The design of clinical trials to support the switching and alternation of biosimilars

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1 Expert Opinion on Biological Therapy ISSN: (Print) (Online) Journal homepage: The design of clinical trials to support the switching and alternation of biosimilars Freddy Faccin, Paul Tebbey, Emily Alexander, Xin Wang, Lu Cui & Teotonio Albuquerque To cite this article: Freddy Faccin, Paul Tebbey, Emily Alexander, Xin Wang, Lu Cui & Teotonio Albuquerque (2016) The design of clinical trials to support the switching and alternation of biosimilars, Expert Opinion on Biological Therapy, 16:12, , DOI: / To link to this article: Accepted author version posted online: 26 Sep Published online: 27 Sep Submit your article to this journal Article views: 1224 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at Download by: [F. Hoffmann - La Roche Inc] Date: 19 December 2016, At: 12:23

2 EXPERT OPINION ON BIOLOGICAL THERAPY, 2016 VOL. 16, NO. 12, REVIEW The design of clinical trials to support the switching and alternation of biosimilars Freddy Faccin a, Paul Tebbey b, Emily Alexander c, Xin Wang d, Lu Cui d and Teotonio Albuquerque e a Biotherapeutics, Global Medical Affairs, AbbVie Inc., San Juan, PR, USA; b Gastroenterology & Biotherapeutics, US Medical Affairs, AbbVie Inc., North Chicago, IL, USA; c Biologics Strategic Development, AbbVie Inc., North Chicago, IL, USA; d Data and Statistical Science, AbbVie Inc., North Chicago, IL, USA; e Biotherapeutics, Global Medical Affairs, AbbVie Lda., Amadora, Portugal ABSTRACT Introduction: Loss of exclusivity for biological therapeutics opens the door for biosimilar development. Biosimilars must demonstrate structural, functional, and clinical similarity with a currently approved biological originator product. A therapeutic alternative for biologic-naive patients, a single switch from an originator to biosimilar has also been studied in clinically stable patients; further, switching therapy multiple times (alternating) between an originator and a biosimilar has been investigated. Because biosimilars are not identical to originators and no robust clinical data have convincingly demonstrated that switching or alternating therapy of stable patients is safe and efficacious, there is an imperative need to understand the characteristics of well-designed clinical trials to support these practices. Areas covered: Clinical trials of biosimilars are reviewed, with an emphasis on trial designs that incorporate therapy switching, including the NOR-SWITCH study as an example. Expert opinion: As currently designed, biosimilar clinical trials provide insufficient information to support switching or alternating between originator products and their biosimilars. Lack of regulatory guidance contributes to this void. More robust data are required to inform the safety and efficacy of switching or alternating therapies, particularly regarding immunogenicity risks. Studies that also include alternations of therapy are needed to address these knowledge gaps. ARTICLE HISTORY Received 14 July 2016 Accepted 15 September 2016 Published online 28 September 2016 KEYWORDS Biosimilar; chronic plaque psoriasis; clinical trial; Crohn s disease; CT-P13; infliximab; psoriatic arthritis; rheumatoid arthritis; spondyloarthritis; ulcerative colitis 1. Introduction Biological therapies have significantly improved patient outcomes for a multitude of diseases. As originator products approach their loss of exclusivity, development of biosimilar molecules (also referred to as follow-on biologics, similar biotherapeutic products, or subsequent entry biologics) has grown. Because of their size and complexity, biosimilars of biologic molecules require a more complex development and regulatory assessment than small-molecule generics to ensure that their safety and efficacy are similar to the originator product. To gain approval, a biosimilar must demonstrate a high degree of structural, functional, and clinical similarity with its originator biological product (sometimes called a reference biological product or an innovator product) that was already approved based on a complete dossier. One or more clinical studies evaluating biosimilars in comparison with the corresponding originator product are required and aim to confirm similarity in safety and efficacy [1,2]. Although cost may be a critical determinant of biosimilar use in the future, regulators are not responsible for assessing product costs. The European Medicines Agency (EMA) has led the way on biosimilars in terms of published guidance and approvals; the first biosimilar (somatotropin) was approved in 2006, and, as of February 2016, another 19 biosimilars have been approved by the EMA [3]. Other regulatory authorities, including Health Canada, the Japanese Pharmaceuticals and Medical Devices Agency, and the Australian Therapeutic Goods Administration, have also approved biosimilars. Historically, biosimilar studies have been head-to-head comparisons to support initial approval and biosimilars were considered primarily as options for biologic-naive patients. More recently, selected biosimilar candidates have attempted to address therapy switching or alternating as part of their clinical program. For the purpose of this article, we refer to switching (either transition or a single switch) as changing a patient on an originator product to a biosimilar a single time and alternating as taking a patient on an originator product back and forth to a biosimilar multiple times. In the United States, the Biologics Price Competition and Innovation Act (BPCIA) [4] gave the US Food and Drug Administration (FDA) new authority to approve two distinct classes of products: biosimilar biological products and interchangeable biological products. As discussed previously, biosimilarity requires establishment of similarity and lack of clinically meaningful differences when compared with the originator product. However, based on the definition in the BPCIA, to garner an interchangeability designation, a manufacturer must also establish that the biosimilar can be expected to produce the same clinical result as the reference product in any given patient and for a biological product that is administered more than once to an individual, the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be CONTACT Freddy Faccin freddy.faccin@abbvie.com Therapeutic Area Lead, Biotherapeutics, Global Medical Affairs, Montehiedra Office Center, AbbVie Inc., 9615 Los Romeros Avenue, Suite 600, San Juan, PR , USA 2016 Informa UK Limited, trading as Taylor & Francis Group

3 1446 F. FACCIN ET AL. Article highlights Biosimilars demonstrate analytical, preclinical, and clinical similarity with an approved biological originator product; they cannot be considered to be identical to their originator products. Currently, the design of switching studies varies considerably from product to product. The design of biosimilar switching trials may be insufficiently sensitive to detect differences in immunogenicity relative to continuing treatment with the initial biologic and will not fully address the uncertainty about changing the therapy of a patient who is responding to their current biologic. Currently, no robust, conclusive clinical trial data have demonstrated that switching the therapy of stable patients is safe and efficacious. Well-designed clinical studies should include an evaluation of multiple therapy switches between the biosimilar and the originator product, as well as other design elements that provide adequate sensitivity to address interchangeability. High-quality data, especially regarding immunogenicity risks, are required to ensure the safety and efficacy of switching and alternating between originator and biosimilar therapies. greater than the risk of using the reference product without alternating or switching. [4] Biosimilars that have earned an interchangeability designation would be eligible for automatic substitution for the originator product by a pharmacist, without the intervention of the prescriber, depending on individual state practice of pharmacy laws. However, no guidance has been provided by the FDA regarding how to demonstrate interchangeability and the agency has yet to designate any product as interchangeable; it has been suggested that clinically testing repeated switches between the originator and biosimilar should be required to demonstrate interchangeability [5]. The driving force for this additional standard of interchangeability was the concern of potential negative immune reactions that may lead to loss of efficacy as well as other adverse events that could be prompted by changing therapy, potentially multiple times. No other central regulatory body has a similar authority to deem a biological product as interchangeable although other national competent authorities may have such authority. For example, the EMA does not evaluate biosimilar interchangeability in the European Union, and the responsibility for how products will be used or dispensed is delegated to the individual member states. Notably, >12 individual member states in the European Union have taken steps to prohibit automatic substitution of biological products, given their unique characteristics when compared with traditional, small-molecule chemical medicines [6]. However, even in the absence of a formal interchangeability designation, some payers and other authorities have sought to encourage the use of biosimilars for nonnaive patients [7,8], a decision often driven by non-medical reasons (i.e. economics). In the absence of a formal interchangeability designation, it is unclear which specific components of study design are needed to demonstrate the safety of this type of therapy change, which can occur either once or multiple times over a patient s course of treatment. The objective of this article was to evaluate the existing therapy switching data as well as switching components of ongoing trials to assess their potential contribution to information supporting biosimilar use in the clinical setting. This article also discusses some of the considerations for assessing the safety of alternating originator and biosimilar therapies. The discussion focuses on anti-tumor necrosis factor (TNF) therapies because of the chronic nature of the inflammatory diseases that these agents treat. Consequently, these patients may undergo switching or alternation of therapy in the future. 2. Clinical trials of biosimilars Biosimilars are not identical to their originator product, and to date, no robust clinical trial data conclusively demonstrate that switching patients who are responding to their current therapy is safe and efficacious. Therefore, an understanding of the strengths and weaknesses of each type of study design is necessary for full appreciation of the resulting data. Although biosimilar studies have similar design issues as other studies of chronic diseases, the focus of this article is on studies that incorporate therapy switching and/or alternating. Biosimilar clinical trials can include transition, single-switch crossover, and multiple-switch designs (Figure 1) [5,9]. In transition studies, patients switch only from one biologic to another (e.g. from an originator to a biosimilar but not vice versa), whereas in single-switch crossover studies, patients starting on the originator product are switched to the biosimilar and patients starting on the biosimilar are switched to the originator product [5]. In both of these study types, each patient experiences only one change in therapy. In studies Figure 1. Study design for (a) originator drugs and biosimilars and (b) possible real-life scenario in clinical practice. TNF = tumor necrosis factor. Figure 1(a) adapted from [5] with permission of Macmillan Publishers.

4 EXPERT OPINION ON BIOLOGICAL THERAPY 1447 with a multiple-switch design, patients undergo a series of switches alternating between the originator product and the biosimilar instead of just one change to therapy. 3. Single-switch crossover or transition trials of biosimilar anti-tnf agents The infliximab biosimilar CT-P13 (Inflectra TM /Remsima TM )was approved in the United States, European Union, and other jurisdictions based on two clinical trials comparing it with its originator product. PLANETAS, a phase 1 study of patients with ankylosing spondylitis (AS; N = 250) [10,11], and PLANETRA, a phase 3 study of patients with rheumatoid arthritis (RA; N = 606) who were also receiving methotrexate [12,13], were 54-week randomized studies that were not sufficiently powered to detect significant differences between groups for adverse events (the studies were powered for efficacy as the primary end point). Although neither study included patients switching from the originator product to the biosimilar during the double-blind period [5], both studies had open-label extensions (up to week 102), during which patients on the infliximab originator product were transitioned to CT-P13, whereas patients who had received CT-P13 continued their treatment (Table 1) [14,15]. Immunogenicity was assessed at weeks 14, 30, 54, 78, and 102. Notably, in the extension study of PLANETAS, the proportion of patients with AS who had 1 mildormoderate treatment-emergent adverse event was lower in the patients continuously treated with CT-P13 than in the patients who switched from treatment with infliximab to CT-P13; anti-drug antibody (ADA) rates were also numerically higher in patients switching therapy [14]. In contrast, in the PLANETRA study of patients with RA, adverse event and ADA rates were comparable, suggesting that there may be differences between patient populations/different diseases in safety and immunogenicity after switching from an originator product to a biosimilar [15]. Therefore, the totality of the clinical data for CT-P13 might suggest that the current evidence from these transition studies is insufficient to address the development and impact of ADAs over time for switching from the originator product to biosimilar infliximab [16]. The investigational adalimumab biosimilar ABP 501 was examined in a randomized, 26-week phase 3 study of patients with moderate to severe RA; this head-to-head study evaluated clinical equivalence by comparing the 90% CIs of the risk ratio for 20% improvement in American College of Rheumatology criteria (ACR20) at week 24 between patients receiving ABP 501 and the originator product (equivalence margin of [1/0.738]; Table 1) [17]. Although the main study did not include a transition element, patients completing the study could enroll in the open-label extension study [18] and receive ABP 501, representing a therapy transition for patients who initially received adalimumab. To date, no data are available from the extension study. Another phase 3 randomized, double-blind study investigated treatment with ABP 501 in patients with moderate to severe plaque psoriasis. In the double-blind portion of the study, patients received ABP 501 or adalimumab for 16 weeks [19]. Patients treated with adalimumab who achieved 50% improvement in Psoriasis Area and Severity Index (PASI50) at week 16 were then rerandomized to treatment with adalimumab (maintenance) or ABP 501 (transition) through week 48 [20,21]. The study evaluated noninferiority for the incidence of ADAs by estimating the 95% CI of the difference in percentages and comparing the upper CI with the noninferiority margin of 21.7% at weeks 16 and 52. Through week 52, the ADA status fell within the prespecified noninferiority margin; however, more patients in the switch arm had neutralizing antibodies at week 52 compared with the ABP 501 arm, though this difference was not significant. Although both of these studies included a single transition element and provide preliminary clinical data while contributing to the safety database for ABP 501, they have several limitations. While the studies were powered for the primary end point, they were not powered for showing immunogenicity-related outcomes. Because only one arm changed therapy, no data were generated regarding the biosimilar to originator switch. Additionally, the FDA did not agree with the rationale for selection of the prespecified noninferiority margin [22]. Like other biosimilar trials, the results from these single-transition studies provide only limited information regarding changing therapy from ABP 501 to the originator adalimumab. Overall, none of the trials discussed earlier were designed to evaluate switching in a real-world scenario in which patients can switch from one biosimilar back to an originator product or from one biosimilar to another biosimilar, and would not support an interchangeability designation in the United States [23]. 4. Nor-switch The NOR-SWITCH biosimilar study has received extensive publicity. NOR-SWITCH (ClinicalTrials.gov NCT ) is a randomized, double-blind, parallel-group study supported by the Norwegian government that compares the originator infliximab with CT-P13 in patients with six immune-mediated inflammatory diseases [24]. In NOR-SWITCH, patients who are stable on therapy with originator infliximab for 6 months receive an equivalent dose of CT-P13 or continue to receive originator infliximab for an additional 52 weeks. The primary study end point, disease worsening, will be evaluated once this period is completed. Although NOR-SWITCH is perceived by some as a critical study in the determination of whether it is safe to switch or alternate biologic therapy [15,25], it has significant design limitations Patient population The diversity of patients included in the NOR-SWITCH study, including patients with RA, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn s disease, and chronic plaque psoriasis, was likely intended as a study strength, with results applying to the greatest number of potential patients and encompassing most of the approved indications for the originator product. However, many of the design elements critically weaken the strength of any conclusions from resultant data and drive potential bias. At inclusion, patients are required only to have a clinical

5 1448 F. FACCIN ET AL. Table 1. Biosimilar study designs. Study Study type Indication Treatment Efficacy Safety ADA CT-P13 (Celltrion) NOR-SWITCH 1-sided transition RA, SpA, PsA, UC, CD, Ps Pts receiving IFX receive CT-P13 at the same dose and frequency as the preinclusion treatment or remain on IFX PLANETAS Parallel arm AS Randomized 1:1 to IFX (n = 125) or CT- P13 (n = 125) 5 mg/kg PLANETAS extension Open-label 102-wk follow-up AS n = 174 (of original 250 randomized); 86 switched from IFX to CT-P13 and 88 continued CT-P13 PLANETRA Parallel arm RA Randomized 1:1 to IFX (n = 304) or CT- P13 (n = 302) 3 mg/kg PLANETRA extension ABP 501 (Amgen) Study (NCT ) Study (NCT ) Study (NCT ) GP2017 (Sandoz) ADACCESS (NCT ) Open-label 102-wk follow-up Singleswitch crossover Parallel arm RA (pts with inadequate response to MTX) Open-label extension of Study Repeated switching RA n = 302 (of original 606 randomized); 144 switched from IFX to CT-P13 and 158 continued CT-P13 Ps Initial 16 wk: Adalimumab (n = 175) or ABP 501 (n = 175), 80-mg loading dose at wk 1, 40 mg SC every 2 wk thereafter Pts achieving PASI50 continued for up to 52 wk: Pts initially randomized to adalimumab rerandomized (1:1) to ABP 501 (n = 77) or adalimumab (n = 79). Pts receiving ABP 501 continued ABP 501 (n = 152) Randomized (1:1) to ABP 501 (n = 264) or adalimumab 40 mg SC (n = 262) every other wk until wk 22 RA Long-term (72-wk) evaluation of ABP 501 safety and efficacy Ps Period 1 (double blind; n = 448): Adalimumab or GP2017 (80-mg loading dose at wk 0, then 40 mg SC every other wk for 52 wk) Period 2: Pts in each group receive GP2017 or adalimumab (i.e. half of pts switch) TBD (disease worsening based on diseasespecific assessment scores) ASAS20 and ASAS40 response rates were similar between groups ASAS20, ASAS40, and ASAS partial remission rates were similar between groups ACR20/50/70 response rates were similar between groups ACR20/50/70 response rates were maintained and were similar in each group Mean treatment difference in percentage improvement from baseline at wk 16 in PASI, 2.18 (95% CI, 7.39 to 3.02); P = ; within predefined equivalence margin ( 15 to 15) (no data provided for patients who transitioned therapy) Primary: Risk ratio of achieving ACR20 at wk 24 (ABP 501 vs. adalimumab), 1.04 (90% CI, ); within prespecified equivalence limit ( ) Secondary: ACR20 (74.6% vs. 72.4% for ABP 501 vs. adalimumab, respectively), ACR50 (49.2% vs. 52.0%), and ACR70 (26.0% vs. 22.9%) at wk 24 were similar TBD TBD Similar rates of TEAEs for CT-P13 (64.8%) and IFX (63.9%) Proportion of pts with 1 TEAE was lower in maintenance (48.9%) vs. switch group (71.4%), mainly owing to fewer mild and moderate AEs Similar rates of TEAEs for CT-P13 (60.1%) and IFX (60.8%) Number of pts with 1 AE or SAE was comparable between the maintenance and switch groups (53.5% vs. 53.8%, respectively) Through wk 16, similar rate of AEs for ABP 501 (67.2%) and adalimumab (63.6%); at wk 52, 86.2% and 78.5%, respectively, for patients who continued their initial treatment (no data provided for patients who transitioned therapy) Common AEs: nasopharyngitis, headache, URTI, arthralgia AEs in 50.0% vs. 54.6% of pts receiving ABP 501 vs. adalimumab, respectively (frequently nasopharyngitis and headache); SAEs, 3.8% vs. 5.0%; AEs leading to discontinuation, 2.7% vs. 0.8% TBD TBD TBD Pt enrollment complete (Planned) Period 1, primary: PASI75 at wk 16 Period 1, secondary: PASI50/75/90/100; percentage change in PASI Period 2: comparative efficacy in pts who switched vs. pts who did not TBD TBD At wk 14, ADAs were detected in 9.1% (CT-P13) and 11.0% (IFX); 27.4% and 22.5%, respectively, at wk 30 At wk 54, ADAs were detected in 22.2% (CT-P13 maintenance) and 26.2% (CT- P13 switch); 23.3% and 27.4%, respectively, at wk 102 At wk 14, ADAs were detected in 25.4% (CT-P13) and 25.8% (IFX); 48.4% and 48.2%, respectively, at wk 30 ADA-positive pts comparable between maintenance and switch groups at wk 54 (49.1% and 48.3%, respectively) and wk 102 (40.3% vs. 44.8%) At wk 16, binding antibodies, 55.2% vs. 63.6%; neutralizing antibodies, 9.8% vs. 13.9% for ABP 501 and adalimumab, respectively At wk 52, binding antibodies in ABP 501 maintenance (68.4%), adalimumab maintenance (74.7%), and switch groups (72.7%) were similar; neutralizing antibodies were 13.8%, 20.3%, and 24.7%, respectively Binding antibodies, 23.5% vs. 23.7% for ABP 501 vs. adalimumab, respectively, at wk 12, 31.8% vs. 35.1% at wk 26, and 38.3% vs. 38.2% any time postbaseline; neutralizing, 3.0% vs. 3.8% at wk 12, 7.2% vs. 9.9% at wk 26, and 9.1% vs. 11.1% any time postbaseline (Continued )

6 EXPERT OPINION ON BIOLOGICAL THERAPY 1449 Table 1. (Continued). Study Study type Indication Treatment Efficacy Safety ADA Period 1: 1 pt receiving ETA was ADA positive at wk 2 and 5 were positive at wk 4; all pts receiving GP2015 were ADA negative Period 2: All analyzed pts were ADA negative Period 1: AEs in 38% vs. 36% of pts receiving GP2015 vs. ETA; SAEs, 2% vs. 1%, respectively; AEs leading to discontinuation, 2% vs. 2% Period 2: AEs in 31% vs. 37% of pts continuing GP2015 vs. switching to ETA and 34% vs. 32% continuing ETA vs. switching to GP2015 Primary: Risk ratio of achieving PASI 75 at wk 12 (GP2015 vs. ETA), 1.1% (90% CI, 8.3% to 6.0%); within prespecified similarity margin (±18%) Secondary: % change in PASI at wk 12 ( 82.6% for GP2015 and 81.7% for ETA); proportion of IGA responders (58.2% and 55.1%, respectively) Ps Period 1 (n = 531): ETA or GP2015 (50 mg twice/wk to wk 12) Period 2: Pts in each group randomized to continue initial treatment or to switch every 6 wks from ETA to GP2015 or vice versa (50 mg/wk to wk 52) Repeated switching GP2015 (Sandoz) EGALITY (NCT ) ACR20/50/70, 20%/ 50%/ 70% improvement in American College of Rheumatology criteria; ADA, antidrug antibody; AE, adverse event; AS, ankylosing spondyloarthritis; ASAS20/40, 20%/ 40% improvement in Assessment of SpondyloArthritis International Society criteria; CD, Crohn s disease; ETA, etanercept; IFX, infliximab; IGA, investigator s global assessment; MTX, methotrexate; PASI50/75/90/100, 50%/ 75%/ 90%/100% improvement in Psoriasis Area and Severity Index; Ps, psoriasis; PsA, psoriatic arthritis; pt, patient; RA, rheumatoid arthritis; SAE, serious AE; SC, subcutaneous; SpA, spondyloarthritis; TBD, to be determined; TEAE, treatment-emergent AE; UC, ulcerative colitis; URTI, upper respiratory tract infection. diagnosis of a disease, rather than fulfilling a set of diseasespecific criteria [24]. Without clear criteria to establish a diagnosis, bias might arise from different interpretations of the criteria by treating physicians. All NOR-SWITCH patients are required to be stable on current infliximab therapy for 6 months [24], but the protocol fails to consider that criteria for stable patients require definition and are typically disease-specific. For example, a patient with RA could be defined as stable with a 70% improvement in American College of Rheumatology criteria (ACR70) response for 6 continuous months in a 1-year period, or be in clinical remission defined by 28-joint Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI), or Simplified Disease Activity Index (SDAI) for 6 months and without dosage and/or dose frequency increases Outcome measures and endpoints Assessments of the primary outcome (disease worsening, measured with variety of instruments depending on the specific disease) are not universally accepted clinical definitions and vary in sensitivity for the specific diseases [24]. For example, in RA, the SDAI and CDAI are considered to be more sensitive/specific than the DAS28, but DAS28 is used in NOR- SWITCH and is considered to be less conservative for defining remission [26,27]. Major changes in concomitant medications are to be considered as indicators of disease worsening, but major is poorly defined [24]; additionally, specific concomitant medications (like methotrexate) have the potential to affect not only disease activity but also immunogenicity. At the analysis stage, grouping results from these six diseases creates bias, heavily complicating the interpretation of results because no end point is common to all diseases examined. Achieving the overall comparability objective cannot be directly translated to any of the individual indications, as a result of potentially insufficient sample sizes in each indication. Therefore, the noninferiority margin is not interpretable to the individual indication. The permissible dosing regimens at entry into the NOR- SWITCH study are another potential source of bias. Changes in dose or frequency of infliximab or comedications are permitted any time before switching occurs [24]. If a dose increase of infliximab or CT-P13 occurs shortly before switching, there may be an imbalance between treatment arms, with one treatment arm potentially starting 52-week therapy with a higher average dose than that used in the other, potentially biasing results toward one of the cohorts. Notably, balance at randomization is essential. Higher overall drug exposure, particularly for immunosuppressives, could potentially favor a specific therapy by hampering the development of immunogenicity, including new ADAs against drug-specific epitopes Immunogenicity Immunogenicity is a major concern with all biologics, including biosimilars. The NOR-SWITCH protocol lists immunogenicity as an end point but provides no information on the frequency of assessments or the analytical method(s) to be used [24]. Patients who develop ADAs late in the 52-week period or beyond (which may occur in patients with chronic

7 1450 F. FACCIN ET AL. diseases like RA) may go undetected and still be considered clinically stable but may show disease worsening after study completion as a consequence of the development of a lateonset immunogenicity response [28,29]. Ideally, using highsensitivity methods for detecting early ADAs and including this as a criterion for disease worsening would provide sufficiently stringent criteria to ensure a more robust interpretation of the results. The larger concern is that patients are not switched back to originator infliximab (and subsequently reexposed to CT-P13), potentially limiting the sensitivity to detect unwanted clinical and immunogenic effects Statistical concerns Multiple statistical concerns are associated with the design of the NOR-SWITCH trial. The total sample size was based on an estimated rate of disease worsening of 30% [24], a number not observed in the disease-modifying antirheumatic drug (DMARD) registry [30], but instead extrapolated from an 18% rate of treatment failure. Further, this registry evaluated only patients with rheumatologic conditions. Individual estimates for each indication would be more appropriate; different sample sizes should be required based on indication-specific noninferiority margins, as it is extremely unlikely that patient populations for all indications are homogenous. In addition, the selected efficacy measures for the primary analysis are not necessarily those used in clinical trials conducted to support the approval of an originator product. Therefore, the noninferiority margin is not directly comparable with the primary efficacy results of the reference product. For example, ACR20 is the primary outcome for the RA indication; however, DAS28 based on C-reactive protein was used to define RA worsening in the NOR-SWITCH study. Furthermore, the selected margin of 15% is insufficiently stringent: with the assumed 30% disease worsening rate with originator infliximab, this margin would allow the test drug to be inferior by up to 50% without reaching statistical significance. End points should have a well-justified statistical analysis that addresses the clinically important questions posed by the study s design. Challenges exist: there is no clear consensus regarding how to most accurately assess similarity in endpoints like safety and/or ADA development between originator and biosimilar products in clinical trials. In the NOR- SWITCH study, the sample size in each indication is underpowered to show if a difference actually exists in either the chosen primary outcome or secondary outcomes [31]. Although per-protocol analyses tend to enhance treatment differences and are usually used for noninferiority or equivalence trials, sensitivity analyses with an intent-to-treat population should show consistent outcomes, with caution exercised in understanding compliance and dropout patterns. Furthermore, the conventional noninferiority or equivalence trial that tests population average difference is not adequate to establish interchangeability. An approach similar to individual bioequivalence on clinical end points should be exercised to account for the population difference in relation to the within-patient variability [32,33]. None of these approaches are present in the NOR-SWITCH study (or the other biosimilar trials discussed in this article) Summary of the NOR-SWITCH trial Because of the limitations in the NOR-SWITCH trial, data must be interpreted with caution. Addressing multiple indications in one trial is a flaw that prevents drawing a meaningful conclusion of the effect of transitioning for any of the indicated diseases. Although attempting to address multiple indications, the study lacks clarity in definitions, including inclusion/exclusion criteria, end points, and use and impact of concomitant medications. Furthermore, it may not be statistically powered to support a robust interpretation of the data, with multiple confounding factors. Taking all of this into consideration, and with the addition that it includes patients with multiple diseases, ultimately the NOR-SWITCH trial is similar to other clinical transition studies of biosimilar therapies [10,12] and provides limited information on the impact of a single transition of therapy. 5. Considerations for multiple-switch studies To date, the biosimilar trials of anti-tnf therapies have not been designed to evaluate alternating in a real-world scenario in which patients can switch from one biosimilar back to an originator or to another biosimilar. Of the three types of study designs (transition, single-switch crossover, and multipleswitch) recognized in the biosimilar clinical programs (Figure 1(a)), the transition study design is common but provides information only about the specific change in therapy that occurred; arguably, transition will not be the behavior with multiple biosimilars in the market (Figure 1(b)). Although the single-switch crossover study would provide additional information (i.e. for two types of therapy changes instead of one), a multiple-switch design in which patients alternate between therapies would be required to provide meaningful evidence for interchangeability. A sudden change in molecular motifs presented to the immune system can trigger an immune response [34], and such antigenic discontinuity may arise when switching or alternating between originator and biosimilar therapies. Further, repeatedly presenting different sets of epitopes (as could be the case for an originator and its biosimilar) may produce a synergistic boost of immune response [35] primed by the initial therapy switch; the timing between these switches could also critically affect the magnitude of the response [36]. Because immunogenicity is not fully predictable from the similarity exercise s analytical assays and in vivo (animal) studies, and also depends on other product- and patient-related factors (such as patient variability, concomitant medications, and comorbidities), specific patient populations should be examined to fully understand the risk involved with switching and alternating between versions of a given biologic. Because repeated switches may increase the likelihood of developing ADAs, which in turn can lead to compromised safety and efficacy [5], trial designs incorporating multiple switches between originator and biosimilar products would provide additional and clinically relevant information about the immunogenicity of biologics. However, the utilization of multiple-switch study design is scarce. One example of a multiple-switch study is the

8 EXPERT OPINION ON BIOLOGICAL THERAPY 1451 ADACCESS study, which is evaluating the adalimumab biosimilar GP2017 in patients with psoriasis [37]. In the initial double-blind, 16-week period, patients receive either adalimumab or GP2017 (80-mg loading dose at week 0, then 40 mg every other week); in the second period (lasting until week 52), patients in each group are then re-randomized to receive GP2017 or adalimumab (i.e. half of patients will switch therapy). The manufacturer has suggested that they are interested in examining repeated switches [38]. However, while publicly available information suggests that this trial will examine the switch from a biosimilar back to an originator, there is less clarity regarding the total number and types of switches to be examined [39]. To date, no data are available from this study. A similar study design was utilized in the EGALITY study of the etanercept biosimilar GP2015 in patients with plaque psoriasis. After an initial 12- week period, patients with 50% reduction in PASI were randomized to maintain their initial treatment (etanercept or GP2015) or undergo multiple switches between the two treatments at 6-week intervals between weeks 12 and 30, followed by an extension period (week 30 52) in which the last assigned treatment was received (Table 1) [40]. 6. Conclusion Suboptimal design of existing biosimilar switching trials limits the amount and potentially the quality and interpretation of data. Therefore, these trials fall short of fully addressing clinically valid questions and concerns regarding the practice of changing therapy to a drug that is not expected to improve clinical outcome in a patient who is responding to their current therapy. Furthermore, they do not reflect real-world clinical practice, in which patients may repeatedly switch between the originator and one or more biosimilars, as well as among biosimilars referencing the same originator product. Importantly, the assessment of immunogenicity in these studies may not be sensitive enough to exclude the possible risks associated with the clinical practice of alternating between biological drugs that are highly similar, but not identical, to one another. Studies that are designed to include all of the necessary elements (e.g. multiple switches, justified treatment intervals before switches, potential surrogate endpoints, adequate sample sizes, assessment of ADAs) to establish that there is no negative clinical impact from exposing patients to changing therapies are needed before making clinically relevant conclusions regarding the safety and effectiveness of switching between originator and biosimilar therapies. 7. Expert opinion The advent of biosimilar agents that are similar but not identical to existing biologic agents highlights the need to have a full and complete understanding of how clinicians should use this therapeutic option in the best interest of patients and healthcare systems. This includes the need to understand the design, and the accompanying strengths and weaknesses, of recent studies purporting to assess the safety of using biosimilars in patients already receiving an originator biologic. Where sponsors have evaluated switching, the clinical trial designs do not yet provide robust, conclusive evidence to support alternating therapies, which is the expected real-world usage of biosimilars and originator products even without a formal interchangeability designation. A lack of regulatory guidance contributes to this void and as long as the true consequences of this type of switching remain unclear and/or rely solely on postapproval pharmacovigilance data, it may be to the detriment of all patients, including those with chronic diseases. Although the PLANETRA and PLANETAS studies used to support initial biosimilar approvals were well-controlled studies that provided important comparative efficacy and safety data, switch-related elements were not included in the trial design until their respective open-label extensions, with the typical weaknesses associated with these study designs (including being underpowered and having selection bias). Thus, studies containing switching elements (like the PLANETRA and PLANETAS open-label extensions, as well as the NOR-SWITCH study) more closely resemble postmarketing studies in their design and limitations and, consequently, are not conclusive in addressing questions related to the efficacy, safety, and immunogenicity of alternating between originator and biosimilar products. As health practitioners, payers, and patients begin to understand the limitations of current switching studies, more robust data will be required to provide clinically meaningful information about the safety and efficacy of alternating between originator and biosimilar therapies. Particularly, current studies are inadequate to assess the full immunogenicity risks that arise from switching and alternating similar biological therapies. Studies that include multiple alternations of therapy will be needed to address these knowledge gaps; specifically, those that reflect the realities of a postapproval environment that will demand multiple switches between originator products and the corresponding biosimilar agents. Postapproval data alone cannot provide sufficient information on safety and immunogenicity of multiple switching. Although pharmacovigilance data are essential, they have limitations, including underrepresentation of safety data because reporting is voluntary, spontaneous, and often inconsistent; possible bias if products are targeted for additional monitoring; and low statistical power. Therefore, randomized, controlled multiple-switch studies designed to provide robust safety and efficacy data are needed to assure patient safety and cannot be replaced by postapproval studies alone. The promise of biosimilar therapies that may be less costly can only be realized after a comprehensive understanding of the benefits and risks relative to the originator biologic. Challenges remain in the design of adequate trials to assess immunogenicity, especially regarding more informative endpoints; for example, in vitro assays that are more sensitive and can better correlate clinical outcomes with immature immunogenic responses at early stages would be valuable. Future studies must robustly evaluate the impact of single and multiple switches between originator and its biosimilars in order to assess the real-world outcome of switching and alternating therapy in patients with chronic diseases. The knowledge gained from the innovative, adaptive clinical study designs may influence subsequent evaluation of related clinical questions, including whether clinical

9 1452 F. FACCIN ET AL. differences observed between originators and their biosimilars can be attributed to structural differences elucidated during the extensive physiochemical characterization of biosimilars. Acknowledgments AbbVie participated in writing, review, and approval of the manuscript. All authors contributed to the development of the content; all authors and AbbVie reviewed and approved the manuscript; and the authors maintained control over the final content. Editorial and medical writing support was provided by Maria Hovenden, PhD, and Tiffany Brake, PhD, of Complete Publication Solutions, LLC, North Wales, PA. Funding This paper was sponsored by AbbVie. Declaration of interest All of the authors are AbbVie employees and may hold AbbVie stock. 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