Pharmacovigilance Considerations for Biosimilars in the USA

BioDrugs (2015) 29:309–321 DOI 10.1007/s40259-015-0137-2 CURRENT OPINION Pharmacovigilance Considerations for Biosimilars in the USA Gustavo Grampp1 • Thomas Felix2 Published online: 29 September 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract In 2015, five or more biosimilars may be approved in the USA. Because no two biologic medicines are identical, postapproval safety monitoring will be critical to detect potential differences in safety signals between a biosimilar, its reference product, and other biosimilars. Postapproval safety monitoring in the USA uses two signal detection systems: spontaneous reporting systems (SRSs) and active surveillance (AS) systems. Both depend on accurate identification of the specific product(s) dispensed or administered to patients, which may be compromised when products from multiple manufacturers share common drug nomenclature or coding. Product identification can present challenges across different healthcare settings, including inpatient and ambulatory care. Common oraldosage drugs are predominantly dispensed directly to patients by pharmacists, whereas most injectable drugs, including biologics, are administered to patients by healthcare professionals in outpatient clinics or hospitals. Thus, the effectiveness of SRS and AS mechanisms in both pharmacy and medical channels must be given greater consideration as biotechnology matures. In this article, we describe these systems and their limitations. We identify challenges and opportunities for product-specific safety & Thomas Felix Gustavo Grampp 1 Amgen Inc., Longmont, CO, USA 2 Amgen Inc., 601 13th Street NW, Washington, DC 20005, USA surveillance of biologics in both the pharmacy and medical settings and provide recommendations to improve biologic safety surveillance under the current and future systems envisioned in the Drug Quality and Security Act. As biosimilars are integrated into existing pharmacovigilance systems, distinguishable nonproprietary names and codes for all biologics, as well as other opportunities to improve traceability (e.g., increased use of barcodes), must be considered to ensure patient safety and confidence in this new class of drugs. Key Points Postapproval safety monitoring for biologic products relies on both active surveillance (AS) and spontaneous reporting systems (SRSs), and these must be effective for biologics dispensed both in the pharmacy and through medical benefit channels. Both SRS and AS approaches rely on accurate identification of the product(s) dispensed or administered to patients, and the effectiveness of these surveillance methods may be compromised when there are multiple manufacturers for products that share common drug nomenclature or coding. Federal, state, and health information technology policies that promote complete, accurate, and accessible tracking of dispensing data in patient medical records are essential to ensure traceability of outcomes for biologic products. These should include, but not be limited to, the application of distinguishable product nomenclature and reimbursement coding. 310 G. Grampp, T. Felix 1 Introduction 2 USA Pharmacovigilance and Biologics 2015 marks an important milestone in the maturity of medical biotechnology, with five or more biosimilar applications pending review by the US Food and Drug Administration (FDA). For the first time, a number of manufacturers will produce a series of highly similar but not identical medicines for the US market. The first biosimilar (ZarxioÒ [filgrastim-sndz]) was approved in the USA in March 2015, indicating that this new era has begun [1]. Accordingly, it will be important that pharmacovigilance systems are able to detect differences between adverse events (AEs) associated with a biosimilar and AEs associated with its reference product [2–4]. Given the structural and manufacturing complexities of biologics and the potential for structural differences between biosimilars and their reference products, the paradigm currently applied for monitoring of drug safety with small-molecule generic drugs is insufficient for biologics, including biosimilars [5]. Long-term patient safety monitoring of biologics is required to properly evaluate the immunogenic effects of both new and established biologics in the market [6]. Postapproval surveillance for immunogenicity and rare AEs may be needed; they may not be apparent during preapproval testing, because of the relatively small patient populations evaluated [2]. Moreover, it is important that the specific biologic or manufacturer is readily identified to ensure accurate tracing of AEs to the administered product [7]. Increased use of barcodes on biologic drugs should improve tracing capabilities, as should implementation of the US Drug Quality and Security Act/Drug Supply Chain Security Act (DQSA/DSCSA), which outlines use of an interoperable electronic system to identify and trace prescription drugs in the USA [8]. The objectives of this article are (1) to describe the spontaneous reporting systems (SRSs) and active surveillance (AS) systems used in the USA and their limitations; (2) to inform regulators, physicians, and pharmacists about the pharmacovigilance challenges for biologics from multiple manufacturers that have similar active substances; (3) to describe the difficulties of product traceability in hospital and physician office settings—the predominant settings for the administration of biologics; (4) to describe challenges and opportunities to improve product-specific safety surveillance of biologics dispensed to patients in retail or mail-order pharmacy settings; and (5) to encourage improvements in the traceability and pharmacovigilance of biologics in the USA by making recommendations for policies and practices that may improve the fidelity of SRSs and AS systems, targeting those recommendations toward the settings where these pharmacovigilance systems are used. In the USA, postapproval safety signal detection is performed primarily using SRS and AS systems [9, 10]. The attributes of each of these systems can be complementary for biologics from multiple manufacturers that have similar active substances, provided that AEs are properly linked to a specific product. SRSs (e.g., MedWatch and institution-based reporting) are considered passive surveillance methods, which rely on voluntary reports from physicians, pharmacists, other healthcare providers, and patients [11]. AS methods include retrospective analysis of medical records at Sentinel-affiliated sites and drug or disease registries, as well as use of drug event monitoring (e.g., surveys of patients identified through electronic prescription data) [12]. SRSs are important for identification of safety signals, including potential rare AEs not identified during clinical trials or premarketing studies [10]. For products (such as biologics) that are relatively sensitive to manufacturing conditi (...truncated)