Adverse drug reactions (ADRs) are a well-recognized public health problem worldwide and a major cause of death and hospitalization in developed countries [1]. Rare and long-term ADRs are difficult to detect during the drug development stage. Detecting new ADRs not previously identified during clinical trials is only possible when the drug begins to be used by a large population after marketing authorization (MA). The safety of a new drug cannot be established until it has been on the market for several years [2]. As such, it is indispensable to keep drug reactions under close surveillance after commercialization through a pharmacovigilance system to continuously evaluate the drug’s safety profile. In most countries, the pharmacovigilance system is based on spontaneous ADR reports made by healthcare professionals and consumers [3]. These reports can be made using paper, telephone, e-mail or through an on-line form and consist of a description of an adverse event apparently caused by a medicine. Spontaneous ADR reporting has been described as an efficient method to detect drug safety signs [4]; however, underreporting is a major issue that undermines the effectiveness of spontaneous reports. Several studies have suggested that less than 10 % of detected ADRs are effectively reported to medicine regulatory authorities [5, 6].

Worldwide, systems using informatics to promote ADR reporting or to detect the occurrence of ADRs in healthcare institutions have been tested and used, such as computer programs that allow voluntary and automated detection of ADR [7, 8] informatics tools created to analyse clinical databases [9] or websites that actively inform healthcare professionals [10].

In addition to signal detection, information and communication technologies can also be used to encourage and facilitate reporting of suspected ADR.

In the present work, a systematic review is presented on the use of information systems in pharmacovigilance. Our main goal is to describe the state of the art information systems for the passive or active promotion of adverse drug reaction reporting.

Our search method found 2519 articles in PubMed, 68 in IEEE, 2603 in ISI and 192 in Scopus. After eliminating duplicate articles, 3835 articles were selected.

Two reviewers (IV and AS) read all 3835 titles/abstracts. In cases of disagreement, which occurred with 151 articles, a consensus meeting was held with the third reviewer (RC) to decide whether the article should be selected.

A total of 643 studies were excluded because they were not related to pharmacovigilance, 85 were excluded because they were not related to information systems and 2993 were excluded for other reasons (mostly because their focus was on data mining in large databases instead of ADR reporting).

A total of 114 of the 3835 articles were selected in this first selection based on the title and abstract.

The team leader (IV) reviewed each of the 114 full-text articles. After this review, 33 articles remained for the final statistical analysis. At this stage, most of the articles were excluded because: (1) they were only related to medication errors; (2) they were focused on ADR detection; (3) they were studies without any information system implemented; (4) they were studies concerning data quality; (5) they were studies focused on website usability; (6) they were only authors’ reflections on the theme; (7) they were studies only related to incidents that occurred at health institutions; (8) they were studies concerning signal detection or (9) they were studies concerning electronic transmission between the authority and other institutions (pharmaceutical companies or regional pharmacovigilance centres).

These 33 articles were grouped into 29 distinct research projects to avoid the distortion created by multiple papers describing the same project (Fig. 1.). All statistical analyses was based on projects and not on articles.

Trends

There was an increasing trend in publication, especially after 2009 (Fig. 2).

Qualitative analysis

The qualitative variables analysed in each project are listed in Table 2 and described below. Globally, we found that there was an increase in the publication of projects over the study period, with 4 projects published before 2001, 4 projects between 2005 and 2007, 8 projects between 2008 and 2010 and 13 projects between 2011 and 2013.

Variable	Time period				Total (%)	Project numbers
	<2004 (4 projects)	2005–2007 (4 projects)	2008–2010 (8 projects)	2011–2013 (13 projects)
Geographic area covered by the project
Regional	4	3	5	6	18 (62)	2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 20, 21, 22, 26, 27, 28, 29
National	0	1	3	6	10 (34)	1, 3, 6, 9, 15, 18, 19, 23, 24, 25
International	0	0	0	1	1 (3)	12
Area covered by the project
Hospital	4	2	5	4	15 (52)	2, 4, 5, 8, 11, 13, 17, 18, 20, 21, 22, 26, 27, 28, 29
Community	0	0	0	6	6 (21)	1, 3, 12, 14, 15, 16
Primary care	0	2	1	1	4 (14)	6, 7, 9, 10
Other healthcare institutions (different from hospitals or primary care)	0	0	1	2	3 (10)	19, 24, 25
Clinical trials	0	0	1	0	1 (3)	23
Type of action promoted by the project
Passive promotion of ADR reporting	3	3	6	10	22 (76)	4, 5, 6, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29
Active promotion of ADR reporting	1	1	2	3	7 (24)	1, 2, 3, 7, 12, 13, 28
Type of software
Web-based	1	3	6	6	16 (55)	2, 3, 5, 7, 9, 12, 13, 14, 15, 16, 19, 20, 22, 23, 27, 28
System inside the Electronic Health Record	3	1	2	6	12 (41)	4, 6, 8, 10, 11, 17, 21, 24, 25, 26, 18, 29
Mobile	0	0	0	1	1 (3)	1
Type of institution promoting the study
Hospital	2	1	3	3	9 (31)	2, 4, 8, 17, 18, 21, 26, 27, 29
University	1	1	3	4	9 (31)	5, 10, 11, 12, 13, 19, 20, 24, 25
National institution	0	2	0	2	4 (14)	1, 9, 15, 22
Regulatory authority	1	0	1	3	5 (17)	6, 7, 14, 16, 28
Othera	0	0	1	1	2 (7)	3, 23
Target
Healthcare professionals	4	2	7	8	21 (72)	4, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 18, 19, 21, 23, 24, 25, 26, 27, 28, 29.
Patients	0	2	1	4	7 (24)	1, 2, 3, 5, 12, 20, 22
Healthcare professionals and patients	0	0	0	1	1 (3)	15
Type of medicine
All	4	1	5	11	21 (72)	3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 16, 17, 18, 19, 20, 21, 24, 25, 26, 28, 29
Vaccines	0	2	1	2	5 (17)	1, 10, 13, 15, 22
Chemotherapy	0	1	0	0	1 (3)	2
Human albumin	0	0	1	0	1 (3)	23
Radiopaque agents	0	0	1	0	1 (3)	27
Type of ADR
All	4	4	8	11	27 (93)	2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29
Serious	0	0	0	2	2 (7)	1, 3

^a Other institutions are: Clinical trial team (project 23) and website producer (project 3)

Types of ADR

Only a small percentage of the projects were specific for serious adverse drug reactions. The majority (93 %) covered all ADR.

Quantitative analysis

From the 29 projects analysed, seven projects met the criteria for inclusion in the quantitative analysis (meta-analysis). The criteria used were the availability of data related to the number of ADR reported before and after each intervention and a follow-up period.

From the seven projects included in the quantitative analysis, six had the same follow-up period (12 months) and only one (project 14) differed on this item (18 months of follow-up). The results are described in Table 3.

Study	ADR reports before	ADR reports after	Rate	CI lower	CI upper
Project 14	287	415	1,44	−0,18	3,07
Project 7	89	111	1,25	−0,51	3,00
Project 29	30	162	5,4	4,56	6,24
Project 6	3279	4716	1,44	−0,20	3,072
Project 17	118	294	2,49	1,25	3,73
Project 27	20	62	3,1	1,99	4,21
Project 20	82	212	2,58	1,37	3,80

We performed a meta-analysis with these seven projects to calculate the aggregated measure of the ADR reporting increase. The overall measure was 2.1, which indicated that the interventions performed in the analysed projects doubled the number of ADR reports (Fig. 3).

Projects 14, 7 and 6, which had similar ADR reporting increases, used different approaches. The authors of project 14 assessed an online ADR reporting form, in project 7 the authors send repeated e-mails with ADR information to healthcare professionals and project 6 evaluated the inclusion of a reporting system inside the clinical information system.

Four of the information systems that contributed to the improvement of ADR reporting used web-based technology. Two used an online reporting form (Project 14 [13] and Project 27 [14]) to facilitate ADR reporting. A Swedish group opted to evaluate the effect of repeated emails to health care professionals that contained attached ADR information (Project 7 [15]). A Portuguese study tested the inclusion of hyperlinks to the online ADR reporting form on hospitals’ electronic patient records (Project 20 [16]) to facilitate access to the ADR form.

Three projects explored the use of electronic health records to directly report the ADRs (projects 29, 6 and 17). Among these, project 29 [17], which had the best result in terms of the ADR reporting increase, was a system that completed the ADR report whenever a physician required assistance.

Although a limited number of projects was included in our work (n = 29), our data suggest that the number of projects that aimed to promote ADR reporting using information technologies increased over time.

Study selection was performed as a manual review; this approach caused a huge workload because we obtained more than 3000 articles. An optimized query would reduce the workload but lose sensitivity.

As expected, most of the projects that aimed to promote adverse drug reactions reporting were developed in hospitals and tailored to healthcare professionals. In fact, most of the serious ADRs were detected in hospitals and reported by healthcare professionals [18]. For example, in Europe direct reporting (ADRs reported by patients) has only been allowed for every country since 2012 [19]. This finding may also explain why most of the projects that targeted direct ADR reporting were developed in the last 3 years of the study period (2011–2013) [18, 20–22].

Most of the authors chose to develop systems for the passive promotion of ADR reporting because busy healthcare professionals only submit their suspected ADR if it does not increase their workload [23, 24]. Active promotion of ADR reporting is difficult and not always ethically acceptable because no material reward can be given to the reporters. Thus, projects that aimed to actively promote ADR reporting involved teaching sessions [25] or e-mails containing ADR information [15, 18, 26, 27].

Our results suggested that there was an increasing trend in the use of web-based software to promote ADR reporting, which could be explained by the dissemination of internet use. Nevertheless, mobile technology was also appearing.

Most of the retrieved projects covered all medicines and ADR, whereas only a few were specific. However, we found 5 projects dedicated to vaccine adverse reactions [21, 22, 27–29] and in the last 3 years two projects were developed to specifically report serious ADR [18, 22].

The institutions that primarily promoted this work were universities and hospitals because universities have the know-how to perform these actions and hospitals have specific needs to be solved. However, regulatory authorities have been increasing their involvement in the development of this type of project.

A limitation of this study is that a grey literature search was not performed. However, we think that this lack does not cause a large bias because regulatory authorities are less likely to produce this type of project. When regulatory authorities are involved in projects of this scope, they usually associate with universities and hospitals that have a greater incentive to publish.

Based on our quantitative analysis, we can conclude that all of the projects analysed increased the ADR reporting numbers (most by approximately two-fold). We found two projects that increased ADR reporting by more than two-fold [14, 17], perhaps because their basal values were much lower compared with the other five projects. A similar effect was noted previously in two other studies when the same population of health care professionals was exposed to the same educational interventions two different times [30, 31]. After the first intervention, the authors achieved a much higher effect and ADR reporting increased compared to the second intervention due to the differences in the initial values.

In our quantitative analysis, we found a limitation concerning the aggregation of the information because we found only 7 studies that provided data concerning its impact on the increase in ADR reporting. These data were not available for the other studies even after we contacted the authors. However, we did not identify any variable that could distinguish these 7 projects from the other 22 projects. We must reiterate the importance of providing quantitative data when publishing studies focused on interventions that aim to promote ADR reporting.

Worldwide underreporting of ADR is a major concern, and many institutions are aware that it is feasible to use information systems to improve ADR reporting. The most commonly used platform is web-based and exhibits an increasing trend, but interventions inside electronic health records also have the potential to improve pharmacovigilance activities and particularly ADR reporting. Direct ADR reporting is being increasingly taken into account when the aim is to improve information on drug safety.

Based on our results, we believe that it would be useful to adopt a system to assist healthcare professionals with completing ADR reporting within electronic health records because this approach seems to be an efficient method to increase the ADR reporting rate. When this approach is not possible, it is essential to have a tool that is easily accessible on the web to report ADR. This tool can be promoted by sending emails or through the inclusion of direct hyperlinks on healthcare professionals’ desktops.

Our systematic review allowed us to note some facts about interventions that aim to improve ADR reporting using information systems. According to our aggregation analysis, these interventions doubled the number of ADR reports. We also found that most projects passively promoted ADR reporting (facilitating the reporting process) and the countries involved in this type of project were Northern America countries (USA and Canada), European countries and in a smaller number Far East countries.