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 week2. 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 event3. 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 arise4.
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 journals5. 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 compliance6.
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 necessary7.
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 databases8. They are not required to monitor or report suspected adverse reactions for active substances to EudraVigilance for substances covered by EMA’s service9.
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) services10.
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