Signal Management in Pharmacovigilance: A Review of Activities and Case Studies.

ABSTRACT

PURPOSE: After nearly 12 decades of pharmaceutical catastrophes and the associated groundbreaking regulatory innovations, pharmacovigilance has come down to us in the present day as 3 interlocking core disciplines case management, signal management, and benefit-risk management. This review provides a state-of-the-art introduction to the great variety of sources of safety information, both dependent on and independent of the Individual Case Safety Report (ICSR), and explains how this content undergoes management-system processes with globally accepted definitions, standards, and structures that make possible the ongoing safe use of a pharmaceutical product throughout its lifecycle. This occurs in the context of (1) new products coming to market with new risks for drug-drug interactions, and (2) new global threats to safe manufacturing and distribution. METHODS: This narrative review, reflective of the author's experience, uses a large-frame system of signal management developed by the Council for International Organizations of Medical Sciences VIII Working Group and modified by the author to include governance. A key feature of the review is the regular inclusion of relevant case studies to provide a backdrop of the unexpected, with resulting tragic outcomes, to the ever-evolving regulatory landscape. FINDINGS: Regarding content, beyond the commonly appreciated sources of safety information that find their way into ICSRs are non-ICSR-based sources, including preclinical data, manufacturing data, findings from subject-matter experts who participate on data-monitoring committees, outside expert panels, advocacy groups, and independent investigator studies. Regarding process, it is important to recognize that governance is crucial in the effective conduct of signal management, in that subject-matter experts are essential to the scientific and medical aspects of decision making, and business and policy executives are essential in determining the final courses of action, as these decisions have implications for the company. IMPLICATIONS Signal management is an integral part of pharmacovigilance practices that strive to obtain all of the information necessary for maintaining the safety profiles of a company's pharmaceutical and biological products, to support favorable benefit-risk balances, and to ensure safe use by health care providers and their patients.