literature review in pharmacovigilance

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Home » Pharmacovigilance: Literature Monitoring Best Practices

Pharmacovigilance: Literature Monitoring Best Practices

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Safe and effective use of health products is a key objective of pharmacovigilance. Information is provided about the safety of these substances to patients, healthcare providers, and the general public as soon as possible. Pharmacovigilance includes reviewing the development, management, and introduction of pharmaceuticals. It is probably the most tightly regulated part of the pharmaceutical industry. Pharmacovigilance aims to identify, detect, assess, and report any adverse drug reaction (ADR) related to pharmaceutical products. In the United States, the European Union, and other parts of the world, regulatory requirements have emerged that have grown in diversity and nuance. These requirements include systematic monitoring and review of medical literature, including comprehensive screening of medical journals for adverse drug reactions, which remain on the rise. Having a robust pharmacovigilance system is paramount for a manufacturer, and any deficiencies can have an adverse effect on patient safety.

Literature monitoring includes published articles, articles, and reviews in indexed or non-indexed journals, any content posted anywhere online, posters and conference abstracts, etc. Holders of a Marketing Authorization (MA) must monitor global and local literature throughout the duration of that authorization, regardless of the availability of the product on the market1. Regulatory reports, clinical trial reports, literature reports, license partner reports, and spontaneous reports all serve as sources of data for deeper analysis of regulatory reporting, signal detection, and aggregate reporting. The individual safety report (ICSR) is valuable for developing risk assessments. It is incumbent upon holders of marketing authorizations to stay up-to-date on potential publications (including ahead of print articles) by reviewing widely used reference databases (e.g., Medline, Embase, Excerpta Medica) every week 2 . Adverse events that meet the criteria for the ICSR are handled per regulatory guidelines on handling and reporting adverse events. When a relevant article has been identified, it will be further screened to determine if it meets the four essential criteria for consideration for Individual case safety report (ICSR) and adverse event reporting: 1) identified source, 2) company product, 3) patient, 4) adverse event 3 . Any analysis regarding the safety profile of a product should be based on scientific and medical publications. Literature searches and monitoring are primarily intended to identify single case reports of adverse effects and to track any changes in benefit-risk profiles associated with the drug, particularly when new safety signals safety concerns arise 4 .

Literature Monitoring: An Overview of Best Practices

When the foundation is compromised, a process can result in a cascade of unintended repercussions. Therefore, an unbiased search is vital for monitoring medical literature accurately and efficiently. The growing volume of data has made it more critical to get the best results without introducing unwanted data. The literature monitoring process is usually characterized by two major challenges, which can be overcome. The first challenge is to come up with the right search strategy, and the second is to deal with duplication. Drug manufacturers must often track hundreds of drugs at once. So how can literature monitoring be accurate and valid?

Optimal Search Strategy Design and Database Selection

Regulatory authorities require marketing authorization holders to conduct medical literature surveillance at least weekly according to the GVP module VI and based on the required frequency as described by the local regulatory authorities, both for globally indexed literature databases and locally (non-indexed) literature journals 5 . When developing search strategies, it is important to consider ICSRs, aggregate reports, and any potential safety-related information. Therefore, it is essential to develop and progressively improve search strategies to limit the risk of overlooking relevant ADR information. Specifically, to retrieve all relevant records, query terms must be highly recallable and carefully crafted to retrieve maximum publications reporting any safety concerns about the product in question.

The database must be comprehensive and meet minimum standards to ensure that safety-critical signals are not missed. Pharmacovigilance searchers typically utilize at least two databases, usually three or more, because having access to multiple databases increases their recall-finding capabilities, ensuring more coverage.

Implement a search approach that balances the need for accuracy and precision. For example, 1) use several Boolean operators, 2) browse a thesaurus of terms, 3) perform proximity search, and 4) incorporate abbreviations to recall results. Using the most recent thesaurus update will ensure accuracy and compliance 6 .

As part of the local literature review, it is recommended to identify the non-indexed journals published locally and to screen those in either an online or print format depending on their availability. There are a few local regulatory agencies that recommend performing local literature searches in a few databases that are locally approved. The MAH handles any publications identified as containing information in local languages in accordance with the translation process established within the institution.

Industry best practice calls for constant review of search terms and updating them based on safety-related updates pertaining to the products. A GOLD standard data set of records is used to validate the modified search strategies. It is recommended to review your search strategy annually and make amendments as necessary 7 .

EMA hosts a robust system for medical literature monitoring. Thousands of records are added daily. It is generally the responsibility of marketing authorization holders to monitor medical literature and report individual cases of suspected adverse reactions into EudraVigilance and national safety databases 8 . They are not required to monitor or report suspected adverse reactions for active substances to EudraVigilance for substances covered by EMA’s service 9 .

Duplicate Data Management

Scientific publications and medical literature are abundant with sources and references, so it’s likely that the same publication could be indexed in multiple formats across a variety of journals, which results in duplicate findings. This creates a whole series of redundant tasks and false signals regarding drug safety. It leads to erroneous evaluations and, ultimately, compliance problems. Duplicate management processes, however, can solve this issue. Even though this is the best way of dealing with articles, it comes with a few challenges. There may be limitations to duplicate identification within the tool due to the presence of special characters, or it may be the case that the same study has been published across different journals or conference abstracts, making the process cumbersome.

It is important to search multiple databases to capture multiple publications across different journals. Keeping track of previous searches will also facilitate the identification of duplicates. To identify duplicate publications, there should not be just a focus on the article title but also the author’s name and, in some cases, the name of the study cited in the article.

According to Article 107(3) of Directive 2001/83/EC, to avoid duplicate submissions of ICSRs, the holder of a marketing authorization must submit the ICSRs that are not already assessed or monitored by EMA through the Medical Literature Monitoring (MLM) services 10 .

Service providers should use a standardized and well-established deduplication system, enabling them to confirm that they are not missing relevant references or creating duplicates inadvertently.

Along with routine literature surveillance, MAH also conducts targeted literature searches, which are searches specifically designed to answer a specific research question. When conducting signal analysis, these searches are conducted to confirm or disprove the association between the adverse event and the product.

Pharmacovigilance involves a substantial amount of literature monitoring . The process of devising a solid search strategy could be challenging but is essential. A professional with the required skills, experience, and training will ensure adverse event-related safety information is never missed. It is necessary to develop and maintain search strategies, elicit ideas from different stakeholders, and develop approved and suitable strategies for the purpose at hand. It is critical to set up a thorough process to handle and manage duplicate articles. Regularly review search strategies, and ensure the documentation is robust to ensure the finest quality results. The following points can be considered to check whether the MAH’s literature monitoring systems meet quality standards;

• A drug safety expert with experience researching literature is needed.
• Conduct risk assessments to ensure that the search criteria are robust and relevant to the objective of the literature search.
• Conduct literature searches and evaluate the results for literature per regional requirements (Global and Local).
• Monitoring and reviewing the Eudravigilance Medical Literature Monitoring (MLM) system, managed by EMA, to identify ICSRs in the literature if your product is included in the active ingredient screened by EMA.
• The search string is reviewed and updated annually to optimize results.

About the Author

Dr. Poonam Wagle; Associate Manager, Pharmacovigilance

Poonam brings expertise in literature management as a pharmacovigilance and safety expert with over eleven years of experience in the areas of ICSR, Literature, Aggregate Reports, and Signal Reviews. She has established and led several projects and programs in the field, including ICSRs, and literature monitoring, in both global and local surveillance.

ClinChoice is a leading global Contract Research Organization (CRO), with over 3400 clinical research professionals across North America, Asia, and Europe. For more than 27 years, ClinChoice has been providing high-quality contract research services to pharmaceutical, biotechnology, medical device, and consumer products clients, encompassing a broad range of services and therapeutic areas. ClinChoice offers cutting-edge, full-service solutions for Clinical Trials, Regulatory Affairs, Medical Device Safety, Toxicology, and Medical Affairs.

• 1) https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medical-literature-monitoring
• 2) https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-vi-management-reporting-adverse-reactions_en-0.pdf
• 3) https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf
• 4) https://database.ich.org/sites/default/files/E2D_Guideline.pdf
• 5) https://europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-iv-pharmacovigilance-audits-rev-1_en.pdf
• 6) https://www.ema.europa.eu/en/documents/other/monitoring-medical-literature-entry-relevant-information-eudravigilance-database-european-medicines_en.pdf
• 7) https://www.elsevier.com/solutions/embase-biomedical-research/coverage-and-content
• 8) https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medical-literature-monitoring
• 9) https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medical-literature-monitoring
• 10) https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medical-literature-monitoring

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A Systematic Review of Pharmacovigilance Systems in Developing Countries Using the WHO Pharmacovigilance Indicators

• Open access
• Published: 03 June 2022
• Volume 56 , pages 717–743, ( 2022 )

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You have full access to this open access article

• Hamza Y. Garashi   ORCID: orcid.org/0000-0002-1969-4765 1 ,
• Douglas T. Steinke 1 &
• Ellen I. Schafheutle 1  

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In the context of the growth of pharmacovigilance (PV) among developing countries, this systematic review aims to synthesise current research evaluating developing countries’ PV systems’ performance.

EMBASE, MEDLINE, CINAHL Plus and Web of Science were searched for peer-reviewed studies published in English between 2012 and 2021. Reference lists of included studies were screened. Included studies were quality assessed using Hawker et al.'s nine-item checklist; data were extracted using the WHO PV indicators checklist. Scores were assigned to each group of indicators and used to compare countries’ PV performance.

Twenty-one unique studies from 51 countries were included. Of a total possible quality score of 36, most studies were rated medium ( n  = 7 studies) or high ( n  = 14 studies). Studies obtained an average score of 17.2 out of a possible 63 of the WHO PV indicators. PV system performance in all 51 countries was low (14.86/63; range: 0–26). Higher average scores were obtained in the ‘Core’ (9.27/27) compared to ‘Complementary’ (5.59/36) indicators. Overall performance for ‘Process’ and ‘Outcome’ indicators was lower than that of ‘Structural’.

This first systematic review of studies evaluating PV performance in developing countries provides an in-depth understanding of factors affecting PV system performance.

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Introduction

Pharmacovigilance (PV) with its ultimate goal of minimising risks and maximising the benefits of medicinal products serves as an important public health tool [ 1 , 2 ]. The World Health Organization (WHO) defines PV as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”(p. 7) [ 3 ].

Prior to approval by regulatory authorities, drug products are required to undergo extensive testing and rigorous evaluation during clinical trials, to establish their safety and efficacy [ 4 , 5 ]. The rationale for post-marketing PV is based on the need to mitigate the limitations of pre-marketing/registration clinical trials including small population sizes, a short length of time and the exclusion of special population groups (e.g. pregnant women and children) [ 6 , 7 ]. Therefore, unexpected or severe adverse drug reactions (ADRs) are often not identified before regulatory approval resulting in increased morbidity, mortality and financial loss [ 8 , 9 ]. PV allows for the post-marketing (i.e. real-world) collection of drug safety and efficacy information thereby reducing patients' drug-related morbidity and mortality [ 10 ]. Moreover, PV reduces the financial costs associated with the provision of care for patients affected by such problems [ 11 , 12 ]. This is achieved by communicating medicines’ risks and benefits thus enhancing medication safety at various levels of the healthcare system [ 13 ] as well as providing information and knowledge informing regulatory actions [ 14 , 15 , 16 ]. It is important to note that PV activities are not limited to protecting patient safety in the post-marketing phase but apply to a drug product’s entire lifecycle and are a continuation and completion of the analysis performed on medicines from the pre-registration clinical trials [ 17 ]. PV also plays a role in helping drug manufacturing firms in carrying out patient outreach through communicating with patients about drug products’ risk–benefit profile thus making them better informed and building their trust in the industry [ 18 ]. As the collective payers for drug products, insurance firms rely on PV information as a measure of drug products’ demonstrated value to patients in making decisions about reimbursement [ 18 , 19 ].

PV systems’ differences in developing countries are influenced by local contextual factors such as healthcare expenditure, disease types and prevalence, and political climate [ 20 ]. These differences can lead to variability in medicine use and the profile of adverse effects suffered by patients which makes it essential that every country establish its own PV system [ 21 ]. Most developed countries started PV activities after the thalidomide disaster in the 1960s by establishing PV systems and joining the WHO Programme for International Drug Monitoring (PIDM) [ 22 , 23 , 24 ]. Developing countries did not join the PIDM until the 1990s or later [ 22 , 23 , 24 ], but since then, the number of developing countries implementing PV and joining WHO PIDM has steadily increased [ 23 , 24 ].

Over the past few decades, both national and international legislative organisations, as well as national medicines regulatory authorities (NMRAs) have published a considerable amount of legislation and guidance to provide countries with a legal foundation and practical implementation guidance for national PV systems [ 25 ]. Among these is the Guidelines on Good Pharmacovigilance Practices (GVP) implemented by the European medicines agency (EMA) in 2012 which aim to facilitate the performance of PV in the European Union (EU) [ 26 ]. Many developing countries wishing to align their new and evolving national PV frameworks with international standards use the EMA’s GVP guidelines as a reference for setting up their national PV systems [ 25 , 27 ].

The WHO recommends that PV systems incorporate evaluation and assessment mechanisms with specific performance criteria [ 28 ]. Despite the growth in PV development and practice among developing countries, a gap remains in efforts to assess, evaluate, and monitor their systems’ and activities’ status, growth, and impact [ 29 ]. To promote patient safety and enhance efforts aimed at strengthening PV systems in developing countries with nascent PV systems, it is imperative to assess existing conditions [ 13 , 30 ]. Such assessment can help define the elements of a sustainable PV strategy and areas for improvements as the basis to plan for improved public health and safety of medicines [ 13 , 29 , 31 ].

This review aims to systematically identify published peer-reviewed research that evaluates the characteristics, performance, and/or effectiveness of PV systems in developing countries.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [ 32 ]. A PRISMA checklist is included in Online Resource 1.

Theoretical Framework

As a theoretical framework, this study adopted the WHO PV indicators, which measure inputs, processes, outputs, outcomes, and impacts. These WHO indicators “provide information on how well a pharmacovigilance programme is achieving its objectives” (p. 4) [ 30 ]. Details on how the WHO PV indicators were derived and validated have been described by Isah and Edwards [ 29 ]. The indicator-based pharmacovigilance assessment tool (IPAT) was considered but not chosen because its sensitivity and specificity as a measurement tool have not been established [ 33 ].

There are 63 WHO PV indicators, which are classified into three main types: 1—Structural (21 indicators): assess the existence of key PV structures, systems and mechanisms; 2—Process (22 indicators): assess the extent of PV activities, i.e. how the system is operating; 3—Outcome/impact (20 indicators): measure effects (results and changes), i.e. the extent of realisation of PV objectives [ 30 ]. Each of these types is further subdivided into two categories: 1—Core (total 27) indicators are considered highly relevant, important and useful in characterising PV, and 2—Complementary (total 36) are additional measurements that are considered relevant and useful [ 30 ].

Information Sources and Search Strategy

Four electronic databases (EMBASE, MEDLINE, CINAHL Plus and Web of Science) were searched for international peer-reviewed research evidence published between 1st January 2012 (the year when the EMA’s guidelines on GVP were due for implementation) and 16th July 2021. The search was initiated using the term ‘pharmacovigilance’ and its synonyms in combination with other groups of keywords that covered ‘evaluation’. The search terms are listed in Table 1 (see Online Resource 2 for search strategy). Reference lists of included studies were also screened.

Data Screening

Once all duplicate titles had been removed, screening of abstracts and then full texts against the inclusion/exclusion criteria (Table 2 ) was conducted by the lead author. Both co-authors were consulted where queries arose, and the decision on which articles to include in the review was discussed and agreed upon by all authors.

Data Extraction, Synthesis and Quality Assessment

Data were extracted independently by the lead author and checked by the co‐authors, using a data extraction tool based on the WHO PV indicators checklist. Data were extracted at two levels: overall study and studied country/countries. For each study, data were extracted related to which of the WHO PV indicators the study provided information, while for individual countries assessed in the studies, data (qualitative and quantitative) relating to each indicator were extracted. The data were placed into Microsoft Excel and NVivo and analysed thematically to aid comparison between studies and particular countries.

A scoring system was developed for the purpose of this review to quantify the indices thus highlighting countries’ PV system strengths and deficiencies in numerical terms. Each of the 63 indicators was scored separately and a final score was calculated for each study. If information relating to an indicator was present, a score of 1 was given. A score of 0 was given where data were not provided, missing, not applicable or not clear. Where information for a particular country was provided by more than one study, the latest study was used. In cases where country data were available for more than one system level (e.g. national level and institutional level), the information from the higher level was used. The final scores were used to benchmark national PV performance and compare countries both within and across regions.

The quality of included studies was evaluated using Hawker et al.’s nine‐item checklist [ 34 ] for appraising disparate studies. The checklist allows scoring of individual parameters and a total score that allows the comparison of strengths and weaknesses within and across studies. Total scores could range from 9 to 36, by scoring studies as “Good” (4), “Fair” (3), “Poor” (2), “Very poor” (1) for each checklist item (title, introduction and aims, method and data, sampling, data analysis, ethics and bias, results, transferability or generalisability, implications and usefulness). To categorise the sum quality ranking of studies, previously used cut-offs were adopted: [ 35 , 36 ] high (30–36 points), medium (24–29 points) and low quality (9–23 points).

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.

Flow diagram of studies included/excluded in the systematic review

Study Characteristics

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 [ 42 ]. 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 [ 56 ] and one study focussed on a country in South America [ 57 ].

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 [ 58 ] alongside the WHO PV indicators [ 30 ]. One study employed a framework that combined indicators from the IPAT and the WHO PV indicators [ 49 ].

Study Quality

Using Hawker et al.’s [ 34 ] 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 [ 51 ], 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 [ 53 ], the institutional level rather than the individual (Healthcare Professional (HCP) or patient) level, exclusion of some types of institutions [ 56 ] and non-testing of questionnaire reliability [ 52 ]. 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. [ 41 ] 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 [ 46 ].

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 [ 39 ] and the lowest was 4.0 [ 45 ]. 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.

Included studies’ aggregate scores (out of 63) for coverage of WHO pharmacovigilance indicators

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.

Aggregate scores (out of 63) of studied countries’ pharmacovigilance systems by region

Aggregate scores (out of 63) of studied countries’ pharmacovigilance systems

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.

Structural Indicators

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 [ 49 ] reported they were absent. In Yemen, Qato [ 49 ] reported the presence of regulations, whereas Alshammari et al. [ 48 ] indicated the opposite. For Cambodia, conflicting information was reported by Suwankesawong et al. [ 53 ] and Chan et al. [ 52 ]. 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 [ 49 ] 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 [ 49 ] and Alshammari et al. [ 48 ] with the former reporting Jordan and Tunisia possessed an advisory committee, the latter reporting the opposite.

Process Indicators

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. [ 53 ] and Chan et al. [ 52 ] 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.

Outcome Indicators

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 [ 49 ] indicating the presence of a computer, whereas Alshammari et al. [ 48 ] 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.

To the best of the authors’ knowledge, this is the first systematic review of studies focussing on PV system performance in developing countries. The review included 21 studies covering 51 countries from different regions across the globe. Using the WHO PV indicators (both ‘Core’ and ‘Complementary’) [ 30 ] as a framework, this review focussed on identifying the areas of strength and weakness within these countries’ PV systems. The review also helped identify where different developing countries’ systems lay on the performance level spectrum. Moreover, the features associated with better performing systems were highlighted. The insights from this review can be used to inform recommendations for addressing areas requiring intervention or modification, particularly within countries with PV systems at a nascent stage of development.

The review revealed a lack of standardisation regarding the methods of evaluating PV systems. While some studies focussed on the WHO indicators, others used assessment tools developed by other organisations including the United States Agency for International Development (USAID), East African Community (EAC), the United States Centre for Disease Control (CDC) or some combination of these. The review also found that, overall, both studies’ coverage of the WHO PV indicators and developing countries’ PV system performance were both low. Furthermore, there was a mix of some indicators which were present in most or all studies/countries, while others were universally absent or only sporadically present. Generally, indicators that were either universally absent or only sporadically present in the studies/countries in this review belonged to the ‘Process’ and ‘Outcome’ indicator classes. In terms of the reviewed studies, both the ‘Complementary Process’ and ‘Complementary Outcome’ indicators’ presence was mixed with some being universally absent (e.g. number of reports from each registered pharmaceutical company received by the NPVC in the previous year and cost savings attributed to PV activities, respectively) and others being sporadically present (e.g. number of face-to-face training sessions in PV organised in the previous year and average number of medicines per prescription, respectively). Most of the ‘Core Process’ and ‘Core Outcome’ and ‘Complementary Structural’ indicators were sporadically present (e.g. percentage of reports on medication errors reported in the previous year, average cost of treatment of medicine-related illness and existence of an essential medicines list which is in use, respectively), whereas most of the ‘Core Structural’ indicators were frequently present (e.g. the NPVC has human resources to carry out its functions properly) and only a few were sporadically present (incorporation of PV into the national curriculum of the various HCPs).

In terms of the studied countries, all the ‘Complementary Outcome’ (e.g. percentage of medicines in the pharmaceutical market that is counterfeit/substandard) indicators were universally absent. The ‘Core Outcome’ and ‘Complementary Process’ indicators' presence was found to be mixed with some being universally absent (e.g. number of medicine-related deaths and percentage of MAHs submitting PSURs to the NMRA, respectively) while others were sporadically present (e.g. number of signals detected in the past five years and percentage of HCPs aware of and knowledgeable about ADRs per facility). Most of the ‘Core process’ (e.g. percentage of submitted ADR reports acknowledgement or issued feedback) indicators were found to be sporadically present. Therefore, PV system performance was found to be low in terms of the ‘Process’ and ‘Outcome’ indicators. This reflects immaturity and the inability to collect and utilise local data to identify signals of drug-related problems and to support regulatory decisions [ 22 , 59 , 60 , 61 ].

With regard to ‘Structural’ indicators, most of the ‘Core’ (e.g. an organised centre to oversee PV activities) and some of the ‘Complementary’ (e.g. existence of a dedicated computer for PV activities) structural indicators were found to be frequently present among the studied countries. Hence, performance with respect to the class of ‘Structural’ indicators was relatively high. This points to government policymakers taking active steps towards establishing a PV system as a means of improving drug safety [ 3 , 21 ].

High-performing PV systems in developing countries in this review were distinguished by the presence of a budget specifically earmarked for PV, a means of communicating drug safety information to stakeholders (e.g. a newsletter or website) and technical assistance via an advisory committee. On the other hand, lack of incorporation of PV into the national curriculum of HCPs and underreporting of ADRs plagued both high- and low-performing systems. This suggests that strengthening PV systems in developing countries requires targeted measures addressing these factors. In what follows, this review’s key findings described above will be discussed in more detail in the context of the WHO PV indicators[ 30 ] and existing research.

The 63 indicators developed by the WHO were not all assessed in the included studies. This meant that the data collection process in some instances necessitated extracting data from other sections of the studies such as the ‘Background’ or ‘Discussion’. In other instances, inferences were made for certain indicators based on information provided for others. A notable example was inferring the presence of a computer for PV activities when it was indicated that a computerised case report management system existed. Evaluation is defined as the systematic and objective assessment of the relevance, adequacy, progress, efficiency, effectiveness and impact of a course of action in relation to objectives while considering the resources and facilities that have been deployed [ 62 ]. An evaluation based only on a few indicators is not likely to provide a complete, unbiased evaluation of the system since multiple indicators are needed for tracking the system’s implementation and effects [ 58 ]. While the optimal number of indicators required to perform a proper assessment is likely to vary depending on the evaluation’s objectives, it could be argued that, based on definition, addressing the full set of ‘Core’ indicators should be required to provide a satisfactory evaluation [ 33 ].

This review found that the presence of a dedicated budget for PV was associated with higher system performance [ 30 , 59 , 60 , 63 ]. The absence of sustained funding for PV hinders effective system operation since it prevents the development of the necessary infrastructure [ 64 ]. According to the WHO, funding is what allows the carrying out of PV activities in the setting [ 30 ] and it “signifies a gesture, the commitment and political will of the sponsors and the general importance given to PV” (p. 20) [ 30 ]. It is only when the other structural components of a PV system are paired with a regular and sustainable budget that real action and long-term planning can be achieved [ 65 , 66 , 67 ]. Any investment in PV should consider the substantial diversity in country characteristics such as size and population as well as the anticipated rate at which the system is going to generate reports [ 21 , 68 ].

In this review, countries that had a PV information dissemination tool as part of the system achieved higher-performance scores than those that did not. The WHO indicates that an expected function of a country’s PV system is the effective dissemination of information related to medicines’ safety to both HCPs and the public [ 3 , 30 , 69 ]. The lack of such a tool in many developing countries systems points to the absence of clear routine and crises communication strategies [ 30 ]. The use of a drug bulletin has been cited as an effective tool for improving safety communication as well as increasing ADR reporting [ 70 , 71 , 72 ].

A feature of better performing PV systems was the presence of a PV (or ADR) advisory committee. The WHO views the existence of such a committee as essential given its influential role in developing a clear communication strategy as well as providing technical assistance to the drug regulatory process. The absence of such a committee negatively impacts system processes such as causality assessment, risk assessment and management, as well as outcomes such as communication of recommendations on safety issues and regulatory actions. Evidence from developed countries has demonstrated the value of such a committee’s scientific and clinical advice to support and promote drug safety [ 73 , 74 ].

PV was found to be absent from the national curricula of HCPs in most of the countries studied, which may explain low levels of competency regarding PV and ADR reporting [ 75 ]. Studies have demonstrated that the implementation of PV-related training as a module or course for HCP students has a positive effect on their PV knowledge [ 76 , 77 , 78 ] and sensitises HCPs to issues regarding drug safety [ 30 ].

This review found that ADR reporting rates were low overall, suggesting underreporting by ADR reporters [ 23 , 79 ], which may be partly due to the passive nature of the reporting systems in these [ 59 ]. Underreporting points to the PV system’s inability to collate data on the safety, quality and effectiveness of marketed drugs that have not been tested outside the confines of clinical trials. Consequently, system processes and outcomes, including data analysis, signal identification, regulatory actions, and communication and feedback mechanisms, will remain stagnant. The WHO’s guidance points to the number of ADR reports received by the system as being an indicator of PV activity in the setting, the awareness of ADRs and the willingness of HCPs to report [ 30 ]. Despite underreporting being a significant barrier to the effective functioning of PV systems in both developing and developed countries [ 65 , 74 ], reporting rates have been found to be lower in developing countries than in developed ones [ 80 ]. Based on international evidence, it is reasonable to expect a developed system to target an annual reporting rate of 300 reports per million inhabitants [ 81 ]. Countries struggling with underreporting should utilise the WHO’s global database (VigiBase) as a reference for monitoring drug-related problems [ 60 ]. Furthermore, data from countries with similar population characteristics and co-morbidities receiving smaller numbers of ADR can be gathered into a single database which would allow an analysis of the pooled data to provide relevant solutions [ 60 , 64 ].

This review has a few limitations. First, the included studies were very heterogeneous and differed in their aim, structure, content, method of evaluation and targeted level of PV system/activity, which may limit the extent of the findings’ generalisability. This was partially overcome by applying the WHO indicators as a means of standardising the extracted information. Second, a limitation of the WHO PV indicators is the lack of a scoring system to quantifiably measure PV system performance. This was overcome by the development of a scoring system thus enabling a comparison of a country’s PV system performance status against the WHO PV indicators and that of other countries.

This is the first systematic review that focuses on studies that evaluate PV performance and activities in developing countries, using WHO PV indicators. The included studies provide an in-depth understanding of the various factors affecting PV system performance and activities. This study’s findings demonstrate that a multistakeholder approach towards strengthening PV systems in developing countries is required and the necessity of resource and data consolidation and the establishment of regional collaborations to assist PV systems that are in their nascent stage. Furthermore, it highlights the need for applying a holistic approach that takes into account the resources and infrastructure available when addressing the policy and programmatic gaps in each country.

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The study was undertaken as part of a PhD fully funded by the Kuwaiti Ministry of Health. The authors were not asked nor commissioned by the Kuwaiti Ministry of Health to carry out this study and had no role in its design, data collection and analysis, decision to publish or preparation of the manuscript. Open Access was funded through PhD fees managed by the University of Manchester.

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Hamza Y. Garashi, Douglas T. Steinke & Ellen I. Schafheutle

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All three authors conceived and designed the study. Planning, data extraction and data analysis were led and performed by HYG and supported by DKS and EIS. Screening and identification of citations were completed by HYG. The manuscript was written by HYG and commented on by DKS and EIS. All authors read and approved the final manuscript for submission for publication.

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Hamza Y. Garashi is an employee on a PhD scholarship from the Kuwaiti Ministry of Health. Douglas T. Steinke and Ellen I. Schafheutle have no conflict of interest that is directly relevant to the content of this study.

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Garashi, H.Y., Steinke, D.T. & Schafheutle, E.I. A Systematic Review of Pharmacovigilance Systems in Developing Countries Using the WHO Pharmacovigilance Indicators. Ther Innov Regul Sci 56 , 717–743 (2022). https://doi.org/10.1007/s43441-022-00415-y

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DOI : https://doi.org/10.1007/s43441-022-00415-y

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Pharmacovigilance

9. Literature reports

“Scientific & medical literature is a significant source of information for the monitoring of the safety profile and of the risk benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues.”

Literature report is any adverse drug reactions reported in

1. Published abstracts or

2. Articles in medical/scientific journals

3. Unpublished manuscripts involving case reports

4. Important safety findings or clinical studies including posters, letters to the editors, and associated communication from scientific meetings.

Current regulatory guidance:

• Per the European Medicines Agency (EMA), MAHs are required to monitor local scientific and medical publications in countries where they have a marketing authorisation, irrespective of commercial status of products.  
• The US Food and Drug Administration (FDA) requires submission of reports of serious, unexpected adverse drug reactions (ADRs) described in the scientific literature for products with the same active moiety as products marketed in the US, even though excipient, dosage forms, strengths, routes of administration and indications may vary.
• The “literature” section of the periodic benefit– risk evaluation report (PBRER) requires a summary of new and significant safety findings for approved products, obtained from published peer-reviewed scientific literature or unpublished manuscripts during the reporting interval.
• EMA guidelines also require inclusion of relevant applicable safety information for other active substances of the same class as the marketed drug. Consequently, any potentially relevant event identified in the literature may be considered an emerging safety issue requiring prompt immediate analysis and, if needed, corrective and preventive action.
• Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase, Eudravigilance) no less frequently than once a week.

Summary of MLM guidelines:

• MAHs should perform a systematic literature review of widely used reference databases no less frequently than once a week, unless the active substances of their products are present in the list of publications monitored by the European Medicines Agency (EMA) pursuant to Article 27 of Regulation (EC) No 726/2004.  
• However, the MAHs need to continue to monitor all other medical literature not covered by the literature reference databases applied for the service by the EMA.
• The MLM services of EMA started on September 1st, 2015. The full monitoring list contains more than 400 active substance groups. The EMA is responsible for monitoring selected medical literature and for entering identified reports of suspected adverse reactions in EudraVigilance.
• The clock for reporting starts (Day 0) with awareness of a publication containing the minimum information for reporting.  
• All the suspect adverse reactions found by the EMA in the listed medical literature, both serious (EU and non-EU) and non-serious (EU only), are not transmitted to MAHs, indeed they are transmitted to EudraVigilance and National Competent Authorities (NCAs) and made available to MAHs via EudraVigilance.  
• The MAHs, however, should download and include these ICSRs in their safety database. They can provide an assessment of the case, describe a disagreement with, and/or alternatives to the diagnoses given by the primary source and/or indicate the degree of suspected relatedness of each medicinal product to the adverse reactions.
• Where the MAH identifies a literature case entered by EMA to be a duplicate of the company’s individual case, which was previously submitted to EudraVigilance, there is a need to send a follow-up with the world-wide unique case identifier to EudraVigilance.  
• In addition to the activities above, MAHs should also monitor the scientific and medical publications in local journals in countries where medicinal products have a MA.
• Reports of suspected adverse reactions from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by MAHs to identify and record possible ICSRs.

How the companies search relevant cases in database:

• It is important that, in addition to searching for adverse events/reactions, the search is constructed to retrieve any special situation reports (e.g. pregnancy and breastfeeding, overdose, abuse, misuse, medication errors, occupational exposure) and, if relevant, use in specific patient populations (e.g. paediatrics).  
• The search strategy should also be able to retrieve reports of off-label and compassionate use.  
• As a general rule, searches should be performed using the active substance.  
• For combination products, all active substances need to be included in the search strategy.  
• Searches should not be routinely conducted that exclude unbranded products.  
• It is common for authors of literature articles to refer to a generic medicinal product and the MAH should assume ownership of the product if it can not, with absolute certainty, confirm that the product is not its own.  
• In addition, where the formulation is not specified, ownership of the product should be assumed.
• For some regulators, reports should not be excluded based on the formulation.  
• Articles referring to a class of drugs that describe a class effect, whilst not appropriate for ICSRs may be relevant for inclusion in periodic reports.  

Safety information: Below safety information is collected from literature reports.

• New, unexpected serious and non-serious ICSR reports with a  reasonable causal association with the product.
• Pregnancy outcomes (including termination) with no adverse  outcomes
• Use in paediatric populations
• Compassionate supply, named patient use
• Lack of efficacy
• Asymptomatic overdose, abuse or misuse
• Medication error where no adverse events occurred
• Important non-clinical safety results

Processing of Confirmed ICSRs

1. For literature reports of confirmed cases which can generate ICSRs, a full text of the citation is obtained and, if not in English, translated into English though it is not specified how/who does this or how long this takes).

2. The article is reviewed and the number of valid ICSRs is determined and seriousness/non-seriousness is noted.

3. An ICSR is then created along with a case narrative for serious cases. No narrative is prepared for non-serious ICSRs.

4. Causality assessment and relatedness also performed.

A regulatory reporting form with relevant medical information should be provided for each identifiable patient. The regulatory reporting time clock starts as soon as the MAH has knowledge that the case meets minimum criteria for reportability.

Examples of new events identified through literature review:

Nifedipine and Fatal Aplastic Anemia (1998): Article described a case- control study linking six cases of fatal aplastic anemia with nifedipine Report identified a Type B ADR (bizarre or idiosyncratic, dose independent and unpredictable reaction) Reference: Laporte JR, Ibanez L, Ballarin E, Perez E, Vidal X. Fatal Aplastic anemia associated with nifedipine. Lancet. 1998;352: 619-20

Tamsulosin and ‘Floppy Iris Syndrome” (2005): 15 cases were described in the literature in April, 2005 At the time of publication, none had been reported to the Regulatory Authorities! Reference: Chang DF, Campbell JR,. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg. 2005;3: 664-73

4 responses to “9. Literature reports”

👍🏼👍🏼 Good information

Indetailed information about literature cases. Thans for your fabulous work.

Great information Author. Can you also provide information on how MLM is actually conducted and where companies can go wrong?

Great Information. It is very informative for all PV profession specifically freshers self understandable. Great efforts. Thank you

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[Literature review on pharmacovigilance of medicines derived from traditional pharmacopoeias. Part II: Risks assessment and prevention]

Affiliations.

• 1 Laboratoire du développement du médicament (LADME), centre de formation, de recherche et d'expertises en sciences du médicament (CEA-CFOREM), école doctorale sciences et santé (ED2S), université Joseph KI-ZERBO, 03 BP 7021 Ouagadougou, Burkina Faso; EA 7307, Centre d'études internationales et européennes (CEIE), faculté de pharmacie, université de Strasbourg, 74, route du Rhin, 67400 Illkirch, France. Electronic address: [email protected].
• 2 EA 4487, Centre de recherches en droit et perspectives du droit, faculté de pharmacie, université de Lille, rue du Professeur-Laguesse, BP 53, 59006 Lille, France.
• 3 EA 7307, Centre d'études internationales et européennes (CEIE), faculté de pharmacie, université de Strasbourg, 74, route du Rhin, 67400 Illkirch, France.
• 4 Laboratoire du développement du médicament (LADME), centre de formation, de recherche et d'expertises en sciences du médicament (CEA-CFOREM), école doctorale sciences et santé (ED2S), université Joseph KI-ZERBO, 03 BP 7021 Ouagadougou, Burkina Faso.
• PMID: 34896380
• DOI: 10.1016/j.pharma.2021.11.007

After the initial stage of the pharmacovigilance process for medicines from traditional pharmacopoeias - which concerns the identification of the risks associated with their use - the risk assessment should now be approached. The latter makes it possible to detect potential signals early and to take preventive measures. We sought to understand, from a review of the literature, the steps and methods of risk assessment relating to traditional medicines, as well as the prevention strategies applied to them. All of the work carried out on the subject has shown that the steps and methods for assessing and preventing drug risks are the same for both conventional and traditional medicines. Risk assessment includes analysis of the quality of individual notifications, assessment of causality, detection and evaluation of signals. The World Health Organization method is the most widely used for causality assessment internationally, while disproportionality measures are the most applied for signal detection. Regarding prevention, risk communication is the main strategy for the risks associated with traditional medicines. This review suggests the involvement of traditional medicine practitioners both in the notification system and in the communication strategy on the risks associated with their products.

Keywords: Assessment; Médicaments traditionnels; Pharmacovigilance; Prevention; Prévention; Risks of use; Risques d’utilisation; Traditional medicines; Évaluation.

Copyright © 2021 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Publication types

• Adverse Drug Reaction Reporting Systems
• Drug-Related Side Effects and Adverse Reactions* / epidemiology
• Drug-Related Side Effects and Adverse Reactions* / prevention & control
• Pharmacovigilance*
• Risk Assessment

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Article Contents

Conflict of interest.

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Reply: Absence of evidence is not evidence of absence for first trimester dydrogesterone-induced birth defects

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Alexander Katalinic, on behalf of the authors Maria Noftz, Juan Garcia-Velasco, Lee Shulman, John van den Anker, and Jerome Strauss III, Reply: Absence of evidence is not evidence of absence for first trimester dydrogesterone-induced birth defects, Human Reproduction Open , Volume 2024, Issue 2, 2024, hoae031, https://doi.org/10.1093/hropen/hoae031

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We would like to thank Quadros et al. (2024) for their letter regarding our article and also wish to thank you for the opportunity to comment on the points that they have raised.

In their letter, Quadros et al. expressed concerns regarding the quality, number of cases, and outcome assessment of the studies included in our systematic review ( Katalinic et al. , 2024 ). They also commented on the inclusion of three additional studies for estimating the prevalence rate associated with dydrogesterone use in the first trimester of pregnancy. They then report the results of an analysis of pharmacovigilance data that they believe shows an association between dydrogesterone and congenital anomalies and suggest that we have overlooked this work. They conclude that our meta-analysis is not robust enough to draw conclusions regarding the safety of dydrogesterone ( Quadros et al. , 2024 ).

First of all, it is possible that Quadros et al. are not familiar with the methodological procedures of a systematic review and the assessment of the results of such a review. The aim of a systematic review is to identify, critically review, and summarize all available evidence on a clearly defined question in a very standardized way, based on a predefined and registered study protocol using up-to-date methodology ( Higgins et al. , 2023 ). This is what we have done. In their letter, Quadros et al. overlook two important aspects. First, the evidence summarized in our systematic review represents the currently best available and valid evidence on dydrogesterone exposure in the first trimester. Flawed, retracted, and critical biased publications, which can be found in the vastness of the internet, were excluded using a clear and reproducible methodology. Even if included, individual studies still have limitations: these limitations were clearly identified, assessed, and reported in a standardized manner. Some of the included studies have serious, but non-critical limitations, and could therefore be considered for the review. Subgroup analyses of high- and low-quality studies led to comparable results, and heterogeneity overall was very low. Therefore, our conclusions can be described as very robust. Second, it must be considered that the main finding of our systematic review was evaluated with regard to safety/uncertainty using the GRADE system. We clearly state that the evidence level for our findings was graded as low (leaving uncertainty), which is also reflected by the confidence interval for the main effect (three congenital anomalies fewer under dydrogesterone exposure; from 17 fewer to 21 more; based on 6 studies with 1512 children).

The assumption that we have overlooked the analysis by Henry et al. (2023) is inaccurate for several reasons. It is stated in the ‘Methods’ section of our article that the literature search extended to September 2022. The analysis in question by Henry et al. is from September 2023, is a half-page congress abstract and has not yet been published in a peer-reviewed format—therefore, it was impossible to include it. Even if this contribution had been eligible for review, it could not have been considered for our meta-analysis owing to a lack of information and the inability to critically evaluate the report according to review guidelines. The abstract leaves many questions open, as well as possible biases since reporting or detection bias cannot be ruled out ( Matsuda et al. , 2015 ; Faillie, 2019 ).

We have already made it clear in our article that pharmacovigilance data can play an important role as a signal giver. However, the results of such analyses should only be interpreted as a sign and not more, because they may just as well be noise or prone to bias. Moreover, results based on pharmacovigilance data alone do not allow any causal conclusions to be drawn, especially if biological plausibility is lacking. Signs must be verified by adequate studies. In the case of dydrogesterone, such studies, which are superior to pharmacovigilance data, are already available and formed the basis of our systematic review.

We do not understand Quadros et al. ’s (2024) objection to the estimation of the prevalence rate of congenital anomalies in dydrogesterone exposure. In order to make the estimate more robust, three cohort studies were included that were judged to be of sufficient quality, and in which all children were exposed to dydrogesterone. The pooled prevalence for congenital anomalies was 2.5% [95% CI 1.5–4.3%], with no big differences in the subgroups analyzed (RCT only: 3.4%, controlled cohort studies: 2.3%, and 1.8% in the three added studies; all with overlapping confidence limits).

To summarize, we disagree with Quadros et al. (2024) on these essential points. Our systematic review represents the best currently available evidence on the question of an increased rate of congenital anomalies after exposure to dydrogesterone in the first trimester. Based on the originally used PubMed/Medline search, no new studies could be identified at the time of writing (performed on 2 April 2024). A significant increase or decrease in the rate of congenital anomalies after dydrogesterone exposure was not detectable. As already discussed in our article ( Katalinic et al. , 2024 ), while there may be a difference in rates of congenital anomalies, based on the confidence interval of the main finding of our systematic review, the difference would presumably be small and open in terms of which direction.

A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023.

Faillie JL. Case-non-case studies: principle, methods, bias and interpretation . Therapie 2019 ; 74 : 225 – 232 .

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Henry A , Santulli P , Bourdon M , Treluyer JM , Chou Chana L. O-150 birth defects reporting and the use of oral dydrogesterone in assisted reproductive technology: a global pharmacovigilance study . Hum Reprod 2023 ; 38 : dead093.177 .

Higgins JPT , Thomas J , Chandler J , Cumpston M , Li T , Page MJ, Welch VA (Editors) . Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane [Internet]. 2023 ; www.training.cochrane.org/handbook (10 April 2024, date last accessed).

Katalinic A , Noftz MR , Garcia-Velasco JA , Shulman LP , van den Anker JN , Strauss III, JF. No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis . Hum Reprod Open 2024 ; 2024 : hoae004 .

Matsuda S , Aoki K , Kawamata T , Kimotsuki T , Kobayashi T , Kuriki H , Nakayama T , Okugawa S , Sugimura Y , Tomita M et al.  Bias in spontaneous reporting of adverse drug reactions in Japan . PLoS One 2015 ; 10 : e0126413 .

Quadros R , Puppalwar G , Mane A , Mehta S. Absence of evidence is not evidence of absence for first trimester dydrogesterone induced birth defects . Hum Reprod Open 2024 ; 2024 :hoae030.

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Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 13-16 May 2024

Hydroxyprogesterone caproate medicines to be suspended from the EU market

EMA’s safety committee (PRAC) has recommended the suspension of the marketing authorisations for medicines containing 17-hydroxyprogesterone caproate (17-OHPC) in the European Union (EU). A review by the PRAC concluded that there is a possible but unconfirmed risk of cancer in people exposed to 17-OHPC in the womb. In addition, the review considered new studies, which showed that 17-OHPC is not effective in preventing premature birth. There are also limited data on its effectiveness in other authorised uses.

In some EU countries, 17-OHPC medicines are authorised as injections to prevent pregnancy loss or premature birth in pregnant women. They are also authorised for the treatment of various gynaecological and fertility disorders, including disorders caused by a lack of a hormone called progesterone.

In view of the concern raised by the possible risk of cancer in people exposed to 17-OPHC in the womb, together with the data on the effectiveness of 17-OHPC in its authorised uses, the PRAC considered that the benefits of 17-OHPC do not outweigh its risks in any authorised use. The Committee is therefore recommending the suspension of the marketing authorisations for these medicines. Alternative treatment options are available. 

More information on the PRAC’s review is available in EMA’s public health communication .

New safety information for healthcare professionals: Hydroxyprogesterone caproate medicines to be suspended from the EU market

The PRAC also discussed a direct healthcare professional communication (DHPC) for 17-hydroxyprogesterone caproate medicines.

The DHPC will inform healthcare professionals of the PRAC’s recommendation to suspend the marketing authorisations of these medicines in the EU.

The DHPC will also advise healthcare professionals to consider alternative treatment options for any indication.

The DHPC for 17-hydroxyprogesterone caproate medicines will be forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). When adopted, the DHPC will be disseminated to healthcare professionals by the marketing authorisation holder, according to an agreed communication plan, and published on the  Direct healthcare professional communications page and in  national registers  in EU Member States.

Agenda of the PRAC meeting 13-16 May 2024

English (EN) (659.24 KB - PDF)

PRAC statistics: May 2024

English (EN) (33.13 MB - PDF)

• Safety signal assessments . A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under ' Signal management '.
• Periodic safety update reports , abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under ' Periodic safety update reports: questions and answers '.
• Risk management plans , abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation. RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under 'Risk-management plans '.
• Post-authorisation safety studies , abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under ' Post-authorisation safety studies '.
• Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under referral procedures .
• Summary safety reports have been introduced as part of the enhanced safety monitoring of COVID-19 vaccines. Marketing authorisation holders are required to submit these reports to EMA, starting on a monthly basis. Their submission complements the submission of PSURs. For more information see Pharmacovigilance plan of the EU Regulatory Network for COVID-19 vaccines . 

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• Pharmacovigilance Risk Assessment Committee (PRAC): 13-16 May 2024
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Abbreviations used in EMA scientific committees and CMD documents, and in relation to EMA’s regulatory activities

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Opportunities and challenges of pharmacovigilance in special populations: a narrative review of the literature

Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China

Tingting Jiang

Haiyan xing, guiyuan xiang.

Department of Pharmacy, Daping Hospital, Army Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China

The relatively new discipline of pharmacovigilance (PV) aims to monitor the safety of drugs throughout their evolution and is essential to discovering new drug risks. Due to their specific and complex physiology, children, pregnant women, and elderly adults are more prone to adverse drug reactions (ADRs). Additionally, the lack of clinical trial data exacerbates the challenges faced with pharmacotherapy in these populations. Elderly patients tend to have multiple comorbidities often requiring more extensive medication, which adds additional challenges for healthcare professionals (HCPs) in delivering safe and effective pharmacotherapy. Clinical trials often have inherent limitations, including insufficient sample size and limited duration of research; as some ADRs are attributed to long-term use of a drug, these may go undetected during the course of the trial. Therefore, the implementation of PV is key to insuring the safe and effective use of drugs in special populations. We conducted a thorough review of the scientific literature on PV systems across the European Union, the United States, and China. Our review focused on basic physiological characteristics, drug use, and PV for specific populations (children, pregnant women, and the elderly). This article aims to provide a reference for the development of follow-up policies and improvement of existing policies as well as provide insight into drug safety with respect to patients of special populations.

Plain language summary

Pharmacovigilance (PV) in special populations: opportunities and challenges

Why is it important to implement PV in special populations?

Due to the particularity of physiological functions, the special population (children, pregnant women, and the elderly) are more susceptible to adverse drug reactions (ADRs) and have more drug safety problems. The implementation of PV is helpful for the detection of safety risks throughout the life cycle of drugs, so that healthcare professionals (HCPs) can take early measures to reduce the drug use risks of patients.

What are the problems to implement PV for special populations?

Many countries have implemented a PV system. However, PV policies and systems for the special population are not complete in various countries, or no independent PV system for the special population has been set up.

What does this article add to our knowledge?

This article discusses the PV systems of the European Union, the United States, and China with special focus on basic physiological characteristics, use of drugs, and the implementation of PV with respect to children, pregnant women, and the elderly. Focus on these problems are of great importance for formulating a more complete drug management scheme in the special population and can provide a reference for the development of follow-up policies and improvement of existing policies.

Introduction

In 1968, the World Health Organization (WHO) established the global individual case safety report (ICSR) database VigiBase, which regularly receives data regarding adverse drug reactions (ADRs) from more than 140 countries. 1 In 1974, the concept of pharmacovigilance (PV) was first proposed in France. In 2002, WHO explicitly defined PV as ‘the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems’. 2 The trend in drug management has shifted from focusing on disease treatment to managing a drug’s development and clinical use. Compared with ADRs, PV has expanded with respect to its terms and definitions, range of coverage, and drug monitoring cycle. An ADR is defined as ‘an unintended harmful reaction of a drug product that occurs in the normal amount of use’. 3 In addition to covering adverse reactions and monitoring of adverse events, PV also covers drug safety issues such as substance abuse, drug quality, medication errors, drug interactions, and reactions to excipients. 4 PV involves not only conventional drugs but also blood products, biological products, and vaccines. PV monitors drug safety events during the whole drug ‘life cycle’ (pre-marketing, post-marketing, and any recall or withdrawal from market).

ADRs can cause serious physical harm to patients and also represent a significant economic burden. In one hospital in the United Kingdom, the cost of hospital admission due to ADRs was £466 million per year. 5 The cost of adverse reactions in the United States is as high as $30.1 billion per year. 6 These figures are striking, especially since in most cases, ADRs can be prevented or effectively treated. 7 PV is critical for discovering unexpected ADRs, and, if properly implemented, can warn of the potential for post-marketing ADRs and thereby reduce harm. Clinical trials are valuable when evaluating drug efficacy, but they are far from thorough in evaluating drug safety. Due to sample size limitation, ADRs or adverse drug events (ADEs) identified during clinical trials typically represent only the most common safety problems of the studied drug. The practice of PV is an effective strategy to systematically and comprehensively evaluate drug safety throughout the drug’s life cycle and to discover any rare ADRs.

There are many challenges facing the safe use of medication in children, pregnant women, and elderly adult populations. As physiologic systems in children are not fully developed, drugs may not behave in children the same way as they do in adults. Therefore, off-label use of drugs (the indication, dosage, course of treatment, administration method, or population of drug use are not within the scope of the medication package insert approved by the drug regulatory department) and the incidence of drug use errors (e.g. wrong dose, prescribing errors, dispensing errors, and administration errors) are more common. 3 , 8 In addition, clinical trials in children often face challenges in subject recruitment, precluding the design of large-scale studies or impeding the use of adequate control groups for a given age range. 9 Clinical trials are also scarce with respect to the study of pregnant patients; therefore, the safety profiles of various drugs with respect to use in pregnancy remain unclear. Elderly patients are particularly prone to ADRs due to functional degradation, decreased immunity, memory decline, and the presence of multiple comorbidities. The implementation of PV systems in the European Union, the United States, and China and their related databases are discussed below, with special focus on the implementation of these systems with respect to special populations. Here, we aim to provide a resource for healthcare professionals (HCPs) with the goal of improving drug safety in children, pregnant women, and elderly adults.

We present a narrative review of the literature about PV in special populations. We searched in MEDLINE (PubMed) using the following Medical Subject Headings terms and their synonyms: ‘adverse effects’ OR ‘adverse drug effects’ OR ‘drug-related side effects’, ‘adverse reactions’ OR ‘adverse drug reactions’, ‘pharmacovigilance’, ‘child’ OR ‘children’, ‘pregnant women’ OR ‘gravida’, ‘elderly’, ‘physiological characteristics’ OR ‘absorption’ OR ‘distribution’ OR ‘metabolism’ OR ‘excretion’, ‘drug use’ OR ‘medication’ OR ‘medication use’. This search includes literature published as of December 2022. We conducted a preliminary screening of the identified records based on their titles and abstracts, and subsequently selected relevant studies for inclusion in this review based on a thorough review of the full text. Three researchers screened the articles, and any differences were resolved by consensus.

Articles included in the narrative review discussed the PV systems of the European Union, the United States, and China. Moreover, we evaluated the included literature related to the basic physiological characteristics, use of drugs, and the implementation of PV with respect to children, pregnant women, and the elderly.

PV implementation around the world

The discipline of PV has been introduced in the European Union, the United States, China, Japan, South Korea, and several other countries; these countries typically have differing institutional settings and ADR reporting systems. The three most famous ADR spontaneous reporting databases in the world are EudraVigilance, FDA Adverse Event Reporting System (FAERS), and VigiBase. The construction of these drug safety monitoring databases is a crucial aspect of PV implementation. Data mining is extensively utilized in medicine, particularly in ADE monitoring, to extract and assess potential rules from vast data sources. The disproportionality analysis is the frequently utilized approach to mine ADE signals. This method can efficiently identify the association between drugs and adverse effects. The disproportionality analysis is categorized into the frequency method and Bayesian method. It mainly compares the ratio of actual and expected ADE reports. A safety signal is indicated when the ratio surpasses a predetermined critical value. The frequency method, including reporting odds ratio (ROR) and proportional reporting ratio (PRR), utilizes statistical methods to examine relative risk ratios. Its logical principles are clear and easy to understand, with simple computations, high sensitivity, and specificity. However, it is prone to generating false positive signals. 10 , 11 Bayesian methods, such as Bayesian confidence propagation neural network (BCPNN) and multiple item empirical Bayesian Gamma Poisson Shrinker (MGPS), are based on the Bayesian principle and are commonly used in data analysis. They provide stable calculation results and have no usage restrictions, making them suitable for analyzing large datasets. However, the use of these methods may lead to false negative signals, which should be taken into account. Despite these limitations, Bayesian methods continue to be an important tool for scientific research due to their reliability and accuracy. 12 , 13 Both the frequency method and the Bayesian method are based on a four-cell table ( Table 1 ). The specific equations and signal generation criteria of the four methods are shown in Table 2 .

Four grid table for the disproportionality analysis.

a , number of reports containing both the target drug and target ADR; b , number of reports containing other ADR of the target drug; c , number of reports containing the target ADR of other drugs; d , number of reports containing other drugs and other ADR.

ADR, adverse drug reaction.

Four major algorithms used for signal detection.

Equation: a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions.

95% CI, 95% confidence interval; χ 2 , chi-squared; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM; IC, information component; IC025, the lower limit of 95% CI of the IC.

The European Union and the United States, as the earliest countries to introduce PV, have more developed systems and policies based on larger bodies of data. Although introduced later, the review of PV systems in China may also be informative. Therefore, we will focus primarily on the implementation and management of PV systems in the European Union, the United States, and China.

PV in the European Union

The current laws and regulations of the European Union regarding PV were revised and improved in 2012 and comprise four parts: directive, regulation, non-legislative acts, and miscellaneous. 14 Member states manage their own individual PV systems within the framework of the larger European Union system. The European Medicines Agency (EMA) and the relative regulatory agencies of member states, respectively, approve and regulate drugs marketed through both centralized and non-centralized review procedures. The ADR reporting system in the European Union employs a combination of spontaneous and mandatory reporting. Among these, spontaneous reporting is the main reporting modality and is primarily used by medical institutions, monitoring agencies, and patients. Mandatory reporting is secondary, and typically used by drug manufacturing companies. Furthermore, PV laws and regulations stipulate that marketing authorization holders (MAHs) establish a ‘Qualified Person for Pharmacovigilance’ (QPPV) to oversee PV-related work and facilitate communication with EMA.

EMA has established seven scientific committees, one of which is the PV Risk Assessment Committee. This committee is responsible for assessing and monitoring drug safety issues in humans and consists of surveillance and management experts, patient representatives, and HCPs.

The main database used by EMA to monitor ADRs is EudraVigilance. Through data mining, potential drug risks are identified to provide the timeliest drug safety information possible to the public with the goal of controlling the impact of ADRs. Adverse reaction reports from the European Union are first sent to the individual member state PV contact or the MAH by way of an online or paper report form. The individual case safety report (ICSR) is only reported to EudraVigilance after it has been reviewed and confirmed as valid. This process is conducive to ensuring the accuracy and quality of data submitted to EudraVigilance and increasing the credibility of conclusions based on subsequent data mining of this database. For any high-risk drugs identified, EMA increases the frequency of surveillance and data analysis. European Union member states can freely access EudraVigilance, facilitating its use by medical and scientific professionals.

PV in the United States

The United States Food and Drug Administration (FDA) began collecting ADR reports in 1961. The agency largely responsible for PV in the United States is the Center for Drug Evaluation and Research (CDER), a subdivision of the FDA. There are no local PV institutions, and CDER is the only national PV center. The main responsibility of CDER is to monitor, identify, evaluate, and control risks throughout the life cycle of drugs. Also under the purview of this institution is the authenticity and integrity of drug-related data. Within CDER are the Office of New Drugs, the Office of Compliance, the Office of Generic Drugs, and the Office of Surveillance and Epidemiology (OSE). OSE is the main department responsible for drug safety work such as PV, drug epidemiology, and drug risk management. The adverse reaction reporting system of the FDA is also divided into two categories: the mandatory reporting system for drug manufacturers and the MedWatch voluntary reporting system for patients and medical professionals. The other two national voluntary reporting systems in the United States are the Institute for Safe Medication Practices Medication Errors Reporting Program (ISMP-MERP) and the United States Pharmacopoeia MEDMARX drug error-reporting system. 15 , 16

The FDA’s active PV monitoring system was first introduced in 2008. The FDA collects and analyzes the electronic data of medical institutions and compiles and publishes drug monitoring information through its website. The FDA also has a passive detection system for safety signals called the FAERS, which contains data on all marketed drugs and is a helpful tool for use in the monitoring of drug safety. Professionals can identify high-risk drugs by reviewing data regarding adverse reactions in this database. From these data, active monitoring rules and any needed emergency measures can be established for the relevant drugs with the intent to reduce patient harm.

PV in China

In June 2017, the China National Medical Products Administration (NMPA) joined the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In December 2019, China’s newly revised Drug Administration Law was officially implemented, in which Article 12 of Chapter I stipulated the establishment of a PV system. In May 2021, China’s first PV Quality Management Standard (No. 65, 2021) was issued; this standard took effect on 1 December 2021, representing China’s shift from monitoring of post-market ADRs to monitoring the safety and risks related to the whole life cycle of a drug. NMPA issued the Guiding Principles of PV Inspection on 15 April 2022 to act as a guide for regulatory authorities with respect to PV inspection and to further improve the overall implementation of PV.

The NMPA is the main organization for PV work in China and is responsible for the monitoring of ADRs and post-marketing safety evaluation. China’s ADR monitoring network is mainly divided into four levels: national, provincial, municipal, and county. Data from these levels combine to form a centralized spontaneous reporting system. ADRs are collected and recorded into the database according to a standardized reporting principle when events are suspected. However, this reporting method has several limitations including omission of information, non-standard filling of relevant forms, and incomplete reporting of events. To improve this system, realize the active monitoring of risk signals, and better promote the reporting and analysis of ADRs, China began to explore the establishment of the Chinese Hospital PV System in 2016. In 2020, the NMPA proposed a ‘one body and two wings’ adverse reaction monitoring system. The ‘one body’ refers to the ADR monitoring organization, which is the professional and technical organization within the system. The ‘two wings’ are the MAH and individual medical institutions, which mainly fulfill the relevant responsibilities set forth by law.

PV in China comprises two main modules. The NMPA is responsible for the supervision of policy implementation within regional drug administrations. The National Adverse Drug Reaction Monitoring Center, directly under the NMPA, is responsible for ADR monitoring and the collection and reporting of ADR information at a national level. Unlike WHO, the European Union, and the United States, China’s ADR database is not open to the public and external personnel have no access to its data.

Child patient

Basic physiological condition of children.

In the context of medicine, children are defined those 0–14 years old. This group can be further divided into several subgroups, including neonates (0–28 days old), infants (0–3 years old), those in early childhood (1–7 years old), and juveniles (7–14 years old). 17 – 21 For children, it is not sufficient to simply regard them as miniature adults [ Figure 1(a) ]. Drug pharmacokinetics (PK) and pharmacodynamics (PD) observed in children are different from those observed in adults. 22 , 23 The underlying reason for this may be that compared to adults, children have higher ratio of water to lipids, lower total plasma protein, and lower intestinal activity of cytochrome P-450 1A1 (CYP1A1). 3 , 24 In addition, children are more vulnerable to external factors as a result of immature organ function. For example, non-alcoholic fatty liver disease is present in about 10% of children 25 ; this impairment of liver function can complicate the safe use medication in children. Furthermore, children of different ages and weights can have varying PK and PD characteristics. 24 , 26 Finally, the characteristics, course, and etiology of diseases in pediatric patients may also be different from those in adults. 22 These multiple factors all contribute to differences in the efficacy and safety of drugs seen in pediatric versus adult patients.

(a) Physiological characteristics of children, (b) Risk factors of ADRs in children, (c) Acts relevant to the safe use of drugs in children and (d) Common drugs causing ADRs in children.

This figure created with BioRender.com.

ADRs, adverse drug reactions; PK, pharmacokinetics; PD, pharmacodynamics.

Use of medication in the child patient

Currently, the issues surrounding drug use in children primarily revolve around challenging clinical trials, limited drug options specifically formulated for children, inadequate or unclear instructions on children’s medication usage in the package inserts, and insufficient production of specialized dosages and specifications tailored for children. A prospective cohort study showed up to 96.4% of newborns were exposed to off-label drugs. 27 The primary classifications associated with the off-label drug use include unapproved age group usage, off-label indications, and unapproved dose administration. 28 Additionally, for the treatment of pediatric patients, both the drug dosing strategy and the course of treatment must be thoroughly studied. The lack of dosages and specifications for children frequently necessitates fragmentation of tablets in clinical settings. This practice can disrupt the integrity of the medication’s dosage structure and lead to imprecise dosing. In clinical trials with children, determining the appropriate dosage is extremely important to ensure the safety and efficacy of drugs. Dosage for children is usually calculated based on body weight, body surface area, and clearance rate. 29 Previously utilized dose calculation rules include: Young’s age rule, Clark’s weight rule, Clark’s surface area rule, and Shirkey’s dosing recommendations. 24 , 30 However, most of these rules are not considered accurate enough for dose calculation in children. A possible reason is that these rules were designed for use with small molecule drugs and did not universally apply well to new drugs. The allometric method and Salisbury Rule are able to predict the appropriate first dose for therapeutic proteins (i.e. monoclonal and polyclonal antibodies and non-antibody proteins) in clinical trials with children. 22 , 31 , 32 However, it is clear that a single-drug administration strategy cannot be applied across all childhood age subgroups. Optimal dosage calculation rules may vary for different ages, body weights, types of drugs, and treatment courses.

Implementation of a PV system for children

Many lessons have been learned in the course of development of a pediatric PV strategy. In October and November of 1901, 22 children died from injection of diphtheria antitoxin contaminated with tetanus bacilli. 33 Subsequently, the Biological Agents Control Act was introduced on 1 July 1902. This act specifies that enterprises that want to produce and sell vaccines and antitoxins must obtain a license. In 1938, 107 children died from administration of oral sulfanilamide formulated with diethylene glycol. 34 Following this tragedy, the United States government enacted the Food, Drug, and Cosmetic Act. With the continuous development of the field of medicine, a large number of drugs intended for use in children are marketed every year. During January 1996 through December 2019, the European Union approved a total of 405 medicinal products and 322 active substances for use in pediatric populations. 9 Ensuring the quality, safety, and effectiveness of all drugs indicated for use in children after marketing is a major challenge that requires serious consideration by all parties involved in drug development, clinical use, and marketing.

In pediatric clinical drug trials, the mechanisms for assessing potential risks are inadequate, the criteria are unclear, and high-quality evidence is lacking. Therefore, there are more drug safety issues arising in pediatric patients than in adults [ Figure 1(b) ]. In order to inform evidence-based decision making with respect to the safety and long-term benefits of pharmacotherapy in children, many policies and regulations support the inclusion of children in relevant clinical studies [ Figure 1(c) ]. In 2001, the European Clinical Trials Directive allowed children to be included in clinical trials. 34 In 2002, the United States enacted the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, implemented in 2003. 35 These bills promote drug manufacturers to conduct clinical drug trials in children. The EMA first published their pediatric PV guidance standard in 2006, which is now included in the Good PV guidance standard in the Population-Specific Considerations IV: Pediatric Population section. 36 The European Pediatric Regulation was officially implemented in 2007, and stipulates that except for certain exemptions, the marketing license applying to drugs must include research conducted in children. 37 Given that children do not have full consent rights, the FDA has established 21 Code of Federal Regulations 50, subpart D [2001/2013] to ensure the safety of children participating in clinical trials. 38 In addition, the FDA human subject protection regulations clearly stipulate that pediatric clinical trials can only be conducted when the benefits outweigh the risks, or there is sufficient evidence to prove that the risks are reasonable and provide the prospect of direct benefit to children. 35 Due to the paucity of evidence regarding drugs intended for use in children the many differences between children and adults, it is difficult to define this ‘direct benefit’. A workshop convened in 2019 by the FDA in collaboration with the Duke-Margolis Center for Health Policy produced expert advice on how to define this term. 39 The seminar mainly evaluated the prospect of direct benefit from five angles: biological plausibility, non-clinical data, clinical data, dosing justification, and trial duration. These efforts were made to ensure the maximum benefit of pediatric patients participating in clinical trials. 35 , 39

With the vigorous development of PV systems and the cooperation and support of international agencies and institutions, more and more drug safety data are publicly obtainable [ Figure 1(d) ]. At present, the three major public ADR databases are EudraVigilance, FAERS, and VigiBase. Rasmussen et al. 40 found that 40% of children experienced drug-induced adverse reactions in cases related to immunoglobulin A (IgA) vasculitis in the French PV database and VigiBase. The drugs implicated included vaccines (measles, rubella, mumps, influenza, poliomyelitis, diphtheria, and tetanus), antibiotics, and immunomodulatory TNF-α blockers (e.g. adalimumab and infliximab). It is critical to analyze database cases like these to determine the mechanisms underlying ADRs and to take appropriate action in withdrawing the drug or providing symptomatic treatment. In addition, Haarman et al. 41 analyzed relevant data in the Netherlands PV Center Lareb and VigiBase and found that neuropsychiatric symptoms (e.g. nightmares, aggression, and depression) and headaches were related to the use of montelukast in children with asthma. Using these databases for risk factor analysis can help identify potential adverse reactions that go undetected in clinical trials due to small pediatric sample sizes. Aside from analyzing data from the database, the researchers also conducted prospective pharmacoepidemiology studies using patients from children’s hospitals. Yori et al. 42 analyzed 111 pediatric patients receiving intravenous immunoglobulin G and found that the incidence of adverse reactions was relatively low and could be treated effectively. A Canadian Pediatric Surveillance Program (CPSP) Study found that if a pediatric patient’s parents have acanthosis nigricans or type 2 diabetes (T2D), blood glucose should be closely monitored when using diabetogenic medication. 43 Another prospective observational study found that approximately 17.7% of treated pediatric patients experienced at least one ADR, and the incidence of adverse reactions in children who had received general anesthesia was more than six times that of non-anesthetized children. 44 It is important to recognize that any neglected adverse reaction may result in long-term consequences that can affect the whole life of a pediatric patient. Therefore, whether in the process of treatment, research, or exploration, HCPs and researchers should approach drug-related issues with a meticulous and rigorous attitude.

Despite many difficulties, there are many professionals working toward improving PV in pediatric populations. The conect4children expert group white paper introduced various considerations regarding pediatric PV, including protocol development, risk management plans, Pediatric Investigation Plans, and collection and analysis of safety data. 34 The EMA also requires a benefit-risk assessment if clinical trial research is to include children. 45 Good PV in pediatrics can help optimize treatment, reduce harm, help prescribing physicians understand the potential long-term effects of drugs, and assist physicians in designing optimal treatment strategies. We believe that over time, the management of drug safety and efficacy in pediatric patients will improve greatly.

Pregnant and lactating patients

Basic physiological condition of pregnant women.

The processes of maternal absorption, distribution, metabolism, and excretion in different stages of pregnancy experience various changes [ Figure 2(a) ]. Therefore, in order to ensure the safety and efficacy of drugs intended for use during pregnancy, it is necessary to adjust the dose and frequency of administration according to these physiological changes. Early pregnancy is prone to physiological reactions that often result in nausea and vomiting, which can in turn cause the reduced absorption and bioavailability of orally administered drugs. In addition, gastric acidity decreases and gastric emptying and peristalsis slowdown, which can also lead to changes in drug absorption. 46 Drug distribution can also vary with the increase in plasma volume and the associated relative decrease in plasma albumin. 47 Changes in hepatic enzyme activity, renal blood flow, and glomerular filtration rate have also been shown to affect drug metabolism and excretion. 46 Besides physiological pregnancy changes, the chance of developing maternal anxiety and antenatal or postpartum depression increases. 48 Furthermore, despite the placental barrier between the mother and fetus, most drugs can still reach the fetus, potentially resulting in fetal drug exposure, and subsequent adverse outcomes. During breastfeeding, drugs can reach the newborn through the milk. However, the extent of the risk to the fetus and newborn for most drugs is still unclear.

(a) Physiological characteristics of pregnant women, (b) Risk factors of ADRs in pregnant women and (c) Evaluation criteria for drug toxicity during pregnancy and lactation.

ADRs, adverse drug reactions.

Medication during pregnancy and lactation

Over 90% of pregnant women will use at least one prescription or over-the-counter medication, with 80% being in the first trimester. Nonetheless, information on PK and drug safety and efficacy in pregnancy is extremely lacking. 49 , 50 There is also little available clinical safety information to guide the rational use of drugs in pregnant and lactating women [ Figure 2(b) ]. Approximately 97.7% of approved drugs do not have safety information relevant to use during pregnancy and lactation. 51 During the COVID-19 pandemic, the majority of clinical trials to treat this disease excluded pregnant women, and both pregnant and lactating women were excluded from COVID-19 vaccine studies. 52 , 53 Population pharmacokinetics (popPKs) modeling and physiologically based pharmacokinetic (PBPK) modeling can be used to predict PK during pregnancy and lactation, providing reference for the formulation of drug dosage and frequency in clinical trials. 53 It is worth noting that these pharmacometric tools, while promising, are not yet fully developed.

The WHO recommends exclusive breastfeeding for the first 6 months of fetal life and breastfeeding until the age of two if conditions permit. 54 , 55 However, more than 50% of women take at least one medication in the postpartum period, and most of these medications have unclear effects with respect to infant health. 56 , 57 As of now, discontinuation of breastfeeding is the safest practice in the event of uncertainty about the safety of a given drug. However, breastfeeding positively affects immune system development in early infancy, promoting subsequent healthy growth of the child. Inadequate information about medicines can lead to premature or inappropriate termination of breastfeeding. Adequate knowledge of drug safety among HCPs is critical to maintain the longest possible duration within the recommended infant age window of breastfeeding.

To better manage medication use in pregnant patients, studies on the safety and effectiveness of prophylactic and therapeutic drugs indicated for use in this population are increasing. According to data published by WHO, 10% of pregnant women and 13% of postpartum women will experience mental disorders. 58 A cross-sectional study in 12 European countries found that approximately 4.3–7.6% of pregnant and postpartum women had moderate to severe depressive symptoms. 59 Another study showed that women over 40 years of age and living in impoverished areas were more likely to use antidepressants. 60 Anxiety and depression in pregnancy are strongly associated with adverse pregnancy outcomes (e.g. miscarriage, preterm birth) and impaired infant development. 61 – 63 Aside from depression and anxiety, primary headache is also common during pregnancy and the postpartum period. One retrospective study found that drugs used to treat primary headache such as antipsychotics, antiepileptics, tricyclic antidepressants, benzodiazepines, β-blockers, acetaminophen, indomethacin, and oral or intravenous magnesium may be associated with adverse fetal reactions. 64 In response to the urgent need to address the treatment of disease in pregnant patients, relevant studies are also underway to provide data for the safe and effective use of certain drugs during pregnancy. Preeclampsia is one of the leading causes of maternal death, and one clinical study (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01717586","term_id":"NCT01717586"}} NCT01717586 ) found that prophylactic use of pravastatin was associated with better pregnancy outcomes in women at high risk. 65 Gestational diabetes causes 5−13% of complications seen during pregnancy. 66 Metformin is commonly used in the treatment of this condition, but the clearance rate of metformin during pregnancy is high; therefore, to achieve the ideal effective concentration, the dose of must be increased. 66 However, Faure et al. 67 showed that metformin exposure in utero may reduce the fertility of male offspring in adulthood. Indomethacin is used to treat preterm labor, but studies have found that as pregnancy progresses, maternal drug exposure decreases while fetal exposure increases. 68 Therefore, the dose of indomethacin should be adjusted as pregnancy progresses to ensure the efficacy of the drug and reduce unnecessary fetal exposure. Tacrolimus, a commonly used immunosuppressive drug in kidney transplant patients, is almost undetectable in breast milk 3 weeks after delivery; as such, it is likely safe to use during lactation. 69 , 70

Maternal physiology during pregnancy is complex, clinical trial protocol design is difficult, and trials involving pregnant women carry many ethical issues. Only 6% of clinical trials registered between 2007 and 2012 included pregnant women, with only 11% of these reporting outcomes. 71 Due to the lack of clinical trials during pregnancy and lactation, most marketed drugs have little available safety and efficacy information with respect to use in these patients. Furthermore, drug effects on human embryos are not fully clear. For these reasons, more attention must be paid to the monitoring and prevention of ADRs during conception and pregnancy. However, it is far from adequate to rely solely on clinical trials and spontaneous reporting adverse drug effects to fully evaluate the safety of drugs indicated for use in pregnant patients. Proper treatment of disease during pregnancy is essential for the health of the mother and fetus; however, medication safety in pregnant patients also impacts both mother and fetus, so the risk assessment at all points of the life cycle of a drug is essential.

Implementation of a PV system for pregnant patients

In addition to considering the therapeutic effect of drugs on the mother, the effect of drugs on the growth and development of the fetus also must be considered [ Figure 2(c) ]. Inappropriate medication regimens can cause serious and even life-long adverse consequences to both mother and fetus. Diethylstilbestrol was used to treat pregnancy complications from the 1940s to the 1960s. It was subsequently found that women with in utero exposure to diethylstilbestrol had a significantly increased risk of infertility, adverse pregnancy outcomes (e.g. spontaneous abortion, preterm delivery, loss of second-trimester pregnancy, ectopic pregnancy, and stillbirth), vaginal and cervical clear cell adenocarcinoma, and breast cancer. 72 , 73 In 1960, the thalidomide tragedy shocked the world, resulting in the birth of tens of thousands of infants with seal deformities. 74 , 75 This event reminds of concerns regarding drug-induced diseases and represents an important inciting factor for the formation of PV systems.

In 1979, the FDA created the pregnancy category labeling system based on reproductive toxicity of drugs. 76 In this system, drugs are classified into five categories: A, B, C, D, and X. 76 Class A and B drugs have no toxicity to the fetus, Class C drugs have uncertain toxicity to the fetus, and Class D and X drugs have been proven to be toxic to the fetus. The first Teratogen Information Service in Brazil has been providing free teratogen information to HCPs and the general public since 1990. This information is especially important for pregnant women and women planning to become pregnant. 77 This organization participated in the discovery of two teratogens, misoprostol and Zika virus. 77 In 1993, the National Institutes of Health recommended that pregnant women be included in clinical studies to obtain more clinical and PK data. 78 In 1994, the FDA established the Office of Women’s Health (OWH) in order to better protect the safety of pregnant and lactating patients with respect to certain drugs and to promote related studies. 79 With advances in medical care and increasingly individualized treatment, the FDA also implemented a new Pregnancy and Lactation Labeling Rule in 2015, which replaced the letter-based categories. 80 The new guidelines require data from both human and animal studies, including information on the risks of drug use during pregnancy and lactation and the effects of drugs on reproductive function. 81 In addition, the United States Congress established the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) in 2017. This organization aims is to investigate the safety and effectiveness of drugs in pregnant and lactating women and provide guidance to the Secretary of Health and Human Services (HHS). 82 Additionally, the EMA highlights PV with respect to drugs used in pregnant and lactating women in their Guidelines on Good PV Practices (GVP), Chapter P.III. 4 In addition to using EudraVigilance, FAERS, and VigiBase for large-scale data analysis, there are many other channels for obtaining relevant drug safety information. For example, Klein et al. 83 collected the data regarding the use of ß-blockers during pregnancy via Twitter and analyzed associated pregnancy outcomes as supplementary data to evaluate the safety of these drugs.

Information about the safety of drugs during pregnancy and lactation is complex and often inconsistent, making the determination of drug safety difficult for many HCPs. Currently, no separate PV system for pregnant patients has been established in any country. However, in view of the characteristics of the use of drugs in this population and the particularity of drug safety during pregnancy, it is necessary to establish pregnancy PV systems. Governments should issue relevant laws and regulations to encourage and guide the establishment of these systems and promote public platforms for the release of drug safety information so medical institutions, pharmaceutical companies, patients, and others can report and understand the necessary drug information.

Elderly patients

Basic physiology of the elderly.

Aging is an increasing trend in population change globally. In 2018, the number of people over 65 years old exceeded the number of people under 5 years old for the first time. 84 It is estimated that the proportion of people aged greater than 60 years will reach 20% by 2050. 85 There are differences in the definition of ‘elderly’ as set forth by various guidelines. For example, JNC 8 defines the elderly as the population older than 60 years, but China defines this group as those older than 65 years. 86 Age and the influence of the surrounding environment combine to affect changes in gene expression, resulting in cellular and metabolic dysfunction. 87 Compared to that of the young, liver volume in elderly adults is reduced by 20–40%, hepatocytes are more susceptible to stress, and the risk of chronic liver disease is greater. 88 With increasing age, the physiological structure of the kidney also changes with the number of functional glomeruli decreasing, leading to the decline of renal function. 89 Once an elderly person develops chronic kidney disease, the probability of acute kidney injury increases. 89 Medication compliance can also be problematic in elderly patients due to hypomnesis and polypharmacy. Most elderly patients with multiple drug prescriptions have been shown to have liver and kidney dysfunction. 90 For elderly patients with multiple diseases and polypharmacy, it is often difficult to determine whether ADRs are caused by a single drug, multiple drugs, or disease itself. Therefore, there are many challenges to the safe, correct, and proper use of drugs in elderly patients. The basic physiological characteristics of the elderly are summarized in Figure 3(a) .

(a) Risk factors of ADRs in elderly, (b) Common drugs causing ADRs in elderly and (c) Common tools for identifying PIMs.

ADRs, adverse drug reactions; MAI, the Medication Appropriateness Index; NSAIDs, non-steroidal anti-inflammatory drugs; PIMs, potentially inappropriate medications.

Use of medication in elderly patients

Among elderly hospitalized patients, approximately 16–25% will experience at least one ADR. 91 , 92 Drug-related factors are the most important predictors of ADR [ Figure 3(b) ]. Common drugs leading to ADRs in elderly patients include diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anticoagulants, benzodiazepines, antithrombotic drugs, analgesics, and digoxin. 92 – 95 Multiple comorbidities present in elderly patients often lead to the use of multiple drugs. As alluded to above, polypharmacy is one of the major risk factors leading to ADRs. Polypharmacy is generally defined as taking five or more drugs per day. 96 An Australian study showed that polypharmacy was present in 36% of people over 70 years old and 44–46% of patients between 80 and 89 years old. 97 In China, the proportion of polypharmacy in elderly patients is 48% and up to 73% in hospitalized elderly patients. 98 Notably, polypharmacy was associated with hospitalization due to any cause, with the likelihood of hospitalization associated with five to nine medications being 34% and with 10 or more medications being up to 98%. 99

Due to the complex physiology of the elderly, ADRs are an important cause of high morbidity, mortality, and hospitalization rates. A United States study found that among the cases of death due to ADRs in 1999–2006, patients older than 75 years had the highest risk of death. 100 Furthermore, the rate of fatal ADRs reported in elderly patients is three times that of younger patients. 101 The proportion of elderly patients hospitalized due to ADRs is 6–35%. 93 , 94 , 102

Implementation of PV systems for elderly patients

Polypharmacy is common in elderly patients, and drug–drug interaction is one of the important causes of ADRs. Most ADRs in elderly patients are caused by common prescription drugs. 103 One study showed that 53.97% of ADRs caused by drug interactions could be prevented. 104 Another study showed that greater than 75% of hospitalizations of elderly patients due to ADRs could be avoided. 94 The study of the predictors of adverse reactions in elderly patients is key to formulating preventive strategies. Cabré et al. 94 analyzed 3292 elderly inpatients and found that the risk factors leading to ADRs included personal factors (e.g. female sex, renal insufficiency) and external factors (e.g. the use of inappropriate medications, multiple medications, or sedatives). The implementation of PV can help to detect risks associated with a given drug, can assist HCPs in selecting drugs with the best therapeutic effect and the smallest chance of ADR, and can help to reduce economic burden.

The complexity of medication use in elderly patients increases with the incidence of potentially inappropriate medications (PIMs) (the potential risks of drugs exceed the potential benefits, and there are safer alternatives). PIMs are closely related to falls, ADRs/ADEs, higher treatment costs, and decline of bodily function in elderly patients. 105 Research shows that PIMs can increase the all-cause hospitalization rate of elderly patients by 27%. 99 Common tools for identifying PIMs include the Medication Appropriateness Index (MAI), HEDIS DAE, Beer’s criteria, STOPP/START criteria and EU-7-PIM list [ Figure3(c) ]. 106 – 109 Wang et al. 110 used Beer’s criteria, STOPP/START criteria, and the EU-7-PIM list to evaluate the use of drugs in 560 elderly inpatients and found that Beer’s criteria best predicted avoidable ADRs. However, for the elderly in Africa (Nigeria and South Africa), PIMs identified using Beer’s criteria did not correlate to ADRs in hospitalized patients. 111 The adjusted Beer’s criteria developed by a consensus of local experts is more applicable to the healthcare environment in Nigeria and South Africa, and may be used as a guide for the prescription of drugs to the elderly in these regions. 112 In Europe, STOPP/START criteria are used to identify PIMs in elderly patients. 113 In a multi-center prospective study in Spain, the STOPP/START criteria were used to evaluate PIMs, and the most common drugs identified were proton pump inhibitors and benzodiazepines. 114 Additionally, Chen and Zhang. 115 used these criteria to evaluate PIMs in elderly outpatients and found that benzodiazepines and hypnotic Z-drugs (zolpidem) were the main drugs identified. In central Portugal, the EU-7-PIM list was used to assess the use of drugs in elderly patients, with 83.7% of these patients found to be at potential risk of inappropriate drug use. 116 There are differences in pharmacotherapy in countries in different levels of development. For example, Yadesa et al. 107 applied the Prediction of ADR in Old Patients (PADROI) model as a risk assessment tool for elderly inpatients (⩾60 years old) in low-income countries.

The resistance of elderly cancer patients is decreased, and the possibility of comorbidity, polypharmacy and PIMs is increased. 117 Because of specific characteristics of cancer treatment, drugs considered as ‘possibly inappropriate’ in the general elderly population may be necessary for the treatment of elderly cancer patients. Therefore, the suitability of the above PIMs assessment tools for elderly cancer patients still needs to be evaluated. As of now, there is no definitive tool for the evaluation of PIMs in this population. Miller et al. 117 suggest that combining Beer’s criteria with MAI may be an effective method to identify PIMs in elderly cancer patients. Alternatively, Whitman et al. 109 suggest that three assessment tools, STOPP/START, the Beer’s criteria, and the MAI be used simultaneously to identify PIMs in this population.

Using real-world data of PV systems for analysis is conducive to identifying drug safety risks and taking countermeasures in a timely fashion. Generally, older patients are more likely to experience ADRs than younger patients. Age is one of the main risk factors for hypertension, and orthostatic hypotension is more likely to be induced by antihypertensive therapy in elderly patients. 86 Salem et al. 118 found that adverse cardiovascular drug reactions caused by ibrutinib mainly occurred in male patients older than 70 years, as identified by analysis of data in VigiBase. Mikami et al. 119 analyzed the FAERS database and found that elderly patients may be more prone to fatal neurologic adverse events when using immune checkpoint inhibitors. However, the incidence of ADRs in elderly patients is not always higher than that in non-elderly adults. Endrikat et al. 120 found that the risk of hypersensitivity reactions in patients older than 65 years after iopromide administration was lower than that in non-elderly adults as identified by analysis of the data in four observational studies and the PV database. Gouverneur et al. 121 found no more or more severe ADRs with the use of drugs targeting metastatic colorectal cancer (mCRC) in elderly patients in their analysis of ICSRs in VigiBase.

Gomes et al. 102 used the Portuguese PV system to identify PIMs and found that cardiovascular and nervous system drugs are common culprits. As such, supervision should be increased when using these drugs. Montastruc et al. 95 used the data in the French Midi-Pyrénées PV Center to analyze the PIMs in patients older than 75 years and found that the risks of benzodiazepines, imipramine antidepressants, and atropine-related drugs were the highest. Dubrall et al. 101 analyzed the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and found that anticoagulants were the most common drugs implicated in ADRs observed in the elderly. In addition to using databases, the analysis of articles published on the Internet is also a good way to identify high-risk drugs in elderly patients. Motter et al. 122 systematically evaluated the articles in PubMed, AgeLine, Academic Search, Academic Search Premier, and CINAHL from January 1991 to April 2017 and found that benzodiazepines and NSAIDs were the most reported PIMs in elderly patients. Aguiar et al. 123 conducted a meta-analysis of articles published on PubMed, MEDLINE, and Google Scholar from 1991 to September 2017 and found that the top three PIMs were tricyclic antidepressants, centrally acting antiadrenergic agents, and NSAIDs.

The WHO and relevant member states jointly formulated the Decade of Health Aging 2020–2030 program with the goal of promoting the maintenance of normal function and obtaining happiness in the elderly. 124 However, there are still many difficulties facing drug management methods, the formulation of relevant policies, and the research and development of helpful tools for elderly patients. In the face of an aging society, it is necessary for people from all walks of life to formulate strategies together in order to achieve the purpose of fine-tuned management of the use of drugs in elderly patients.

Problems and suggestions

Due to their specific physiology, special populations are more prone to ADRs. The implementation of PV can improve the speed and increase the quantity and quality of ADR reporting. Pre-marketing clinical research is more conducive to identifying common ADRs, while post-marketing monitoring is indispensable for finding rare or long-term ADRs. To fully understand the safety of a drug requires the study of large numbers of patients and long-term monitoring data. PV is a useful tool for evaluation of drugs. Real-world data based on PV can aid in discovering potential drug risks and bridging gaps in drug safety information. The most up-to-date data will provide HCPs more insight into drug risks and aid in the close monitoring of patients, with the ultimate goal of reducing patient harm and societal financial burden.

The following problems still exist with respect to the implementation of PV:

• Most medical staff have not received PV training, the training provided by professional courses and talents related to PV is not perfect, and the number of PV professionals in practice is insufficient.
• MAHs are ultimately responsible for drug safety. However, MAHs are faced with the challenge of ensuring drug quality without increasing costs. Moreover, with the increase of users, the workload of PV is also increasing.
• The sufficient quantity and quality of data is the basis of relevant research and necessary conditions for establishing and improving PV systems.
• Public databases for specific populations are deficient in providing important information pertaining to drug combinations, comorbidities, and laboratory indicators for relevant tests. As a result, establishing a causal relationship between drugs and adverse events can prove to be challenging.

Suggestions on how to better develop PV in special populations are as follows:

• Focus on drug safety risk monitoring for special populations, set up corresponding system segments based on these populations, and establish and improve management norms and institutional systems. Different special populations should be equipped with corresponding pharmacists to review prescriptions with the goal of effectively intercepting inappropriate prescriptions and achieving early detection and resolution of any issues.
• Strengthen cooperation between countries with the help of information systems to create an efficient global pattern of PV cooperation.
• In addition to mining drug safety data, PV professionals should also provide timely information to patients, the public, and HCPs to promote the safe and effective use of drugs.
• To improve the accuracy and analyzability of reported medical data, it is highly recommended that comprehensively report complete medical records, excluding any identifying patient information. As an incentive to increase the enthusiasm for reporting, a certain reward will be offered to individuals who submit complete medical records. This will also help address the ongoing issue of missing or incomplete reports, ultimately improving the overall quality of medical research.
• By establishing a collaborative drug safety legislation, drug manufacturers are compelled to proactively shoulder accountability, and companies that show exemplary PV practices for particular demographics are incentivized to extend drug patent protection duration. This approach fosters greater responsibility and diligence in the pharmaceutical industry, while also prioritizing the well-being of patients.

Pregnant women and children are considered ‘treatment orphans’, and the deterioration of physiological functions in elderly patients leads to an increase in drug-related risks. Therefore, more evidence and careful consideration are needed to ensure safe and effective use of drugs in these special populations. In the face of contradictory evidence, doctors must rely on personal experience and more unified treatment standards. PV can monitor the whole life cycle of a drug and provide reference for HCPs to use drugs safely in special populations. Complete safety data are a prerequisite for risk minimization, and a scientific and comprehensive assessment of these data is the basis for the development of appropriate management strategies. However, there are differences in PV systems, disease diagnostic criteria, and treatment protocols in different countries, leading to the challenge of multi-country safety data analysis. To establish a global PV system for special populations and develop unified standards for diagnosis, treatment and risk management require the participation of global academic, medical, pharmaceutical, and information experts.

Acknowledgments

Contributor Information

Yanping Li, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Yuanlin Wu, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Tingting Jiang, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Haiyan Xing, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Jing Xu, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Chen Li, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Rui Ni, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Ni Zhang, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Guiyuan Xiang, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Li Li, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Ziwei Li, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Lanlan Gan, Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China.

Yao Liu, Department of Pharmacy, Daping Hospital, Army Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.

Declarations

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contributions: Yanping Li: Conceptualization; Investigation; Methodology; Writing – original draft; Writing – review & editing.

Tingting Jiang: Conceptualization; Investigation; Writing – original draft.

Haiyan Xing: Conceptualization; Investigation; Writing – original draft.

Jing Xu: Investigation; Writing – original draft.

Chen Li: Investigation; Writing – original draft.

Rui Ni: Investigation; Writing – original draft.

Ni Zhang: Investigation; Writing – original draft.

Guiyuan Xiang: Investigation; Writing – review & editing.

Li Li: Investigation; Writing – review & editing.

Ziwei Li: Investigation; Writing – review & editing.

Lanlan Gan: Investigation; Writing – review & editing.

Yao Liu: Conceptualization; Funding acquisition; Investigation; Methodology; Supervision; Writing – original draft; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Chongqing Special Project for Technological Innovation and Application Development (No. CSTC2021jscx-gksb-N0013) and the Chongqing Clinical Pharmacy Key Specialties Construction Project.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of data and materials: Not applicable.