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Screening Scientific Literature for Adverse Drug Reactions: Relevant for Patient Safety or Just a Time-Consuming Regulatory Obligation?
Posted on November 16th, 2015 by Joyce de Langen in Pharmacovigilance
An adverse drug reaction (ADR) is defined as any response to a medicinal product which is noxious and unintended. ADRs are a major public health problem, accounting for up to 5% of all hospital admissions and 28% of the emergency visits. Of all hospitalized patients, 5% experience an ADR during the hospitalizationand ADRs are the fifth most common cause of hospital death, resulting in about 197,000 deaths per year in EU alone with societal costs of €79 billion per year (1). Comparable numbers are available for the US.
Historically, pharmacovigilance depends highly on analyzing safety information obtained from spontaneous reporting systems (SRSs) for ADRs reported by healthcare professionals reported to the regulatory authorities. Drug safety data obtained from SRSs have been analyzed using quantitative data mining procedures to identify associated drug-ADR combinations. However, research suggest that data retrieved from SRSs are limited due to incomplete or incorrect clinical information, underreporting, reporting bias and longtime latency (2,3).
In order to reduce the burden of ADRs and in order to improve patient’s safety and public health, regulatory authorities, clinicians and researchers are more and more focusing on the relevance of other sources of safety information in addition to spontaneous reporting systems. Furthermore, new data analyzing methods are being developed to analyze aggregated safety data. Consequently, in the recent years it became clear that additional sources of safety information such as clinical trials, scientific literature and other epidemiology databases are proven, useful complimentary sources of safety information, and therefore may contribute to reducing the impact of ADRs on public health. Furthermore, the interest for other sources of safety information such as social media and electronic health records is increasing (5).
Scientific literature as complimentary source of ADRs
Due to the complexity and variety of the data sources available, scientific literature management for pharmacovigilance is a complex process. However, scientific literature is an important source of ADRs. Literature is the fourth largest source of ADRs, as described in Elsevier’s white paper, Rethinking Literature Monitoring and Review. Pontes et al. discussed the relevance of scientific literature by discussing four practical examples of scientific articles of safety signals that actually had major impact on patient’s safety or on the life-cycle of the drug (6).
McBride’s well-known letter published in the Lancet in 1961 demonstrated the causal relationship between the use of thalidomide by pregnant women and an increased risk for birth defects. However, several other safety signals from more recent years demonstrate that scientific literature is actually an important source of new safety information.
In the past years, regulatory authorities have shown increased attention for the role of scientific literature as a source of ADRs. Good Vigilance Practice (GVP) Module VI describes that Market Authorization Holders (MAHs) should therefore perform a systematic review of widely used reference databases (such as Medline and Embase) at least once a week.
MAHs should implement a systematic approach to collect safety information from scientific and medical literature. MAHs should ensure that the literature review includes the use of reference databases that contain the largest reference of articles in relation to the medicinal product properties. In addition, MAHs should have procedures in place to monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorisation, and to bring them to the attention of the company safety department as appropriate.
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 ICSRs originating from spontaneous reports or non-interventional post-authorisation studies.
Literature screening to support monitoring benefit-risk profile of product
MAHs also have an obligation to screen the scientific and medical literature as significant sources of information relevant 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. This so-called safety relevant information can be obtained from review articles, meta-analyses, observational studies, epidemiologic studies, etc. Epidemiologic studies are important when detecting ADRs that are not-detectable within SRSs; for example, ADRs that are frequent in the population or that have a long time interval between onset and manifestation of the ADR. Review of aggregated data and statistical analyses may also point to an elevated risk of an adverse event to be further investigated as a signal. Published results of relevant studies should be identified by MAHs by screening the scientific literature.
With respect to the benefit-risk profile of a medicinal product, the MAH has an obligation to review the worldwide experience with medicinal product in the period between the submission of the marketing authorisation application and the granting of the marketing authorisation. The worldwide experience includes also monitoring published scientific and medical literature. For the period between submission and granting of a marketing authorisation, literature searching should be conducted to identify published articles that provide information that could impact on the risk-benefit assessment of the product under evaluation.
Does EMA MLM Monitoring Cover all MAH’s Literature management responsibilities?
In order to better overcome variability of reporting of adverse events from medical literature by MAHs, the EMA has launched, by contract, their own service of literature screening, named Medical Literature Monitoring (MLM), covering 300 generic medicinal products and 100 herbals. However, the EMA MLM service does not cover all MAHs’ reporting obligations for literature searching.
According to the recently published Q&A about EMA’s MLM Services, MAHs need to continue to monitor all other medical literature not covered by the literature reference databases applied for the EMA MLM service. This includes scientific and medical publications in local journals in countries where medicinal products have a marketing authorisation. For very specialised medical fields, for certain types of medicinal products or where safety concerns are subject to non-clinical research, MAHs should establish the most relevant source of published literature for each product.
In summary, MAHs need to continue to screen the scientific and medical literature to fulfill their other pharmacovigilance obligations, e.g., in the context of preparing Periodic Safety Update Reports (PSURs) or Risk Management Plans (RMPs), as applicable. MAHs also have an obligation to screen the scientific and medical literature as 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.
More about this topic in my next blog post!
Read more about the potential impact of EMA’s MLM service.
1. Lazarou J et al. Incidence in hospitalized patients. JAMA 1998; 279 (15): 1200-1205
2. Hasford et al. Physician’s knowledge and attitudes regarding the spontaneous reporting system for adverse drug reactions. J Clin Epidemiol 2002; 55(9): 945-50.
3. Alvarez-Requejo A et al. Underreporting of adverse drug reactions estimate based on a spontaneous reporting scheme and a sentinel system. Europ J Clin Pharmacol 1998; 54 (6):483-8.
4. Sarker A et al. Utilizing social media data for pharmacovigilance: a review. Journal of Biomedical Informatics 2015; 54: 202-212
5. Trifiro G et al. Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor? Pharmacoepidemiology and Drug Safety 2009; 18: 1176-1184.
6. Pontes H et al. Safety Signal Detection: The relevance of literature review. Drug Safety 2014; 37: 471-479
7. GVP Module VI Management and reporting of adverse reactions to medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129135.pdf
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Joyce de Langen
Senior Solution Manager Pharmacovigilance
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