italy, and Norway), they were also less aware of the cardiologists, and pharmacists were familiar with DHPCs. diclofenac issue (Fig. 4b). For the valproate issue, cardi- Familiarity was lowest for some professions in Sweden (i.e. ologists were less aware than GPs and/or pharmacists in Safety Communication Tools and Awareness of Drug Safety Issues 719 HCPs who completed the Completers survey: N = 3,625 Other profession: N = 337 Target populaon: N = 3,288 Profession GPs: N = 1,766 (54%) Cardiologists: N = 222 (7%) Pharmacists: N = 1,300 (40%) Included in the analyses of aim 1: familiarity with DHPCs No: N = 272* (8%) Familiarity with Yes: N = 3,016 DHPCs Respondents with a missing answer to all of the four safety issues: N = 3 Addionally excluded per safety issue due to missing answers: Included per safety issue: - Contracepves: N = 12 Response to specific - Contracepves: N = 3,001 - Diclofenac: N = 18 safety issue - Diclofenac: N = 2,995 - Valproate: N = 24 - Valproate: N = 2,989 - Ivabradine: N = 432† - Ivabradine: N = 2,581† Included in the analyses of aim 2: Awareness of specific safety issues Not aware of the safety issue: - Contracepves: N = 390 (13%) Included per safety issue: Awareness of - Diclofenac: N = 205 (7%) - Contracepves: N = 2,611 specific safety issues - Valproate: N = 752 (25%) - Diclofenac: N = 2,790 - Ivabradine: N = 771† (30%) - Valproate: N = 2,237 - Ivabradine: N = 1,810† Included in the analyses of aim 3: Sources through which HCPs became aware Fig. 1 Flowchart of number of healthcare professionals (HCPs) (DHPCs), but had never seen one; 136 had never heard of DHPCs; included per study aim. *272 responding HCPs were excluded: 135 and 1 skipped the question. This safety issue was not included in the had heard of Direct Healthcare Professional Communications survey in Norway. GPs general practitioners five countries (i.e. Italy, the Netherlands, Norway, Spain, Some differences between GPs and pharmacists were and the UK) (Fig. 4c). In Sweden, GP awareness of the also observed (Fig. 4). Pharmacists were more aware of the valproate issue was low and cardiologists were more aware contraceptives’ safety issue than GPs (Croatia 96 vs 83%, of this safety issue; respectively, 38 vs 69%, P = 0.033. P = 0.003; Italy 97 vs 88%, P = 0.009). They were also For the ivabradine issue, cardiologists were more aware more aware of the ivabradine issue (Netherlands 56 vs than GPs in four countries (i.e. Croatia, the Netherlands, 21%, P\0.001). An inconsistent pattern across the coun- Sweden, and the UK) (Fig. 4d). tries was shown for the diclofenac and valproate issue. For the diclofenac issue, pharmacists were more aware than 720 S. T. de Vries et al. message on a website or in a newsletter (range: 37% of those aware of the valproate issue to 39% of those aware of Sweden: Norway: ay: the other issues) (see Electronic Supplementary Material 3). For many cardiologists, DHPCs were also mentioned as UK: an important source (range: 33% for the contraceptives Denmark: Ireland: d 67 issue to 61% for the valproate issue), but in addition, Netherlands: hl d medical journals were often mentioned for the contracep- tives issue (46%), ivabradine issue (42%), and diclofenac issue (34%). A message on a website or in a newsletter was Croaa: the source for 20% (contraceptives issue) to 30% (val- Spain: Italy: proate issue) for the cardiologists. The sources most often mentioned by pharmacists were DHPCs (range: 41% for the contraceptives issue to 51% of the ivabradine issue) and information on a website or in a newsletter (range: 42% for General praconers Pharmacists Cardiologists the contraceptives and valproate issues to 46% for the Croaa 85 4 104 Denmark 25 7 35 diclofenac and ivabradine issues). Ireland 144 5 281 There was variation across the countries in the sources Italy 183 63 104 through which HCPs had become aware of the safety issues Netherlands 72 17 64 Norway 105 40 381 (see Electronic Supplementary Material 3). For instance, Spain 847 56 13 information provided by professional bodies was more Sweden 108 15 N/A often the source for HCPs in the Netherlands than for HCPs UK 197 15 318 in the other countries. Another example is the ‘‘other’’ Fig. 2 Total number of respondents and per profession by country source through which somewhat more HCPs from Norway became aware of the issues compared to the number of GPs in the UK (99 vs 95%, P = 0.009), but less aware in HCPs from other countries. This other source contained the Ireland (83 vs 93%, P = 0.006). For the valproate issue, NCA’s own information centre, which was only specifi- pharmacists were more aware than GPs in Ireland (90 vs cally evaluated in the Norwegian survey. More HCPs from 65%, P\0.001), in the UK (86 vs 68%, P\0.001), and in Italy became aware through a DHPC than did HCPs from the Netherlands (69 vs 45%, P = 0.006), but they were less other countries. aware in Norway (66 vs 81%, P = 0.008). 3.3 Sources 4 Discussion Most of the GPs who were aware of a specific safety issue This study shows that most GPs, cardiologists, and phar- indicated that they had heard about this through a DHPC macists across Europe are familiar with DHPCs. In general, (range: 45% of those aware of the contraceptives issue to GPs and pharmacists were more aware of the safety issues 60% of those aware of the valproate issue), followed by a concerning contraceptives and diclofenac than Fig. 3 Familiarity with Direct P = 0.004 100% Healthcare Professional 90% Communications (DHPCs) by 80% profession per country. Despite 70% not being targeted, a few 60% pharmacists from Spain completed the survey. In 50% Sweden, pharmacists were not 40% actively targeted and no 30% pharmacists completed the 20% survey. GPs general 10% practitioners 0% GPs Cardiologists Pharmacists Safety Communication Tools and Awareness of Drug Safety Issues 721 Combined Hormonal Contracepves Diclofenac 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% GPs Cardiologists Pharmacists GPs Cardiologists Pharmacists Overall GPs vs Cards vs GPs vs Overall GPs vs Card vs GPs vs Card Pharm Pharm Card Pharm Pharm Croaa 0.073 Croaa 0.010 0.427 0.721 0.003 Denmark 0.162 Denmark 0.000 0.001 0.000 Ireland 0.020 0.256 0.837 0.006 Ireland 0.714 Italy 0.000 0.000 0.000 0.461 Italy 0.000 0.003 0.000 0.009 Netherlands 0.089 Netherlands 0.010 0.002 0.049 0.187 Norway 0.002 0.001 0.001 0.413 Norway 0.000 0.000 0.000 0.043 Spain 0.000 0.000 0.066 0.588 Spain 0.000 0.000 0.002 0.768 Sweden 0.820 Sweden 0.292 UK 0.001 0.002 0.000 0.367 UK 0.021 0.691 0.045 0.009 Valproate Ivabradine 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% GPs Cardiologists Pharmacists GPs Cardiologists Pharmacists Overall GPs vs Card vs GPs vs Overall GPs vs Card vs GPs vs Card Pharm Pharm Card Pharm Pharm Croaa 0.069 Croaa 0.038 0.020 0.061 0.138 Denmark 0.068 Denmark 0.092 Ireland 0.000 0.493 0.478 0.000 Ireland 0.296 Italy 0.000 0.000 0.000 0.053 Italy 0.078 Netherlands 0.000 0.008 0.000 0.006 Netherlands 0.000 0.000 0.162 0.000 Norway 0.000 0.000 0.000 0.008 Norway 1 1 Spain 0.000 0.000 0.000 0.134 Spain 0.254 2 2 Sweden 0.033 Sweden 0.000 UK 0.000 0.001 0.000 0.000 UK 0.024 0.009 0.018 0.267 Fig. 4 Awareness of four specific safety issues by profession and Sweden, pharmacists were not actively targeted and no pharmacists P values for differences between professions within countries. P val- completed the survey. The ivabradine safety issue was not assessed ues in bold are considered statistically significant. Despite not being in Norway. Card cardiologists, GPs general practitioners, Pharm targeted, a few pharmacists from Spain completed the survey. In pharmacists 722 S. T. de Vries et al. cardiologists, whereas cardiologists were more aware of in our study. One reason could be differences between the ivabradine issue, which is largely expected given its use countries in uptake of a certain drug and healthcare systems in the specialist setting only. We showed some differences (e.g. whether treatment is confined to the specialised set- between GPs and pharmacists, but these differed across the ting in clinics/hospitals or initiated/repeated by GPs). countries. DHPCs were most often mentioned by all three Another reason could be differences across European professions as the source through which HCPs had become countries in NCAs’ communication strategies. Although a aware of the safety issues, but other sources were also previous study showed that NCAs use similar methods to relevant depending on the safety issue and profession as communicate about drug safety issues [8], the current study well as the country. showed differences across the countries in the sources A previous study conducted in the Netherlands showed through which HCPs had become aware of the specific differences between GPs and hospital pharmacists in their safety issues. Moreover, there were differences between familiarity with DHPCs [6]. Our study showed a difference and within countries with respect to the format, the target between GPs and pharmacists only in Italy. This previous population, and the sender of the communication about the study found that 28% of the GPs were not familiar with specific safety issues (Table 1). Various factors related to DHPCs compared to 14% of the GPs from the Netherlands these strategies, such as trust in the sender of the infor- in our study. This may imply that familiarity with DHPCs mation, may have influenced the uptake of the information among GPs in the Netherlands has increased over the years. [10]. Future studies should focus more on the explanations In general, there seems to be still room for improvement, for differences across European countries. In addition, with less than 80% of respondents in some professions future studies should focus on whether high awareness reporting to be familiar with DHPCs (Croatia and Norway). actually translates into improved drug utilisation and health Of the four presented safety issues, GPs and pharmacists outcomes; however, study methods other than surveys are were least aware of the ivabradine issue. This lower needed for such evaluations [11]. A recent systematic awareness may be due to the fact that ivabradine is a newer review showed that in more than half of the reviewed active substance, likely to be prescribed by specialists, and studies evaluating the impact of regulatory interventions, authorised for a relatively narrow indication. Not surpris- administrative claims databases or electronic health records ingly, this was the safety issue of which cardiologists were databases were used [12]. most aware. On the other hand, cardiologists were less Although there is room for improving HCPs’ familiarity aware of safety issues of drugs that are primarily prescribed with DHPCs, this communication tool was the most com- in general practice (i.e. contraceptives and diclofenac), mon source through which the HCPs became aware of the which is still of cause for concern since the communica- safety issues included in our study. Information on a website or in a newsletter was also reported as an important tions referred to cardiovascular-related risks. A previous study had also shown that specialists were less aware than source for many HCPs; in some cases these are likely to be GPs and community pharmacists of a safety issue for a the websites and newsletters of NCAs, which are long drug prescribed and dispensed in primary care [6]. An established in some countries [8]. Interestingly, medical important explanation may be that DHPCs about contra- journals were also commonly used by cardiologists aware ceptives and diclofenac were not sent to cardiologists in all of the contraceptive, diclofenac, and ivabradine issues. To countries (Table 1). This indicates that in the evaluation of improve HCPs’ awareness of safety issues and ultimately the effectiveness of safety communication strategies, their actual prescribing/dispensing behaviour, it is therefore awareness among the targeted professions should be important that the strategies for safety communication assessed rather than awareness among HCPs in general. should be tailored to specific professions. There may also Findings, however, were not completely consistent as some be differences in the use of sources per country. For professional groups received a DHPC but were less aware. instance, in the Netherlands, awareness of the contracep- Further studies should assess whether cardiologists and tives and diclofenac safety issues were higher than the other specialists are also interested in receiving DHPCs awareness of the valproate and ivabradine issues. This may about adverse effects relevant for their specialty, instead of be related to the role of ‘‘professional bodies’’ that were only receiving DHPCs for drugs used to treat specialty- indicated in the Netherlands as an important source, and related diseases. that thus may amplify safety messages from NCAs. In three countries (i.e. Ireland, the Netherlands, and the Interestingly, several HCPs claimed to have heard about UK), pharmacists were more aware of a safety issue about the diclofenac safety issue via educational materials despite a drug primarily prescribed by specialists (i.e. valproate) these materials not being disseminated for this drug safety than GPs. However, in Norway, GPs were more aware of issue. This finding indicates that HCPs may have confused this issue than pharmacists. There may be various reasons the regulatory term ‘‘educational materials’’ with other for this and for other observed differences across countries educational activities, despite examples of educational Safety Communication Tools and Awareness of Drug Safety Issues 723 Author Contributions All authors contributed to the development materials being presented within the survey for clarity, and formulation of the research question. STdV, MJMvdS, and suggesting a broader interpretation of this term than the PGMM collected data in the Netherlands; AMC in Ireland; YE, ARP, regulatory meaning. and MAMM in Spain; AC and IB in Italy; IS and AA in Croatia; and A strength of this study is the inclusion of survey LM in Denmark; and the other SCOPE Work Package 6 members collected data in the other countries. STdV and MJMvdS analysed the respondents from a wide range of European countries; thus data. All authors contributed to the interpretation of the results. STdV it was possible to assess the associations per country. wrote the manuscript. MJMvdS, AMC, YE, ARP, MAMM, AC, IB, However, the study also has some limitations. One limi- IS, AA, LM, PD, and PGMM reviewed and edited the manuscript. PD tation relates to the use of a survey methodology which has been involved involved primarily in the development, interpre- tation and writing of this project. She is mentioned implicitly (like all could have introduced biases such as recall bias and other authors) for the first two aspects and individually mentioned for answering tendencies [13]. Moreover, survey answering the writing part. All authors have read and approved the final tendencies such as socially desirable answering may differ manuscript. across countries [14, 15], which could have influenced our Compliance with Ethical Standards results. Another limitation is the low statistical power in some countries due to the small sample size, particularly Ethical approval was not considered necessary for this study because the low number of included cardiologists. Results should of the nature of the study, in which healthcare professionals were therefore be interpreted cautiously. Due to the low sample asked to complete a survey about safety communication strategies. Participants were assured that all sensitive data would be kept size, we did not assess the sources by profession per confidential. country, and this also limits the generalisability of the findings. Previously, we compared the GPs included in our Funding The work was conducted in the context of a European study with the total GP population in the different countries Commission sponsored joint action, Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE). Any opinions, and we observed a similar pattern in terms of age and sex conclusions and proposals in the text are those of the authors and do distribution [8]. However, representativeness cannot be not necessarily represent the views of the European Commission or guaranteed, particularly in countries with small sample national competent authorities. The survey was made possible sizes. In addition, pharmacists were not actively recruited through a tendered subcontract ITT-1301, ECM-2294. in Spain and Sweden and other specialists that would have Conflict of interest Sieta T. de Vries, Maartje J.M. van der Sar, been relevant to the specific safety issues studied (e.g. Anna Marie Coleman, Yvette Escudero, Alfonso Rodrı ´guez Pascual, neurologists or epileptologists) were not included. Miguel-Angel Macia ´ Mart´ ınez, Amelia Cupelli, Ilaria Baldelli, Ivana Sipic ´, Adriana Andric ´, Line Michan, and Petra Denig have no con- flicts of interest that are directly relevant to the content of this study. Peter G.M. Mol is an employee of the Dutch Medicines Evaluation 5 Conclusion Board. We observed high familiarity with DHPCs across all three Open Access This article is distributed under the terms of the professions; however, there were differences between Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which per- professions in awareness of specific safety issues. GPs and mits any noncommercial use, distribution, and reproduction in any pharmacists were more aware of the safety issues con- medium, provided you give appropriate credit to the original cerning contraceptives and diclofenac than cardiologists, author(s) and the source, provide a link to the Creative Commons whereas cardiologists were more aware of the ivabradine license, and indicate if changes were made. issue. Different strategies may be needed to reach spe- cialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their References field of specialisation. Aside from DHPCs, other sources such as websites, newsletters, professional bodies, or 1. European Medicines Agency. European Medicines Agency rec- medical journals can be relevant sources for HCPs to ommends suspension of Avandia, Avandamet and Avaglim. become aware of safety issues. Our findings suggest that [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2010/09/WC500096996.pdf. Accessed 23 NCAs should explore the use of other information sources Jan 2018. to complement the current tools used to disseminate safety 2. European Medicines Agency. European Medicines Agency rec- information. ommends suspension of marketing authorisations for sibutramine. [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ Acknowledgements The healthcare professionals from Croatia, library/Press_release/2010/01/WC500069995.pdf. Accessed 23 Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, Jan 2018. and the UK who responded to the survey are greatly appreciated. 3. Dusetzina SB, Higashi AS, Dorsey ER, Conti R, Huskamp HA, Other SCOPE Work Package 6 members: J. Ahlqvist-Rastad, F. Zhu S, et al. Impact of FDA drug risk communications on health Bouder, M. Foy, J. Garcı ´a, J. Hearn, Y. Knudsen, L. Loughin, D. care utilization and health behaviors: a systematic review. Med Montero, H. Samdal, and A. Wennberg. Care. 2012;50(6):466–78. 724 S. T. de Vries et al. 4. Piening S, Haaijer-Ruskamp FM, de Vries JT, van der Elst ME, 9. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R, et al. de Graeff PA, Straus SM, et al. Impact of safety-related regula- Ivabradine in stable coronary artery disease without clinical heart tory action on clinical practice: a systematic review. Drug Saf. failure. N Engl J Med. 2014;371(12):1091–9. 2012;35(5):373–85. 10. Lindell MK, Perry RW. The protective action decision model: 5. Piening S, Reber KC, Wieringa JE, Straus SM, de Graeff PA, theoretical modifications and additional evidence. Risk Anal. Haaijer-Ruskamp FM, et al. Impact of safety-related regulatory 2012;32(4):616–32. action on drug use in ambulatory care in the Netherlands. Clin 11. Banerjee AK, Zomerdijk IM, Wooder S, Ingate S, Mayall SJ. Pharmacol Ther. 2012;91(5):838–45. Post-approval evaluation of effectiveness of risk minimisation: 6. Piening S, Haaijer-Ruskamp FM, de Graeff PA, Straus SM, Mol methods, challenges and interpretation. Drug Saf. PG. Healthcare professionals’ self-reported experiences and 2014;37(1):33–42. preferences related to direct healthcare professional communi- 12. Goedecke T, Morales DR, Pacurariu A, Kurz X. Measuring the cations: a survey conducted in the Netherlands. Drug Saf. impact of medicines regulatory interventions—systematic review 2012;35(11):1061–72. and methodological considerations. Br J Clin Pharmacol. 2017. 7. European Medicines Agency. Guideline on good pharmacovigi- https://doi.org/10.1111/bcp.13469. lance practices (GVP) Module XV – Safety communication. 13. Althubaiti A. Information bias in health research: definition, [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ pitfalls, and adjustment methods. J Multidiscip Healthc. library/Scientific_guideline/2013/01/WC500137666.pdf. Acces- 2016;9:211–7. sed 23 Jan 2018. 14. Harzing A, Brown M, Ko ¨ ster K, Zhao S. Response style differ- 8. De Vries ST, van der Sar MJM, Cupelli A, Baldelli I, Coleman ences in cross-national research. Manage Int Rev. AM, Montero D, Andric ´ A, Wennberg A, Ahlqvist-Rastad J, 2012;52(3):341–63. Denig P, Mol PGM, on behalf of SCOPE Work Package 6. 15. Tellis GJ, Chandrasekaran D. Does culture matter? Assessing Communication on safety of medicines in Europe: current prac- response biases in cross-national survey research. International tices and general practitioners’ awareness and preferences. Drug Journal of Research in Marketing 2010. [Internet]. https://ssrn. Saf 2017;40(8):729–42. com/abstract=1659911. Accessed 23 Jan 2018. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Safety Springer Journals

Safety Communication Tools and Healthcare Professionals’ Awareness of Specific Drug Safety Issues in Europe: A Survey Study

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Abstract

Drug Saf (2018) 41:713–724 https://doi.org/10.1007/s40264-018-0643-5 OR IGINAL RESEARCH ARTIC L E Safety Communication Tools and Healthcare Professionals’ Awareness of Specific Drug Safety Issues in Europe: A Survey Study 1 1,2 3 • • • Sieta T. de Vries Maartje J. M. van der Sar Anna Marie Coleman 4 4 4 • • • Yvette Escudero Alfonso Rodr´ ıguez Pascual Miguel-Angel Macia ´ Martı ´nez 5 5 6 6 • • ´ • ´ • Amelia Cupelli Ilaria Baldelli Ivana Sipic Adriana Andric 7 1 1,2 • • • Line Michan Petra Denig Peter G. M. Mol on behalf of SCOPE work package 6 Published online: 2 March 2018 The Author(s) 2018. This article is an open access publication Abstract Methods GPs, cardiologists, and pharmacists from nine Introduction National competent authorities (NCAs) use European countries (Croatia, Denmark, Ireland, Italy, the Direct Healthcare Professional Communications (DHPCs) Netherlands, Norway, Spain, Sweden, and the UK) com- to communicate new drug safety issues to healthcare pro- pleted a web-based survey. The survey was conducted in fessionals (HCPs). More knowledge is needed about the the context of the Strengthening Collaboration for Oper- effectiveness of DHPCs and the extent to which they raise ating Pharmacovigilance in Europe (SCOPE) Joint Action. awareness of new safety issues among HCPs. Respondents were asked about their familiarity with Objective The objective was to assess and compare gen- DHPCs in general and their awareness of safety issues that eral practitioners’ (GPs’), cardiologists’, and pharmacists’ had recently been communicated and involved the fol- familiarity with DHPCs as communication tools, their lowing drugs: combined hormonal contraceptives, awareness of specific drug safety issues, and the sources diclofenac, valproate, and ivabradine. Those HCPs who through which they had become aware of the specific were aware of the specific safety issues were subsequently issues. asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a 2 2 The other members of SCOPE work package 6 are listed in Pearson v test per country and post hoc Pearson v tests in Acknowledgements. the case of statistically significant differences. Results Of the 3288 included respondents, 54% were GPs, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40264-018-0643-5) contains supple- 40% were pharmacists, and 7% were cardiologists. The mentary material, which is available to authorized users. number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with & Peter G. M. Mol DHPCs, with one significant difference between the pro- p.g.m.mol@umcg.nl fessions: pharmacists were more familiar than GPs in Italy Department of Clinical Pharmacy and Pharmacology, (99 vs 90%, P = 0.004). GPs’ awareness ranged from 96% University of Groningen, University Medical Center for the diclofenac issue to 70% for the ivabradine issue. A Groningen, Groningen, The Netherlands similar pattern was shown for pharmacists (91% aware of Dutch Medicines Evaluation Board, Utrecht, The Netherlands the diclofenac issue to 66% of the ivabradine issue). Car- Health Products Regulatory Authority (HPRA), Dublin, diologists’ awareness ranged from 91% for the ivabradine Ireland issue to 34% for the valproate issue. Overall, DHPCs were Spanish Agency for Medicines and Medical Devices a common source through which GPs (range: 45% of those (AEMPS), Madrid, Spain aware of the contraceptives issue to 60% of those aware of Italian Medicines Agency (AIFA), Rome, Italy the valproate issue), cardiologists (range: 33% for the Agency for Medicinal Products and Medical Devices of contraceptives issue to 61% for the valproate issue), and Croatia (HALMED), Zagreb, Croatia pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the Danish Medicines Agency (DKMA), Copenhagen, Denmark 714 S. T. de Vries et al. specific safety issues, followed by information on websites authorities (NCAs) inform HCPs about these risks and the or in newsletters. actions that they should take to minimise or manage them. Conclusions GPs, cardiologists, and pharmacists were to a Research, however, has shown that the safety advice in similar extent (highly) familiar with DHPCs, but they communications from regulators is not always followed differed in awareness levels of specific safety issues. Car- [3–5]. Before HCPs can act on a safety issue, they first diologists were less aware of safety issues associated with need to become aware of it. A study published in 2012 non-cardiology drugs even if these had cardiovascular among a sample of Dutch HCPs showed mixed awareness safety concerns. This implies that additional strategies may of drug safety issues, ranging from 56% of HCPs being be needed to reach specialists when communicating safety aware of new safety issues with etoricoxib up to 88% for issues regarding drugs outside their therapeutic area but clopidogrel [6]. Moreover, it was shown that awareness with risks related to their field of specialisation. DHPCs varied among professions, where pharmacists were gener- were an important source for the different professions to ally more aware of safety issues than general practitioners become aware of specific safety issues, but other sources (GPs) [6]. were also often used. NCAs should consider the use of a Direct Healthcare Professional Communications range of sources when communicating important safety (DHPCs) are an important tool that NCAs use to commu- issues to HCPs. nicate new drug safety information to HCPs [7]. DHPCs are letters predominantly distributed by pharmaceutical companies following content approval by the NCAs. Some research suggests that about one-fifth of HCPs are not Key Points familiar with these communications. Again, differences between professions were seen, with GPs being more Familiarity with Direct Healthcare Professional familiar with these communications than pharmacists [6]. Communications (DHPCs) was high among general Besides DHPCs, NCAs can use additional tools to raise practitioners (GPs), cardiologists, and pharmacists awareness of safety issues, such as the NCA’s own com- across Europe. munications (e.g. newsletters) [7]. Currently, it is not Cardiologists were more aware than GPs of the known how HCPs become aware of safety issues (i.e. via safety issue for a drug within their field of expertise DHPCs or other sources) and whether this differs between (ivabradine) and less aware than GPs and professions. A previous study showed that NCAs from pharmacists of safety issues of other drugs European countries generally use similar methods for (contraceptives, diclofenac, and valproate), despite safety communication, but that GPs’ awareness of safety some of these relating to cardiovascular risks. communication tools differ across countries [8]. The aim of this study was to expand the current knowledge DHPCs were an important source for GPs, about differences between professions in familiarity with cardiologists, and pharmacists to become aware of DHPCs and awareness of safety issues in various European specific safety issues, but other sources, such as countries. More specifically, our aims were to compare GPs, websites or newsletters and medical journals, were cardiologists, and pharmacists regarding their familiarity with also relevant. DHPCs, their awareness of specific recent drug safety issues, and the sources through which they have become aware of these issues. This knowledge is important for NCAs in the evaluation of their current safety communication strategies and to facilitate improvement in the future. Knowing how 1 Introduction different professions perceive current drug safety communi- cation tools and the sources they used most in informing There have been some high-profile drug safety issues in themselves of important updates can help NCAs to optimise recent years where re-evaluation of the risks associated their safety communication strategies. with drugs such as rosiglitazone and sibutramine led to their removal from the market by European regulators as the benefit–risk balance was judged to be negative [1, 2]. 2 Methods More often, however, important new safety issues emerge where the overall benefit–risk balance of the drug remains 2.1 Study Design and Data Collection positive provided healthcare professionals (HCPs) take into account certain warnings and precautions and the drug Cross-sectional data from a web-based survey about HCPs’ remains on the market. In these cases, national competent views and experiences regarding drug safety information Safety Communication Tools and Awareness of Drug Safety Issues 715 were used for this study. The data were collected in the in the period just prior to the survey being conducted year 2015 in the context of the Strengthening Collaboration [following review within safety referral procedures by the for Operating Pharmacovigilance in Europe (SCOPE) Joint Pharmacovigilance Risk Assessment Committee (PRAC)], Action Work Package 6 (http://www.scopejointaction.eu/). and to have a representative sample of drugs used in pri- The active partners in this work package developed the mary care (contraceptives and diclofenac) along with spe- survey in the English language (see Electronic Supple- cialised care (valproate and ivabradine). The safety issue mentary Material 1). This survey was translated by an for ivabradine was not included in the Norwegian survey official translation agency in the following languages: because this drug is not on the market in Norway. Croatian, Danish, Dutch, Italian, Norwegian, Spanish, and Finally, when respondents indicated that they were Swedish. Thereafter, the surveys were back-translated and aware of a certain safety issue, they were asked how they pilot tested to check whether the translations had the same had heard about it. The source options provided were as meaning as the English version and whether the survey was follows: via a DHPC, a website or newsletter, educational understandable for people not involved in the project. materials, a professional body, a colleague, a medical Unipark software (http://www.unipark.com/en/) was used journal, lay media (newspaper/television), or other source. to create the web-based format of the survey. Ethical The Norwegian survey included an additional answer approval was not considered necessary because of the option, i.e. through the national medicines agency. It was nature of the study, in which HCPs were asked to complete possible to provide multiple answers on how HCPs became a survey about safety communication strategies. aware of the safety issues. 2.2 Participants 2.4 Analyses The survey was distributed among HCPs in nine European Descriptive information about the included population is countries that were active partners in Work Package 6 of presented as frequencies with percentages for the total the Joint Action; i.e. Croatia, Denmark, Ireland, Italy, the population and per profession. Netherlands, Norway, Spain, Sweden, and the UK. HCPs HCPs’ familiarity with DHPCs and awareness of each of were recruited via a link to the survey on websites, in the four specific safety issues are presented as percentages newsletters, and/or in an email sent by the NCA, a pro- per profession within each country. Only HCPs who were fessional body, or a commercial organisation to all their familiar with DHPCs were included in the assessment of subscribers or members. HCPs that were actively targeted awareness of the safety issues. Differences in familiarity and included in this study were GPs, cardiologists, and with DHPCs and awareness between professions were tested using a Pearson v pharmacists. In Spain and Sweden, only GPs and cardiol- test per country. In the case of a ogists were actively targeted. statistically significant result (P value of\0.05), Pearson v tests were used to assess which professions differed 2.3 Outcome Assessment from each other. A Bonferroni adjustment to correct for multiple testing (N = 3) was used for these post hoc tests, To assess HCPs’ familiarity with DHPCs the survey con- implying that a P value of\0.016 was considered statis- tained a short introduction about DHPCs with two exam- tically significant. ples pictured, after which respondents were asked the Data from the sources through which the HCPs heard of following closed-ended question: ‘‘Are you familiar with the safety issues were analysed descriptively. The results of this type of safety communication?’’ Respondents these analyses are presented per profession using percentages answering ‘‘Yes’’ were considered familiar, whereas per safety issue and per country for those HCPs who were respondents answering ‘‘No, I have heard of DHPCs, but I aware of the safety issue. The additional answer option in the have never seen one’’ or ‘‘No, I have never heard of Norwegian survey was classified as ‘‘other’’ sources. DHPCs’’ were considered unfamiliar with DHPCs. All analyses were conducted using Stata version 13 (Stata HCPs’ awareness of specific safety issues was assessed Corp., College Station, TX, USA), and Microsoft Excel 2010 using the following question: ‘‘Are you aware of updates to was used for the graphical presentation of the results. the safety profiles of the following medicines?’’ The pre- sented drug safety issues were updates on the risk of thrombosis with combined hormonal contraceptives (con- 3 Results traceptives), cardiovascular harms with diclofenac, terato- genicity with valproate, and cardiovascular events with In total, 3625 HCPs completed the survey, of whom 337 ivabradine (Table 1). These safety issues were chosen as had a profession different than the target population of they had been the subject of NCA safety communications GPs, cardiologists, and pharmacists. Of the remaining 3288 716 S. T. de Vries et al. Table 1 Summary of the drugs for which the safety updates were assessed in this study Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Indicated for/ Contraception Relieving pain and Generalised, partial or other Symptomatic treatment of treatment of inflammation epilepsy; bipolar disorder chronic stable angina pectoris. Treatment of chronic heart failure Most common GPs GPs Neurologists, psychiatrists Cardiologists prescriber New safety Risk of VTE. Confirmation Risk of cardiovascular events. Risk of teratogenicity. Further Risk of cardiovascular events. information that the absolute risk of VTE The same cardiovascular characterisation of the A small but significant with all CHCs is small and precautions now apply for teratogenic effects: children increase of the combined ranges from 5 to 12 cases of diclofenac as for selective exposed in utero are at a risk of cardiovascular death, VTE per 10,000 women per COX-2 inhibitors, i.e. high risk of serious myocardial infarction, and year, but that differences ‘coxibs’ developmental disorders (in cardiac failure was seen in exist depending on the type up to 30–40% of cases) and/ patients with symptomatic of progestogen they contain or congenital malformations angina [9] and for a given dose of (in approximately 10% of oestrogen, with cases) levonorgestrel, norethisterone or norgestimate (so called second generation) having the lowest risk as per the available evidence Implications of Careful consideration to be Use contraindicated in Valproate should not be used Ivabradine is indicated only the new given to the new evidence ischaemic heart disease, in female children/ for symptomatic treatment safety when prescribing CHCs in peripheral arterial disease, adolescents of childbearing of chronic stable angina information addition to emphasising cerebrovascular disease, and potential or pregnant women pectoris because ivabradine existing contraindications congestive heart failure. unless other treatments are has no benefits on for use and evaluating the Careful consideration to be ineffective or not tolerated. cardiovascular outcomes individual woman’s current given to an individual’s risk It must be started and (e.g. myocardial infarction risk factors for VTE factors for cardiovascular supervised by a doctor or cardiovascular death) in events before prescribing experienced in managing patients with symptomatic (e.g. hypertension, diabetes, epilepsy or bipolar disorder. angina. Serial heart rate hyperlipidaemia, and All female patients must be measurements are required smoking) informed of and fully prior to initiation of therapy understand the risks of use or prior to dose titration. during pregnancy Concomitant use with verapamil or diltiazem is contraindicated. Treatment should only be initiated in patients with a resting heart rate of at least 70 bpm Year of DHPC 2014 2013 2014 2014 Distribution of DHPC per country Format Croatia Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts Hardcopy, point-of-care alerts for HCPs at primary level, for HCPs at primary level, for HCPs at primary level, for HCPs at primary level, NCA website and newsletter NCA website and newsletter NCA website and newsletter NCA website and newsletter Denmark Electronic and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Ireland Hardcopy letter (also Hardcopy letter (also Hardcopy letter (also Hardcopy letter (also published on NCA website published on NCA website published on NCA website published on NCA website and article included in and article included in and article included in and article included in electronic NCA newsletter) electronic NCA newsletter) electronic NCA newsletter) electronic NCA newsletter) Italy Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Netherlands Hardcopy, NCA website and Hardcopy, NCA website and Hardcopy, NCA website and Hardcopy, NCA website and NCA newsletter NCA newsletter NCA newsletter NCA newsletter Norway Hardcopy and point-of-care- Hardcopy and point-of-care- Hardcopy and point-of-care- N/A alerts alerts alerts Safety Communication Tools and Awareness of Drug Safety Issues 717 Table 1 continued Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Spain Electronic and NCA website Electronic and NCA website Electronic and NCA website Electronic and NCA website Sweden Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website Hardcopy and NCA website UK Electronic cascade Hardcopy letter and NCA Electronic cascade Hardcopy letter and NCA distribution and NCA website distribution and NCA website website website Targeted HCPs Croatia Gynaecologists, GPs, Internists, rheumatologists, Neurologists, psychiatrists, Cardiologists, internists, GPs, pharmacists, selected GPs, pharmacists gynaecologists, GPs, selected learned societies, learned societies, hospitals’ pharmacists, selected hospitals’ medicines medicines committees learned societies, hospitals’ committees medicines committees Denmark Danish medical societies, GPs GPs, pharmacists, internists, GPs, neurologists, GPs, cardiologists, internists association, Danish medical rheumatologists psychiatrists, paediatricians, in cardiology departments, association, medical society clinical pharmacologists, medical societies for for gynaecology and industrial medical officers, cardiology and GPs, Danish obstetrics medical societies for Heart Association neurology, psychiatry and clinical pharmacology, patient societies for epilepsia and psychiatry Ireland GPs, family planning clinics, GPs, all consultants Neurologists, psychiatrists, GPs, cardiologists, pharmacists, obstetricians, (specialists), pharmacists, GPs, obstetricians, geriatricians, general gynaecologists dentists gynaecologists, family medicine consultants, planning centres, pharmacists pharmacists, relevant HCP professional organisations Italy Gynaecologists, emergency GPs, internists, cardiologists, Neurologists, psychiatrists, Internists, cardiologists, GPs, room physicians, rheumatologists, GPs, obstetricians/ relevant learned societies pneumologists, orthopaedics, geriatrics, gynaecologists, family cardiologists, pharmacists planning centres, midwife, haematologists, hospital pharmacists (community and pharmacists, relevant hospital), relevant scientific scientific and HCP and HCP organisations/patient organisations/patient organisations organisations Netherlands GPs, gynaecologists, GPs, rheumatologists, Neurologists, psychiatrists, Cardiologists, GPs, hospital pharmacists, hospital internists, pharmacists, gynaecologists, pharmacists pharmacists hospital pharmacists, paediatricians and paediatric orthopaedics nurses, obstetricians, pharmacists Norway GPs, pharmacists, GPs, pharmacists, internists, GPs, pharmacists, N/A gynaecologists, midwifes, rheumatologists, surgeons, gynaecologists, neurologists, public health nurses, orthopaedists, emergency psychiatrists, midwifes, emergency medical services, medical services industrial medical officers hospital surgical and internal medicine wards Spain GPs, gynaecologists, clinical GPs, geriatricians, internal Psychiatrists, neurologists, Cardiologists, GPs, internal pharmacologists, medicine specialists, GPs, paediatricians, clinical medicine specialists, community pharmacists, rheumatologists, pharmacologists, geriatricians, clinical PhV centres traumatologists, pharmacists (community and pharmacologists, rehabilitation specialists, hospital), PhV centres pharmacists (community and pharmacists (community and hospital), PhV centres hospital), PhV centres 718 S. T. de Vries et al. Table 1 continued Characteristic Combined hormonal Diclofenac Valproate Ivabradine contraceptives Sweden GPs, gynaecologists, midwifes GPs, specialists in internal Neurologists, psychiatrists, Cardiologists, specialists in medicine (including gynaecologists, specialists in internal medicine, GPs rheumatologists and internal medicine, learned cardiologists), orthopaedist, societies (neurology, pharmacies, county council epilepsy, psychiatry), county drug committees council drug committees UK GPs, family planning clinics, GPs, retail pharmacists, chief GPs, pharmacists (community GPs, internal medicine nurses, gynaecologists, all pharmacists in secondary and hospital), secondary specialists, cardiologists, pharmacists (community and care, dentists in practice, care chief pharmacists hospital), midwives dentists in mainstream hospitals, dental hospitals Sender of the DHPC Croatia MAH MAH MAH MAH Denmark NCA MAH MAH MAH Ireland MAH MAH MAH MAH Italy MAH MAH MAH MAH Netherlands MAH MAH MAH MAH Norway MAH MAH MAH N/A Spain Learned societies of targeted Learned societies of targeted Learned societies of targeted Learned societies of targeted HCPs HCPs HCPs HCPs Sweden MAH MAH MAH MAH UK NCA MAH NCA MAH CHCs combined hormonal contraceptives, COX cyclo-oxygenase, DHPC Direct Healthcare Professional Communication, GP general practitioner, HCP healthcare professional, MAH marketing authorisation holder, N/A not applicable, NCA national competent authority, PhV pharmacovigilance, VTE venous thromboembolism respondents, 54% were GPs, 40% were pharmacists, and GPs), Croatia (i.e. cardiologists), and Norway (i.e. 7% were cardiologists (Fig. 1). The number of respondents pharmacists). ranged from 67 in Denmark to 916 in Spain. Most of the GPs, cardiologists, and pharmacists were from, respec- 3.2 Awareness of the Four Specific Safety Issues tively, Spain (N = 847), Italy (N = 63), and Norway (N = 381) (Fig. 2). More than half of the respondents per Overall, GPs were most aware of the safety issue con- country were female, except for Italy (42% female) and the cerning diclofenac (96%), followed by contraceptives Netherlands (31% female) (see Electronic Supplementary (88%), valproate (76%), and ivabradine (70%). The same Material 2). pattern was shown for the pharmacists, with highest awareness of diclofenac (91%), followed by contraceptives 3.1 Familiarity with DHPCs (90%), valproate (80%), and ivabradine (66%). For the cardiologists, the pattern was different, with highest Most respondents (92%) were familiar with DHPCs, and in awareness of the ivabradine safety issue (91%), followed general there were only small differences between GPs, by diclofenac (79%), contraceptives (61%), and valproate cardiologists, and pharmacists in terms of their familiarity (34%). (Fig. 3). Only in Italy a significant difference between the Cardiologists were significantly less aware of the con- professions was shown (P = 0.016). More pharmacists traceptives safety issue than GPs and/or pharmacists in six were familiar with DHPCs than GPs (99 vs 90%, countries (i.e. Denmark, Italy, the Netherlands, Norway, P = 0.004). Familiarity was highest in Ireland, Italy, Spain, and the UK) (Fig. 4a). In three countries (i.e. Spain, Spain, and the UK, where more than 90% of the GPs, Italy, and Norway), they were also less aware of the cardiologists, and pharmacists were familiar with DHPCs. diclofenac issue (Fig. 4b). For the valproate issue, cardi- Familiarity was lowest for some professions in Sweden (i.e. ologists were less aware than GPs and/or pharmacists in Safety Communication Tools and Awareness of Drug Safety Issues 719 HCPs who completed the Completers survey: N = 3,625 Other profession: N = 337 Target populaon: N = 3,288 Profession GPs: N = 1,766 (54%) Cardiologists: N = 222 (7%) Pharmacists: N = 1,300 (40%) Included in the analyses of aim 1: familiarity with DHPCs No: N = 272* (8%) Familiarity with Yes: N = 3,016 DHPCs Respondents with a missing answer to all of the four safety issues: N = 3 Addionally excluded per safety issue due to missing answers: Included per safety issue: - Contracepves: N = 12 Response to specific - Contracepves: N = 3,001 - Diclofenac: N = 18 safety issue - Diclofenac: N = 2,995 - Valproate: N = 24 - Valproate: N = 2,989 - Ivabradine: N = 432† - Ivabradine: N = 2,581† Included in the analyses of aim 2: Awareness of specific safety issues Not aware of the safety issue: - Contracepves: N = 390 (13%) Included per safety issue: Awareness of - Diclofenac: N = 205 (7%) - Contracepves: N = 2,611 specific safety issues - Valproate: N = 752 (25%) - Diclofenac: N = 2,790 - Ivabradine: N = 771† (30%) - Valproate: N = 2,237 - Ivabradine: N = 1,810† Included in the analyses of aim 3: Sources through which HCPs became aware Fig. 1 Flowchart of number of healthcare professionals (HCPs) (DHPCs), but had never seen one; 136 had never heard of DHPCs; included per study aim. *272 responding HCPs were excluded: 135 and 1 skipped the question. This safety issue was not included in the had heard of Direct Healthcare Professional Communications survey in Norway. GPs general practitioners five countries (i.e. Italy, the Netherlands, Norway, Spain, Some differences between GPs and pharmacists were and the UK) (Fig. 4c). In Sweden, GP awareness of the also observed (Fig. 4). Pharmacists were more aware of the valproate issue was low and cardiologists were more aware contraceptives’ safety issue than GPs (Croatia 96 vs 83%, of this safety issue; respectively, 38 vs 69%, P = 0.033. P = 0.003; Italy 97 vs 88%, P = 0.009). They were also For the ivabradine issue, cardiologists were more aware more aware of the ivabradine issue (Netherlands 56 vs than GPs in four countries (i.e. Croatia, the Netherlands, 21%, P\0.001). An inconsistent pattern across the coun- Sweden, and the UK) (Fig. 4d). tries was shown for the diclofenac and valproate issue. For the diclofenac issue, pharmacists were more aware than 720 S. T. de Vries et al. message on a website or in a newsletter (range: 37% of those aware of the valproate issue to 39% of those aware of Sweden: Norway: ay: the other issues) (see Electronic Supplementary Material 3). For many cardiologists, DHPCs were also mentioned as UK: an important source (range: 33% for the contraceptives Denmark: Ireland: d 67 issue to 61% for the valproate issue), but in addition, Netherlands: hl d medical journals were often mentioned for the contracep- tives issue (46%), ivabradine issue (42%), and diclofenac issue (34%). A message on a website or in a newsletter was Croaa: the source for 20% (contraceptives issue) to 30% (val- Spain: Italy: proate issue) for the cardiologists. The sources most often mentioned by pharmacists were DHPCs (range: 41% for the contraceptives issue to 51% of the ivabradine issue) and information on a website or in a newsletter (range: 42% for General praconers Pharmacists Cardiologists the contraceptives and valproate issues to 46% for the Croaa 85 4 104 Denmark 25 7 35 diclofenac and ivabradine issues). Ireland 144 5 281 There was variation across the countries in the sources Italy 183 63 104 through which HCPs had become aware of the safety issues Netherlands 72 17 64 Norway 105 40 381 (see Electronic Supplementary Material 3). For instance, Spain 847 56 13 information provided by professional bodies was more Sweden 108 15 N/A often the source for HCPs in the Netherlands than for HCPs UK 197 15 318 in the other countries. Another example is the ‘‘other’’ Fig. 2 Total number of respondents and per profession by country source through which somewhat more HCPs from Norway became aware of the issues compared to the number of GPs in the UK (99 vs 95%, P = 0.009), but less aware in HCPs from other countries. This other source contained the Ireland (83 vs 93%, P = 0.006). For the valproate issue, NCA’s own information centre, which was only specifi- pharmacists were more aware than GPs in Ireland (90 vs cally evaluated in the Norwegian survey. More HCPs from 65%, P\0.001), in the UK (86 vs 68%, P\0.001), and in Italy became aware through a DHPC than did HCPs from the Netherlands (69 vs 45%, P = 0.006), but they were less other countries. aware in Norway (66 vs 81%, P = 0.008). 3.3 Sources 4 Discussion Most of the GPs who were aware of a specific safety issue This study shows that most GPs, cardiologists, and phar- indicated that they had heard about this through a DHPC macists across Europe are familiar with DHPCs. In general, (range: 45% of those aware of the contraceptives issue to GPs and pharmacists were more aware of the safety issues 60% of those aware of the valproate issue), followed by a concerning contraceptives and diclofenac than Fig. 3 Familiarity with Direct P = 0.004 100% Healthcare Professional 90% Communications (DHPCs) by 80% profession per country. Despite 70% not being targeted, a few 60% pharmacists from Spain completed the survey. In 50% Sweden, pharmacists were not 40% actively targeted and no 30% pharmacists completed the 20% survey. GPs general 10% practitioners 0% GPs Cardiologists Pharmacists Safety Communication Tools and Awareness of Drug Safety Issues 721 Combined Hormonal Contracepves Diclofenac 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% GPs Cardiologists Pharmacists GPs Cardiologists Pharmacists Overall GPs vs Cards vs GPs vs Overall GPs vs Card vs GPs vs Card Pharm Pharm Card Pharm Pharm Croaa 0.073 Croaa 0.010 0.427 0.721 0.003 Denmark 0.162 Denmark 0.000 0.001 0.000 Ireland 0.020 0.256 0.837 0.006 Ireland 0.714 Italy 0.000 0.000 0.000 0.461 Italy 0.000 0.003 0.000 0.009 Netherlands 0.089 Netherlands 0.010 0.002 0.049 0.187 Norway 0.002 0.001 0.001 0.413 Norway 0.000 0.000 0.000 0.043 Spain 0.000 0.000 0.066 0.588 Spain 0.000 0.000 0.002 0.768 Sweden 0.820 Sweden 0.292 UK 0.001 0.002 0.000 0.367 UK 0.021 0.691 0.045 0.009 Valproate Ivabradine 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% GPs Cardiologists Pharmacists GPs Cardiologists Pharmacists Overall GPs vs Card vs GPs vs Overall GPs vs Card vs GPs vs Card Pharm Pharm Card Pharm Pharm Croaa 0.069 Croaa 0.038 0.020 0.061 0.138 Denmark 0.068 Denmark 0.092 Ireland 0.000 0.493 0.478 0.000 Ireland 0.296 Italy 0.000 0.000 0.000 0.053 Italy 0.078 Netherlands 0.000 0.008 0.000 0.006 Netherlands 0.000 0.000 0.162 0.000 Norway 0.000 0.000 0.000 0.008 Norway 1 1 Spain 0.000 0.000 0.000 0.134 Spain 0.254 2 2 Sweden 0.033 Sweden 0.000 UK 0.000 0.001 0.000 0.000 UK 0.024 0.009 0.018 0.267 Fig. 4 Awareness of four specific safety issues by profession and Sweden, pharmacists were not actively targeted and no pharmacists P values for differences between professions within countries. P val- completed the survey. The ivabradine safety issue was not assessed ues in bold are considered statistically significant. Despite not being in Norway. Card cardiologists, GPs general practitioners, Pharm targeted, a few pharmacists from Spain completed the survey. In pharmacists 722 S. T. de Vries et al. cardiologists, whereas cardiologists were more aware of in our study. One reason could be differences between the ivabradine issue, which is largely expected given its use countries in uptake of a certain drug and healthcare systems in the specialist setting only. We showed some differences (e.g. whether treatment is confined to the specialised set- between GPs and pharmacists, but these differed across the ting in clinics/hospitals or initiated/repeated by GPs). countries. DHPCs were most often mentioned by all three Another reason could be differences across European professions as the source through which HCPs had become countries in NCAs’ communication strategies. Although a aware of the safety issues, but other sources were also previous study showed that NCAs use similar methods to relevant depending on the safety issue and profession as communicate about drug safety issues [8], the current study well as the country. showed differences across the countries in the sources A previous study conducted in the Netherlands showed through which HCPs had become aware of the specific differences between GPs and hospital pharmacists in their safety issues. Moreover, there were differences between familiarity with DHPCs [6]. Our study showed a difference and within countries with respect to the format, the target between GPs and pharmacists only in Italy. This previous population, and the sender of the communication about the study found that 28% of the GPs were not familiar with specific safety issues (Table 1). Various factors related to DHPCs compared to 14% of the GPs from the Netherlands these strategies, such as trust in the sender of the infor- in our study. This may imply that familiarity with DHPCs mation, may have influenced the uptake of the information among GPs in the Netherlands has increased over the years. [10]. Future studies should focus more on the explanations In general, there seems to be still room for improvement, for differences across European countries. In addition, with less than 80% of respondents in some professions future studies should focus on whether high awareness reporting to be familiar with DHPCs (Croatia and Norway). actually translates into improved drug utilisation and health Of the four presented safety issues, GPs and pharmacists outcomes; however, study methods other than surveys are were least aware of the ivabradine issue. This lower needed for such evaluations [11]. A recent systematic awareness may be due to the fact that ivabradine is a newer review showed that in more than half of the reviewed active substance, likely to be prescribed by specialists, and studies evaluating the impact of regulatory interventions, authorised for a relatively narrow indication. Not surpris- administrative claims databases or electronic health records ingly, this was the safety issue of which cardiologists were databases were used [12]. most aware. On the other hand, cardiologists were less Although there is room for improving HCPs’ familiarity aware of safety issues of drugs that are primarily prescribed with DHPCs, this communication tool was the most com- in general practice (i.e. contraceptives and diclofenac), mon source through which the HCPs became aware of the which is still of cause for concern since the communica- safety issues included in our study. Information on a website or in a newsletter was also reported as an important tions referred to cardiovascular-related risks. A previous study had also shown that specialists were less aware than source for many HCPs; in some cases these are likely to be GPs and community pharmacists of a safety issue for a the websites and newsletters of NCAs, which are long drug prescribed and dispensed in primary care [6]. An established in some countries [8]. Interestingly, medical important explanation may be that DHPCs about contra- journals were also commonly used by cardiologists aware ceptives and diclofenac were not sent to cardiologists in all of the contraceptive, diclofenac, and ivabradine issues. To countries (Table 1). This indicates that in the evaluation of improve HCPs’ awareness of safety issues and ultimately the effectiveness of safety communication strategies, their actual prescribing/dispensing behaviour, it is therefore awareness among the targeted professions should be important that the strategies for safety communication assessed rather than awareness among HCPs in general. should be tailored to specific professions. There may also Findings, however, were not completely consistent as some be differences in the use of sources per country. For professional groups received a DHPC but were less aware. instance, in the Netherlands, awareness of the contracep- Further studies should assess whether cardiologists and tives and diclofenac safety issues were higher than the other specialists are also interested in receiving DHPCs awareness of the valproate and ivabradine issues. This may about adverse effects relevant for their specialty, instead of be related to the role of ‘‘professional bodies’’ that were only receiving DHPCs for drugs used to treat specialty- indicated in the Netherlands as an important source, and related diseases. that thus may amplify safety messages from NCAs. In three countries (i.e. Ireland, the Netherlands, and the Interestingly, several HCPs claimed to have heard about UK), pharmacists were more aware of a safety issue about the diclofenac safety issue via educational materials despite a drug primarily prescribed by specialists (i.e. valproate) these materials not being disseminated for this drug safety than GPs. However, in Norway, GPs were more aware of issue. This finding indicates that HCPs may have confused this issue than pharmacists. There may be various reasons the regulatory term ‘‘educational materials’’ with other for this and for other observed differences across countries educational activities, despite examples of educational Safety Communication Tools and Awareness of Drug Safety Issues 723 Author Contributions All authors contributed to the development materials being presented within the survey for clarity, and formulation of the research question. STdV, MJMvdS, and suggesting a broader interpretation of this term than the PGMM collected data in the Netherlands; AMC in Ireland; YE, ARP, regulatory meaning. and MAMM in Spain; AC and IB in Italy; IS and AA in Croatia; and A strength of this study is the inclusion of survey LM in Denmark; and the other SCOPE Work Package 6 members collected data in the other countries. STdV and MJMvdS analysed the respondents from a wide range of European countries; thus data. All authors contributed to the interpretation of the results. STdV it was possible to assess the associations per country. wrote the manuscript. MJMvdS, AMC, YE, ARP, MAMM, AC, IB, However, the study also has some limitations. One limi- IS, AA, LM, PD, and PGMM reviewed and edited the manuscript. PD tation relates to the use of a survey methodology which has been involved involved primarily in the development, interpre- tation and writing of this project. She is mentioned implicitly (like all could have introduced biases such as recall bias and other authors) for the first two aspects and individually mentioned for answering tendencies [13]. Moreover, survey answering the writing part. All authors have read and approved the final tendencies such as socially desirable answering may differ manuscript. across countries [14, 15], which could have influenced our Compliance with Ethical Standards results. Another limitation is the low statistical power in some countries due to the small sample size, particularly Ethical approval was not considered necessary for this study because the low number of included cardiologists. Results should of the nature of the study, in which healthcare professionals were therefore be interpreted cautiously. Due to the low sample asked to complete a survey about safety communication strategies. Participants were assured that all sensitive data would be kept size, we did not assess the sources by profession per confidential. country, and this also limits the generalisability of the findings. Previously, we compared the GPs included in our Funding The work was conducted in the context of a European study with the total GP population in the different countries Commission sponsored joint action, Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE). Any opinions, and we observed a similar pattern in terms of age and sex conclusions and proposals in the text are those of the authors and do distribution [8]. However, representativeness cannot be not necessarily represent the views of the European Commission or guaranteed, particularly in countries with small sample national competent authorities. The survey was made possible sizes. In addition, pharmacists were not actively recruited through a tendered subcontract ITT-1301, ECM-2294. in Spain and Sweden and other specialists that would have Conflict of interest Sieta T. de Vries, Maartje J.M. van der Sar, been relevant to the specific safety issues studied (e.g. Anna Marie Coleman, Yvette Escudero, Alfonso Rodrı ´guez Pascual, neurologists or epileptologists) were not included. Miguel-Angel Macia ´ Mart´ ınez, Amelia Cupelli, Ilaria Baldelli, Ivana Sipic ´, Adriana Andric ´, Line Michan, and Petra Denig have no con- flicts of interest that are directly relevant to the content of this study. Peter G.M. Mol is an employee of the Dutch Medicines Evaluation 5 Conclusion Board. We observed high familiarity with DHPCs across all three Open Access This article is distributed under the terms of the professions; however, there were differences between Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which per- professions in awareness of specific safety issues. GPs and mits any noncommercial use, distribution, and reproduction in any pharmacists were more aware of the safety issues con- medium, provided you give appropriate credit to the original cerning contraceptives and diclofenac than cardiologists, author(s) and the source, provide a link to the Creative Commons whereas cardiologists were more aware of the ivabradine license, and indicate if changes were made. issue. Different strategies may be needed to reach spe- cialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their References field of specialisation. Aside from DHPCs, other sources such as websites, newsletters, professional bodies, or 1. European Medicines Agency. European Medicines Agency rec- medical journals can be relevant sources for HCPs to ommends suspension of Avandia, Avandamet and Avaglim. become aware of safety issues. Our findings suggest that [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2010/09/WC500096996.pdf. Accessed 23 NCAs should explore the use of other information sources Jan 2018. to complement the current tools used to disseminate safety 2. European Medicines Agency. European Medicines Agency rec- information. ommends suspension of marketing authorisations for sibutramine. [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ Acknowledgements The healthcare professionals from Croatia, library/Press_release/2010/01/WC500069995.pdf. Accessed 23 Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, Jan 2018. and the UK who responded to the survey are greatly appreciated. 3. Dusetzina SB, Higashi AS, Dorsey ER, Conti R, Huskamp HA, Other SCOPE Work Package 6 members: J. Ahlqvist-Rastad, F. Zhu S, et al. Impact of FDA drug risk communications on health Bouder, M. Foy, J. Garcı ´a, J. Hearn, Y. Knudsen, L. Loughin, D. care utilization and health behaviors: a systematic review. Med Montero, H. Samdal, and A. Wennberg. Care. 2012;50(6):466–78. 724 S. T. de Vries et al. 4. Piening S, Haaijer-Ruskamp FM, de Vries JT, van der Elst ME, 9. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R, et al. de Graeff PA, Straus SM, et al. Impact of safety-related regula- Ivabradine in stable coronary artery disease without clinical heart tory action on clinical practice: a systematic review. Drug Saf. failure. N Engl J Med. 2014;371(12):1091–9. 2012;35(5):373–85. 10. Lindell MK, Perry RW. The protective action decision model: 5. Piening S, Reber KC, Wieringa JE, Straus SM, de Graeff PA, theoretical modifications and additional evidence. Risk Anal. Haaijer-Ruskamp FM, et al. Impact of safety-related regulatory 2012;32(4):616–32. action on drug use in ambulatory care in the Netherlands. Clin 11. Banerjee AK, Zomerdijk IM, Wooder S, Ingate S, Mayall SJ. Pharmacol Ther. 2012;91(5):838–45. Post-approval evaluation of effectiveness of risk minimisation: 6. Piening S, Haaijer-Ruskamp FM, de Graeff PA, Straus SM, Mol methods, challenges and interpretation. Drug Saf. PG. Healthcare professionals’ self-reported experiences and 2014;37(1):33–42. preferences related to direct healthcare professional communi- 12. Goedecke T, Morales DR, Pacurariu A, Kurz X. Measuring the cations: a survey conducted in the Netherlands. Drug Saf. impact of medicines regulatory interventions—systematic review 2012;35(11):1061–72. and methodological considerations. Br J Clin Pharmacol. 2017. 7. European Medicines Agency. Guideline on good pharmacovigi- https://doi.org/10.1111/bcp.13469. lance practices (GVP) Module XV – Safety communication. 13. Althubaiti A. Information bias in health research: definition, [Internet]. http://www.ema.europa.eu/docs/en_GB/document_ pitfalls, and adjustment methods. J Multidiscip Healthc. library/Scientific_guideline/2013/01/WC500137666.pdf. Acces- 2016;9:211–7. sed 23 Jan 2018. 14. Harzing A, Brown M, Ko ¨ ster K, Zhao S. Response style differ- 8. De Vries ST, van der Sar MJM, Cupelli A, Baldelli I, Coleman ences in cross-national research. Manage Int Rev. AM, Montero D, Andric ´ A, Wennberg A, Ahlqvist-Rastad J, 2012;52(3):341–63. Denig P, Mol PGM, on behalf of SCOPE Work Package 6. 15. Tellis GJ, Chandrasekaran D. Does culture matter? Assessing Communication on safety of medicines in Europe: current prac- response biases in cross-national survey research. International tices and general practitioners’ awareness and preferences. Drug Journal of Research in Marketing 2010. [Internet]. https://ssrn. Saf 2017;40(8):729–42. com/abstract=1659911. Accessed 23 Jan 2018.

Journal

Drug SafetySpringer Journals

Published: Mar 2, 2018

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