Reporting guidelines used in this protocol
The present protocol has been developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines (PRISMA-P) 2015 statement (Additional file 1) (21). We will refer separately to the systematic review of efficacy and safety (systematic review 1) and switching (systematic review 2) because the two systematic reviews address two separate objectives and, therefore, need varying methodologies and approaches.
PROSPERO synopses
Synopses for the two systematic reviews were prospectively registered in the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO/). The first systematic evaluation will focus on the efficacy and safety of biosimilars compared to biologics (PROSPERO number: CRD42019137152), whereas the second systematic review will examine the clinical impact of switching from reference biologics to biosimilars on the management of RA patients whose treatment has already been started (PROSPERO: CRD42019137155).
Adopted reporting standards
Both systematic reviews will be conducted and presented in accordance with Preferred reporting items for systematic review and meta-analysis (PRISMA Statement) (22). Besides, since there are specific aspects related to the conduct, interpretation and reporting of equivalence and noninferiority trials, we will also adopt the US Agency for Healthcare Research and Quality recommendations (23).
Electronic searches
Search strategies were built using controlled vocabulary according to each database and free-text terms based on the research question. We will use the following electronic databases (from inception to September 2020): MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Latin American and Caribbean Health Science (LILACS). A detailed description of the search strategy is available in the additional file 2.
Other sources
We will also search for non-published or ongoing trials in the EU Clinical Trial Register (https://www.clinicaltrialsregister.eu), International Clinical Trials Registry Platform-World Health Organization (http://apps.who.int/trialsearch/) and Clinicaltrials (https://clinicaltrials.gov/). The search strategies to be used in these platforms are described in the additional file 2. When necessary, we will contact corresponding authors for supplementary information. Additionally, we will manually screen the references of all included trials as well as previous systematic reviews. Finally, we will employ Google Scholar and Epistemonikos (https://www.epistemonikos.org/) to retrieve relevant reports citing all relevant included articles. No language limitation will be imposed.
Eligibility Criteria
Types of biosimilars
We will assess any biosimilars of adalimumab, etanercept and infliximab. We chose these three main biologics because they are the most prescribed first-line biologics DMARDs in RA (24). Also, these three DMARDS have the highest numbers of approved biosimilars for RA in the market (13, 25).
Types of control interventions
We will consider as control interventions the reference biologic drugs (i.e, adalimumab, etanercept and infliximab originals). No restrictions on dosages, treatment schedules, co-treatment or combined therapies will be imposed.
Types of trials
Types of trials: Systematic review on efficacy and safety (systematic review 1)
To assess the efficacy and safety of biosimilars (“biosimilarity”) (26), we will include randomized controlled trials (RCTs) or quasi-randomized controlled trials. We will include all trials comparing biosimilars to biologic drugs irrespective of the type of statistical design (superiority, equivalence, or non-inferiority). A quasi-randomised trial was defined as a prospective interventional study whose allocation sequence was not truly random (e.g., consecutive order, day of the week, date of birth etc.). For trials with a 2-part study design, we will consider results from the first period (biosimilarity) only to avoid carry over effects.
Types of trials: Systematic review on switching (systematic review 2)
To assess the impact of switching on clinical outcomes of RA patients, we will include RCTs with two or multiple-part designs. The following four main designs of switching trials will be considered:
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Single-switch design (27, 28): Trials in which there is a single switch from each treatment to the other. All patients receive the study interventions in successive periods. Firstly, patients are randomly allocated to either a biosimilar or a biologic drug (first period). Then, in the second period, treatments are randomly switched in both directions (Group 1: biologic → biosimilar, Group 2: biosimilar → biologic; Group 3: biologic→ biologic; Group 4: biosimilar→ biosimilar).
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Transition design 1 (two non-switching groups as a control): Trials in which there is a single switch from one treatment (biologic drug) to another (biosimilar drug), but not the contrary. Firstly, patients are randomly allocated to either a biosimilar or a biologic drug (first period). Then, in the second period, the trial becomes a three-arm trial in which patients in the biologic drug group are re-randomized to either continue in the biologic group or to switch to the biosimilar drug treatment. Patients initially allocated to the biosimilar group continue to receive a biosimilar throughout the study period (Experimental group: biologic → biosimilar; Control arm 1: biologic → biologic; Control arm 2: biosimilar → biosimilar).
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Transition design 2 (randomized trials with an open label extension; single non-switching group as a control): Trials in which there is a single switch from a biologic drug to a biosimilar drug, but not the contrary. Firstly, patients are randomly allocated to either a biosimilar or a biologic drug (first period). Then, in open label extended phase (second period), all patients (intervention and control groups) receive the biosimilar drug (Experimental group: biologic → biosimilar; Control arm 1: biosimilar → biosimilar).
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Multiple switches design: Also known as interchangeability design (27, 28), in which multiple switches between treatments are allowed throughout the trial follow-up.
Type of participants
Trials will be included if patients with RA had been diagnosed with validated and established international criteria. No limitation will be imposed on age, baseline RA severity, sex, lines of treatment (e.g., treatment-naïve patients or second line of treatment), or any other major demographic characteristics.
Types of outcomes measures
All outcomes were prespecified in the registered PROSPERO synopses and were categorized into three types: efficacy (encompassing outcomes related to disease activity, functional capacity, quality of life and structural damage progression), safety, and immunogenicity. For efficacy outcomes, we will extract data at the following timepoints: 1 month (± 2 weeks), 3 months (± 4 weeks), 6 months (± 4 weeks), 8 months (± 4 weeks), 12 months (± 4 weeks), 36 months (± 4 weeks) and 48 months (± 4 weeks). For safety and immunogenicity outcomes, we will collect data from longest follow-up available.
Primary outcomes (efficacy)
For both systematic reviews, we prespecified a primary outcome, a co-primary outcome, and all secondary outcomes. A co-primary outcome was adopted because the demonstration of superiority or equivalence in a single outcome is insufficient to support clinical decisions. The choice of primary and co-primary outcomes was decided on a panel composed of two RA specialists supervised by two researchers with experience in evidence synthesis. The rationale was to evaluate equivalence between biosimilars, and reference biologic drugs based both on physician-reported and patient-reported outcomes. Similar approaches have been used previously in RA trials (29, 30).\
Systematic review on efficacy and safety (systematic review 1)
The primary outcome will be treatment success at 6 months according to the American College of Rheumatology 20 (ACR20) (31). If trials report results at different time points, we will use the time point closest to 6 months. ACR20 is a composite and binary outcome, requiring patients to have ≥ 20% improvement in the number of swollen and tender joint plus ≥ 20% improvement in at least three out of five domains:
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Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]).
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Patient's global assessment of disease activity (measured on a 0-to-10 Likert scale).
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Physician's global assessment of disease activity (measured on a 0-to-10 Likert scale).
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Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]).
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C-Reactive Protein levels.
The co-primary outcome will be HAQ-DI, which assesses the functional status of patients through the evaluation of eight domains of daily-life activities (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities) with 20 questions in total. For each question, there are four possible responses: 0 = without difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do. The highest score reported for any component question in each domain determines the final score for that domain. By convention, the overall disability index is expressed on a 0 to 3 scale, representing an average score across the domains. A HAQ-DI of 0 indicates no functional disability, whereas a HAQ-DI of 3 denotes severe functional disability (32).
Systematic review on switching (systematic review 2)
The primary outcome will be rate of treatment success at 6 months after the first switch (i.e. 6 months after re-randomization or 6 months after the first switch on the open-label extension phase) defined by the ACR20 (dichotomous outcome). The co-primary outcome will be the HAQ-DI index also measured at 6 months after the first switch (continuous outcome). If outcome data are reported at different time points, we will use the time point closest to 6 months.
Secondary outcomes (efficacy, safety, and immunogenicity)
Secondary outcomes: Efficacy
Secondary outcomes of efficacy will include disease activity, prevention of structural damage progression and quality of life measures:
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Measures of disease activity: the American College of Rheumatology criteria with 50% (ACR50) and 70% (ACR70) responses, simplified disease activity score (SDAI), clinical disease activity score (CDAI), disease activity score in 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR), disease activity score in 28 joints with four components based on C-reactive protein (DAS28-CRP) and the numeric index of the ACR response (ACR-N).
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Functional capacity/quality of life: scores of HAQ-DI and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) (physical and mental components summaries).
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Prevention of structural damage progression: scores of Sharp/ Van der Heijde or Sharp-Van Der Heidje Modified Score Method (mTRSS). A full description of secondary outcomes can be found in the additional file 3.
Secondary outcomes: Safety
We will evaluate the safety of biosimilars compared to biologics by the proportion of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, infusion-related reactions (IRRs), hypersensitivity, malignancies, active tuberculosis, serious infections, all-cause mortality, and treatment-related mortality. Also, we will evaluate discontinuation rates in both treatments. A full list of safety outcomes can be found in the additional file 3.
Secondary outcomes: Immunogenicity
Immunogenicity will be evaluated by the proportion of patients with positive anti-drug antibodies (ADAs) and the proportion of patients with positive neutralizing antibodies (Nabs).
Study Screening And Selection
We developed a customized web platform for data extraction and curation using Ragic (https://www.ragic.com/). This database was carefully designed to simultaneously allow for study screening and selection, and data extraction for both systematic reviews 1 and 2.
During the screening phase, two review authors will independently evaluate titles and abstracts. Disagreements will be solved by a consensus. Next, for each study selected, full-length articles will be downloaded, and two independent reviewers will re-assess the eligibility of each pre-selected trial. In cases of disagreements, a third reviewer will be consulted. Reasons for exclusions will be described in detail in subsequent publications.
Data Extraction And Management
Analysis population
Trials may report two populations for the analysis: an intention-to-treat (ITT) population and a per-protocol (PP) population (23). In both systematic reviews 1 and 2, preference will be given to results based on the PP population, because of the conservative effect of the per-protocol approach on equivalence testing (23). Since there may be a substantial variety in the definition of what constitutes a PP population or an ITT analysis, we will collect and tabulate in detail the definition of PP and ITT used in each trial.
Numerical and graphical results
All data will be extracted independently by two investigators. Discrepancies will be solved via a consensus. We will extract all pertinent quantitative information, including the number of participants at baseline, the number of participants analyzed, and measures of central tendency, variability, and precision. Specifically, whenever available, we will collect means, mean changes, the difference between means at follow-up, medians, standard deviations, interquartile ranges, standard errors, confidence intervals (and their coverage, e.g., 90% or 95%), P-values (one- or two-sides), and t statistics. These data will be used to approximate means and standard deviations when necessary (33). For continuous outcomes, we will use preferentially follow-up data but will use the mean change from baseline when follow-up values are not available (34).
Quantitative data from figures and graphs will be extracted independently using digitizing software (Digitizelt 2.2.2, Germany, https://www.digitizeit.de/). Estimates from the digitizing software will be averaged out to generate the final value. When necessary, data for the same trial will be extracted from multiple sources (e.g., multiple related publications and trial registries).
Ongoing trials
We will summarize all identified ongoing trials, detailing the primary author, research question(s), methods, outcome measures, study start date along with an estimate of study completion date.
Assessment Of Risk Of Bias
Two review authors will independently assess the risk of bias in the included studies. Each domain will be classified as being at a low, unclear, or high risk of bias. Disagreements will be resolved by consensus or discussion with a third reviewer. The studies will be assessed by outcome level. If the trial has one or more domains with a high risk of bias, it will be considered as a high risk of bias study. If the trial has more than two domains at uncertain risk of bias, we will judge the risk of bias to be uncertain. If the trial has a low risk of bias in all domains or one domain as uncertain bias, it will be considered as a low risk of bias study.
Assessment of risk of bias in efficacy and safety trials
We will use criteria recommended by the Cochrane collaboration (Cochrane Risk of bias tool 1.0) (35). The following domains will be evaluated: random sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessors, and incomplete outcome data (PP and ITT population analysis). To specifically address equivalence or non-inferiority trials, we will refer to the recommendations by the US Agency for Healthcare Research and Quality (23) (Table 1). Specifically, we will assess inconsistent application of inclusion/exclusion criteria, patients selected for anticipated nonresponse or good response in one arm, patient behavior changes (poor adherence, use of concomitant treatments, and protocol violations), inadequate outcome measurement techniques and incomplete outcome data (PP and ITT population analysis: ITT population analysis may underestimate the treatment effect in equivalence/non-inferiority trials). More information on the criteria used in each domain can be found in the additional file 4.
Table 1. Risk of bias domains to be evaluated on equivalence or non-inferiority trials.
Type of Bias
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Domain
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Source
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Selection bias
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Random sequence generation
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Cochrane RoB tool 1.0
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Allocation concealment
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Cochrane RoB tool 1.0
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Inconsistent application of inclusion/exclusion criteria
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US Agency for Healthcare Research and Quality
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Performance bias
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Blinding of participants and investigators
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Cochrane RoB tool 1.0
|
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Participants behavior changes
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US Agency for Healthcare Research and Quality
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Detection bias
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Blinding of outcome assessment
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Cochrane RoB tool 1.0
|
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Outcome measurement techniques
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US Agency for Healthcare Research and Quality
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Attrition bias
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Incomplete outcome data
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Cochrane RoB tool 1.0 and US Agency for Healthcare Research and Quality
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Sources: Cochrane Risk of Bias in randomized trials (RoB 1.0.) described in the Cochrane Handbook for Systematic Reviews of Interventions (35) and the US Agency for Healthcare Research and Quality recommendations (23).