Following the removal of duplicates (n = 2175), 8482 studies were screened, with 8462 studies excluded following title, abstract, and full-text review. Screening of reference lists of the remaining studies (n = 20) lead to a total of 21 included studies. Figure 1 presents a PRISMA flowchart demonstrating this process.
The 21 included studies (Table 3) evaluated PV systems in 51 countries across single or multiple countries’ National PV Centres (NPVCs), Public Health Programmes (PHPs), healthcare facilities (e.g. hospitals) or pharmaceutical companies. Most of the studies (n = 13) had been published since 2016. Eleven studies focusesd on African countries [37,38,39,40,41,42,43,44,45,46,47] with one of these also including India . Four studies involved Middle Eastern and/or Eastern Mediterranean countries [48,49,50,51], and four covered East or South-East Asian countries [52,53,54,55]. One study dealt with countries in the Asia–Pacific region  and one study focussed on a country in South America .
Ten studies employed self-completion questionnaires for data collection [45, 48,49,50,51,52,53, 55,56,57], and nine employed mixed-methods [37,38,39,40,41, 43, 44, 46, 47] including interviewer-administered questionnaires alongside a documentary review. Two studies [42, 54] employed only qualitative methods including interviews and literature or documentary review. Sixteen studies [37,38,39,40,41,42,43,44,45,46,47, 49, 53,54,55,56,57] evaluated or assessed PV practice or performance. The remaining five studies [48, 50,51,52, 55] surveyed or provided an overview of countries’ PV situation and offered insights into the maturity of PV systems.
Eight studies [39, 44, 48, 50, 52,53,54,55] focussed on national PV centre(s), while three [37, 38, 41] took more of a system-wide approach by also including other levels, i.e. healthcare facilities and PHPs. Three studies [43, 46, 51] focussed on PV at the regional level within a country. Five studies [40, 45, 47, 56, 57] focussed on PV in stakeholder institutions including pharmaceutical companies/manufacturers, Public Health Programmes (PHPs), drugstores and medical institutions.
Thirteen studies [37,38,39,40,41,42,43,44, 46, 47, 49, 53, 55] employed an analytical approach that relied on the use of a framework. The most frequently used frameworks (n = 3) used were the IPAT framework [37, 38, 41] and the WHO PV indicators [46, 47, 55]. Two studies used the East African Community (EAC) harmonised pharmacovigilance indicators tool [39, 40] and two used the WHO minimum requirements for a functional PV system [42, 53]. Two studies [43, 44] employed the Centres for Disease Control and Prevention (CDC) updated guidelines for evaluating public health surveillance systems  alongside the WHO PV indicators . One study employed a framework that combined indicators from the IPAT and the WHO PV indicators .
Using Hawker et al.’s  nine-item checklist, the overall quality of included studies was deemed as ‘medium’ for seven and ‘high’ for 14. See Online Resource 3 for detailed scoring. The lowest scoring parameter was “ethics and bias” (Average = 1.9, Standard Deviation ± 0.6); the highest scoring parameter was “abstract and title” (3.9 ± 0.3). The methods used were considered appropriate for all included studies; however, seven did not provide sufficient detail on the data collection and recording process [38, 44, 45, 50,51,52, 57]. Clear sample justification and approaches were only described in three studies [43, 44, 46]. Only three studies [45, 50, 57] were rated poorly or very poorly with respect to data analysis due to limited or no detail. Apart from one study , studies provided clear descriptions of findings. Only three studies [41,42,43] detailed ethical issues such as confidentiality, sensitivity and consent. No studies described or acknowledged researcher bias/reflexivity. Study transferability or generalisability was affected by the use of small sample sizes [37, 41], survey non-response [45, 48,49,50, 55], focus on the national PV centre , the institutional level rather than the individual (Healthcare Professional (HCP) or patient) level, exclusion of some types of institutions  and non-testing of questionnaire reliability . Only four studies [41, 52,53,54] achieved a score of 4 for the “implications and usefulness” parameter by making suggestions for future research and implications for policy and/or practice.
The main limitation described by the reviewed studies related to information validity and completeness. Eight studies [39, 40, 42, 43, 48, 50, 52, 56] cited limitations that included pertinent data missing, reliance on the accuracy of information provided or inability to verify or validate information. The second limitation was related to the collected data's currency [39, 48, 50, 56].
Finally, two studies [41, 46] reported limitations related to the evaluation tools used to evaluate PV performance. Kabore et al.  highlighted four limitations inherent to the IPAT including 1—Its sensitivity and specificity had not been established, 2—Possible imprecision in the quantification of responses in the scoring process, 3—The assessment’s reliance on respondents’ declarations and 4—The necessity of local adaptation due to the tool's limited testing and validation. Two studies [46, 47] raised limitations of using the WHO PV indicators including lack of trained personnel, poor documentation and the need for in-depth surveys which nascent systems are unable to execute. Furthermore, the WHO PV indicators were said to lack a scoring system that could quantify the indices thereby highlighting system deficiencies numerically .
Studies’ Coverage of WHO Pharmacovigilance Indicators
When investigating the number of all 63 WHO PV indicators, the studies achieved an average score of 17.2 (see Fig. 2). The highest score was 33.0  and the lowest was 4.0 . Studies placed a higher emphasis on evaluating ‘Core’ compared to ‘Complementary’ indicators as demonstrated by the median and average scores obtained for ‘Core’ (12.0 and 11.6/27, respectively) versus 4.0 and 5.6/36 for ‘Complementary’. Studies obtained higher median and average scores for ‘Structural’ indicators (8.0 and 7.0/10 for ‘Core’ and 4.0 and 3.3/11 for ‘Complementary’, respectively) compared to ‘Process’ (3.0 and 2.7/9 for ‘Core’ along with 1.0 and 1.5/13 for ‘Complementary’, respectively) and ‘Outcome’ indicators (2.0 and 1.9/8 for ‘Core’ and 0 and 0.8/12 for ‘Complementary’). Further detail is supplied in Online Resource 4.
Regions’ and Countries’ Pharmacovigilance Performance
Total Pharmacovigilance System Performance
The average and median scores achieved by all countries were 14.86 and 15.0/63, respectively. Although 51% of countries had a higher-than-average total score and 49% had a score above the median, none of them achieved more than 40% of the WHO indicators. The Middle East and North Africa achieved the highest average total score (15.89), and Latin America and the Caribbean the lowest (10.5). In comparison, the highest median score was achieved by the Middle East and North Africa (18.0), and the lowest was achieved by South Asia (10.0). The highest achieving country was Tanzania (26.0). Bahrain, Syria, Djibouti and Myanmar all scored zero. See Figs. 3 and 4 for the regions’ and countries’ aggregate scores, respectively, Online Resource 4 for detailed information relating to each indicator, and Online Resource 5 for detailed information on aggregate scores.
Core Indicators Performance
Out of a possible score of 27 for ‘Core’ indicators, the average was 9.27 while the median was 9.0. East Asia and the Pacific achieved the highest average score (10.17), whereas South Asia had the lowest (7.3). On the other hand, in terms of the median score, the highest was observed in Sub-Saharan Africa (11.5). And the lowest was in South Asia (7.0). The highest scoring countries among the different regions were Nigeria, Indonesia and Malaysia (15.0), whereas Bahrain, Syria, Djibouti and Myanmar scored zero.
For ‘Core Structural’ indicators, the average score for the 51 countries was 6.5 and the median was 7.0. The highest average and median scores, regionally, were observed in Sub-Saharan Africa (7.07 and 8.5, respectively), whereas the lowest were observed in Latin America and the Caribbean (5.0 and 5.5, respectively). Egypt had the highest country-level score (10.0) while Bahrain and Syria, Djibouti and Myanmar scored zero.
A facility for carrying out PV activities was reported as existing in 92% of countries, and PV regulations existed in 80% of countries. There were inconsistencies in the reported information concerning PV regulations in Oman, Yemen and Cambodia. In Oman, two studies [48, 50] reported that such regulations were present, whereas a third  reported they were absent. In Yemen, Qato  reported the presence of regulations, whereas Alshammari et al.  indicated the opposite. For Cambodia, conflicting information was reported by Suwankesawong et al.  and Chan et al. . In all such cases, the latest published results were adopted.
Concerning resources, regular financial provision for conducting PV activities was reported as present in only 35% of countries, most of which were among the highest achieving countries overall. There was an inconsistency in the information provided for this indicator in Oman and the United Arab Emirates (UAE) with two studies [48, 50] stating that this was present, and one  that it was not. In terms of human resources, 75% of countries were found to possess dedicated staff carrying out PV activities.
Most countries (86%) were found to possess a standardised ADR reporting form. However, it was only highlighted in 16 countries whether the form included medication errors; counterfeit/substandard medicines; therapeutic ineffectiveness; misuse, abuse, or dependence on medicines; or reporting by the general public.
For only four countries (China, Egypt, Ethiopia and Uganda) was it reported that PV was incorporated into the national HCP curriculum. In 22 countries (43%), it was either unknown if a PV information dissemination mechanism existed, or it did not exist. Sixty-three per cent of countries had a PV advisory committee. Information regarding this indicator was inconsistent between Qato  and Alshammari et al.  with the former reporting Jordan and Tunisia possessed an advisory committee, the latter reporting the opposite.
The overall average and median scores for ‘Core Process’ indicators were 2.06 and 2.0/9, respectively. The highest average score was in East Asia and the Pacific (2.9), whereas South Asia (1.0) achieved the lowest. Similarly, in terms of the median score, East Asia and the Pacific (3.0) was the highest while South Asia (1.0) was the lowest. No country achieved a higher score than Malaysia (7.0), while seven countries scored zero.
The absolute number of ADR reports received per year by the countries’ PV system ranged from zero (Afghanistan, Bahrain, Comoros, Qatar, and Rwanda) to 50,000 (Thailand). Most countries (n = 27) received less than 10,000 reports per year, with Iran reporting the highest yearly rate (7532 reports) and Laos and Lebanon reporting the lowest (3 reports). Only four countries reported receiving 10,000 reports or more yearly, namely China (32,513 reports), Malaysia (10,000 reports), Singapore (21,000 reports) and Thailand (50,000 reports). The remaining 20 countries either did not receive any reports or no data were provided.
The number of ADR reports increased over time in 12 countries (Algeria, Cambodia, Egypt, Iraq, Jordan, Kuwait, Morocco, Oman, Palestine, Saudi Arabia, Tunisia and Yemen), whereas they decreased in eight countries (Laos, Malaysia, Philippines, Singapore, Sudan, Thailand, the UAE and Vietnam). The percentage of total annual reports satisfactorily completed and submitted to the PV centre was reported only in Nigeria (maximum of 84.6%).
Only Singapore and Thailand reported cumulative numbers of reports as more than 100,000, while 17 countries had fewer than 20,000 reports cumulatively. Some inconsistencies for this indicator were reported by Suwankesawong et al.  and Chan et al.  for Malaysia, the Philippines, Singapore and Vietnam, with the numbers reported by the former higher than the latter.
Overall, the provision of ADR reporting feedback was poor, with all the countries either not performing this or no information being provided. Documentation of causality assessment was also poor, with only Ethiopia (2%), Kenya (5.5%), Tanzania (97%) and Zimbabwe (100%) reportedly performing this. The percentage of reports submitted to WHO was reported only in Vietnam (28%) and Zimbabwe (86%).
Among the countries which reported performing active surveillance, Algeria was the most active with 100 projects followed by Tunisia and Morocco with 50 and 10 activities, respectively. All remaining countries had fewer than seven.
The average and mean scores overall for the ‘Core Outcome’ indicators were 0.69 and 1.0/8, respectively. Countries from East Asia and the Pacific (0.92) had the highest average score collectively, whereas South Asia (0.33) had the lowest. In terms of the median score, sub-Saharan Africa (1.0) had the highest, whereas South Asia (zero) had the lowest. Nine countries achieved the highest score (2.0), while 25 countries only scored zero.
Signal detection was reported to have occurred in 10 countries, with the highest number observed in Kenya (31 signals), whereas seven countries scored zero. The reported number of signals detected was above 10 in only three countries: Kenya, Tanzania (25 signals) and Singapore (20 signals). Among the 23 countries where information regarding the number of regulatory actions taken was reported, the highest number of actions taken was in Egypt (930 actions), whereas in 15 countries, no actions had been taken.
The number of medicine-related hospital admissions per 1000 admissions was only reported in Nigeria and ranged from 0.01 to 1.7. The reporting of pertinent data regarding the remaining five Core Outcome indicators (CO3–CO8) was inadequate as no information was provided for any of the countries.
Complementary Indicators Performance
For ‘Complementary’ indicators, the overall average and median scores were 5.59 and 6.0/36, respectively. The Middle East and North Africa (6.89 and 8.5, respectively) achieved the highest average and median scores among the regions, whereas Latin America and the Caribbean (3.5 and 4.0, respectively) achieved the lowest. The highest scoring country was Tanzania (12.0), whereas Bahrain, Syria, Djibouti and Myanmar scored zero.
For ‘Complementary Structural’ indicators, the average and mean scores were 4.24 and 4.0/11, respectively. The highest average and median scores were achieved by the Middle East and North Africa (5.44 and 6.0, respectively), whereas Latin America and the Caribbean (2.5 and 3.0, respectively) had the lowest. Five countries achieved a score of 8.0, namely Jordan, Saudi Arabia, the UAE, Ethiopia and Tanzania. Seven countries scored zero.
Three-fourths of the countries were reported to possess dedicated computer facilities to carry out PV activities as well as a database for storing and managing PV information. There was inconsistency in the data reported for Libya, with Qato  indicating the presence of a computer, whereas Alshammari et al.  reported it absent. It was indicated that in 47% of the countries, functioning communication facilities such as telephone, fax, or internet were available. A library containing reference materials on drug safety was found to be available in only 19 countries. For all the countries, it was either reported that they did not have a source of data on consumption and prescription of medicines, or no information was available.
In all 51 countries investigated, it was either reported that web-based PV training tools for both HCPs and the public were not available, or no information was reported. It was found that in 30 (60%) of countries training courses for HCPs were organised by the PV centre. There was insufficient information about the availability of training courses for the public in all countries. Less than half (41% and 49%, respectively) of countries possessed a programme with a laboratory for monitoring drug quality or mandated MAHs to submit Periodic Safety Update Reports (PSURs). Only 8% of countries had an essential medicines list and only 18% used PV data in developing treatment guidelines.
The 51 countries achieved average and median scores of 1.4 and 1.0/13, respectively, for the ‘Complementary Process’ indicators. Regionally, the highest average and median scores were achieved by the Middle East and North Africa (1.44 and 2.0, respectively), while the lowest scores were achieved by Latin America and the Caribbean (both 1.0). The highest total scores were achieved by Kenya and Tanzania (both 4.0), while 12 countries scored zero.
Data regarding the percentage of healthcare facilities possessing a functional PV unit (i.e. submitting ≥ 10 reports annually to the PV centre) was reported for seven countries. However, only three of these reported a number above zero (Kenya 0.14%, Tanzania 0.26% and Zimbabwe 2.2%).
In terms of the total number of reports received per million population; it was found that Singapore had the highest number (3853 reports/year/million population), while Laos had the lowest (0.4 reports/year/million population). In 17 countries, it was indicated that HCPs represented the primary source of submitted ADR reports. Medical doctors were reported as the primary HCPs to submit ADR reports in five countries, namely Lebanon (100%), Libya (50%), Morocco (50%), Tunisia (96%) and Yemen (90%). In eight countries, manufacturers were found to be the primary source of ADR reports, namely Algeria (71%), Jordan (90%), Kuwait (93%), Mexico (59%), Pakistan 88%), Palestine (100%), Saudi Arabia (50%) and the UAE (72%).
The number of HCPs who received face-to-face training over the previous year was only reported in Ethiopia (90,814), Tanzania (76,405), Rwanda (43,725) and Kenya (8706).
No information was found in any of the studies concerning the ‘Complementary Process’ indicators 4, 6 and 9–13.
Out of a possible score of 12, the overall average and median scores achieved for the ‘Complementary Outcome’ indicators of the studied countries were both zero, with no information reported concerning these indicators.