BioDrugs (2018) 32:267–280 https://doi.org/10.1007/s40259-018-0281-6 ORIGINAL RESEARCH ARTICLE Knowledge of Adverse Drug Reaction Reporting and the Pharmacovigilance of Biological Medicines: A Survey of Healthcare Professionals in Ireland 1,2,3 1,2 1 2 • • • J. O’Callaghan B. T. Grifﬁn J. M. Morris Margaret Bermingham Published online: 2 May 2018 The Author(s) 2018 Abstract concept of additional monitoring but awareness rates dif- Background In Europe, changes to pharmacovigilance fered between some groups. Among those who knew about legislation, which include additional monitoring of additional monitoring, there was higher awareness of the medicines, aim to optimise adverse drug reaction (ADR) inverted black triangle symbol among pharmacists reporting systems. The legislation also makes provisions ([86.4%) compared with hospital doctors (35.1%), GPs related to the traceability of biological medicines. (35.6%), and nurses (14.9%). Hospital pharmacists had Objective The objective of this study was to assess more experience and knowledge of ADR reporting than (i) knowledge and general experience of ADR reporting, (ii) other practising HCPs. knowledge, behaviours, and attitudes related to the pharma- Conclusion This study highlights the important role hos- covigilance of biologicals, and (iii) awareness of additional pital pharmacists play in post-marketing surveillance. monitoring among healthcare professionals (HCPs) in Ireland. There is a need to increase pharmacovigilance awareness Methods Hospital doctors (n = 88), general practitioners of biological medicines and improve systems to support (GPs) (n = 197), nurses (n = 104) and pharmacists their batch traceability. (n = 309) completed an online questionnaire. Results There were differences in mean knowledge scores Key Points relating to ADR reporting and the pharmacovigilance of biologicals among the HCP groups. The majority of HCPs There were differences in experience and knowledge who use biological medicines in their practice generally of ADR reporting as well as conﬁdence in the ability record biologicals by brand name but practice behaviours to report ADRs among hospital doctors, general relating to batch number recording differed between some practitioners, nurses, and pharmacists professions. HCPs consider batch number recording to be valuable but also regard it as being more difﬁcult than Healthcare-professional awareness of additional brand name recording. Most respondents were aware of the monitoring was high. However, pharmacists were signiﬁcantly more aware of the inclusion of the inverted black triangle symbol . on the product Electronic supplementary material The online version of this information of such medicines than hospital doctors, article (https://doi.org/10.1007/s40259-018-0281-6) contains supple- mentary material, which is available to authorized users. general practitioners, and nurses Overall, healthcare professionals were more familiar & Margaret Bermingham Margaret.email@example.com with the term biological medicine than biosimilar medicine. Biological medicines are typically Regulatory Science Ireland, c/o School of Pharmacy, recorded by brand name but batch numbers are University College Cork, Cork, Ireland recorded to a lesser extent. This may negatively School of Pharmacy, University College Cork, Cork, Ireland impact the traceability of biologicals to batch level in Health Products Regulatory Authority, Kevin O’Malley ADR reporting databases House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland 268 J. O’Callaghan et al. through a rigorous comparability exercise conducted at the 1 Introduction quality, pre-clinical and clinical levels . All newly approved biological medicines, including biosimilars, are Pharmacovigilance refers to the ongoing assessment of a subject to additional monitoring for a period of 5 years medicine’s safety throughout its lifecycle . Adverse drug after approval. reaction (ADR) reporting is a key source of information for The traceability of biologicals is essential so that the safety signal detection activities and is useful in the iden- impact of suspected ADRs can be properly evaluated to tiﬁcation of rare adverse events . However, it is esti- both product and batch level. Contrary to naming approa- mated that only 6% of ADRs are reported . Factors that ches taken in the United States , a biosimilar in Europe may contribute to underreporting among healthcare pro- has the same international non-proprietary name (INN) as fessionals (HCPs) include knowledge, negative attitudes, its reference medicine, even though it is not its generic lack of time and motivation . Lack of standardised equivalent. Therefore, inclusion of the brand name in ADR reporting processes and gaps in healthcare information reports allows differentiation to be made between products. systems also contribute to underreporting . New phar- Product-speciﬁc pharmacovigilance also allows changes in macovigilance legislation, which came into effect in Eur- product quality or characteristics that may result in clini- ope in July 2012, resulted in speciﬁc changes related to cally meaningful differences arising between products with ADR reporting including provision for direct patient the same INN [9, 16] to be captured. Traceability to batch reporting of ADRs and additional monitoring of medicines level is necessary to signal batch-speciﬁc issues or ﬂag . Additional monitoring aims to encourage ADR adverse reactions attributable to manufacturing process reporting, thereby allowing additional safety data to be changes . Consequently, HCPs are advised to system- gathered for medicines containing new active substances or atically record and report detailed exposure information for medicines with emerging safety issues. The additional all biological medicines . monitoring status of a medicine is indicated by the pres- In most cases, biologicals are prescribed in specialised ence of an inverted black triangle symbol ., accompanied hospital settings; however, patients receiving these by an explanatory statement encouraging the reporting of medicines are usually cared for by multidisciplinary teams ADRs, on the Summary of Product Characteristics (SmPC) composed of hospital doctors, nurses, general practitioners and the Package Leaﬂet (PL) . The revised pharma- (GPs) and pharmacists. Biological medicines have speciﬁc covigilance legislation also made provisions related to the pharmacovigilance considerations and all newly approved traceability of biological medicines. As such, brand name biologicals are subject to additional monitoring. An and batch numbers should be included in ADR reports for appreciation of these considerations by HCPs helps to biological medicines . ensure the safe and effective use of biological medicines. Biological medicines pose speciﬁc challenges for phar- Several studies on knowledge of ADR reporting among macovigilance. A recent guideline published by the Euro- HCPs have been conducted previously [19–23] and the pean Medicines Agency (EMA) highlights four key ﬁndings suggest knowledge of, as well as communication considerations for the pharmacovigilance of biologicals; and training on ADR reporting could be improved. How- namely immunogenicity, manufacturing variability, sta- ever, there appear to be no studies that address HCP bility/cold chain requirements and product traceability . knowledge of the pharmacovigilance of biological medi- Biological medicines are inherently variable and although cines. It is also not known if HCPs in Europe are aware of different batches of the same biological medicine are not additional monitoring. A survey of a diverse group of identical, the quality of each batch is tightly controlled to HCPs in Ireland was conducted in order to assess and ensure the safety and efﬁcacy of the medicine . How- compare (i) knowledge and general experience of ADR ever, necessary manufacturing process changes  can reporting, (ii) knowledge, behaviours and attitudes related impact quality attributes of the biological and this can to the pharmacovigilance of biologicals and (iii) awareness occur unbeknownst to healthcare professionals and patients of additional monitoring. . In rare instances, these changes can have unforeseen effects on the immunogenicity of a product . Biological medicines including biosimilars are becoming increasingly 2 Methods available . Biosimilars are distinct from the generics of chemical medicines as, owing to the complexities of bio- 2.1 Questionnaire Design logical substances and their manufacturing processes, biosimilars are not completely identical to the original A questionnaire was developed based on previously pub- medicine on which they are based (reference medicine). lished studies [13, 19, 24–27]. The questionnaire wording Similarity to the reference medicine is demonstrated was agreed by a panel of experts with backgrounds in Knowledge of ADR Reporting and Pharmacovigilance of Biologicals Among HCPs in Ireland 269 regulation, clinical pharmacy, pharmacovigilance, acade- College of GPs, respectively. The Ofﬁce of Nursing and mia and regulatory affairs. The face validity of the ques- Midwifery Services in the Irish Health Service Executive tionnaire was tested in a pilot study using a convenience requested senior nurses to distribute the survey link to their sample of 18 HCPs. Minor modiﬁcations were made to nursing staff. Finally, the Pharmaceutical Society of Ire- some of the questions after the pilot study to improve land provided details of members’ email addresses to one clarity. On the basis of the pilot study it was estimated that member of the research team (JOC). One reminder email the questionnaire would take 5–10 min to complete. was sent to nurses and GPs. Due to project time constraints, The questionnaire consisted of an information letter with hospital doctors and pharmacists did not receive any informed consent statement and a total of 26 questions, reminders. No honorarium was provided to respondents. including questions consisting of multiple choice state- ments. Not all questions had to be answered as respondents 2.3 Statistical Analysis were directed towards questions that were relevant to them using an in-built ‘survey-monkey logic’ tool. Two sets of All data were analysed using IBM SPSS Statistics Version closed questions were used to measure knowledge. Each 23. Each respondent’s knowledge level relating to (i) ADR set of closed questions contained eight statements and reporting and (ii) the pharmacovigilance of biologicals was respondents were asked to respond ‘yes’, ‘no’ or ‘don’t calculated by summing all correct items and dividing by know’ to each statement. The ﬁrst set related to ADR the total number of items. Comparison between categorical reporting. Seven of the eight statements had been used in variables was performed using the Chi square test for previous surveys of medical students, pharmacy students independence. Independent t tests or one-way Analysis of and pharmacists [19, 24, 25]. The second set of closed Variance (ANOVA) was used to compare mean knowledge questions contained eight statements relating to speciﬁc scores with baseline characteristics. The Mann–Whitney pharmacovigilance considerations for biological medi- U test or the Kruskal–Wallis test were used to conﬁrm cines. A brief explanation of the term biological medicine ﬁndings in cases where not all assumptions of the para- was provided. The questionnaire is provided in the elec- metric tests were met. A 5% signiﬁcance level applies tronic supplementary material (ESM). throughout all hypothesis testing. A Bonferroni correction Two dichotomous closed questions were used to estab- was applied when multiple group comparisons were made. lish respondent’s knowledge of the concept of ‘additional In cases where 15 comparisons were made, the alpha level monitoring’ (a brief explanation of this term was provided) was adjusted to 0.003, where ﬁve comparisons were made, and the presence of the inverted black triangle . on pro- the alpha level was 0.01. duct information. A 5-point Likert scale was used to 2.4 Analysis of Adverse Drug Reaction (ADR) establish awareness and behaviours related to additional monitoring among HCPs who had knowledge of this con- Database cept. Familiarity with the terms ‘biological medicine’ and ‘biosimilar medicine’ was established using two multiple- Information on the sources of suspected new ADR reports choice questions. Respondents who prescribed, dispensed was obtained from annual reports published by the Health or administered biological medicines were asked questions Products Regulatory Authority (HPRA, formerly Irish related to traceability of biologicals in their practice. Medicines Board) for a 5-year period (2012–2016). Attitudes related to the value and difﬁculty of brand name Reports are published on the HPRA website . ADR and batch number recording were assessed on two different reports for biological medicines containing epoetins, ﬁl- scales. The ﬁrst scale was anchored by ‘Worthless (1) to grastims and inﬂiximab were extracted from the HPRA Valuable (7)’ and the second scale by ‘Easy (1) to Difﬁcult ADR database. The reports covered a 5-year period (7)’. (2013–2017). These substances were chosen as both ref- erence and biosimilar products were available on the Irish 2.2 Questionnaire Distribution marketplace. Reports were reviewed for inclusion of brand name and batch number details. The questionnaire was made available to HCPs online (hosted at http://www.surveymonkey.com) from May to 2.5 Ethical Considerations July 2017. The HCP groups were hospital doctors (prac- tising at consultant [specialist] or non-consultant level), The research study was approved by the Social Research GPs (doctors working in primary care), nurses and phar- Ethics Committee (SREC) in University College Cork, macists. Hospital doctors and GPs were invited to complete Ireland (Log 2017-039). the questionnaire in emails circulated to members by the Royal College of Physicians in Ireland and the Irish 270 J. O’Callaghan et al. knew this. Nurses had lower awareness of this fact than 3 Results each of the other groups (p\0.001 in all cases, Chi square A total of 821 responses were received. The email invite test for independence). GPs were also less aware of this than community or hospital pharmacists (p = 0.002 and was sent to a total of 2360 hospital doctors (97 responses received), 2900 GPs (238 responses received) and 5837 p\0.001, respectively, Chi square test for independence). pharmacists (349 responses received). This corresponded to response rates of 4, 8 and 6% for hospital doctors, GPs 3.2 Sources of ADR Reports and pharmacists respectively. Responses were also received from 121 nurses. Response rates could not be The HPRA received an average of 2910 ADR reports annually over a 5-year period (2012–2016). On average, calculated for nurses as it could not be determined how 26% of reports came directly from HCPs. Reports also many senior nurses forwarded the link to their nursing came from pharmaceutical companies (67%), patients staff. A total of 16 respondents categorised themselves as (5%), others (2%) and clinical trials (1%). A breakdown ‘other’. There were 708 complete responses. Of this number, eight did not meet the inclusion criteria (i.e. of reports is provided in Table S3 (see ESM). Reports submitted by pharmaceutical companies would initially hospital doctor, GP, nurse or pharmacist) and were excluded from the ﬁnal analysis. Two pharmacists that have been notiﬁed to them by HCPs and members of the public. did not provide details of their practice area were also excluded. Consequently, responses from 698 HCPs were 3.3 ADR Reporting Experience analysed. Nurses had the least experience of ADR reporting, whereas 3.1 Demographics hospital pharmacists had the most (Fig. 1). There was no statistically signiﬁcant difference in the proportions of Respondents were grouped according to profession. hospital doctors, GPs, community and ‘other’ pharmacists Pharmacists were further categorised according to their practice setting. Those pharmacists who did not work in with no experience of ADR reporting (p = 0.247, Chi square test for independence). Those with longer profes- community and hospital pharmacies were classiﬁed as ‘other’ pharmacists. This group generally represented sional experience were more likely to have reported an ADR on one or more occasions. There was a signiﬁcantly pharmacists working in industry, academia or regulation, and as such this group were not considered to be prac- higher proportion of non-reporters in those who had \ 10 years’ experience compared with those who had tising HCPs. A total of 88 hospital doctors completed the questionnaire. The majority of hospital doctors were [ 10 years’ experience (59.9% vs 35.8%, p\0.001, Chi square test for independence). consultants (specialists) (67%, n = 59) and 33% (n = 29) were non-consultant hospital doctors. The hospital doctors came from a wide variety of specialities (see Table S1, 3.4 Knowledge of ADR Reporting ESM). Almost half (47%, n = 42) worked in specialities where biological medicines are commonly used. Only one Overall responses to the ADR knowledge items are pro- vided in Table 2 and the sub-group analyses are presented hospital doctor did not prescribe medicines to their patients. Nurses also came from a variety of backgrounds in Table S4 (see ESM). The average knowledge level across all eight items was 5.66 correct items out of 8 (SD (see Table S2, ESM). Nurses had the most experience, with over 74% of nurses surveyed having 20 or more 1.60). Responses to some of the individual knowledge items varied across HCPs (Table S4, see ESM) and this is years’ professional experience. The ‘other’ pharmacists indicated by differences in mean knowledge score between were the least experienced, with 44% of this group having groups (p\0.001, one-way ANOVA) (Table 3). \ 10 years of experience. Respondents were also asked if Mean knowledge scores were also associated with pre- biological medicines were prescribed, dispensed or administered in their practice. Group demographics are vious experience of ADR reporting (p\0.001, one-way ANOVA). Tukey post-hoc analysis (a = 0.05) found that summarised in Table 1. The majority of respondents knew that ADRs could be those who had reported an ADR more than three times in the past had signiﬁcantly higher knowledge scores (6.46, reported directly to the HPRA. Analysis by profession found that 60.6% (n = 63) of nurses, 82.2% (n = 162) of SD 1.24) than those who had never reported an ADR (5.31, SD 1.68), those who had reported an ADR once (5.47, SD GPs, 86.4% (n = 76) of hospital doctors, 93.5% (n = 158) of community pharmacists, 96.2% (n = 51) of ‘other’ 1.59) and those who had reported an ADR on two or three occasions (5.85, SD 1.47). There was no association pharmacists and 98.9% (n = 86) of hospital pharmacists Knowledge of ADR Reporting and Pharmacovigilance of Biologicals Among HCPs in Ireland 271 Table 1 Healthcare professional demographics Profession Hospital General Nurse Community Hospital ‘Other’ Total a c doctor practitioner pharmacist pharmacist pharmacist Group size (n) 88 197 104 169 87 53 698 Biological medicines used in practice, % (n) Yes 78.4 (69) 74.2 (144) 52.9 (54) 88.7 (149) 83.9 (73) 29.4 (15) 73.0 (504) No 18.2 (16) 19.1 (37) 21.6 (22) 9.5 (16) 13.8 (12) 49.0 (25) 18.6 (128) Don’t know 3.4 (3) 6.7 (13) 25.5 (26) 1.8 (3) 2.3 (2) 21.6 (11) 8.4 (58) Years in practice, % (n) \ 5 10.2 (9) 17.3 (34) 3.8 (4) 13.6 (23) 4.6 (4) 20.8 (11) 12.2 (85) 5–9 13.6 (12) 15.7 (31) 1.9 (2) 21.3 (36) 21.8 (19) 22.6 (12) 16.0 (112) 10–19 31.8 (28) 23.4 (46) 20.2 (21) 31.4 (53) 40.2 (35) 26.4 (14) 28.2 (197) 20–29 21.6 (19) 22.8 (45) 39.4 (41) 18.9 (32) 24.1 (21) 20.8 (11) 24.2 (169) [ 30 22.7 (20) 20.8 (41) 34.6 (36) 14.8 (25) 9.2 (8) 9.4 (5) 19.3 (135) ESM electronic supplementary material Hospital doctors practised in a wide variety of specialities—see Table S1 in the ESM Nurses came from a wide variety of specialities—see Table S2 in the ESM ‘Other pharmacists’ were not considered to be practising healthcare professionals. This group worked in industry (n = 22), academia (n = 12), administration (n = 1), defence forces (n = 1), Health Service Executive (n = 5), medicines information (n = 2), primary care (n = 1), regulatory (n = 7), representative organisation (n = 1) and retired (n = 1) Nurse* (n=104) 76% 7% 12% 6% Community pharmacist (n=169) 45% 21% 20% 14% Hospital doctor (n=88) 43% 15% 16% 26% 'Other' pharmacist (n=53) 42% 19% 23% 17% General Praconer (n=197) 35% 29% 18% 18% Hospital pharmacist+‡ (n=86) 15% 19% 23% 43% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% No (0 mes) Yes (1 me) Yes (2 or more mes) Yes (> 3 mes) Fig. 1 Differences in adverse drug reaction reporting experience the hospital pharmacist group was lower than non-reporting propor- among healthcare professionals. Survey question: ‘‘Have you ever tions in each of the other groups (p B 0.001 in all cases). Double reported an adverse reaction?’’ Reporting rates compared using Chi dagger: a higher proportion of hospital pharmacists had reported an square test for independence. A Bonferroni correction was applied. ADR on more than three occasions when compared with general Asterisk: the proportion of non-reporters in the nurse group was practitioners (p\0.001), nurses (p\0.001), community pharmacists higher than non-reporting proportions in each of the other groups (p\0.001) and ‘other’ pharmacists (p = 0.003) (p\0.001 in all cases). Plus sign: the proportion of non-reporters in 3.5 Familiarity with the Terms Biological Medicine between ADR knowledge scores and duration of profes- sional experience (p = 0.870, one-way ANOVA). and Biosimilar Medicine The majority of respondents agreed that they have adequate knowledge to report ADRs, however some dif- Survey respondents were asked how familiar they were with the term (i) biological medicine and (ii) biosimilar ferences between groups were observed (Fig. 2). medicine. Differences in familiarity rates across groups were observed (Table 4). 272 J. O’Callaghan et al. Table 2 Adverse drug reaction reporting: responses to individual knowledge items Question n % % % don’t correct incorrect know All serious ADRs are known before a medicine is marketed (no) 696 86.4 8.0 5.6 HCPs should report serious ADRs even if uncertain that the medicine caused the event (yes) 698 89.0 2.4 8.6 You have adequate knowledge on how to report ADRs (yes) 697 60.0 30.8 9.2 One case reported by an HCP does not contribute much to knowledge on medicine risks (no) 696 82.5 8.0 9.5 HCPs should report serious ADRs even if they do not have all the details of the event (e.g. complete 696 78.2 10.3 11.5 patient history, demographic data) (yes) HCPs should report ADRs associated with overdose, misuse or error (yes) 695 60.7 15.0 24.3 Patients can report ADRs independent of a HCP (yes) 697 63.0 6.0 31.0 HPRA will not disclose an ADR reporter’s identity in response to a request from the public (yes) 696 45.7 7.5 46.8 ADR adverse drug reaction, HCP healthcare professional, HPRA Health Products Regulatory Authority Correct answer is shown in brackets Table 3 Mean knowledge Profession n Mean knowledge score out of 8 Standard deviation scores relating to adverse drug reaction reporting and the Adverse drug reaction reporting pharmacovigilance of biological Hospital doctor 88 5.45 1.58 medicines among healthcare General practitioner 193 5.12 1.57 professional groups Nurse 100 5.49 1.54 Community pharmacist 166 5.69 1.53 Hospital pharmacist 87 6.30 1.37 ‘Other’ pharmacist 52 7.17 1.13 Total 686 5.66 1.60 Pharmacovigilance of biological medicines Hospital doctor 85 6.25 1.41 General practitioner 192 5.50 1.84 Nurse 99 4.41 1.67 Community pharmacist 167 5.97 1.68 Hospital pharmacist 85 6.94 1.15 ‘Other’ pharmacist 53 7.08 1.1 Total 681 5.85 1.78 Data is compared using 1-way ANOVA with post-hoc analysis using Tukey test (a = 0.05) ADR adverse drug reaction Knowledge scores were calculated from responses to eight knowledge items on (i) ADR reporting and (ii) pharmacovigilance of biological medicines. A correct answer was given a score of 1. An incorrect answer or a ‘don’t know’ response was given a score of 0 General practitioners had lower mean knowledge scores relating to ADR reporting than community pharmacists Hospital pharmacists had higher mean knowledge scores relating to ADR reporting than hospital doctors, general practitioners, nurses and community pharmacists ‘Other’ pharmacists had higher mean knowledge scores relating to ADR reporting than all other healthcare professional groups General practitioners had lower mean knowledge scores relating to the pharmacovigilance of biologicals than hospital doctors, hospital pharmacists and ‘other’ pharmacists Nurses had lower mean knowledge scores relating to the pharmacovigilance of biologicals than other healthcare professional groups Hospital pharmacists had higher mean knowledge scores relating to the pharmacovigilance of biologicals than community pharmacists and hospital doctors ‘Other’ pharmacists had higher mean knowledge scores than community pharmacists and hospital doctors Knowledge of ADR Reporting and Pharmacovigilance of Biologicals Among HCPs in Ireland 273 Fig. 2 Healthcare professional 100% 89% 89% self-perception of their own 90% knowledge of adverse drug reaction (ADR) reporting. 80% Survey question: ‘‘You have 63% 70% adequate knowledge on how to report ADRs?’’ Reporting rates 60% 49% 49% compared using Chi square test. 47% 44% 50% 41% 41% A Bonferroni correction was 40% applied. *Higher proportions of both hospital pharmacists and 24% 30% other pharmacists agreed with 20% 13% 12% this statement than hospital 11% 8% 8% 7% doctors, general practitioners, 5% 4% 10% nurses and community 0% pharmacists (p B 0.001) Hospital General Nurse Community Hospital Other doctor praconer (n=103) pharmacist pharmacist* pharmacist* (n=88) (n=197) (n=169) (n=87) (n=53) Yes No Don't know Interestingly, 16 respondents (2.3%) indicated that they (Table S6, see ESM). Respondents were asked if, in their were familiar with the term biosimilar medicine but not practice, batch numbers of biological medicines that were with the term biological medicine. administered/dispensed to patients were generally recor- ded. Practice behaviours were observed to differ between 3.6 Knowledge of Pharmacovigilance professions (Fig. 3), although large proportions of hospital Considerations for Biological Medicines doctors (39%) and nurses (24%) were unable to answer this question. Respondents who indicated that their batch Overall responses to knowledge items relating to the number recording practices varied by medicine were asked pharmacovigilance of biologicals are presented in Table 5 to give speciﬁc examples. A variety of responses were and the sub-group analysis is presented in Table S5 (see given; examples included batch number recording for ESM). The average knowledge scores across all eight items speciﬁc monoclonal antibodies, vaccines, blood-derived was 5.85 correct items out of 8 (SD 1.78). Responses to medicines, or medicines that were aseptically compounded some of the individual knowledge items (Table S5, see by the pharmacy. ESM) varied across HCP groups and this is indicated by ADR reports for biological medicines containing ﬁl- differences in mean knowledge scores between groups grastims, epoetins and inﬂiximab were extracted from the (p\0.001, one-way ANOVA) (Table 3). HPRA database and analysed for inclusion of brand name In order to conﬁrm questionnaire robustness, mean and batch number details (Fig. 4). High levels of brand knowledge scores of those familiar and those not familiar name reporting were observed with lower levels of batch with the term ‘biological medicine’ were compared. Mean number reporting, which varied across product types. As knowledge scores were signiﬁcantly higher among those some reports arose from literature/clinical trial settings, claiming to be familiar with the term ‘biological medicine’ follow-up to identify brand name or batch number would (6.08, SD 1.70) compared with those who were not familiar not have been feasible. with the term (4.88, SD 1.78) (p\0.001, independent HCPs who used biological medicines in their practice t test). were asked to rate the value of brand name and batch number recording on two different scales. The mean score for batch number recording on a 7-point scale anchored by 3.7 Traceability of Biologicals ‘worthless (1) to valuable (7)’ was 5.47 (SD 1.65), sug- The majority of respondents (73%, n = 504) answered that gesting that HCPs perceive batch number recording as biological medicines were prescribed/dispensed or admin- valuable. However, on a 7-point scale anchored by ‘easy istered in their practice (Table 1). HCPs who used bio- (1) to difﬁcult (7)’, HCPs perceived batch number logicals were asked questions pertaining to their recording (4.61, SD 2.04) to be more difﬁcult than brand traceability. The majority conﬁrmed that they generally name recording (3.60, SD 2.25) (Table S7, see ESM). recorded details of biological medicines by brand name 274 J. O’Callaghan et al. Table 4 Familiarity with the terms ‘biological medicine’ and pharmacists had higher awareness of the black triangle than ‘biosimilar medicine’ among healthcare professional groups hospital doctors, GPs and nurses (Table 6). a b Those who knew about additional monitoring were Profession n Familiar Not familiar asked if they were aware when this applied to medicines Familiarity with the term biological medicine used in their practice. Of this number, 39.7% (n = 225) Hospital doctor 88 90.9 9.1 were frequently or always aware, 36.4% (n = 207) were General practitioner 197 80.2 19.8 sometimes aware and 23.7% (n = 134) were never or Nurse 103 45.6 54.4 rarely aware. Community pharmacist 169 87.0 13.0 Among HCPs who worked directly with patients Hospital pharmacist 87 95.4 4.6 (n = 506), over half (57.9%, n = 293) indicated that they Other pharmacist 53 100 0 never or rarely informed patients when their medicines Total 697 81.4 18.5 were subject to additional monitoring. The subgroup Familiarity with the term biosimilar medicine analysis is provided in Table S8 (see ESM). Hospital doctor 88 69.3 30.7 General practitioner 197 47.2 52.8 Nurse 104 26.9 73.1 4 Discussion Community pharmacist 169 79.9 20.1 Hospital pharmacist 87 95.4 4.6 There are no recent studies assessing knowledge of ADR Other pharmacist 53 98.1 1.9 reporting among HCPs in Ireland. More generally, it is not known whether HCPs in Europe are aware of ‘additional Total 698 64.8 35.2 monitoring’. Although issues associated with the pharma- Awareness rates compared using Chi square test for independence. covigilance of biological medicines are well documented, A Bonferroni correction was applied again it is not known to what degree HCPs are cognisant of HCP healthcare professional these issues. A cross-sectional survey of HCPs in Ireland HCPs responded that they were ‘very familiar – complete under- standing’ or ‘familiar – basic understanding’ was conducted in order to address these knowledge gaps. The majority of HCPs were aware that ADRs could be HCPs responded that they had ‘heard of the term – can’t deﬁne it’ or ‘never heard of the term’ reported directly to the Regulatory Authority in Ireland. General practitioners were less familiar with the term ‘biological However, nurses were less aware than other groups, sup- medicine’ than hospital pharmacists and ‘other pharmacists’ porting recent conclusions by de Angelis et al.  that (p = 0.002 and p\0.001, respectively) nurses are not fully aware of their role in ADR reporting. Nurses were less familiar with the term ‘biological medicine’ than all Nurses are responsible for drug administration and record other HCP groups (p\0.001 in all cases) e keeping, and of all the HCP groups surveyed, nurses may General practitioners were less familiar with the term ‘biosimilar often have the most contact with patients, making them medicine’ than hospital doctors and community pharmacists (p = 0.001 and p\0.001, respectively) more likely to be present when an ADR occurs or is Nurses were less familiar with the term ‘biosimilar medicine’ than all identiﬁed . ADR reports from nurses have been shown other HCP groups (p B 0.001 in all cases) to be valuable and of acceptable quality [31, 32], thus Hospital pharmacists were more familiar with the term ‘biosimilar corroborating the important contribution nurses can make medicine’ than hospital doctors, general practitioners and community to pharmacovigilance and highlighting the need to increase pharmacists (p\0.001, p\0.001 and p = 0.002, respectively) awareness about ADR reporting among nurses. On the ‘Other’ pharmacists were more familiar with the term ‘biosimilar other hand, hospital pharmacists had the most experience medicine’ than hospital doctors, general practitioners and community pharmacists (p\0.001, p\0.001 and p = 0.003, respectively) of ADR reporting, echoing ﬁndings from a US study that found that pharmacists in general were more likely to have reported an ADR in the past than hospital doctors . Our results suggest that pharmacy practice setting is an 3.8 Additional Monitoring important determinant of ADR reporting experience. Hospital pharmacists had signiﬁcantly more experience The majority of HCPs were aware of the concept of with ADR reporting than community pharmacists, and the additional monitoring, however awareness rates differed proportion of non-reporters among community pharmacists between some groups (Table 6). A total of 568 HCPs was in fact similar to the proportion of non-reporters claimed to know about additional monitoring, but among among hospital doctors and GPs. The important contribu- this number there were differences in awareness of the tion made by hospital pharmacists to ADR reporting is also inverted black triangle across HCP groups. In particular, conﬁrmed when ADR reports made directly to the HPRA by HCPs are considered. Over a 5-year period, the number Knowledge of ADR Reporting and Pharmacovigilance of Biologicals Among HCPs in Ireland 275 Table 5 Pharmacovigilance considerations for biological medicines: response to individual knowledge items Question n % % % don’t correct incorrect know ADRs associated with a patient changing between different brands of biological medicines should be 694 92.1 1.0 6.9 reported (yes) In an ADR report it is better to identify a biological medicine by its non-proprietary name (e.g. insulin 695 59.9 27.3 12.8 glargine) instead of its brand name (no) Biosimilars are the same as generic medicines (no) 693 75.2 10.7 14.1 Rare ADRs resulting from changes to the manufacturing process of a biological medicine can always be 696 82.9 1.3 15.8 predicted (no) Keeping a biological medicine outside its recommended storage conditions may introduce or alter 694 80.1 1.0 18.9 immunogenicity (yes) Different batches of the same biological medicine are always identical (no) 695 71.4 7.9 20.7 It is more important to include batch numbers in ADR reports for non-biological medicines than it is for 693 61.3 17.7 20.9 biological medicines (no) In general, biological medicines pose a greater risk of immunogenicity than non-biological (chemical) 693 61.9 7.6 30.4 medicines (yes) ADR adverse drug reaction Correct answer is shown in brackets Fig. 3 Batch number recording Hospital doctors (n=69) 28% 26% 7% 39% of biological medicines. Survey question: ‘‘In your practice are the batch numbers of biological General praconers (n=144) 50% 32% 9% 9% medicines that have been administered/dispensed to Nurses (n=54) 26% 39% 11% 24% patients generally recorded?’’ Community pharmacists (n=149) 5% 88% 3%4% Hospital pharmacists (n=73) 45% 19% 32% 4% Other pharmacists (n=15) 80% 20% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Yes No Speciﬁc meds Don't know of reports received by the HPRA directly from community Previous research suggests that knowledge of ADR pharmacists, GPs, nurses, hospital doctors and hospital reporting among HCPs could be improved [19–21, 23, 35]. pharmacists was approximately even (Table S3, see ESM). Knowledge was measured using eight items (Table 2) and This suggests that hospital pharmacists made a very sig- correct answers for four of the knowledge items were high niﬁcant contribution to ADR reporting, as according to ([ 78%). Importantly, most HCPs know that individual 2017 ﬁgures, the number of hospital pharmacists working ADR reports are capable of contributing to knowledge on in Ireland (651 ) was much lower than the numbers of medicine risks. This is reassuring, considering that indi- practising community pharmacists [3612 (see footnote 1)], vidual ADR reports can lead to re-evaluation of beneﬁt– GPs (approx 2500) , hospital doctors (9160 in public risk balances for medicines . Interestingly, almost one health service) and nurses (approx 36,000 in public health in three HCPs (31.0%) did not know that patients can service) . report ADRs independent of a HCP. Although research on the impact of patient ADR reporting is limited , reports from patients do offer a different perspective from HCP reports, are more detailed [37–40] and contribute to safety Personal communication with the Pharmaceutical Society of signals . The ‘other’ pharmacist group had the highest Ireland. 276 J. O’Callaghan et al. Fig. 4 Percentage of reports 100% 97% 100% submitted to the Health Products Regulatory Authority 90% 82% that contained brand name and 80% batch number details for biological medicines containing 70% ﬁlgrastim, epoetin and 57% 60% inﬂiximab over a 5-year period 50% (2013–2017) 50% 40% 30% 17% 20% 10% 0% Filgrasm (n=169) Epoen (n=109) Inﬂiximab (n=175) % Reports containing brand name % Reports containing batch number mean knowledge scores on ADR reporting (Table 3), immunogenicity may rely heavily on ADR reports from reﬂecting the fact that many of this group worked in the observant HCPs . Almost one in ﬁve (18.9%, n = 131) pharmaceutical industry (41.5%) and medicines regulation did not know that keeping a biological outside its recom- (13.2%). Among practising HCPs, hospital pharmacists had mended storage conditions could introduce or alter the highest mean knowledge scores, which is also reﬂected immunogenicity, suggesting that the importance of storage in the fact that they have the most experience with ADR and handling requirements for biologicals need to be better reporting. Indeed, hospital pharmacists and ‘other’ phar- communicated. Interestingly, statements relating to trace- macists were more conﬁdent in their own knowledge of ability of biologicals had the lowest proportions of correct ADR reporting than other HCP groups (Fig. 2). answers. Knowledge gaps relating to the inclusion of brand More hospital doctors, nurses and GPs were familiar names and batch numbers in biological ADR reports were with the term ‘biological medicine’ than with the term identiﬁed. Knowledge of biological pharmacovigilance ‘biosimilar medicine’ (Table 4). This could reﬂect the fact was also observed to differ among HCP groups, with that Ireland has low uptake of biosimilar medicines com- hospital pharmacists and hospital doctors having higher pared with other European countries [13, 42, 43]. Famil- mean knowledge scores than GPs and nurses (Table 3). iarity with the term biosimilar differed among HCP groups The EMA advise that the brand name and batch numbers (Table 4). For instance, fewer community pharmacists of biologicals are recorded at all levels in the medicines (79.9%) were familiar with the term ‘biosimilar medicine’ supply chain, including prescription, dispensing and patient than hospital pharmacists (95.4%), corroborating ﬁndings administration . HCPs indicated that they generally from a 2015 survey carried out in France, where a higher recorded biologicals by brand name (Table S6, see ESM), proportion of community pharmacists responded that they reﬂecting the fact that electronic information recording were not at all informed about biosimilars compared with systems in Ireland generally default to brand name hospital pharmacists . A survey of HCPs conducted in recording. Traceability to batch level was lower and Ireland the year before this current study (2016) found recording practices differed between some professions similar proportions of GPs and community pharmacists (Fig. 3). These recording practices are reﬂected in ADR claimed they were familiar with the term biosimilar. reports submitted directly to the HPRA. Analysis of reports However, there were higher familiarity rates among hos- for certain biological medicines indicated high levels of pital doctors in the earlier survey, which may be attributed brand name inclusion in ADR reports with lower levels of to the fact that this survey was conducted among doctors batch number reporting (Fig. 4). However, the levels of who worked in specialities where biological medicines are batch number traceability in ADR reports were higher than commonly used . levels seen in other European spontaneous ADR databases Knowledge of the pharmacovigilance of biological [17, 45, 46]. This may reﬂect efforts made by the HPRA to medicines was measured using eight items (Table 5). A (i) actively inform HCPs about ADR reporting require- sizeable proportion of HCPs (30.4%, n = 211) did not ments and (ii) follow-up with reporters for missing infor- know that biological medicines pose a greater risk of mation. Nevertheless, the results indicate that information immunogenicity than non-biological medicines. This is recording systems in Ireland may not fully support batch concerning, considering that rare events related to traceability of biologicals. In Irish hospitals, clinical Knowledge of ADR Reporting and Pharmacovigilance of Biologicals Among HCPs in Ireland 277 Table 6 Awareness of additional monitoring among healthcare number in an ADR report depends on availability of the professionals original packaging, whether exposure information is rou- tinely recorded in medical, nursing or pharmacy records, Profession n Percentage aware and whether the reporter has access to such records . Proportion aware of additional monitoring Willingness to report this information could also be an Hospital doctor 88 84.1 inﬂuencing factor. HCPs were asked to rate brand and General practitioner 197 67.0 batch number recording on scales anchored by worthless Nurse 104 71.2 (1) to valuable (7) and easy (1) to difﬁcult (7). The results Community pharmacist 168 91.7 show that HCPs perceive batch number recording as Hospital pharmacist 87 96.6 valuable but also that recording batch numbers is difﬁcult. Other pharmacist 53 94.3 Steps aimed at improving batch number traceability of Total 697 81.5 biologicals in Ireland and elsewhere are needed. Trace- Proportion aware of black triangle ability needs to be fully integrated into healthcare settings. Hospital doctor 74 35.1 For instance, future information recording systems, General practitioner 132 35.6 including the roll-out of seamless electronic patient health Nurse 74 14.9 records, could be designed to allow automatic recording of Community pharmacist 154 86.4 brand and batch details upon dispensing and administra- Hospital pharmacist 84 88.1 tion. Record linkage would also ensure that ADR reporters Other pharmacist 50 94.0 have access to the necessary information. The majority of respondents were aware of additional Total 568 59.5 monitoring (Table 6). However, awareness of the black Awareness rates compared using Chi square test for independence. triangle symbol . that appears on the SmPC and the PL A Bonferroni correction was applied was much higher among the three pharmacist groups than Survey question: ‘‘Prior to this survey were you aware that some medicines are subject to additional monitoring’’ (Brief explanation of among other HCPs. This suggests that the black triangle is additional monitoring provided) an effective way of communicating the additional moni- General practitioners had lower awareness rates of additional mon- toring status of a medicine to pharmacists. However, itoring than community, hospital and ‘other’ pharmacist groups improved communication on the meaning of the black (p\0.001 in all cases) triangle is needed for hospital doctors, nurses and GPs. Nurses had lower awareness rates of additional monitoring than Over half of HCPs (57.9%, n = 293) who worked directly community, hospital and ‘other’ pharmacist groups (p\0.001, p\0.001 and p = 0.002, respectively) with patients and who knew about additional monitoring Survey question: ‘‘Prior to this survey did you know that when a never or rarely informed patients when their medicines medicine is subject to additional monitoring an inverted black triangle were subject to additional monitoring (Table S8, see ESM). symbol . appears beside the name of the medicine in the summary of HCPs are considered an effective medium to inform product characteristics and package leaﬂet?’’ (this question was only patients about additional monitoring  and are in a asked to those who previously responded that they were aware of position to encourage ADR reporting from patients additional monitoring) [40, 48]. Improving HCP awareness of the value of ADR Nurses had lower awareness rates of the black triangle than general practitioners (p\0.001) reporting by patients and encouragement of HCPs to Community pharmacists had higher awareness rates of the black inform their patients about medicines subject to additional triangle than hospital doctors, general practitioners and nurses monitoring may be a mechanism by which additional (p\0.001 in all cases) safety information can be gathered. Hospital pharmacists had higher awareness rates of the black triangle This study revealed some differences in knowledge and than hospital doctors, general practitioners and nurses (p\0.001 in experience of ADR reporting among a diverse group of all cases) HCPs. It is important that all HCPs involved in the care of ‘Other’ pharmacists had higher awareness rates of the black triangle than hospital doctors, general practitioners and nurses (p\0.001 in patients receiving medicines are appropriately informed all cases) and empowered to contribute to the ongoing safety moni- toring of medicines. Different strategies have been applied records are almost exclusively paper based, so manual in order to address underreporting and to improve knowl- recording of batch number is necessary. In pharmacies, edge of and attitudes to pharmacovigilance [49, 50]. Sus- there is no prompt for dispensing pharmacists to manually tained education and training  will enable HCPs to record batch number details. keep abreast of changes such as the introduction of addi- The person responsible for ADR reporting is likely to tional monitoring of medicines. For example, speciﬁc vary according to the practice setting and ADR reporting education  and practical training (e.g. ADR reporting processes in place. Inclusion of the brand name and batch assignments)  for nurses is likely to encourage ADR 278 J. O’Callaghan et al. reporting from this cohort. Further to improving ADR of additional monitoring is high, poor knowledge of the reporting, the increasing availability of biological medici- inverted black triangle among hospital doctors, GPs and nes, including biosimilars, make it necessary for HCPs to nurses suggest that alternative methods to alert these implement appropriate practice behaviours in order to groups of the additional monitoring status of a medicine ensure their traceability. As such, education on biological may be warranted. One in three HCPs were unaware that medicines needs to be incorporated at undergraduate level patients could report ADRs. Improved HCP awareness of and beyond. The use of sustained awareness campaigns on the contribution patients make to ADR reporting may help importance of ADR reporting including traceability issues generate additional safety data, especially for medicines for biological medicines, along with further research into subject to additional monitoring. There appears to be a appropriate educational interventions is warranted. knowledge gap relating to immunogenicity, storage and the Low response rates were the main limitation of this traceability of biological medicines for the purpose of ADR survey. However, in the case of GPs, the response rate was reporting. HCPs in Ireland perceive that recording batch not unexpected as we received similar response rates using numbers for biological medicines is valuable, but they also the same method of dissemination in a survey conducted the perceive that the recording of batch numbers is more dif- year previously . Response rates for nurses could not be ﬁcult than the recording of brand names. Further research calculated owing to the method of survey distribution. and measures to improve batch traceability of biologicals Although non-response biases must be considered in the in healthcare settings are needed. interpretation of the results, this is a large multidisciplinary Acknowledgements The following groups are thanked for providing study from which the results may be generalisable to other advice and access to their network: Irish College of General Practi- European countries where the same regulations and similar tioners, Royal College of Physicians in Ireland, Pharmaceutical HCP education standards apply. There were baseline dif- Society of Ireland and the Ofﬁce of Nursing and Midwifery Services, ferences among the practising HCPs in terms of reported Health Service Executive. The authors wish to thank the following for advice with this study: Colleagues in Human Products Monitoring— experience with biologicals. The majority of hospital doc- Health Products Regulatory Authority (HPRA), Una Moore (HPRA), tors, GPs, community and hospital pharmacists responded Sean Barry (HPRA), Maeve Lally (HPRA), Jeanette Mc Callion that they used biological medicines in their practice. (HPRA), Anna Cunney (HPRA), Olive Smyth (HPRA), Rebecca However, this proportion was lower for nurses as just over Cramp (IPHA), Colm Galligan (MSD), Syzana Hasani (AbbVie), Sean Leavey, Sinead Kelly, Lisa Fagan and Claire Collins. half answered that biological medicines were used and one in four indicated that they did not know. Respondent loca- Compliance with Ethical Standards tion and educational institution may have impacted responses received and this was not explored in the current Funding This work was supported by the Health Products Regula- tory Authority (HPRA), Regulatory Science Ireland and University study. Questions pertaining to knowledge of the HPRA College Cork. Brendan T. Grifﬁn is also supported in part by the Irish (Q12, see ESM) and awareness of additional monitoring Pharmaceutical Healthcare Association (IPHA) in the form of a (Q15 and Q16, see ESM) were phrased ‘‘Prior to this survey research grant to support regulatory science research. Open access did you know…’’. This may have introduced some bias as it publication of this article was funded by the Irish Pharmaceutical Healthcare Association (IPHA) in the form of a research grant to depended on the HCP reﬂection on their own prior knowl- support regulatory science research. edge. Finally, an analysis of the HPRA ADR database was conducted in order to determine traceability details in Conﬂict of interest Joan O’Callaghan, Brendan T. Grifﬁn, J. reports for speciﬁc biological medicines, this may not be Michael Morris and Margaret Bermingham declare that they have no conﬂict of interest. representative of overall traceability of biologicals in ADR reports received by the HPRA. 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