The Efficacy, Safety, and Immunogenicity
of Switching Between Reference
Biopharmaceuticals and Biosimilars:
A Systematic Review
Liese Barbier
1,*, Hans C. Ebbers
2, Paul Declerck
1, Steven Simoens
1, Arnold G. Vulto
1,3,†and Isabelle Huys
1,†To date, no consensus exists among stakeholders about switching patients between reference biological products (RPs) and biosimilars, which may have been curbing the implementation of biosimilars in clinical practice. This study synthesizes the available data on switching and assesses whether switching patients from a RP to its biosimilar or vice versa affects efficacy, safety, or immunogenicity outcomes. A total of 178 studies, in which switch outcomes from a RP to a biosimilar were reported, was identified. Data were derived from both randomized controlled trials and real-world evidence. Despite the limitations stemming from a lack of a robust design for most of the studies, the available switching data do not indicate that switching from a RP to a biosimilar is associated with any major efficacy, safety, or immunogenicity issues. Some open-label and observational studies reported increased discontinuation rates after switching, which were mainly attributed to nocebo effects. Involvement of the prescriber in any decision to switch should remain and attention should be paid to the mitigation of a potential nocebo effect.
Following the expiry of exclusivity rights on original biological medicines (further called the reference products (RPs)), the mar-ket opens up for biosimilar versions. Due to the intrinsic vari-ability that is inherent to biological medicines and the complex manufacturing process of these products, a biosimilar cannot be an exact copy to the RP, but needs to demonstrate that it is a highly similar version of the RP. As defined by the European Medicines Agency (EMA), a biosimilar is “a biological medicinal product that contains a version of the active substance of an already au-thorized original biological medicinal product in the European Economic Area. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and effi-cacy based on a comprehensive comparability exercise needs to be established.”1
Since the authorization of the first biosimilar in 2006 in Europe (somatropin, Omnitrope by Sandoz GmbH), > 50 biosimilars for a wide range of products and therapeutic areas have been approved in the European Union (EU).2 The first wave of approved biosim-ilars included mainly relatively small therapeutic proteins, such as hormones (e.g., somatropin and insulin glargine) and growth fac-tors (e.g., filgrastim and epoetin). Over the last years, more com-plex biosimilars, such as monoclonal antibodies (mAbs) and fusion proteins used in rheumatology, gastroenterology, and oncology, have been approved and entered the market in Europe.2 Since the first biosimilar approval in 2015 in the United States (filgrastim, Zarxio by Sandoz), the US Food and Drug Administration (FDA)
approved > 20 biosimilar products.3 An overview of approved bio-similars in Europe and the United States can be found in Table 1.
The market entry of biosimilars can play an important role in containing escalating healthcare expenditures, as they can be of-fered at lower prices than the RP and lead to price competition. The adoption of biosimilars can also lead to increased patient ac-cess to biological treatments and free healthcare budgets for the reimbursement of innovative medicines.4
An approved biosimilar is similar in efficacy, safety, and quality to the RP and any observed differences are deemed clinically irrel-evant.1 Therefore, biological treatment of a bio-naïve patient (i.e., a patient without previous treatment with a particular biological medicine) can be initiated with a corresponding biosimilar with-out any efficacy or safety concerns, other than those proclaimed for the RP. However, the case of switching patients under treatment with the RP to its biosimilar has been questioned and there are still concerns remaining among many healthcare professionals (HCPs) and patients.5,6 Concerns have been raised that switching between highly similar, but not identical versions of a biological medicine, may lead to an increase in immunogenicity, due to the subsequent exposure to potentially different sets of epitopes (for example, due to differences in glycosylation between the products7),8 although this has never been observed in clinical studies. The formation of anti-drug antibodies (ADAs), although these uncommonly result in a clinically harmful effect, could subsequently lead to safety is-sues or a loss of efficacy (LOE) to the treatment.9
Received June 18, 2019; accepted February 7, 2020. doi:10.1002/cpt.1836
1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Medicines Evaluation Board (MEB) Agency, Utrecht, The Netherlands; 3Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. *Correspondence: Liese Barbier (liese.barbier@kuleuven.be)
Table 1 Overview of approved biosimilars in Europe and the United States
Product Europe United States
INN Reference product Biosimilar(s)2 Reference product Biosimilar(s)a,3
Adalimumab Humira Amgevita
Halimatoz/Hefiya/Hyrimoz Hulio
Idacio/Kromeya Imraldi
Humira Amjevita (adalimumab-atto)
Cyltezo (adalimumab-adbm) Hyrimoz (adalimumab-adaz)
Bevacizumab Avastin Mvasi
Zirabev
Avastin Mvasi (adalimumab-awwb)
Enoxaparin Clexane Inhixa
Thorinane Lovenox –
Epoetin alfa Epoetin zeta
Eprex Abseamed
Binocrit Epoetin Alfa Hexal
Retacrit Silapo
Epogen/Procrit Retacrit (epoetin alfa-epbx)
Etanercept Enbrel Benepali
Erelzi Enbrel Eticovo (etanercept-ykro)Erelzi (etanercept-szzs)
Filgrastim Neupogen Accofil, Grastofil
Filgrastim Hexal/Zarzio Nivestim Ratiograstim/Tevagrastim
Neupogen Zarxio (filgrastim-sndz)
Nivestym (filgrastim-aafi)
Follitropin alfa Gonal-F Bemfola
Ovaleap Gonal-F –
Infliximab Remicade Flixabi
Inflextra/Remsima Zessly
Remicade Inflectra (infliximab-dyyb)
Renflexis (infliximab-abda) Ixifi (infliximab-qbtx) Insulin
glargine Lantus AbasaglarSemglee Lantus –
Insulin lispro Humalog Insulin lispro Sanofi Humalog –
Pegfilgrastim Neulasta Fulphila
Grasustek Pelgraz Pelmeg Udenyca Ziextenzo
Neulasta Fulphila (pegfilgrastim-jmdb)
Udenyca (pegfilgrastim-cbqv)
Rituximab Mabthera Blitzima/Ritemvia/Rituzena/
Truxima Rixathon/Riximyo
Rituxan Truxima (rituximab-abbs)
Somatropin Genotropin Omnitrope Genotropin –
Teriparatide Forsteo Movymia
Terrosa
Forteo –
Trastuzumab Herceptin Herzuma
Kanjinti Ogivri Ontruzant Trazimera
Herceptin Herzuma (trastuzumab-pkrb)
Ogivri (trastuzumab-dkst) Ontruzant (trastuzumab-dttb) Trazimera (trastuzumab-qyyp) Europe: Biosimilar candidates are evaluated by the European Medicines Agency and subsequently authorized by the European Commission in case of a positive opinion. The centralized marketing authorisation for biosimilars is valid in all EU Member States as well as in the European Economic Area countries Iceland, Liechtenstein, and Norway. Over 50 biosimilars have been approved, since the approval of the first biosimilar (biosimilar of somatropin) in 2006.2
United States: Biosimilar candidates are evaluated and subsequently approved by the US Food and Drug Administration (FDA). Over 20 biosimilars haven been approved by the FDA, since the approval of the first biosimilar (biosimilar of filgrastim) in 2015.3
INN, international nonproprietary name.
Products separated with a “/” are duplicates of each other (i.e., these products contain identical active substances, but are licensed under a different tradename).
aIn the United States, biosimilars of some early biologic drugs, such as somatropin and insulin, have been approved as generics, due to differences between the regulatory pathway of some protein originator products (historically approved under the Food, Drug, and Cosmetic (FD&C) Act) and later originator biological medicines. The FDA will transition these products to be regulated as biologicals under the Public Health Service Act.85 The FDA assigns four-letter suffixes to approved reference biologics, biosimilars, and (future) interchangeable biosimilars. Recent FDA draft guidance states that suffixes will not be retroactively assigned to previously authorized biologicals without suffix or transition products.86
KEY CONCEPTS AND TERMINOLOGY
Switching is the act by the treating physician “to exchange one med-icine for another with the same therapeutic intent.”10 Switching can refer to a change between two different molecules (with a different international nonproprietary name (INN) e.g., inflix-imab to adalimumab) or a change between a RP and its biosimilar version (e.g., infliximab to CT-P13) or between biosimilars of the same RP. Switching from a RP to a biosimilar (or vice versa) or be-tween biosimilars is also referred to as nonmedical switching (i.e., switching merely for cost-saving reasons). Dörner and colleagues proposed the term transitioning for this type of switching,11 in an effort to delineate the different types of switches reported in the literature. In this paper, the term switching refers to the switch from a RP to a biosimilar (or vice versa). Automatic substitution is “the act of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without con-sulting the prescriber.”10 The practice of substitution is regulated on a member state level and for biological medicines prohibited or advised against in most European countries.12 Interchangeability is a characteristic of two medicines and “refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a ref-erence product with a biosimilar (or vice versa) or replacing one biosimilar with another,”10 either prior to the start of a biological treatment or during (stable) treatment.
Switching and substitution practices and the designation of in-terchangeability are not regulated on an EU level as prescribing practices fall within the responsibilities of the different EU mem-ber states.10 In the United States, the FDA has created a regulatory designation pathway for the scientific evaluation of interchange-ability. An interchangeable product needs to meet additional re-quirements in addition to being authorized as a biosimilar.13 For the proposed interchangeable product, it needs to be shown that it “can be expected to produce the same clinical result as the RP in any given patient; and for a product that is administered more than once to an individual, the risk in terms of safety or diminished effi-cacy of alternating or switching between use of the product and its RP is not greater than the risk of using the RP without such alter-nation or switch.”13 According to the Biologics Price Competition and Innovation Act (BPCI Act) section 351(k)(4), the pharmacist would be allowed to substitute a prescribed biological RP with an interchangeable biosimilar without the involvement of the pre-scriber, if allowed by state laws.13 Thus far, no biosimilars have yet been deemed interchangeable by the FDA.3
In 2012, Ebbers et al. investigated the safety of switching between therapeutic proteins, addressing the key question surrounding the use in practice of biosimilars. The study did not find evidence from clinical trial data or postmarketing surveillance (PMS) data that switching to and from different biological medicines led to safety concerns.14 Since then, many more biosimilars have been approved and entered the market.2 Increasingly, national competent author-ities and HCP organizations formulated guidance about switch-ing.15 However, switching remains a highly debated topic and the arrival of the more complex mAb biosimilars to the market further sparked the discussion.8,16 Various biological medicines, especially blockbuster mAbs, are used in a chronic setting, stressing the need
to address these questions in an effort to aid (clinical) decision making. Furthermore, the uncertainty about switching limits the competition potential of biosimilars to curb the increasing burden on healthcare budgets and to increase treatment access for patients.
This systematic literature review aims to synthesize the cur-rently available data on switching and to assess the safety, im-munogenicity, and efficacy of switching between RPs and their respective biosimilar version(s). This review broadens the scope of previous studies14,17 by reviewing switch data for biologicals of every therapeutic class for which a European market autho-rization has been granted, more specifically: (i) recombinant human growth hormones (rhGHs), (ii) erythropoietins, (iii) granulocyte colony stimulating agents, (iv) insulins, (v) tumor necrosis factor alpha inhibitors (anti-TNFs), (vi) gonadotropins, (vii) low-molecular-weight heparins, and (viii) mAbs used in on-cology. Further, we aim to provide a critical insight on the current state-of-the-art related to switching. This overview can be useful for HCPs and other stakeholders in their (clinical practice) deci-sion making.
Information on the methodology of this systematic literature re-view is shown in the online Supplementary Information (Box S1, Figure S1, Tables S1 and S2).
STUDIES SWITCHING BETWEEN BIOLOGICAL REFERENCE PRODUCTS AND BIOSIMILARS
In total, 178 studies (accumulating up to approximately 21,000 switched patients) were identified and included in the systematic literature review. Switch studies were identified for somatropin, epoetin, filgrastim, insulin, anti-TNFs (adalimumab, etanercept, and infliximab), follitropin, and mAbs used in oncology (ritux-imab and trastuzumab). No switch data were identified for pa-tients treated with enoxaparin. Figure 1 provides an overview of the number of identified studies across products. The majority of the studies related to switching from an anti-TNF RP to a biosimi-lar (132/178), and more specifically most studies related to switch-ing from the infliximab RP to CT-P13 (Remsima/Inflectra).
Different types of study design were identified. Figure 2 illus-trates the main different switch designs. Most of the studies con-sisted of a single switch (i.e., patients changed one time from the RP to a biosimilar). Only six studies with a multiple switch design (i.e., patients changed multiple times between the RP and the bio-similar, alternating back on forth) were identified.18–23 No studies on switching between biosimilars were identified.
Data are originating from two main classes of studies. First, 38 studies (21%) can be categorized as randomized controlled trials (RCTs) and open-label extension studies (mostly these studies are part of the phase I/III clinical development of the proposed biosimilar, but also include for example the NOR-SWITCH trial).24 An overview of the study design and switch results of this first class of switch studies, across products and disease areas, can be found in Table 2. Second, the bulk of the data (N = 140; 79%) is originating from studies conducted in the real-world setting (i.e., real-world evidence (RWE), defined as nonrandomized studies outside the biosimilar candidate’s clini-cal development). The identified RWE consists of parallel arm, nonrandomized, nonblinded studies and predominately studies
following a single arm design (i.e., the total patient cohort that (systematically, sometimes driven by procurement decisions) switches from the RP to the biosimilar, without a comparator arm). Further, registries, such as the DANBIO registry for the switch from the infliximab RP to CT-P13 and the switch from the etanercept RP to SB4, were identified.
In addition to efficacy and safety outcomes, the measurement of trough levels (TLs) and ADAs upon switching was screened. TLs
and ADAs were reported in 71 of 178 studies. Figure 3 shows the number of studies reporting on ADA and/or TL across products.
Based on the conclusion of the authors, the majority of the stud-ies did not identify major efficacy, safety, or immunogenicity issues due to switching from a RP to its biosimilar version.
Study-specific results per product are further discussed below and shown in Tables S3–S11 in the online Supplementary Information.
Figure 1 Overview of number of switch studies across products.
Ta bl e 2 O ve rv ie w o f R C T a nd o pe n l ab el e xte ns io n s w itc h s tu di es A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e S ing le s w it ch s tud ie s A da lim um ab b io sim ila rs C oh en et a l. (2 0 17 ) 50 Ad al im um ab – AB P 5 01 RA O LE o f R C T ph as e III t ria l 2 37 4 6 w ee ks S im ila r e ff ic ac y b et w ee n s w it ch a nd B S c on t. a rm s. R at e o f T E AE s a nd AD A s im ila r b et w ee n s w it ch a nd B S co nt . a rm s. Ye s Lo ng -te rm s af et y, im m un og eni ci ty , a nd ef fic ac y r es ul ts s im ila r be tw ee n s w itc h a nd co nt . a rm s C oh en et a l. (2 0 1 8 ) 54 Ad al im um ab – BI6 9 5 5 0 1 RA R and om iz ed , do ub le -b lin d, pa ra lle l a rm , ph as e I II t ri al (V O LT AIRE -R A) 1 47 3 4 w ee ks AC R 2 0/ 5 0/ 70 r es po ns e r at es , sa fe ty a nd i m m un og en ic it y ( AD A , AD A t it er s, a nd n eu tr al iz in g an ti bo di es ) w er e s im ila r a cr os s t he 3 a rm s (R P -B S s w it ch, R P c on t. , B S co nt .) Ye s Th e s w itc h h ad no i m pa ct o n ef fic ac y, s af et y, a nd im m un og en ic it y H od ge et a l. (2 0 17 ) 53 Ad al im um ab – C H S -1 4 2 0 Ps a nd P A D ou bl e -b lin d, ra nd om iz ed , pa ra lle l a rm , ph as e III t ria l 1 24 8 w ee ks PA S I7 5 a ch ie ve d i n 8 4 .6 % , 8 1 .6 % , an d 8 8 .3 % p ts i n B S c on t. , s w it ch, an d R P c on t. a rm s. T E AE r ep or te d in 2 0 .1 % , 1 9 .4 % , a nd 1 6 .3 % p ts i n B S c on t. , s w it ch, a nd R P c on t. a rm s. AD A r ep or te d i n 4 .0 % , 0 .8 % , a nd 2 .3 % i n B S c on t. , s w it ch, a nd R P co nt . a rm s Ye s S im ila r s af et y a nd ef fic ac y b et w ee n sw itc he d a nd no ns wi tc he d p ts Pa pp et a l. (2 0 17 ) 51 Ad al im um ab – AB P 5 01 Ps R and om iz ed , do ub le -b lin d, pa ra lle l a rm , ph as e III t ria l 77 3 6 w ee ks PA S I p er ce nt ag e i m pr ov em en ts f ro m ba se lin e s im ila r a cr os s a rm s (R P -B S s w it ch, R P c on t. , B S c on t. ). N o si gn if ic ant d if fe re nc es a cr os s a rm s in p er ce nt ag es o f P AS I 5 0 , 7 5 , 9 0 , an d 1 0 0 r es po nd er s. N o n ew s af et y si gn al s d et ec te d. A Es b al an ce d be tw ee n a rm s. I nc id en ce o f o ve ra ll AD A c om pa ra bl e a cr os s a rm s. Ye s S im ila r e ff ic ac y, s af et y, an d i m m un og eni ci ty pr of ile s a ft er s in gl e sw itc h b et w ee n a rm s We in bl at t et a l. (2 0 1 8 ) 52 Ad al im um ab – S B 5 RA E xt en si on, do ub le -b lin d, ra nd om iz ed , con tro lle d ph as e III t ria l 1 25 2 8 w ee ks AC R r es po ns e r at es c om pa ra bl e be tw ee n s w it ch a nd c on t. a rm s. C om pa ra bl e t re nd s i n D AS 2 8 , S D AI , a nd C D AI a cr os s a rm s. T he sa fe ty p ro fil e w as c on si st en t a cr os s ar m s. P ro po rt io n o f p ts w it h A D A , ne ut ra liz in g A D A a nd s us ta in ed A D A w as s im ila r b et w ee n a rm s. Ye s S w itc hi ng h ad no tr ea tm en t-em er gen t i ss ue s, su ch a s i nc re as ed A E s, i nc re as ed im m un og eni ci ty , o r l os s of ef fic ac y (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e Et an er ce pt b io si mi la rs Em er y et a l. (2 0 17 ) 55 Et an er ce pt – S B 4 RA O LE o f ra nd om iz ed , do ub le -b lin d, ph as e III t ria l 1 1 9 4 8 w ee ks AC R r es po ns e r at es s us ta in ed an d c om pa ra bl e b et w ee n B S c on t. an d s w it ch a rm s ( AC R 2 0 r es po ns e ra te s a t w ee k 1 0 0 7 7. 9 % v s. 7 9 .1 % , re sp ec ti ve ly ). T E AE r at es 4 7. 6 % v s. 4 8 .7 % , r es pe ct iv el y. O ne p at ie nt i n ea ch a rm d ev el op ed n on -n eu tr al iz in g ADA . Ye s Ef fic ac y, s af et y, a nd im m un og en ic it y co m pa ra bl e b et w ee n th e c on t. a nd s w itc h ar m s. N o r is k a ss oc ia te d w ith s w itc hi ng p ts f ro m R P t o S B 4 . O’ D el l e t a l. (2 0 17 ) 56 Et an er ce pt – C H S -0 2 14 RA R and om iz ed , do ub le -b lin d, pa ra lle l a rm stu dy 220 24 w ee ks R es po ns e r at es m ai nt ai ne d i n c on t. an d s w it ch a rm s ( 9 3 .8 % v s. 9 2 .7 % fo r A C R 2 0 , 7 5 .0 % v s. 7 3 .6 % f or AC R 5 0 , 4 9 .6 % v s. 5 1 .4 % f or A C R 70 , re sp ec ti ve ly ). A Es i n 7 4 .4 % v s. 76 .6 % p ts , S AE i n 4 .6 % v s. 7 .5 % p ts , S AE s r el at ed t o s tu dy d ru g i n 0 .9 % vs . 1 .9 % p ts . T re at m en t-em er ge nt bi nd in g A D A i n 1 .4 % p ts r ec ei vi ng B S co nt . a nd 0 .7 % o f s w it ch ed p ts . Ye s N o c lini ca lly m ea ni ng fu l di ff er en ce s i n ef fic ac y, s af et y, o r im m un og en ic it y be tw ee n s w itc h a nd B S co nt . a rm s M atu cc i-C er in ic et a l. (2 0 1 8 ) 57 Et an er ce pt – G P 2 01 5 RA R and om iz ed , do ub le -b lin d, pa ra lle l a rm , ph as e I II s tu dy (EQ U IR A) 16 6 24 w ee ks Th e m ea n c ha ng e i n D AS 2 8 -C R P w as c om pa ra bl e b et w ee n t he c on t. an d s w it ch a rm s. E U LA R a nd A C R 2 0/ 5 0/ 70 r es po ns e r at es w er e co m pa ra bl e b et w ee n a rm s. T E AE s in 4 2 .9 % v s. 3 8 .0 % , S AE s i n 2 .3 % vs . 2 .4 % p ts , i nj ec ti on s it e r ea ct io ns in 0 % v s. 3 .6 % p ts i n t he c on t. v s. sw it ch a rm . 2 .4 % p ts i n t he c on t. ar m h ad s in gl e -e ve nt , v er y l ow t it er , no n -n eu tr al izi ng A D A . Ye s Th e s w itc h d id n ot a ff ec t ef fic ac y a nd s af et y o f et an er ce pt t re at m en t i n pt s w ith m od er at e-to -se ve re R A S on g et a l. (2 0 1 8 ) 58 Et an er ce pt – L B EC 01 01 RA O LE o f ra nd om iz ed con tro lle d do ubl e -bl in d ph as e III t ria l 78 4 8 w ee ks D AS 2 8 -E S R s co re m ai nt ai ne d i n co nt . a nd s w it ch a rm s. R es po ns e ra te s a t w ee k 1 0 0 : 7 9 .7 % v s. 8 3 .3 % f or A C R 2 0 , 6 5 .2 % v s. 6 6 .7 % fo r A C R 5 0 , a nd 4 4 .9 % v s. 4 2 .3 % fo r A C R 70 f or c on t. a nd s w it ch ar m s, r es pe ct iv el y. A E i nc id en ce co m pa ra bl e b et w ee n a rm s ( 70 .0 % vs . 7 0 .5 % ). P ro po rt io n o f p ts w it h n ew ly d ev el op ed A D A s im ila r be tw ee n a rm s ( 1 .4 % v s. 1 .3 % ). Ye s Ef fic ac y a nd s af et y co m pa ra bl e i n b ot h co nt . a nd s w itc h a rm s Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e In fli xim ab b io sim ila rs Al te n et a l. (2 0 1 8 ) 40 Inf lix im ab – P F-064 3 8 17 9/ G P1111 RA R and om iz ed , do ub le -b lin d, pa ra lle l a rm ph as e I II s tu dy 14 3 24 w ee ks AC R 2 0 r at es a nd D AS 2 8 -C R P sc or es c om pa ra bl e b et we en a rm s. In ci de nc e o f T E AE 3 6 .8 % , 3 3 .6 % , an d 3 7. 8 % , S AE s ( 4 .6 % , 7 .7 % , a nd 2 .8 % ) a nd i nf us io n -r el at ed r ea ct io ns (3 .2 % , 8 .4 % , a nd 4 .2 % ) c om pa ra bl e be tw ee n t he c on t. B S , c on t. R P a nd sw it ch a rm . P re do se a nd p os td os e AD A r at es we re c om pa ra bl e b et we en ar m s. Ye s S tu dy s ho w ed t he ab se nc e o f c lini ca lly m ea ni ng fu l d if fe re nc es in e ff ic ac y, s af et y, an d i m m un og eni ci ty be tw ee n s w itc h a nd co nt . a rm s Jø rg en sen e t al . (2 0 17 ) 24 G ol l e t a l. (2 0 17 ) 38 Inf lix im ab – C T-P1 3 Inf lix im ab – C T-P1 3 R A , C D , U C , P s, PA , S pA R A , C D , U C , P s, PA , S pA R and om iz ed , do ub le -b lin d, pa ra lle l a rm , si ng le s w it ch no ni nf er io ri ty ph as e I V t ri al (NO R -S WI TC H ) O LE , pa ra lle l a rm NO R -S WI TC H 2 41 183 52 w ee ks 26 w ee ks D is ea se w or se ni ng o cc ur re d i n 2 6 % a nd 3 0 % o f p ts i n t he c on t. an d s w it ch a rm s, r es pe ct iv el y. T he 9 5 % C I o f t he a dj us te d t re at m en t di ff er en ce ( − 4 .4 % ) w as − 1 2 .7 – 3 .9 , f el l w it hi n t he p re sp ec if ie d no ni nf er io ri ty m ar gi n. T he f re qu en cy of A Es w as s im ila r b et w ee n a rm s. Tr ou gh d ru g c on ce nt ra ti on s s im ila r in t he t w o a rm s. I nc id en ce o f A D A de te ct ed d ur in g t he s tu dy w as 7 % vs . 8 % f or c on t. a nd s w it ch a rm , re sp ec ti ve ly . D is ea se w or se ni ng o cc ur re d i n 1 6 .8 % a nd 1 1 .6 % o f p ts i n t he c on t. an d s w it ch a rm s, r es pe ct iv el y. T hr ee an d 5 p ts i n t he c on t. a nd s w it ch ar m s, r es pe ct iv el y, d ev el op ed A D A . TL s a nd t he f re qu en ci es o f r ep or te d AE s c om pa ra bl e b et we en a rm s. Ye s Ye s N O R -S W IT C H s ho w ed th at s w itc hi ng t o C T-P1 3 w as n ot i nf er io r to c on t. t re at m en t w ith t he R P b as ed o n no ni nf er io ri ty m ar gi n o f 1 5% . N o n oni nf er io ri ty w as s ho w n i n i nd iv id ua l di se as es ( st ud y n ot po w er ed f or t hi s) . O LE o f N O R -S W IT C H tr ia l d id n ot s ho w a ny di ff er en ce b et w ee n p ts w ho m ai nt ai ne d C T-P1 3 vs . p ts w ho s w itc he d K im et a l. (2 0 17 ) 42 In fli xi m ab – C T-P1 3 o r vi ce ve rs a CD R and om iz ed , co nt ro lle d, si ng le s w it ch, pa ra lle l a rm ph as e III t ria l 1 10 24 w ee ks C lin ic al r em is si on a nd C D AI -7 0 re sp on se r at es m ai nt ai ne d a nd si m ila r a m on g a rm s (B S c on t. , R P co nt ., R P -B S s w it ch, a nd B S -R P sw itc h) af te r s w itc hi ng . O ne -ye ar sa fe ty s im ila r a m on g a rm s. A t w ee k 3 0 , 1 I R R r ep or te d a ft er s w it ch in g (p t A D A p os it iv e a t t im e o f s w it ch ). N o f ur th er I R R r ep or te d i n s w it ch ar m s a ft er . N o c lin ic al ly m ea ni ng fu l dif fe re nc es in im m uno ge ni ci ty rep or te d. Ye s Th e s w itc h a rm w as co m pa ra bl e t o R P a nd B S c on t. a rm s i n t er m s of e ff ic ac y a nd s af et y pr of ile s Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e Pa rk et a l. (2 0 17 ) 36 Inf lix im ab – C T-P1 3 AS O LE s tu dy o f do ubl e -bl in d R C T ( PL A N E TA S ex te ns io n) 86 4 8 w ee ks AS AS 2 0 , AS AS 4 0 , a nd AS AS p ar ti al re m is si on r at es s im ila r b et w ee n ar m s. P ro po rt io n o f p ts w it h a t le as t o ne T E AE w as 4 8 .9 % v s. 71 .4 % i n t he c on t. a nd s w it ch a rm s, re sp ec ti ve ly . P ro po rt io n o f p ts w it h AD A s im ila r i n c on t. a nd s w it ch a rm s. Ye s S w itc hi ng f ro m R P t o C T-P1 3 i s p os si bl e w ith ou t ne ga tiv e e ff ec ts o n sa fe ty or ef fic ac y S m olen e t a l. (2 0 1 8 ) 37 Inf lix im ab – S B 2 RA E xt en si on ra nd om iz ed con tro lle d ph as e III t ria l 94 24 w ee ks AC R 2 0 w as c om pa ra bl e a cr os s sw it ch, R P c on t. , B S c on t. a rm s. TE AE s i n 3 6 .2 % , 3 5 .6 % , a nd 4 0 .3 % , re sp ec ti ve ly . N ew ly d ev el op ed AD As i n 1 4 .6 % , 1 4 .9 % , a nd 1 4 .1 % , re sp ec ti ve ly . Ye s Ef fic ac y, s af et y, a nd im m un og en ic it y co m pa ra bl e b et w ee n sw itc h a nd c on t. a rm s. N o t re at m en t-em er gen t is su es o r c lini ca lly re le va nt imm un og en ic it y af te r s w itc hi ng . Ta na ka e t a l. (2 0 17 ) 41 Inf lix im ab – C T-P1 3 RA O LE o f p ha se I / II t ria l 33 6 9 .0 ± 2 9 .5 w ee ks Th e t yp e a nd f re qu en cy o f A Es w er e si m ila r b et w ee n a rm s. N um be r o f AD A -p os it iv e p ts 4 8 .5 % v s. 3 1 .6 % in s w it ch a nd m ai nt en an ce a rm , re sp ec ti ve ly . Ye s C T-P1 3 w as w el l to le ra te d i n p ts w ho sw itc he d K ay et a l. (2 0 1 6 ) 39 Inf lix im ab – B O W 01 5 RA O LE o f d ou bl e -bl in d R C T 5 3 3 2 w ee ks N o s ig nif ic ant d if fe re nc e i n pr op or ti on o f p ts a ch ie vi ng A C R 2 0 , 5 0 , o r 7 0 r es po ns es b et w ee n a rm s. M ea n i m pr ov em en ts i n C R P, E S R , an d t en de r a nd s w ol le n j oi nt c ou nt s di d no t d if fe r s ig nif ic ant ly b et w ee n ar m s. NR D ur ab ili ty o f r es po ns e to B O W 01 5 h as b ee n dem on st ra te d. N o sw it ch a dv ic e Vo lk er s et a l. (2 0 17 ) 87 In fli xi m ab – in flix im ab B S IB D R and om iz ed , do ub le -b lin d, si ng le s w it ch, pa ra lle l a rm , ph as e I V n on -in fe ri ori ty t ri al 15 3 0 w ee ks O ne p t ( sw it ch a rm ) ex pe ri en ce d re la ps e o f I B D . T w o p ts ex pe ri en ce d an S AE , n ot r el at ed t o t he s tu dy dr ug. NR Pr el imi na ry r esu lt s sh ow t ha t s w itc hi ng fr om i nf lix im ab R P t o in fli xi m ab B S i s f ea si bl e an d s af e Yo o et a l. (2 0 17 ) 35 Inf lix im ab – C T-P1 3 RA O LE o f d ou bl e -bl in d R C T (P LA N ET RA ex te ns io n) 14 4 4 8 w ee ks S im ila r A C R 2 0 , A C R 5 0 , a nd A C R 70 ra te s b et w ee n t he c on t. a nd s w it ch ar m s. P ro po rt io n o f p ts w it h a t l ea st on e T E AE c om pa ra bl e b et w ee n co nt . a nd s w it ch a rm ( 5 3 .5 % a nd 5 3 .8 % , r es pe ct iv el y) . P ro po rt io n o f pt s d ev el op in g A D A s im ila r b et w ee n ar m s. Ye s S wi tc hi ng no t as so ci at ed w ith a ny de tr im en ta l e ff ec ts on e ff ic ac y, s af et y, o r im m un og en ic it y Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e m Ab s i n onc ol og y Von M in ck wi tz et a l. (2 01 8) 69 Tr as tu zum ab – A B P 9 8 0 E ar ly b re ast ca nc er ( ad ju va nt ph as e) R and om iz ed , do ub le -b lin d, ph as e I II s tu dy 17 1 NR Pe rc en t o f p ts w it h d is ea se pr og re ss io n/ re cu rr enc e/ de at h wa s 5 .3 % v s. 2 .9 % i n t he R P c on t. a nd R P/ B S s w it ch a rm , r es pe ct iv el y. N o in cr ea se i n f re qu en cy o r s ev er it y of A Es a nd n o u nex pe ct ed s af et y si gn al s. N o i nc re as e i n c ar di ot ox ic it y. In a dj uv an t p ha se , 1 p t i n t he sw it ch a rm d ev el op ed b in di ng n on -ne ut ra liz in g A D A . I n n eo ad ju va nt ph as e ( pr e -s w it ch ), 2 p ts i n t he R P c on t. a nd i n t he B S c on t. a rm dev el op ed b in di ng n on -n eu tr al izi ng ADA . Ye s S w itc hi ng f ro m tr as tu zu m ab t o A B P 9 8 0 w as s af e. S w itc hi ng di d n ot i nc re as e t he fr eq ue nc y o r s ev er it y of A E s, n o u ne xp ec te d sa fe ty s ig na ls w er e no te d, a nd i t d id n ot in cr ea se t he i nc id en ce of d ev el op in g A D A s. Ev en t-f re e s ur vi va l w as al so s im ila r b et w ee n tr ea tm en t gro up s. C oh en et a l. (2 0 1 8 ) 66 R it uxi ma b – PF -0 5 2 8 05 8 6 RA R and om iz ed ex te ns io n s tu dy (RE FL ECT IO N S ) 1 26 9 6 w ee ks N o n ot ab le d if fe re nc es i n d ru g con ce nt ra ti on s b et w ee n g ro ups , a nd no a pp ar en t r el at io ns hi p b et w ee n IR R a nd A D A w it h o r w it ho ut s w it ch . Lo ng -te rm s af et y a nd t ol er ab ili ty of P F-0 5 2 8 0 5 8 6 a cc ep ta bl e i n a ll gr ou ps . P er ce nt ag e o f s ub je ct s w it h a l ow d is ea se a ct iv it y s co re a nd di se as e ac ti vit y s co re re m iss io n wa s si m ila r a cr os s g ro up s f or a ll t im e poin ts . Ye s To le ra bi lit y a nd ac ce pt ab le s af et y of a s in gl e s w itc h w as dem on st ra te d. N o i nc re as ed im m un og eni ci ty d ue to s w itc hi ng b as ed on e ith er A D A o r I RR re por ts . Pa rk et a l. (2 0 17 ) 63 R it uxi ma b – C T-P10 RA O LE p ha se I stu dy 20 24 w ee ks Al l e ff ic ac y e nd p oi nt s ( D AS 2 8 -ES R , D AS 2 8 -C R P, a nd E U LA R re sp on se ) c om pa rab le b et w ee n c on t. an d s w it ch a rm s, n o s ta tis ti ca lly si gn if ic ant d if fe re nc es . N o si gn if ic an t d if fe re nc es i n A Es . A D A in ci de nc e s im ila r b et w ee n c on t. a nd sw itc h a rm s. Ye s S w itc hi ng h ad n o no ta bl e i m pa ct o n t he ef fic ac y o r s af et y o f tr ea tm en t S hi m et a l. (2 0 17 ) 64 R it uxi ma b – C T-P10 RA O LE p ha se I II stu dy 10 9 24 w ee ks D AS 2 8 a nd A C R r es po ns e r at e co m pa ra bl e b et w ee n a rm s, B -c el l de pl et io n c om pa ra bl e a ft er t he fir st i nf us io n a nd m ai nt ai ne d un til 2 4 w ee ks i n a ll a rm s. S af et y pr of iles c om pa ra bl e b et we en ar m s. N o r em ar ka bl e c ha ng es i n im m un og en ic it y p ro fil e f ol lo w ed t he sw it ch. Ye s S w itc h a rm s w er e co m pa ra bl e t o B S a nd R P a rm s g ro up s i n ef fic ac y, s af et y, a nd im m un og en ic it y Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e To ny e t a l. (2 0 17 ) 65 R it uxi ma b – G P 2 01 3 RA R and om iz ed , do ub le -b lin d, pa ra lle l-gr ou p t ri al (A S S IS T-R T) 5 3 24 w ee ks H yp er se ns it iv it y r ea ct io ns , A D A , a nd th e r at e o f A Es w er e s im ila r b et w ee n ar ms Ye s Th e s af et y o f p ts be tw ee n s w itc h an d c on t. a rm s w as co m par ab le N aso no v et a l. (2 017 ) 62 R it uxi ma b – B C D -0 2 0 RA D ou bl e -bl in d R C T, p ar al le l cr os sov er sw it ch 80 24 w ee ks Th er e w er e no s ig nif ic ant d if fe re nc es in A C R 2 0 a ft er p ar ti al c ro ss ov er a t 4 8 w ee ks ( 2 4 -w ee k s w it ch ). A Es ra te s: 4 4 .4 4 % f or c on t. B S , 3 8 .4 6 % fo r c on t. R P, 5 7. 1 4 % i n R P -B S s w it ch ar m , 6 2 .5 0 % i n B S -R P s w it ch a rm . In ci de nc e o f A D A w as 3 .8 5 % i n c on t. B S a rm , n o b in di ng A D A i n o th er gro ups . Ye s O ne -y ea r d at a s ho w th at s w itc hi ng b et w ee n pr od uc ts d oe s n ot a ff ec t tr ea tme nt o ut come s S m al le r b io logic s R om er et a l. (2 0 0 9 ) 25 S om at ro pi n –O m ni tro pe G H D i n c hi ld re n R and om iz ed , op en -la be l ph as e III cl in ic al stu dy 45 7 5 m on th s 6 .8 % p ts d ev el op ed l ow A D A ti te rs . A t t he f in al v is it , n o p ts h ad de tec ta bl e AD A Ye s S w itc h b et w ee n r hG H pr ep ar at io ns wa s w el l-to le ra te d a nd s af e H ad jiy iann i et a l. (2 01 6) 88 Ins ul in gl ar gi ne – LY 2 9 6 3 0 1 6 T1 D & T 2 D R and om iz ed , con tro lle d cl ini cal s tu dy 3 62 24 w ee ks TD 1 : no s ig nif ic ant d if fe re nc es in e ff ic ac y p ar am et er s, b ut m or e w ei gh t g ai n i n s w it ch a rm c om pa re d to c on t. N o s ig ni fi ca nt d if fe re nc es i n TE AE s a nd S AE s. T D 2 : n o s ig ni fi ca nt di ff er en ce s i n e ff ic ac y p ar am et er s. N o s ig ni fi ca nt d if fe re nc es i n T E AE s. S ig ni fi ca nt ly , f ew er p ts i n s w it ch a rm ex pe ri en ce d ≥ 1 S AE . P ro po rt io n of d et ec ta bl e A D A i n s w it ch a rm st ati sti ca lly s ig ni fi ca ntl y h ig he r co m pa re d t o c on t. a rm ( po te nt ia lly du e t o b as el in e i m ba la nc es ). Ye s P ts w ho s w itc he d fr om R P t o i ns ul in B S ha ve s im ila r e ff ic ac y an d s af et y o ut co m es co m pa re d t o p ts u nd er co n. R P t re at m en t G oh et a l. (2 0 07 ) 2 6 O ri gi nat or –G er EP O He m od ia ly si s pts R and om iz ed , op en -la be l, pa ra lle l a rm , si ng le s w it ch stu dy 87 1 2 w ee ks B ot h a rm s s ho w ed a s im ila r d ec lin e in H b. M or e p ts i n s w it ch a rm re po rt ed A Es d ue t o s ub je ct iv e sy m pt om s, m or e p ts i n s w it ch ar m w er e w it hd ra w n d ue t o A E o r de cr ea se i n H b ( si m ila r H b d ec lin e i n bo th a rm s) . NR R es ul ts a re c on vi nc in g w ith r es pe ct t o e ff ic ac y m ea su re d i n t er m s of H b r es po ns e, t he du ra tio n o f t ri al w as on ly 3 m on th s, w hi ch i s in su ff ic ie nt f or s af et y ev alu at io n Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e H aag -W eb er et a l. (2 0 0 9) 27 Ep oe tin – H X57 5 CK D R and om iz ed , co nt ro lle d, op en -la be l cl ini cal t ri al 31 4 5 4 w ee ks M ea n c ha ng es i n H b l ev el s w er e 0 .1 5 ± 0 .0 9 g /d l a nd 0 .0 6 ± 0 .1 2 g / dl i n s w it ch a nd c on t. a rm re sp ec ti ve ly . Di ff ere nc e b et w ee n ar m s: 0 .0 8 g /d l ( 9 5 % C I: − 0 .1 7 to 0 .3 4) . N o a nt ib od y f or m at io n de te cte d. Ye s N o d if fe re nc es i n sa fet y, im m un og en ic it y, or e ff ic ac y p ro fil es fo llo wi ng t he s wi tc h. Th e l on g-te rm s af et y pr of ile o f t he B S w as co m pa ra bl e t o t he R P. H ar za llah e t a l. (2 0 1 5 ) 28 Ep oe tin H em ax – B S ep oe tin Ep om ax He m od ia ly si s pts Ph as e III t ria l 5 3 4 3 d ay s N o s ig nif ic ant d if fe re nc e i n m ea n H b l ev el s b et w ee n a rm s. F iv e p ts di sc on ti nu ed a ft er s w it ch ( 2 d ue t o un re lat ed a bd om ina l p ai n, un cl ea r fo r o th er 3 ). NR Ep om ax w as e ff ec tiv e at m ai nt ai ni ng t he H b l ev el s a t t ar ge t conc en tr at ion s a nd w as w el l-t ol er at ed K rivos hi ev e t a l. (2 0 10) 29 Ep oe ti n z et a – R P CK D R and om iz ed , ob se rv er -bl in d, con tro lle d ph as e III t ria l 23 0 2 8 w ee ks Pe rc en ta ge o f p ts w it h i nf ec ti on s an d i nf es ta ti on s w as s im ila r. N o p ts de ve lo pe d A D A . Ye s Ep oe tin z et a i s eq ui va le nt t o e po et in al fa i n r es pe ct o f i ts cl ini ca l e ff ic ac y. T he sa fe ty p ro fil e o f b ot h pr od uc ts i s s im ila r: no u ne xp ec te d A E s w er e o bs er ve d, no p ts d ev el op ed an ti -e ry th rop oi et in ant ib od ie s. N o s w it ch a dv ic e. G at ze m ei er et a l. (2 0 0 9) 31 Fi lg ra st im – X M 0 2 N P i n p ts u nd er che m ot he ra py R and om iz ed , con tro lle d ph as e I II s tu dy 80 M ax 6 che m ot he ra py cy cl es Th e A E p ro fil e w as s im ila r b et w ee n co nt . a nd s w it ch a rm s NR XM 02 i s s af e a nd w el l-to ler at ed. N o s w it ch ad vi ce. En ge rt et a l. (2 0 0 9 ) 32 Fi lg ra st im – X M O 2 N P i n p ts u nd er che m ot he ra py R and om iz ed , co nt ro lle d, ph as e III t ria l 29 M ax 6 che m ot he ra py cy cl es (3 -we ek /c ycle ) In ci de nc e of o bs er ve d/ pr ot oc ol de fin ed F N w as 3 1 .7 % a nd 4 1 .4 % in t he c on t. a nd s w it ch a rm s, re sp ec ti ve ly . T he A E p ro fil e w as si m ila r b et w ee n s w it ch a nd c on t. ar m s. S er um co nc ent rat io ns XM 02 h as a s im ila r ef fic ac y p ro fil e a nd do es n ot s ee m t o h av e di ff er en t s af et y p ro fil es as c om pa re d w ith t he R P. X M 02 i s s af e a nd w el l-t ol er at ed. N o s w it ch ad vi ce. S tro wi tz ki e t a l. (2 01 6) 61 Fo lli tr op in – O va le ap Ass ist ed f er til it y O LE p ha se I II tr ial 67 C yc le 2 & 3 (t reat m ent up t o 2 0 -d ay / cy cl e) S af et y a nd e ff ic ac y f in di ng s w er e co m pa ra bl e t o t he o ut co m es i n t he m ai n p ha se I II s tu dy , c om pa ri ng O va le ap a nd G on al -f Ye s R es ul ts i n s up po rt o f t he sa fe ty a nd e ff ic ac y o f a sw itc h t o O va le ap Ta bl e 2 ( C onti nue d) (C on ti nu ed )
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e Mu lt ipl e s w it ch s tud ie s B la uv el t et a l. (2 0 17 ) 19 Ad al im um ab – G P 2 0 17 o r vi ce v er sa Ps Pa ra lle l a rm , ra nd om iz ed , do ubl e -bl in d ph as e I II t ri al (A DA C C ES S ) 4 x s w it ch : a t w ee k 1 7, w ee k 2 3 , w ee k 2 9, an d w ee k 3 5 . Fo llo w -u p u nt il w ee k 51 . 1 26 3 4 w ee ks N o c lin ic al ly r el ev an t d if fe re nc es in e ff ic ac y a nd s af et y b et w ee n t he co nt . a nd s w it ch a rm s (R P c on t. , B S c on t. , R P -B S s w it ch, a nd B S -R P sw it ch ) a cr os s t he s tu dy d ur at io n. O ve ra ll, d if fe re nc es i n t he f re qu en cy of A D A d et ec ti on w er e < 1 1 % a m on g th e a rm s. Ye s Th er e w er e n o c lini ca lly m ea ni ng fu l d if fe re nc es in l on g-te rm e ff ic ac y be tw ee n t he c on t. a nd m ul tip le R P -G P 2 01 7 swi tc h g ro up s. S wi tc hi ng w as w el l-t ol er at ed. G en ov es e et a l. (2 0 17 ) 20 Ad al im um ab – F K B 3 27 RA R and om iz ed O LE o f R C T ph as e I II t ri al (A R AB ESC -O LE ) 2 x s w it ch : a t w ee k 0 ( st ar t O LE ) a nd w ee k 2 8 . F ol lo w -u p un til w ee k 7 6 . 2 16 4 8 –76 w ee ks In te ri m a na ly si s: A C R 2 0 r es po ns e ra te a t w ee k 3 0 c om pa ra bl e be tw ee n c on t. (B S -B S 8 2 .5 % ; R P -R P 8 4 .3 % ) a nd s w it ch (B S -R P 8 6 .5 % ; R P -B S 8 9 .1 % ) a rm s. S af et y pr of ile s c om pa ra bl e f or a ll t re at m en t se qu en ce s ( gr ou p s iz es r ed uc ed af te r s w itc hi ng ). N o c on si st en t d if fe re nc es i n A D A pr of ile s b et w ee n c on t. a nd s w it ch ar m s. Ye s In te ri m O LE r es ul ts in di ca te t ha t l on g-te rm sa fe ty , e ff ic ac y, a nd im m un og eni ci ty w er e co m pa ra bl e b et w ee n co nt . a nd s w itc h a rm s G er des e t a l. (2 0 17 ) 21 Et an er ce pt – G P 2 01 5 Ps R and om iz ed , do ub le -b lin d, pa ra lle l a rm , m ul tip le s w it ch ph as e I II s tu dy (EG AL IT Y ). 3 x s w it ch : a t w ee k 1 2 , w ee k 1 8 , a nd w ee k 24 . Fo llo w -u p u nt il w ee k 52 . 1 9 6 4 0 w ee ks ( 6 -w ee k in te rv al ) PA S I 5 0 , P AS I 7 5 , a nd P AS I 9 0 re sp on se r at es , p er ce nt c ha ng e f ro m ba se lin e i n P AS I s co re s a nd a ll o th er ef fi ca cy p ar am et er s s im ila r b et w ee n sw it ch a nd c on t. a rm s. I nc id en ce of T E AE s, i nc lu di ng i nj ec ti on s it e re ac ti on s c om pa ra bl e b et w ee n a rm s. N o p ts p os it iv e f or b in di ng A D A . Ye s S im ila r e ff ic ac y b et w ee n co nt . a nd s w itc h a rm . N o c lini ca lly r el ev an t di ff er en ce s i n s af et y or i m m un og eni ci ty be tw ee n a rm s, in di ca tin g n o i m pa ct of r ep ea te d s w itc he s be tw ee n G P 2 01 5 a nd R P. W iz em ann e t a l. (2 0 0 8 ) 18 Ep oe ti n a lfa – ep oe ti n z et a or vi ce v er sa C K D , a ne mia D ou bl e -b lin d, cr os sov er ph as e III t ria l 2 x s w it ch : at w ee k 0 , a t w ee k 1 2 23 9 1 2 w ee ks H b l ev el s w er e e qu iv al en t. P ts un de rw en t m in or d os e a dj us tm en ts du ri ng t re at m en t c ro ss ov er . A E pr of ile w as s im ila r. N o p ts d ev el op ed ne ut ral izi ng A D A . Ye s Ep oe tin z et a i s th er ap eu tic al ly eq ui va le nt t o e po et in al fa i n t he m ai nt en an ce of t ar ge t H b l ev el s i n p ts w ith r en al a na em ia . N o un ex pe ct ed A E s w er e se en. Ta bl e 2 ( C onti nue d) (C on ti nu ed )
SWITCH STUDIES FOR SOMATROPIN
One biosimilar (Omnitrope) of somatropin (RP Genotropin), a rhGH, has been authorized in the EU.2 Eight switch studies from the RP of somatropin to Omnitrope have been identified (Table S3 in the online Supplementary Information). Seven studies consisted of a single arm study design and one was a randomized open-label phase III trial.25 All studies consisted of a single switch from the RP to the biosimilar. Overall, none of these studies indicated safety or efficacy issues related to switching.
SWITCH STUDIES FOR EPOETIN ALFA/ZETA
Five biosimilars (representing two unique products) of epo-etin alfa (RP Eprex) are EU approved (Epoepo-etin Alfa Hexal/ Abseamed/Binocrit, and Silapo/Retacrit).2 The marketing authorization holder of Silapo/Retacrit requested another INN for their active substance (i.e., epoetin zeta).2 A total of 20 switch studies were identified for epoetin alfa and epoetin zeta (Table S4 in the online Supplementary Information). Five switch RCTs were identified, of which one trial can be con-sidered as a multiple switch study.18,26–29 In this study, patients were treated with an originator prior to enrollment. Upon the start of the trial, a part of these patients were switched to a bi-osimilar, followed by a second switch to the originator during the study duration.18 Further, 14 single arm studies were identi-fied. One of the studies, a retrospective matched control study in hemodialysis patients, demonstrated a dosing penalty (i.e., re-quiring higher doses to maintain Hb level) after switching.30 In this study, 163 patients were switched and followed up during 24 weeks. Higher doses of 40% were reported to be required to maintain anemia control.30
SWITCH STUDIES FOR FILGRASTIM
Seven biosimilars (representing four unique products) of filgras-tim (RP Neupogen) have been approved in the EU (i.e., Zarzio/ Filgrastim Hexal, Tevagrastim/Ratiograstim, Nivestim, and Grastofil/Accofil).2
Five studies included a switch from the filgrastim RP to a fil-grastim biosimilar (Table S5 in the online Supplementary Information). Three of these consisted of a randomized phase III trial design, of which one study included a multiple switch.31,32,23 The other two studies consisted of a retrospective chart/database review. Overall, none of these studies indicated safety or efficacy issues related to switching. In all these studies, patients were treated with chemotherapy.
SWITCH STUDIES FOR INSULIN GLARGINE/LISPRO
Two unique biosimilars of insulin glargine (RP Lantus) are ap-proved in the EU (i.e., Abasaglar and Semglee).2 Insulin lispro Sanofi is an EU-approved biosimilar of the insulin lispro RP (Humalog).2
Four studies incorporating a switch between the insulin glargine RP and a biosimilar were identified (Table S6 in the online Supplementary Information). One of these studies, based on a retrospective chart review, indicated an increase in insulin dosage by 2.4 units after switching 24 patients to the
A ut hor s Pr odu ct P op ula tion St ud y d es ig n N o. pa ti ent s sw itc he d Fo llo w -u p a Ef fi ca cy , s af et y, a nd i m m un og en ic it y ou tc om es A DA r ep . R ep or te d c on cl us io n/ swi tc h a dv ic e B la ck w el l e t a l. (2 0 1 5 ) 23 Fi lg ra st im – E P 2 0 0 6 N P i n p ts u nd er che m ot he ra py R and om iz ed , ph as e III t ria l 5 x s w it ch : a t ea ch c he m o cy cl e e ve ry 3 w ee ks 10 9 4 t reat m ent cy cl es Al te rn at in g b et w ee n b io si m ila r a nd R P o r vi ce v er sa s ho w ed n o c lin ic al ly m ea ni ng fu l d if fe re nc es r eg ar di ng ef fi ca cy a nd s af et y. N o i nc re as ed ris k o f d ev el op in g A D A u nd er rep ea te d a lte rn at in g. Ye s Al ter na tin g b et w een B S a nd t he R P o r vi ce v er sa s ho w ed n o clin ic all y m ea nin gf ul di ff er en ce s r eg ar di ng ef fic ac y a nd s af et y. T he im m un og eni c r es po ns e to f ilg ra st im a ss es se d und er c ond iti on s o f re pe at ed a lte rn at in g and n on al -te rn at in g a ls o sh ow ed n o i nc re as ed ri sk o f d ev el op in g a nt i-G -C S F a nt ib od ie s. AC R , A m er ic an C ol le ge o f R he um at ol og y; A D A , a nt id ru g a nt ib od y; A D A r ep ., A D A m ea su re m en ts r ep or te d; A E, a dv er se e ve nt ; B S , b io si m ila r; C I, c on fi de nc e i nt er va l; C D , C ro hn ’s d is ea se ; C K D , c hr on ic k id ne y di se as e; c on t. , c on ti nu ou s; C R P, C r ea ct iv e p ro te in ; D AS , D is ea se A ct iv it y S co re ; E S R , E ry th ro cy te S ed im en ta ti on R at e; F N , f eb ri le n eu tr op en ia ; G -C S F, g ra nu lo cy te c ol on y-st im ul at in g f ac to r; G H D , g ro w th h or m on e de fi ci en cy ; H b, h em og lo bi n; I B D , i nf la m m at or y b ow el d is ea se ; I R R , i nf us io n -r el at ed r ea ct io n; m A bs , m on oc lo na l a nt ib od ie s; N P, n eu tr op en ia ; N R , n ot r ep or te d; O LE , o pe n l ab el e xt en si on ; P A , p so ri at ic a rt hr it is ; PA S I, P so ri as is A re a a nd S ev er it y I nd ex ; P s, c hr on ic p la qu e p so ri as is ; p ts , p at ie nt s; R A , r he um at oi d a rt hr it is ; R C T, r an do m iz ed c on tr ol le d t ri al ; r hG H : r ec om bi na nt h um an g ro w th h or m on e; R P, r ef er en ce p ro du ct ; S A E, s er io us a dv er se e ve nt ; S pA , S po nd yl oa rt hr it is ; T 1 D , t yp e 1 d ia be te s; T 2 D , t yp e 2 d ia be te s; T E A E, t re at m en t-em er ge nt a dv er se e ve nt ; T L, t ro ug h l ev el ; U C , u lc er at iv e c ol it is . aFo llo w -u p a ft er s w it ch . Ta bl e 2 ( C onti nue d)
biosimilar.33 The results of another retrospective chart review, of 73 patients switched from Basalin to Lantus showed further reductions in blood glucose, although the insulin glargine dose did not increase.34 The hypoglycemia incidence was low during both Basalin and Lantus treatment (2.4% vs. 1.2%, respectively), with no cases of severe hypoglycemia. Authors concluded that further studies are needed to verify these findings.34 Basalin is not approved in the EU or in the United States, thus, not to be considered a true biosimilar evaluated by a stringent regulatory framework. A lack of true biosimilarity could, thus, potentially explain the observed pre- and post switch differences. The retro-spective design poses further a limitation to the interpretation of the results. No insulin lispro switch studies were identified. SWITCH STUDIES FOR ANTI-TNFS
The study parameters and results of the RCT and open-label switch studies for infliximab, adalimumab, and etanercept are shown in Table 2. A complete overview of all the anti-TNF switch stud-ies can be found in Tables S7–S9 in the online Supplementary Information.
Infliximab
Four biosimilars (representing three unique products) of inflix-imab (RP Remicade) have been EU-approved (i.e., Remsima/ Inflectra, Flixabi, and Zessly).2 One hundred studies incorpo-rating a switch between the RP and one of its biosimilars have been identified. The study parameters and results of the switch studies for infliximab can be consulted in Table S7 in the online Supplementary Information.
Results of RCTs and extension trials investigating the switch from the infliximab RP to a biosimilar
Most RCTs investigating switching from the infliximab RP to one of its biosimilars incorporated a switch after the assessment of the primary trial end point in the main clinical trial (i.e., in an extension trial). Extension studies of the pivotal PLANETAS and PLANETRA trials, investigating the switch from the infliximab RP to CT-P13 (Remsima/Inflectra) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis respectively, showed no reduced efficacy nor an increase in adverse events (AEs) between the maintenance and the switch groups.35,36 However, during the
second year of the PLANETAS extension study, the incidence of more than one treatment-emergent adverse events (TEAEs) was 48.9% vs. 71.4% patients in the maintenance CT-P13 and the RP-CT-P13 switch group, respectively.36 ADA incidence and hypersensitivity reactions observed in both extension tri-als (PLANETRA and PLANETAS) did not significantly differ between maintenance and switch group.35,36 Further, a phase III double-blind RCT investigating the single switch from infliximab RP to SB2 (Flixabi) has been conducted in patients with RA (94 patients switched).37 The efficacy, safety, and immunogenicity profiles were reported to remain comparable between groups up to the end of 24 weeks of follow-up, indicating that there were no TEAEs or clinically relevant differences after switching from the RP to SB2.37 The landmark NOR-SWITCH trial, supported by the Norwegian government, is an independent randomized, dou-ble-blind, noninferiority (NI) study with 52 weeks of follow-up.24 The NOR-SWITCH trial aimed to evaluate maintenance of efficacy and the monitoring of AEs in patients after the switch from the infliximab RP to CT-P13 in comparison with the effi-cacy and AEs in patients under continued treatment with the RP. Patients across the six therapeutic indications of infliximab were included (i.e., patients with RA, spondyloarthritis, psoriatic ar-thritis, chronic plaque psoriasis, Crohn’s disease (CD), and ulcer-ative colitis (UC)). The primary end point of the study was disease worsening (determined by worsening in disease-specific compos-ite measures or a consensus about disease worsening between the investigator and the patient, which lead to a major change in the treatment). The NI margin was set at 15% at 52 weeks, assuming 30% disease worsening in each group. Almost 500 adult patients on stable treatment with the RP for at least 6 months were 1:1 randomized to switch to CT-P13 or to continue treatment with the RP. Disease worsening occurred in 26% of patients in the RP group and in 30% of patients in the CT-P13 group. The lower limit of the 95% confidence interval of the adjusted risk difference fell within the predefined NI margin of 15% (–4.4%; 95% CI –12.7 to 3.9), showing that switching from the RP to CT-P13 was not in-ferior to continued treatment with the RP. Further, the frequency of serious AEs, overall AEs, and AEs leading to discontinuation was similar between groups. Serum trough concentrations and the incidence of ADAs were also similar between groups. A draw-back of this study is the fact that it was not powered to show NI in Figure 3 Number of studies with ADA and/or trough level measurements. ADA, antidrug antibody; TL, trough level.
the individual therapeutic indications.24 Patients who completed the 12-month treatment were asked to enter in an open-label fol-low-up study in which all patients received CT-P13 for 26 weeks. The extension study did not show any difference between patients who maintained CT-P13 compared with patients who switched from the RP to CT-P13.38 Further, the single switch from the in-fliximab RP to BOW015 was investigated in an open-label exten-sion phase III trial in patients with RA.39 The impact of a single switch from the RP to PF-06438179/GP1111 (Zessly) was inves-tigated in an RCT phase III trial40 and the single switch from RP to CT-P13 was investigated in an open-label extension phase I/II trial41 and in a RCT phase III trial.42 Overall, the switch did not negatively affect efficacy, safety, or immunogenicity outcomes in these studies.
Real-world clinical studies investigating the switch from the infliximab RP to a biosimilar
Several studies (91/100) aimed to collect real-world data about the switch from the infliximab RP to one of its biosimilars, mostly for CT-P13 (first approved infliximab biosimilar). An overview of the study design and results of these studies is available in Table S7 in the online Supplementary Information. A study based on the data from the DANBIO registry reported outcomes of a systematic, nationwide switch from the infliximab RP to CT-P13 of Danish patients with RA, spondyloarthritis, and psoriatic ar-thritis under infliximab treatment.43 Investigators reported that the disease activities were similar 3 months pre- and post switch. After 1 year of follow-up, ~ 84% of patients were still under CT-P13 treatment, which was lower than in the NOR-SWITCH trial (96%). Authors indicated that this difference could be explained by the real-world setting of the study. The 1-year retention rate was slightly lower (3.4%) compared with patients treated with the RP in a historic cohort.43
Some infliximab switch studies reported a difference in efficacy, safety, immunogenicity, retention rate, or product dosage before and after switching or between the switch and maintenance group in their final conclusion.44–48 Multiple studies reported a higher number of discontinued treatment, mainly driven by worsening in patient-reported outcomes, without changes in objective parame-ters (e.g., in TL, ADAs, and C reactive protein). Mostly, authors concluded that this was probably driven by nocebo effects (i.e., patients’ negative expectations leading to experienced AEs or a per-ceived decrease in response49).44–47
Adalimumab
Eight biosimilars (representing five unique products) of adali-mumab (RP Humira), have been approved in the EU (i.e., Imraldi, Solymbic/Amgevita, Halimatoz/Hefiya/Hyrimoz, Cyltezo, and Hulio).2 Seven switch studies from the RP to one of its biosimilars were identified (Table S8 in the online Supplementary Information). These are all double-blind or open-label extension studies of phase III trials as part of the biosimilar development program. Two studies investigated switching from the RP to ABP 501 (Amgevita/Solymbic) in two different patient settings (RA and plaque psoriasis).50,51 The trial in RA was a phase III open-label extension trial,
incorporating a single switch from the RP to ABP 501 in 237 patients with a follow-up of 46 weeks.50 The trial by Papp and colleagues investigated a single switch from the RP to ABP 501 in 77 patients with moderate to severe plaque psoriasis, during a phase III RCT.51 Data from both trials indicated that safety, in-cluding immunogenicity, was similar among groups after a sin-gle switch.50,51 One phase III RCT trial investigated the single switch from the RP to SB5 (Imraldi) in 125 patients with RA. Efficacy, safety, and immunogenicity profiles were reported to be comparable between groups. It was stated that no TEAEs or clinically relevant immunogenicity arose by switching.52 The trial by Blauvelt and colleagues consisted of a sequence of four switches (multiple switch design; switch at week 17, 23, 29, and 35) between the RP and GP2017 (126 patients switched, 34 weeks follow-up after initial switch at week 17). Efficacy, safety, and immunogenicity were reported to be similar among the switch and nonswitch groups.19 A randomized open-label extension study investigated the impact of a second switch at week 48, after the first switch at week 24 during the dou-ble-blinded part of the study, between the RP and FKB327 in patients with RA. The interim results suggest that safety, effi-cacy, and immunogenicity were comparable between the main-tenance and switch groups.20 Further, for both CHS-1420 and BI695501, a randomized double-blind RCT investigated a sin-gle switch from the RP. Overall, no efficacy, safety, or immuno-genicity issues were reported.53,54
Etanercept
Benepali and Erelzi are two unique EU-approved biosimilar ver-sions of etanercept (RP Enbrel).2 In total, 25 etanercept biosim-ilar switch studies have been identified. Five of these consist of a double-blind or open-label RCT of which four were conducted in rheumatology indications.55–58 The other study consisted of a multiple switch double-blind RCT (EGALITY) investigating repeated switching between the etanercept RP and GP2015 in patients with plaque psoriasis.21 Patients were switched at week 12, 18, 24, and 30 and followed up to 52 weeks. It was concluded that the repeated switches between the RP and GP2015 had no negative impact on safety or immunogenicity outcomes.21 Of 20 RWE studies, 18 were conducted in rheumatology and 2 in dermatology. A multiple switch was performed between the RP and SB4 with patients with rheumatic disease in clinical prac-tice, switching from RP to SB4 and back again after approxi-mately a year and one half.22 It was reported that the multiple switch did not negatively impact the disease activity. However, a high proportion of patients discontinued SB4 after the first switch. The authors attributed this to nocebo effects, as no worsening in disease activity measures was observed.22 In a sin-gle switch study from etanercept RP to SB4 in patients with rheumatic disease, 39% of patients experienced side effects.59 The authors underlined the need to improve the patients’ ex-perience of switching as a way to decrease side effects.59 This need was echoed in a single switch from etanercept RP to SB4 in patients with rheumatic disease in a single center in France.60 Approximately 17% of patients discontinued the biosimilar, whereas no objective parameter concluded a lower efficacy or a
