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

PurposeAfter 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.MethodsThis 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.FindingsRegarding 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.ImplicationsSignal 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.     

Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance database

Nefopam is widely used for the relief of moderate acute pain. Its safety profile remains to be specified. The objective of the study was to review adverse reactions to nefopam spontaneously reported to the French Pharmacovigilance system. All cases of adverse drug reactions (ADRs) associated with nefopam, registered in the French Pharmacovigilance database from January 1, 1995 to December 31, 2004, were reviewed. For each reported ADR, information about patient (age, gender, medical history), drug exposure (suspected and concomitantly used drugs), characteristics of ADRs (imputability score, time of onset, seriousness, outcome) were collected. A total of 114 ADRs with an imputability rated from 'plausible' (I2) to 'likely' (I3) and 'very likely' (I4) was analysed. The most frequent ADRs included 'expected' ADRs such as sweating, nausea, tachycardia, malaise or vomiting; 61 ADRs were 'unexpected. No overdose was reported; 26 ADRs (23%) were considered as 'serious'. Most of them were 'unexpected', including neuropsychiatric (hallucinations, convulsions) or cutaneous (pruritus, erythema, urticaria) ADRs. Six cases of anaphylactic ADRs (two angioedema and four anaphylactic shocks) were reported, all occurring shortly after use of nefopam during the post-operative period. Physicians should be aware of the possible occurrence of some serious ADRs when using nefopam such as convulsions and anaphylactic shocks, especially when the drug is used in special medical conditions, like post-operative periods.     

Pharmacovigilance in Crisis: Drug Safety at a Crossroads

Pharmacovigilance (PV) is under unprecedented stress from fundamental changes in a booming pharmaceutical industry, from the challenges of creating and maintaining an increasingly complex PV system in a globally diverse regulatory environment, and from unpredicted consequences of historical PV cost-reduction strategies. At the same time, talent availability lags demand, and many PV professionals may no longer be finding personal fulfillment in their careers. The situation creates risks for companies. Advantages and disadvantages of potential strategies to address this increasing problem at a corporate and industry level and in collaboration with regulatory agencies are discussed, as well as opportunities to adopt new technologies, including artificial intelligence and machine-learning to automate pharmacovigilance operations. These approaches would address burdensome and wasteful effort assuring regulatory compliance and free up resources to support the original mission of PV as an important public health activity and to reinvest in the development of new drugs.     

Artificial Intelligence in Pharmacovigilance: Scoping Points to Consider

Artificial intelligence (AI), a highly interdisciplinary science, is an increasing presence in pharmacovigilance (PV). A better understanding of the scope of artificial intelligence in pharmacovigilance (AIPV) may be advantageous to more sharply defining, for example, which terms, methods, tasks, and data sets are suitably subsumed under the application of AIPV. Accordingly, this article explores relevant points to consider regarding defining the scope of AIPV and offers a potential working definition of the scope of AIPV.     

Bortezomib and heart failure: case‐report and review of the French Pharmacovigilance database

Bortezomib is a proteasome inhibitor commonly indicated for the treatment of multiple myeloma and non Hodgkin lymphoma. Cardiac adverse drug reactions of this drug are not clearly established. We report case where direct involvement of bortezomib in the occurrence of heart failure is strongly suspected and 22 other cases spontaneously reported to the French Pharmacovigilance System. This report should increase cardiologist awareness about the risk of heart failure related to this drug. Moreover, these cases underline the need for a systematic cardiac screening in patients exposed to bortezomib.     

Pharmacovigilance is Everyone's Concern: Let's Work It Out Together

In recent decades, the field of drug safety/pharmacovigilance (PV) has advanced dramatically in some ways and yet has remained stagnant or progressed slowly in others. One way to assess the PV landscape is to view it through both a regulatory lens and a science and technology lens. This commentary highlights some of the current PV issues that can be resolved by sustained collaboration among all relevant stakeholders.     

Pharmacovigilance and biosimilars: considerations,needs and challenges

Introduction: Biosimilars are biologic medicines that are highly similar to approved biologics, notwithstanding minor differences in clinically inactive components. Since 2007, biosimilars have been approved for use in patients in the European Union (EU) and other regions. European experience provides several lessons as the United States (US) healthcare system prepares for biosimilar approvals. These lessons emphasize the need for adequate efficacy and safety studies, post-marketing surveys and a robust pharmacovigilance system that can accurately track and trace biologics, including biosimilars and their reference products, from the patient to the manufacturer.

Areas covered: We review the EU experience with biosimilar pharmacovigilance and discuss the implications for biosimilar pharmacovigilance in the USA. Furthermore, we review several aspects of biosimilar pharmacovigilance, including cohort event monitoring, traceability, biosimilar interchangeability, pharmacovigilance system development, nomenclature and counterfeit tracking.

Expert opinion: The availability of biosimilars as lower-cost biologics must carefully consider issues of safety, efficacy and traceability. Stringent pharmacovigilance procedures are required to detect potential differences in safety signals between biosimilars and their reference products. Pharmacovigilance of biologics should include processes that are easily used by prescribing practitioners to ensure that data are consistent and new safety signals are properly reported and assigned to the correct product.     

Gender differences in adverse drug reactions: analysis of spontaneous reports to a Regional Pharmacovigilance Centre in France

The aim of this study was to investigate putative gender-related differences in adverse drug reactions (ADRs). Data were ADRs recorded in the database of the French Midi-Pyrénées Pharmacovigilance Centre in 1998. A total of 927 ADRs were spontaneously reported to the Centre in 1998, of which 53.1% were in females (difference vs. males not statistically significant). There was no statistically significant difference in the incidence of reported ADRs in males (3.6/10,000 inhabitants) vs. females (3.9/10,000 inhabitants) for the total population of the Midi-Pyrénées area. The number of reported ADRs was similar across different age groups (10-year age ranges). However, 'serious' ADRs were more frequently reported in males in the 0-9 and 60-69 age groups (and in females between 20 and 29 years old). There were significantly more neuropsychiatric (69 vs. 43, P = 0.05) and fewer cardiovascular (8 vs. 2, P = 0.05) ADRs reported in females than in males. ADRs were more frequently reported in females for some classes of drugs (such as genito-urinary, sex hormone, antineoplastic, antiparasitic and respiratory drugs). These results confirm that female gender is a risk factor for the development of ADRs.     

Drug-induced hearing loss: a case/non-case study in the French pharmacovigilance database

Hearing loss is defined as a decrease in the ability to perceive sounds which can occur suddenly or gradually and affects one ear or both. It is related to various etiologies, in particular drugs. The identification of all drugs that could be associated with hearing loss is essential for the patients' life quality. The objective of our study was to identify signals of hearing loss involving drugs approved in the last 20 years. The occurrence in association with drugs known for their ototoxicity was also analyzed. We used a case/non-case method in the French Pharmacovigilance Database (FPVD). The cases were reports of hearing loss in the FPVD between January 2007 and August 2017. Non-cases were all reports over the same period. We calculated the reporting odds ratio (ROR) with 95% confidence intervals. Among the 555 reports of hearing loss, significant RORs were found for 68 drugs. The main therapeutic classes implicated were antineoplastic agents (n = 240), systemic anti-infective agents (n = 182), immunosuppressants (n = 42) loop diuretics (n = 26), and salicylate analgesics (n = 26). We found signals of hearing loss with azacitidine, vaccines and nevirapine, immunosuppressants such as leflunomide, and biotherapies such as panitumumab and vandetanib. Prescribers should be informed about the potential associations with all these drugs. The role of the pathology itself and the known ototoxic drugs that can be associated do not allow to conclude definitively. Audiograms for the early detection of hearing loss induced by drugs known to be ototoxic are rarely carried out. Preventive treatments exist and must be considered.     

Identification and Management of Lupus Nephritis: An Overview

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of organs systems in the body. Active SLE can put a patient at risk for life-threatening complications such as lupus nephritis (LN), an inflammation of the kidneys that can cause permanent, irreversible organ damage. LN can mimic other illnesses, and medical management may be challenging. The purpose of this article is to aid nurse practitioners in identifying and managing LN as a complication of SLE to provide safe and quality care to patients.     

Drug‐induced progressive multifocal leukoencephalopathy: a case/noncase study in the French pharmacovigilance database

Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system. As effective treatment is unavailable, identification of all drugs that could be associated with PML is essential. The objective of this study was to investigate the putative association of reports of PML and drugs. We used the case/noncase method in the French PharmacoVigilance database (FPVD). Cases were reports of PML in the FPVD between January 2008 and December 2015. Noncases were all other reports during the same period. To assess the association between PML and drug intake, we calculated an adverse drug report odds ratio (ROR) with its 95% confidence interval. We have studied the delay of onset of PML for each drug concerned. Among the 101 cases of PML, 39 drugs were mentioned as suspect. The main therapeutic classes suspected with significant ROR were antineoplastic agents (n = 85), immunosuppressants (n = 67), and corticosteroids. A latent interval from the time of drug initiation to the development of PML is established: the median time to onset was 365 days (123–1095 days). The onset of PML is highly variable and differs among drug classes [from 1 to 96 months (IQR: 39.0–126)]. An association between PML and some immunosuppressant drugs was found as expected, but also with antineoplastic agents and glucocorticoids. An important delay of PML onset after stopping treatment is suspected and should alert prescribers. Prescribers but also patients should be informed about the potential associations with all these drugs. Monitoring could be necessary for many drugs to early detect PML.     

Biodiversity: An Overview

Biodiversity is the very basis of human survival and economic well-being, and encompasses all life forms, ecosystems and ecological processes. The current estimates of the total number of species on earth vary from 5 to more than 100 million, with a more conservative figure of 13.6 million species. Of these, only 1.78 million species have yet been described and awarded scientific names. Thus, our knowledge of diversity is remarkably incomplete. Biodiversity at any point in time is the balance between the rates of speciation and extinction. Biodiversity is not uniformly distributed on the earth and shows prominent latitudinal and altitudinal gradients. At least five major mass extinctions have occurred in the past at geologic-time boundaries. Studies indicate that we have entered into the sixth phase of mass extinctions. In all ecosystem types, terrestrial, freshwater and marine, species populations are declining. The current rates of species extinction are 100–1000 times higher than the background rate of 10⁻⁷ species/species year inferred from fossil record. It is now in the order of 1,000 species per decade per million species. Today we seem to be losing two to five species per hour from tropical forests alone. This amounts to a loss of 16 m populations/year or 1,800 populations/h. Major drivers for changes of biodiversity in future, in decreasing rank of their impact are land use change, climate change, N deposition, biotic exchange and atmospheric loading of CO₂. Accuracy of estimates of the total number of resident species and current rates of extinction remains undetermined, and the impact of species deletions on ecosystem function and stability is still a subject of debate among ecologists. There are two basic, often complementary strategies for biodiversity conservation. The in situ strategy emphasizes the protection of ecosystems for the conservation of overall diversity of genes, populations, species, communities and the ecological processes which are crucial for ecosystem services. Establishment of networks of protected areas are effective in this regard as these have the possibility to conserve primary forests and red-listed ecosystems. The concept of biodiversity banking could induce public participation. Establishment of the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services, an independent, international science panel (like IPCC) would help coordinate and highlight research on pressing topics, conduct periodic assessments on regional as well as global scales and provide predictions.

     

Cardiomyopathy: An Overview

Cardiomyopathies and their resultant systolic and diastolic heart failure remain the main cause of cardiovascular morbidity and mortality in both children and adults and are a frequent indication for cardiac transplantation. According to the American Heart Association 2005 Heart and Stroke Update, more than 26,000 deaths each year in the United States are caused by cardiomyopathy. Cardiomyopathy is second to coronary artery disease for the most common direct cause of sudden death in the United States and is a leading cause of heart failure. This article provides an overview of the pathophysiology, causes, signs and symptoms, diagnosis, and treatment of the different types of cardiomyopathies. Newer therapeutic modalities and pharmacologic interventions are discussed, with an emphasis on improving symptoms and long-term survival.