Nomenclature and Traceability Debate for Biosimilars: Small-Molecule Surrogates Lend Support for Distinguishable Nonproprietary Names

To view enhanced content go to www.advancesintherapy.com Received: August Nomenclature and Traceability Debate for Biosimilars: Small-Molecule Surrogates Lend Support for Distinguishable Nonproprietary Names Jingdong Chao 0 1 Martha Skup 0 1 Emily Alexander 0 1 Namita Tundia 0 1 Dendy Macaulay 0 1 Eric Wu 0 1 Parvez Mulani 0 1 0 D. Macaulay E. Wu Analysis Group , New York, NY , USA 1 J. Chao (&) M. Skup E. Alexander N. Tundia P. Mulani AbbVie Inc. , North Chicago, IL , USA Introduction: The purpose of the present study was to investigate the traceability of adverse events (AEs) for branded and generic drugs with identical nonproprietary names and to consider potential implications for the traceability of AEs for branded and biosimilar biologics. Methods: Adverse event reports in the Food and Drug Administration AE Reporting System (FAERS) were compared with those in a commercial insurance claims database (Truven Health MarketScan ) for 2 drugs (levetiracetam and enoxaparin sodium) with manufacturing or prescribing considerations potentially analogous to those of some biosimilars. Monthly rates of branded- and genericattributed AEs were estimated pre- and post- - generic entry. Post-entry branded-to-generic AE relative rate ratios were calculated. Results: In FAERS, monthly AE rate ratios during the post-generic period showed a pattern in which AE rates for the branded products were greater than for the generic products. Differences in rates of brand- and generic-attributed AEs were statistically significant for both study drugs; the AE rate for the branded products peaked at approximately 10 times that of the generic levetiracetam products and approximately 4 times that of the generic enoxaparin sodium products. In contrast, monthly ratios for the MarketScan data were relatively constant over time. Conclusion: Use of the same nonproprietary name for generic and branded products may contribute to poor traceability of AEs reported in the FAERS database due to the significant misattribution of AEs to branded products (when those AEs were in fact associated with patient use of generic products). To ensure accurate and robust safety surveillance and traceability for biosimilar products in the United States, improved product identification mechanisms, such as related but distinguishable nonproprietary names for biosimilars and reference biologics, should be considered. Biologic therapies are medicinal products made by or derived from the living cells of humans, animals, or microorganisms [1]. Examples of biologic therapies include vaccines, blood products, cytokines, and monoclonal antibodies. Biosimilars, or follow-on biologics, are biologic therapies that are approved for marketing on the basis of data demonstrating that they have physicochemical and functional characteristics comparable to those of a previously licensed biologic therapy (i.e., the reference biologic). The manufacturing process for biologics, including biosimilars, is complex and prevents biosimilars from being exact replicas of the reference biologic. Differences in manufacturing processes could lead to small differences in a biosimilars overall efficacy and safety profile, including immunogenicity [24], which may not be detected in the abbreviated clinical and non-clinical premarket studies required for regulatory approval of the biosimilar product [3, 5]. Differences between a biosimilar and its reference product may also emerge over time due to manufacturing changes [6]. Further, biosimilars that share the same reference product need not meet regulatory standards of similarity with respect to each other, and thus may have different clinical profiles [7]. For these reasons, precise post-market traceability of biosimilars and reference biologics to further develop the adverse event (AE) profiles of, and identify any unexpected safety signals associated with, each biosimilar product is a point of key interest to health care providers, drug manufacturers, regulators, and policymakers. Whether biosimilars will or should be considered interchangeable with their reference biologics is a subject of debate [8 10]. The pathway to approval of a biosimilar therapy in the United States (US) is dictated by the Biologics Price Competition and Innovation Act of 2009 [7]. This legislation established a standard for demonstrating that a proposed product is biosimilar to the reference biologic as well as a separate standard for demonstrating that a biosimilar is interchangeable with the reference biologic [7]. In the European Union (EU), interchangeability is regulated at the Member State level [2]. The potential for reference biologics and biosimilars to be interchanged by prescribers or substituted for one another by pharmacists complicates traceability. Experience with biosimilar therapies is relatively limited. The EU was the first jurisdiction to develop a robust regulatory pathway for the approval of biosimilars. It approved its first biosimilar, Omnitrope (somatropin; Sandoz GmbH, Holzkirchen, Germany), in 2006. No biosimilar products have been approved in the US as of January, 2015, although a generic version of enoxaparin sodium, a product that is regulated as a biosimilar in the EU, was approved by the US Food and Drug Administration (FDA) via the standard generic drug (Abbreviated New Drug Application) pathway in 2010. Experience from biosimilars marketed in the EU emphasizes the need for accurate tracking and tracing of biologics, including biosimilars, so that their safety can be adequately monitored post-market [4, 11]. Misattribution of AEs to the reference biologic rather than the responsible biosimilar product (or vice versa) could result in an inaccurate safety profile for both products or impede the identification and attribution of safety signals. In addition to distinct brand names and batch numbers, another method to facilitate differentiation and traceability of biosimilars and reference biologics in the marketplace would be to assign each biosimilar a nonproprietary name that is related to, but distinguishable from, the reference biologics nonproprietary name. Several publications have advised that using identical nonproprietary names may complicate, and in some cases thwart, post-market traceability of biologic and biosimilar products [8, 1114], including a study that found that AEs reported in the FDA AE Reporting System (FAERS) often are attributed to the branded product when a patient likely received a generic product with the same nonproprietary name [14]. In the present study, we aimed to further investigate the traceability of AEs attributed to branded and generic drugs. We selected 2 drugs, levetiracetam and enoxaparin sodium, because they have manufacturing or prescribing considerations potentially analogous to those of some biosimilars. We compared branded-togeneric AE rates as reported in FAERS [15] to those reported in an insurance claims database [16] that has more strict r (...truncated)