Switching Reference Medicines to Biosimilars: A Systematic ...

1 Systematic REVIEWS witching Reference Medicines to Biosimilars: A SystematicLiterature review of Clinical OutcomesHillel P. Cohen1 Andrew Blauvelt2 Robert M. Rifkin3 Silvio Danese4 Sameer B. Gokhale5 Gillian Woollett6 Published online: 3 March 2018 The Author(s) 2018. This article is an open access publicationAbstractIntroductionTo evaluate the possibility that switchingfrom Reference biologic Medicines to biosimilars could leadto altered clinical outcomes, including enhanced immuno-genicity, compromised safety, or diminished efficacy forpatients, a Systematic literature review was conducted of allswitching studies between related biologics (includingbiosimilars).

2 MethodsA Systematic search was conducted using theMedline and Embase databases up to 30 June 2017employing specific medical subject heading terms. Addi-tionally, the snowball method and a hand search were alsoapplied. Publications were considered if they containedefficacy or safety information related to a switch from areference medicine to a biosimilar. Non-English, non-hu-man studies, editorials, notes, and short surveys data were available from 90 studies thatenrolled 14,225 unique individuals. They included proteinmedicines used in supportive care as well as those used astherapeutic agents.

3 The Medicines contained seven differ-ent molecular entities that were used to treat 14 great majority of the publications did not report dif-ferences in immunogenicity, safety, or efficacy. The natureand intensity of safety signals reported after Switching fromreference Medicines to biosimilars were the same as thosealready known from continued use of the referencemedicines alone. Three large multiple switch studies withdifferent biosimilars did not show differences in efficacy orsafety after multiple switches between Reference medicineand biosimilar.

4 Two publications reported a loss of efficacyor increased dropout use of each biologic must be assessedindividually, these results provide reassurance to healthcareprofessionals and the public that the risk of immuno-genicity-related safety concerns or diminished efficacy isunchanged after Switching from a Reference biologic to abiosimilar supplementary materialThe online version of thisarticle ( ) contains supple-mentary material, which is available to authorized P. Inc., 100 College Road West, Princeton, NJ 08540,USA2 Oregon Medical Research Center, Portland, OR, USA3 Rocky Mountain Cancer Centers, Denver, CO, USA4 IBD Center, Humanitas Clinical and Research Hospital,Milan, Italy5 Novartis Ltd.

5 , Hyderabad, India6 Avalere Health, Washington, DC, USAD rugs (2018) 78:463 478 literature (1993 up to 30 June 2017) wasreviewed to identify publications that containedprimary data on single or multiple Switching fromreference biological Medicines to total of 90 studies were identified involving sevenmolecular entities that treated 14 disease indications,and enrolled a total of 14,225 great majority of studies did not reportdifferences in safety, efficacy, or immunogenicityafter a single switch event compared to patients thatwere not switched. Only a small number (three) ofmultiple switch studies have been published to date,but likewise no differences were , the results suggest a low risk of either asafety concern or a loss of efficacy after Switching toa IntroductionBiological Medicines (biologics) are Medicines made inliving systems.

6 Biosimilars are copies of already licensedbiologics (referred to as the Reference medicine) that arehighly similar, but that are made by different sponsorsusing independently-derived cell lines and separately-de-veloped manufacturing processes [1,2]. Biosimilars canonly be approved if a manufacturer demonstrates that thereare no clinically meaningful differences in safety, efficacy,and immunogenicity when directly compared with thereference medicine [3].The experience with the Reference medicine, in both pre-approval clinical trials and post-approval routine clinicalpractice of medicine, provides a baseline for the safety andefficacy expected for both Reference Medicines and theircorresponding biosimilars.

7 To date, no new safety or effi-cacy concerns have been detected in the over 10 years andgreater than 700 million days of patient experience withbiosimilars [4].Nonetheless, concerns have been raised that switchingpatients from Reference Medicines to biosimilars, or otherstructurally-related biologics, may lead to increasedimmunogenicity and consequential safety problems, oreven a loss of efficacy. A review of Switching studiesreported in the literature is an important first step to con-firm or deny any existing pattern that may exist related tobiologic Switching .

8 Switches occur when patients receivemedicines formally designated as biosimilars, but may alsooccur after manufacturing process changes have occurred,if the process changes lead to structural modifications orchanges in the impurity profile of the biologic drug [5].A commonly expressed concern is whether there is anincrease in immunogenicity related to the act of switchingitself. Anti-drug antibody (ADA) assays likely offer themost sensitive method to detect immunogenicity; andneutralizing antibodies (NAB) assays are the most directmethod to signal the potential clinical relevance of , efficacy and certain safety events maybe additional measures to detect clinically product class or treatment specific literaturereviews of Switching studies from Reference Medicines tobiosimilars have been published [6 8].

9 The aim of thissystematic literature review was to provide a single surveythat includes all Switching studies of biologics to biosimi-lars, providing a baseline in one manuscript of all switch-ing studies published prior to 30 June Data Sources and SearchesA Systematic search using the Medline and Embase databases up to 30 June 2017 was conducted. Medicalsubject heading (MeSH) terms like biosimilar pharma-ceuticals OR biologic factors were employed. A bio-logical drug was included if a copy version of the referencemedicine was approved in either the USA or EU as abiosimilar.

10 Additional MeSH terms of all the smaller andlarger protein biologics (erythropoietin, human growthhormone, filgrastim, etanercept, adalimumab, infliximab,and rituximab) were added to the search string. This stringwas combined with the MeSH term drug substitution. Asthe medical subject heading biosimilar was first intro-duced by National Center for Biotechnology Information in2012 [9], further references within eligible papers werealso scrutinized for related evidence with the snowballmethod [10,11]. Additional hand search was appliedthrough citation review of identified Study SelectionPublications were considered if they contained efficacy orsafety information related to a switch from a referencemedicine to a biosimilar.