The Role of Literature Reviews in Safety Signal Detection in Europe

Literature reviews | Safety signal detection

The Role of Literature Reviews in Safety Signal Detection in Europe

Adverse drug reactions (ADRs) represent an important risk for patients and have a significant economic impact on health systems. ADRs are the fifth most common cause of hospital death, with a burden estimated at 197,000 deaths per year in the EU. Because of this strong impact on public health, regulatory authorities (RAs) worldwide are implementing new pharmacovigilance legislation to promote and protect public health by reducing the burden of ADRs through the detection of safety signals.

The ultimate goal of the pharmacovigilance guidelines and regulations published by RAs is to establish that pharmaceutical manufacturers ensure the evaluation of the benefit-risk profile of their medical product during its whole lifecycle. This is done by providing the RAs with individual case safety reports (ICSRs) involving their products, emerging safety issues that may lead to changes in the known benefit-risk balance of a medicinal product, and safety update reports through a periodic benefit-risk evaluation report during the post-approval phase, during which the manufacturer assesses the benefit-risk balance of a product in real-life situations.

Literature Search and Review as a Source of Safety Signals

Scientific literature is a significant source of efficacy, effectiveness, and safety information for the monitoring of the safety profile and of the benefit-risk balance of medicinal products, particularly in relation to the detection of ICSRs, new safety signals, or emerging safety issues.

According to Module VI of the Guideline on Good Pharmacovigilance Practice, published by the European Medicines Agency, manufacturers must implement a systematic approach to collect information about suspected ADRs from literature sources, which should be clearly documented and submitted to periodic quality control (QC) of a sample of retrieved references to ensure the quality of this approach. The approach should be defined in a standard operating procedure that details all the activities performed for a literature search and how they should be documented. Namely, manufacturers should track:

  • Search construction
  • Databases used
  • Date of search
  • Results of search (particularly in the event of zero results)
  • Date of review
  • Identification of the person who performed the search/review
  • Date of QC and identification of the person who performed the QC

Systematic literature reviews should consist of widely used reference databases (e.g. MEDLINE or Embase) as well as local journals in countries in which products are marketed. The literature search should cover published scientific literature (e.g., full-text or abstract publications and information presented at scientific meetings, systematic reviews and meta-analyses, data from competitors, “grey literature” [documents that are protected by intellectual property rights, but not controlled by commercial publishers], and lay literature, such as newspapers, health magazines, internet sources).

During the literature search, manufacturers should search for articles reporting ICSRs and articles containing safety-relevant information. These four criteria should be present for a valid ICSR:

  • An identifiable patient
  • A suspected medicinal product
  • A suspected ADR
  • An identifiable reporter who, for scientific publications, is the first author

If an ICSR is identified during the literature screening, it must be reported by the company (or designee) to the RAs in a similar way as spontaneous reports.  Manufacturers’ responsibilities apply to reports related to medicinal products for which ownership cannot be excluded.

If any new safety information that may have a significant impact on the benefit-risk balance of the product is found, it should be notified immediately as an emerging safety issue to the competent authorities where the product is authorized.

Safety signals detected from literature reports can have a significant impact on the lifecycle of a drug. Contact us to discuss how literature review processes and other real-world evidence solutions can be leveraged for your product.