Factors associated with underreporting of adverse drug reactions by patients: a systematic review

Background Spontaneous reporting is the most used method to monitor post-marketing safety information. Although patient involvement in spontaneous reporting has increased overtime, little is known about factors associated with patients’ adverse drug reaction (ADR) reporting. Aim To identify and assess the sociodemographic characteristics, attitudes and knowledge that influence spontaneous reporting and the reasons associated with ADR underreporting by patients. Method A systematic review was conducted according to PRISMA guidelines. A search on the MEDLINE and EMBASE scientific databases was performed to retrieve studies published between 1 January 2006 and 1 November 2022. Studies were included if they addressed knowledge and attitudes associated with ADR underreporting. Results A total of 2512 citations were identified, of which 13 studies were included. Sociodemographic characteristics were frequently identified with ADR reporting in 6 studies, being age (3/13) and level of education (3/13) the most often reported. Older age groups (2/13) and individuals with higher level of education (3/13) were more likely to report ADRs. Underreporting was shown to be motivated by reasons related to knowledge, attitudes, and excuses. Ignorance (10/13), complacency (6/13), and lethargy (6/13) were the most frequent reasons for not reporting. Conclusion This study highlighted the scarcity of research conducted with the aim of assessing ADR underreporting by patients. Knowledge, attitudes, and excuses were commonly observed in the decision to report ADRs. These motives are characteristics that can be changed; hence strategies must be designed to raise awareness, continually educate, and empower this population to change the paradigm of underreporting. Supplementary Information The online version contains supplementary material available at 10.1007/s11096-023-01592-y.

Although in the early years of pharmacovigilance, reporting ADRs was restricted to healthcare professionals (HCPs), HCPs and patients can now report suspected ADRs to spontaneous reporting systems [12,13].In 2012, there was a major change at the European Commission level, with the publication of pharmacovigilance legislation: Directive 2010/84/EU and Regulation No 1235/2010 [14].One of the major changes comprised the empowerment and emphasis given to citizens as an additional source of information, enabling them to directly report suspected ADRs [15][16][17].
It is acknowledged that the type of information reported by patients and HCPs is different [18].Patients' reports provide new information, including more subjective and detailed symptom descriptions of how ADRs impact daily life.HCPs report more objective and clinically related information [19].The information provided by both populations demonstrates a positive contribution to obtain a more complete and full knowledge of reported ADRs [15,[20][21][22].
ADRs are significantly underreported worldwide, with estimates that more than 94% are not reported by HCPs [23].Underreporting can delay the detection of safety signals, making it difficult to evaluate and quantify risk factors, and consequently, compromising the full knowledge of the drug safety profile [11,23,24].Furthermore, although direct patient reporting has been increasing over time, the overall contribution is still very low, representing only 9% of the total reports in 2014 [19,[25][26][27][28].
Little is known about factors associated with ADR reporting by patients; however, studies have been emerging in recent years.Identifying the main barriers is crucial to understand gaps and to design specific strategies that can positively impact the quantity and quality of ADR reports and ultimately increase the safety of medicines.One systematic review was performed in 2006 regarding patient reporting of suspected ADRs, however none of the included studies concerned spontaneous reporting [29].More recently, a systematic review assessed the motives and/ or barriers that influence patient reporting of ADRs [30].Our review assessed the factors associated with underreporting of ADR, including sociodemographic characteristics, reasons, and attitudes (modelled using Inman's seven deadly sins [31][32][33]), as well methodological quality, thereby adding more information to the body of evidence.Together with previous reviews, this covers the entire period of direct patient reporting worldwide.

Aim
The purpose of this systematic review was to identify and assess the sociodemographic characteristics, attitudes and knowledge that influence spontaneous reporting, and the reasons associated with underreporting of ADRs by patients.

Method
This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [34] and a research protocol was registered in PROSPERO network database (CRD42021227944).

Eligibility criteria
Studies were considered eligible for inclusion if: (i) the target population were patients and/or consumers; (ii) written in English, French, Portuguese, or Spanish; (iii) aimed to assess factors (personal characteristics as well as the reasons) associated with ADR underreporting; (iv) addressed ADR reporting through spontaneous reporting.The studies included could be either observational or interventional as they comprised original data.However, in interventional studies only baseline data were collected.
Conference abstracts/proceedings, reviews, editorials, letters to the editor, comments, theses/dissertations, systematic reviews and/or meta-analysis were excluded.Studies in which the target population were HCPs and/or students, focused on a specific pathology or treatment, and performed through intensive monitoring schemes or clinical trials were also excluded.For studies with no access, the authors were contacted.Finally, studies that identified attitudes and knowledge but did not directly associate underreporting reasons were excluded.
All articles retrieved were independently screened by 2 reviewers (CC and PA or CC and DR), who conducted full-text analysis to assess suitability for inclusion.For any divergent decisions, a third reviewer (CT, TH or AF) acted as referee to reach consensus.

Risk of bias and quality assessment
Critical assessment of the quality and risk of bias of the included studies were assessed using the Appraisal tool for Cross-Sectional Studies (AXIS) [35].This tool was created in 2016 to appraise reporting quality, study design quality and risk of bias.It consists of a 20-component questionnaire, in which 7 questions focus on assessing the quality of the reports, 7 on the study design, and the remaining 6 assess the possibility of bias in the study.Fifteen out of the twenty items cover the methods and results sections, which reveals the importance of these two sections for critical appraisal of this tool.Two reviewers (CC and PA or CC and DR) independently conducted the critical assessment for each study, and in case of disagreement, a third reviewer (CT, TH or AF) was responsible for resolving discrepancies.

Data extraction and synthesis
Data from the eligible studies were extracted based on Lopez-Gonzalez et al. [36].Reasons for ADR underreporting were based on a list of 7 attitudes described as the "seven deadly sins" (i.e., complacency, diffidence, ignorance, indifference, lethargy, greed: financial incentives, fear and guilty).This list was proposed in 1976 and further amended in 1986 and in 1996 [31][32][33].Additionally, to update and complement this list, other reasons influencing ADR underreporting were added according to those described in the literature.Therefore, 4 categories were created: (i) attitudes relating to professional activities (e.g., financial incentives, legal aspects); (ii) problems associated with ADR-related knowledge and attitudes (e.g., fear, complacency, diffidence, indifference, ignorance, insecurity); (iii) excuses made by the individual (e.g., lethargy); and (iv) others (e.g., lack of feedback, ADR resolved, poor reporting system).All these categories are described in the Electronic supplement material 2.
The extraction was performed by 2 authors (CC and PA or CC and DR) independently and included: author (year of publication), country, study design, setting, study population, response rate, sample size, data source, personal characteristics associated to reporting and reasons for not reporting ADRs.In case of inconsistencies, a third reviewer (CT, TH or AF) made the final decision.If further information was needed the corresponding authors were contacted.

Data analysis
The characteristics of the included studies were assessed through a descriptive analysis with each reason of underreporting reported numerically as a percentage (i.e.either extracted directly from the study (one specific question for each reason) or calculated using the mean/median when more than one question within the same study was associated to the same reason category mentioned above).

Characteristics of selected studies
The general characteristics of included studies are presented in Table 1 and the main study findings in Table 2.
The sample size ranged from 15 to 4981 subjects and the response rate from 6.0 to 100%, being above 50.0% in 8 of the studies.The study with the highest number of recruited subjects (n = 4981) had the lowest response rate (6.0%) [48].

Quality assessment
Six studies [37,39,[41][42][43][44] met ≥ 17 AXIS criteria, and therefore were considered of high methodological quality and low susceptibility to bias.Five studies [38,40,[45][46][47] were evaluated as having a moderate level of methodological quality and risk of bias, and the remaining of low methodologically quality and high susceptibility to bias.In general, the criteria least met were sample size justification, selection process and measures to address non-responders.None of the studies included any description of non-responders (Electronic supplement material 3).

Sociodemographic characteristics
The two most prevalent factors associated with the act of reporting were the level of education (n = 3) and age (n = 3).Age did not reach consensus since 1 study [42] revealed that the younger population was more likely to report ADRs than older age groups, whereas 2 studies [44,50] showed the opposite.In all studies, individuals with higher levels of education were more likely to report ADRs.The remainder reported factors were sex [41,45], region [44], monthly income [41], social grade [49] and profession/ employment status [50].Specifically, it was found that males [41,45], subjects living in urban areas (vs rural areas) [44], with higher monthly income [41] and higher social grades [49] were associated with higher intention to report ADRs.Additionally, a significant association was found between private sector employees and self-employed subjects and the higher likelihood to report as compared to unemployed, student, government employee and retired people [50].

Reasons for underreporting ADRs
The reasons that influenced the reporting of ADRs by patients were restricted to four categories.Ignorance (n = 10; with values ranging between 10.8 and 72.6%) [37-42, 44-46, 49] about the identification/recognition of ADRs, the possibility and importance of reporting them, as well as not knowing the needed requirements to report.Complacency (n = 6; values ranging from 14.7 to 35.6%) [40,42,45,[47][48][49] mostly related with the conviction that only safe drugs are on the market and that serious ADRs are well documented by the time the drug is marketed.Lethargy (n = 6; values ranging from 3.7 to 17.1%) [37-48, 48, 49, 49-81], with patients referring that ADR reporting is timeconsuming, generates work and that they would do it if the process was easier.In this category, forgetfulness and procrastination were also mentioned, but at a lower frequency.Other reasons (n = 11) [37-41, 43-46, 48, 49] that made patients reluctant to report ADRs included: (i) responsibility for 'reporting lies' with HCPs, (ii) ADR resolved or already expected; (iii) stopped taking the medicine; (iv) absence or difficulty in communicating with the HCP (e.g.unsupportive physician, diminishing ADR importance, lack of guidance, feeling it has to be reported to a physician and not another HCP); (v) lack of feedback or action taken by the authorities regarding previously submitted reports; and (vi) being Table 2 Studies that assessed the sociodemographic characteristics and reasons associated with underreporting adverse drug reactions ✔-In studies where the reasons were stated but whose numerical measures were not mentioned, the symbol ✔ was used NR Not reported a Article with information on HCPs and patients, however only patient information was retrieved b Sociodemographic characteristics reported to be statistically significantly associated with ADR reporting c The total numerical percentage regarding each reason for underreporting ADRs within each study was either extracted directly from the study (one specific question for each reason) or calculated using the mean/median (i.e. when more than one question within the same study was associated to a certain reason) abroad.Two studies did not present descriptive statistics for their assessment [40,44].

Main findings
This review showed that sociodemographic characteristics were commonly observed with ADR reporting whereas knowledge, attitudes, and excuses were frequently identified with ADR underreporting by patients.This review also highlighted the scarcity of research conducted with the aim of assessing ADR underreporting by patients.Over the last 15 years, most of the studies were conducted in African countries, where the pharmacovigilance framework is weak and relatively new [51].The individual case safety reports retrieved by African countries represents only < 1% of the global reports [52] and to overcome this, patient reporting initiatives have been developed [53].Over the review period, only 3 studies were conducted in European countries, despite the permission to allow ADR reporting by patients since 2012.Australia was the first country to allow direct patient reporting (1964) [12,13] and had last evaluated this topic in 2013.Although Canada, USA and New Zealand shortly followed Australia [12], only Canada recently conducted one study to assess reasons for ADR underreporting.

Strengths and weaknesses
Our review has some limitations.Firstly, a search for studies in grey literature was not carried out.However, we believe that our results would not be affected since studies with this type of objective are usually associated with academic institutions where the incentive and ambition for publication is higher.We decided not to include conference abstracts/ proceedings and editorials as these materials often reflect preliminary analysis, and it is less likely that methods and results are described with the necessary detail for the purpose of our study.Moreover, the percentages associated with each barrier might be subject to bias as means/medians were calculated if two or more statements were grouped in the same category within the same study.Finally, we acknowledge that our systematic review is limited by the details that authors have reported.However, an assessment of quality was performed for all included studies.Despite these acknowledged limitations, we believe that our main findings are relevant, and the data collected are comprehensive to assess the factors associated with underreporting of ADRs, thereby adding information to the body of evidence.

Interpretation of study findings
Regarding sociodemographic characteristics, the age factor was not unanimous.One study showed that the younger population is more likely to report ADRs [42], as they are well informed and may be of their relatives who might be more susceptible to experience an ADR.Since this population is a consumer of technologies, they can have a great impact on both learning and information sharing [13,54].However, 2 studies [44,45] reported quite the opposite, as expected given that age is a well-known predisposing factor for the occurrence of ADRs [55].Concerning education levels, all 3 studies [45,47,49] revealed that individuals with higher levels of education were more likely to report ADRs, a finding which is in line with the literature [56,57].
Reasons related to ignorance were widely reported as obstacles to ADR reporting.These reasons may be associated with the fact that they have never heard about pharmacovigilance and may not recognize its importance.This ignorance may also be described as poor knowledge dissemination given that reporting systems might be more aligned with HCPs than patients [58].
Complacency was another reported reason as patients might believe that an ADR is not serious enough, or that it is not necessary to report.Complacency and ignorance could be highly related to the belief that marketed drugs are well-documented and safe.Lethargy justifies statements about forgetfulness, procrastination, lack of time or interest to report, and difficulty filling out the report.Simplifying reporting, promoting easier access, and boosting strategies that demonstrate that it is neither burdensome nor a bureaucratic process can overcome this barrier.
A previous systematic review identified additional reasons for not reporting such as postal mailing costs or the limitation of restricting reporting to telephone during working hours [30].However, these barriers probably no longer apply given the alternative methods of reporting ADRs (e.g.on-line platforms, mobile apps), which do not have associated costs or time limitations [13].Of note, countries with an online reporting system option were associated with higher patient reporting rates [28].
The lack of interventions for patients was highlighted in a systematic review [81] which comprised 28 studies conducted with the aim of assessing if interventions targeting HCPs and patients were effective in improving ADR reporting.Only 1 study targeted patients, highlighting the need to develop tailored interventions for this population.
Several altruistic and personal motives that encourage patients to report ADRs have been described, such as contributing to increase safety knowledge, the need to be heard and to prevent harm to other patients [45,47,57,66].Other motives reported were related to the severity of the ADR, asking for feedback, feeling uncomfortable sharing information with HCPs [36,59,60] or the fact that HCPs did not take the case seriously [43,44,47,57].
From the methodological point of view, only 6 studies of our systematic review were considered of high quality and low susceptibility to bias, which emphasizes the need for improvement when conducting future studies.Most of the included studies used a convenience sample and representativeness may be lacking, leading to potential selection bias.Most studies did not present a denominator and although some studies attempted to address non-responder rates, none was completely successful.

Future research
There is an urgent need to develop and conduct high quality, intervention based studies in this population to optimize ADR reporting and to provide evidence of effectiveness.Different communication, educational and promotional strategies targeted to patients should be designed and implemented to overcome the potentially modifiable barriers.Training and dissemination related to online platforms with clear, simple, and interactive content could be an efficient option to overcome these barriers.

Conclusion
This review highlighted the scarcity of studies conducted with the aim of assessing the influencing factors of underreporting ADRs by patients.
Sociodemographic characteristics appear to influence spontaneous reporting, with age and level of education being the most frequently reported.Patients' attitudes observed linked to underreporting included ignorance, complacency, lethargy.These can be improved through the implementation of awareness campaigns and theoretical/practical educational programs tailored to different knowledge levels.Increasing engagement and encouraging active participation of patients is needed to reverse the current paradigm of underreporting.

Fig. 1
Fig. 1 PRISMA 2020 flow diagram summarizing the study selection process

Table 1
Characteristics of the included studies that assessed factors associated with adverse drug reactions underreporting by patients a Article with information on HCPs and patients, however only patient information was retrieved b Study designs as reported by the authors c Quality of the studies was assessed using the Appraisal tool for Cross-Sectional Studies (AXIS)