From the EU point of view

Posted on January 9th, 2020 by Jean-Dominique Pierret in Pharmacovigilance

Signal detection is traditionally based on case reporting from healthcare professionals and national regulatory authorities. Yet, there are a number of very notable examples where a safety signal actually came from the scientific literature, such as in the cases of thalidomide, GM-CSF, nifedipine and tamsulosin. (You can learn more about how safety signals detected from a literature report had an impact on the lifecycle of these drugs here.)

The importance of the literature to signal detection is also backed up by the data. For instance, a 2018 report on EudraVigilance, the European database for adverse drug reaction (ADR) reports, showed that scientific literature screening gave rise to 17.8% of 2,204 potential signals reviewed by the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC prioritized and assessed 114 signals in 2018, with 44% of the assessed signals resulting in a recommendation for updated safety & efficacy guidance on use of the product for patients and healthcare professionals.

Clearly scientific
literature is a vital part of the signal management process as a source of data
and information. Furthermore, it is crucial for identifying emerging and major
safety issues. But, from the EU perspective, what is the best way to find and manage
the data?

The GVP Module VI provides the guidance for collecting, managing and reporting such data. Reports of suspected adverse reactions to medicinal products are key to signal management, and the GVP VI has set the framework for literature screening for signal management and case reporting. That framework advises:

• Searching at least once a week on a widely-used database that contains a large reference of articles in relation to the medicinal product properties (e.g. Embase, Medline) and that also includes published abstracts from meetings and local journals. (The marketing authorization holder should establish the most relevant source of published literature for each product.)

• Building a search
  strategy, using free text or indexing, and learning what terms to include (such
  as ‘death,’ pregnancy-related terms, asymptomatic overdose, misuse, etc.)

Other aggregated reports – GVP VII for Periodic Safety Update Report (PSUR), and ICH guidelines for Periodic Benefit-Risk Evaluation Report (PBRER) and Development Safety Update Report (DSUR) – expand the scope of the search to clinical and non-clinical studies, and if relevant and applicable to information on drugs of the same class. Literature is addressed in more detail in the PSUR guidance, and signals are specifically addressed in PSUR and PBRER in sections devoted to signal overview and risk evaluation. A major goal of PSURs and PBRERs is to assess if the benefit-risk ratio of a drug has changed.

In a research paper assessing the publicly available evidence supporting post-marketing withdrawals, revocations and suspensions of marketing authorizations in the EU since 2012, the literature is shown to be an important source of evidence for supporting the regulatory decisions of the PRAC. The evidence from literature was in published case reports, as well as animal studies and observational/cohort/cross-sectional and clinical studies.

As these EU-focused references show, the importance of scientific literature as a source for signal detection is undeniable. Access to the literature and the best tools for searching it is critical to pharmacovigilance, no matter which part of the world you are in.

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