Effectiveness and safety of switching IBD patients from the originator to the biosimilar infliximab
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of the review is to evaluate whether switching IBD patients from the originator to the biosimilar IFX is safe and effective in patients with quiescent IBD receiving maintenance therapy.
Background
Description of the condition
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease affecting the gastrointestinal tract. Patients with IBD suffer from bloody diarrhoea, abdominal pain, weight loss and fatigue. In the past, the main goal for treating IBD patients was to alleviate symptoms, however the focus of treatment has switched to achieving mucosal healing. The introduction of anti‐tumour necrosis factor‐alpha (TNF‐α) antagonists revolutionized the treatment of IBD and other inflammatory autoimmune diseases. Previous studies showed that infliximab (IFX), one of the available anti‐TNF‐α agents, is effective for inducing and maintaining clinical remission and achieving mucosal healing (Hanauer 2002; Rutgeerts 2005). Despite the great benefit provided by TNF‐α antagonists, these agents are the main drivers of health care costs for IBD, accounting for 30‐60% of costs associated with IBD. The patent expiration of Remicade® led to the introduction of biosimilar IFX CT‐P13. Although biosimilars are known to be highly similar to the originator product, these drugs are not identical to the reference biologics due to the structural complexity and manufacturing procedures. The European Medicines Agency (EMA) approved CT‐P13 in 2013 for the treatment of autoimmune disorders. This approval was based on preclinical studies and two landmark clinical trials carried out in patients with ankylosing spondylitis and rheumatoid arthritis. These trials showed that CT‐P13 demonstrated an equivalent pharmacokinetic profile, efficacy and safety to that of the originator IFX (Park 2013; Yoo 2013).
The data from these studies suggests that CT‐P13 could be used for all indications that IFX was registered for, including IBD. The decision of the EMA to extrapolate these results led to considerable initial concern amongst gastroenterologists since pharmacokinetic behaviour can vary between different diease types. In the course of 2016, the use of biosimilar IFX was also approved for other indications by the United States and the Canadian regulators. The main reason to use biosimilars is to reduce healthcare costs and to increase accessibility. After the introduction of CT‐P13, the European Crohn's and Colitis Organisation (ECCO) position statement indicated that biosimilars are not comparable to generic small molecules, due to subtle molecular changes that can have profound effects on clinical efficacy and immunogenicity (Danese 2013). ECCO therefore concluded that the efficacy and toxicity of biosimilars are difficult to predict and evidence of safety and benefit would be needed from clinical trials in IBD populations. However, the ECCO position statement did not provide clear advice about switching patients from Remicade® to biosimilar IFX. Increasing comfort in prescribing CT‐P13 was brought on by real life data with CT‐P13 in IBD demonstrating a comparable safety and efficacy profile as originator IFX (Farkas 2015a; Gecse 2016; Kang 2015). For the achievement of mucosal healing equivalent numbers were seen in trials performed in IBD patients treated with CT‐P13 compared to former trials performed with the originator IFX (Farkas 2015b; Farkas 2016;Jung 2015). In addition, similarity in the immunogenicity (i.e. the formation of drug anti‐drug antibodies) profile was reported (Ben‐Horin 2016; Jahnsen 2015). Some countries were forced to switch their patients because of regulatory pressure, but most awaited evidence about switching in IBD patients. The NOR‐SWITCH trial, a large Norwegian randomised controlled trial in patients with CD, UC, psoriasis, psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis found no differences in terms of disease worsening or adverse events in patients switched to CT‐P13 compared with those receiving originator IFX (Jorgensen 2017). In this large, government‐sponsored, Norwegian clinical trial patients were randomised to continued originator IFX treatment or switch to biosimilar IFX. No differences were observed in maintenance of remission, immunogenicity, pharmacokinetics, or adverse events. The results of this trial, together with other clinical trials demonstrating similar clinical efficacy, safety and immunogenicity after switching, increased the confidence of gastroenterologists to switch their patients (Diaz Hernandez 2016; Kolar 2016). The most recent version of the ECCO statement about biosimilars stated that patients should be well informed about switching and that the decision should be made according to shared decision making with close monitoring of the patient (Danese 2017). This review will give an overview of the available literature about switching from originator IFX to biosimilar IFX in adult IBD patients on maintenance IFX treatment.
Description of the intervention
IFX is a chimeric monoclonal antibody with a half life of approximately eight to ten days and a high binding affinity to TNF‐α. It is registered for multiple auto‐immune diseases and has proven to be effective for induction and maintenance of clinical remission in IBD patients. IFX is administered intravenously with an induction phase of three infusions of 5 mg/kg at week zero, two and six followed by a maintenance phase of 5 mg/kg every eight weeks. It can be given as monotherapy or in combination with immunomodulators such as methotrexate or thiopurines to decrease the chance of immunogenicity. In patients with signs of loss of response in combination with a low serum trough concentrations, IFX therapy is escalated by either increasing the dosage or decreasing the dosing interval. Although anti‐TNF‐α agents are one of the most potent classes of drugs available for treatment of IBD, treatment with these drugs is very expensive. After the introduction of the cheaper biosimilar IFX, clinical trials were performed to investigate the efficacy and safety. Since costs are the main reason to use biosimilars, switching patients from originator IFX to biosimilar was the next step. In this review, clinical trials in which IBD patients were switched from originator to biosimilar IFX will be included.
How the intervention might work
Since 2005 there have been several biosimilars developed different diseases, mainly with a relatively low molecular weight and a predictable pharmacokinetic/pharmacodynamic profile. Some of these biosimilars including erythropoietin and somatropin have received approval from regulatory agencies. The approval of a biosimilar is only possible when a high similarity to the original product is demonstrated. This is due to the fact that molecular or structural differences or both could potentially effect the safety or efficacy of the drug. Since monoclonal antibodies are large complex molecules with a variable pharmacokinetic profile across patients, subtle molecular differences might lead to pharmacokinetic changes in patients, which can effect the safety and efficacy of a biosimilar treatment. The exact mechanism behind the high variability in pharmacokinetics of monoclonal antibodies is not fully understood, but disease characteristics, concomitant medication and certain patient factors are likely to play a role. An approved biosimilar is highly similar to the originator, however clinical trials are needed to confirm safety and efficacy in patients. Biosimilar IFX CT‐P13, a monoclonal antibody approved for the same indications as originator IFX, has the same mechanism of action as the originator, namely the blockage of TNF‐α. After extensive preclinical studies, the two clinical trials that led to the initial approval of the IFX biosimilar CT‐P13 (Park 2013; Yoo 2013), demonstrated similarity in safety, clinical efficacy, immunogenicity and pharmacokinetic profile between biosimilar IFX and the originator in patients with rheumatoid arthritis and ankylosing spondylitis. Post‐marketing clinical trials performed in IBD patients soon followed (Diaz Hernandez 2016; Jorgensen 2017; Kolar 2016; Smits 2016). Papamichael 2015 published a review about the pharmacological properties of anti‐TNF‐α biosimilars in IBD. At that time in 2015, pharmacokinetic data from IBD patients was scarce and came from small retrospective trials, or post‐marketing registries and case series. Nevertheless, a comparable efficacy and safety profile was seen between biosimilar IFX and originator in IBD patients (Diaz Hernandez 2016; Jorgensen 2017; Kolar 2016; Smits 2016). Furthermore, a large randomised controlled trial from Norway showed comparable safety and efficacy after switching from the originator to the biosimilar IFX (Jorgensen 2017). Likewise, no differences were seen in pharmacokinetics and no increase in immunogenicity was observed. This trial, performed in multiple auto‐immune diseases, showed the overall equivalence of biosimilar IFX to the originator and was not powered to draw any conclusions per disease group. Meanwhile, more switch studies with biosimilar IFX were performed in IBD patients demonstrating bioequivalence to the originator (Arguelles‐Arias 2017; Eberl 2017; Razanskaite 2017; Sieczkowska 2016; Smits 2016).
Why it is important to do this review
Healthcare costs are rising worldwide and the use of biologicals accounts for a large part of the cost of treatment for IBD. The main motivation for performing this review is to present all scientific data available with regard to switching from the originator to the biosimilar IFX in IBD patients.
Objectives
The objective of the review is to evaluate whether switching IBD patients from the originator to the biosimilar IFX is safe and effective in patients with quiescent IBD receiving maintenance therapy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and prospective observational studies will be considered for inclusion.
Types of participants
Eligible patients are older than 18 years and were previously diagnosed either with CD or with UC based on clinical, biochemical, endoscopic and histological findings. Patients with quiescent disease should be receiving maintenance treatment with the originator IFX at the initiation of the study and need to be switched to the biosimilar IFX.
Types of interventions
Studies that compare maintenance treatment with biosimilar IFX to originator IFX will be considered for inclusion.
Types of outcome measures
Primary outcomes
The primary outcome will be the proportion of patients who maintain clinical remission as defined by the included studies. This definition could include the use of validated disease indices such as the Harvey‐Bradshaw Index, the Crohn's Disease Acitivity Index and the partial Mayo score.
Secondary outcomes
Secondary outcomes will include:
1) Time to clinical relapse;
2) The proportion of patients who maintained biochemical remission, as defined by a C‐reactive protein (CRP) < 5 or fecal calprotectin (FC) < 250, unless otherwise specified according to individual measurements;
3) The absolute change in inflammatory biomarkers from baseline (i.e. CRP or FC);
4) Pharmacokinetic response (serum IFX trough levels);
5) The proportion of patients who maintained endoscopic remission, as defined by the Mayo score or Simple Endoscopic Score for CD or absence of ulcers or physicians’ global assessment, as defined by the included studies (if available);
6) The absolute change in endoscopic scores from baseline (as defined by the included studies if available);
7) Immunogenicity as measured by the proportion of patients developing drug anti‐drug antibodies; and
8) Safety outcomes including the proportion of patients with adverse events, serious adverse events and withdrawal due to adverse events.
Search methods for identification of studies
Electronic searches
We will search the following bibliographic databases from inception to date: MEDLINE, Embase, CENTRAL and the Cochrane IBD Group Specialized Register. The search strategies are reported in Appendix 1.
Searching other resources
We will search the reference lists of potentially relevant trials and papers to identify additional studies. Abstracts presented at Digestive Disease Week, United European Gastroenterology Week and the European Crohn's and Colitis Organisation Congress will be hand searched for relevant studies. We will also search for ongoing studies using the clinicaltrials.gov database, the European Union Clinical Trials Register and the World Health Organization International Clinical Trials Registry.
Data collection and analysis
Selection of studies
Titles of studies retrieved using the search strategy and those from additional sources will be independently screened by two authors (AS and ED) to identify studies that potentially meet the inclusion criteria outlined above. The full text of these potentially eligible studies will be retrieved and independently assessed for eligibility by three review team members (AS, MS, ED). A fourth reviewer (GD) will be introduced to resolve any disagreement between the three reviewers about the eligibility of particular studies. A standardised, pre‐piloted data extraction form will be used to extract data from the included studies for assessment of study quality and evidence synthesis.
Data extraction and management
A data extraction form will be used to collect information from the relevant studies. Extracted information will include:
‐ General information (title, journal, year, publication type)
‐ Study information (study design, randomisation method, recruitment and study completion rates, trial characteristics, power calculation, a priori and post hoc analysis);
‐ Outcomes (primary and secondary outcomes);
‐ Eligibility (total number of patients screened and randomised);
‐ Patient baseline characteristics (age, gender, race, disease severity, duration of IFX use and concomitant medication, Montreal classification);
‐ Details about the intervention (IFX dose, time of switching, infusion duration originator/biosimilar, pre‐medication such as anti‐histamines/corticosteroids prior to infusion); and
‐ Information about follow‐up (length of follow‐up, withdrawals, number of patients lost to follow‐up).
If additional information is required, we will contact the original investigator. Two review authors (AS and ED) will extract data independently, discrepancies will be identified and resolved through discussion with a third author (GD) if necessary.
Assessment of risk of bias in included studies
Two review authors (AS and ED) will independently assess the risk of bias in included RCTs using the Cochrane risk of bias tool (Higgins 2011). This risk of bias tool assesses six domains including selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. For each item a judgement of high, low, or unclear risk of bias along with a support for the judgement will be given. The Newcastle‐Ottawa Scale will be used to assess the quality of non‐randomised studies. A case control or cohort study is judged on three broad perspectives: the selection of the study groups, the comparability of the groups; and the ascertainment of either the exposure or outcome of interest. Disagreements between the review authors over the risk of bias in particular studies will be resolved where necessary by a third review author (GD).
We will use the GRADE approach to evaluate the overall quality of evidence supporting the following outcomes: the proportion of patients who maintain clinical remission, biochemical remission, change in CRP, adverse events, serious adverse events and withdrawal due to adverse events (Guyatt 2008; Schünemann 2011). Although evidence from RCTs can be considered high quality, the quality of evidence can be downgraded due to:
‐ Risk of bias;
‐ Indirect evidence;
‐ Inconsistency;
‐ Imprecision; and
‐ Publication bias.
Measures of treatment effect
To evaluate the treatment effect, the following parameters will be measured: clinical disease activity, endoscopic disease activity (when available), biomarkers for disease activity, such as CRP and FC (when available), IFX serum trough concentration and drug anti‐drug antibody formation (when available). For dichotomous outcomes, we will calculate the odds ratios (OR), risk ratio (RR) or risk difference and corresponding 95% confidence interval (95% CI) as appropriate. For time to event outcomes, we will calculate the hazard ratio (HR) and corresponding 95% CI. For continuous outcomes, we will calculate the mean difference (MD) and corresponding 95% CI.
Unit of analysis issues
When studies report multiple observations for the same outcome, outcomes will be combined for fixed intervals of follow‐up (e.g. maintenance of clinical remission at one year). Cross‐over studies will only be included if data before cross‐over are available.
Dealing with missing data
Whenever possible, we will contact the original investigators to request missing data. Only available data will be analysed and the potential impact of missing data on the findings of the review will be mentioned in the Discussion section.
Assessment of heterogeneity
Heterogeneity will be assessed using the Chi2 test (a P value of 0.10 will be considered statistically significant) and the I2 statistic. An I2 value of 25% indicates low heterogeneity, 50% indicates moderate heterogeneity and 75% indicates high heterogeneity (Higgins 2003). We will visually inspect forest plots and use sensitivity analyses to explore potential explanations for heterogeneity.
Assessment of reporting biases
We will compare outcomes listed in the methods section of published manuscripts to those described in the results section. If a sufficient number of studies are included (i.e. > 10) in the pooled analyses, we plan to investigate
potential publication bias using funnel plots (Egger 1997).
Data synthesis
Data from individual trials will be combined for meta‐analysis when patient groups and outcome parameters are sufficiently similar (as determined by consensus). The pooled OR or RR and corresponding 95% CI will be calculated for dichotomous outcomes. For continuous outcomes, the pooled MD and corresponding 95% CI will be calculated. We will calculate the standardized mean difference (SMD) and 95% CI when different scales are used to measure the same underlying construct. For time to event outcomes, we calculate the pooled HR and corresponding 95% CI using the generic inverse‐variance method. We will not pool data for meta‐analysis if a high degree of heterogeneity (I2 ≥75%) is detected. If data cannot be pooled, we plan to provide a narrative synthesis of the findings. We anticipate a limited scope for the meta‐analysis due to the range of different outcomes measured across the small number of available studies. However, when possible, we will pool studies using a random‐effects model.
Subgroup analysis and investigation of heterogeneity
A subgroup analysis will be performed according to type of IBD (CD or UC).
Sensitivity analysis
Sensitivity analyses will examine the impact of the following variables on the pooled effect estimate:
‐ Random‐effects versus fixed‐effect modelling
‐ Low risk of bias only versus unclear or high risk of bias
‐ Relevant loss to follow up (> 10%): Best‐case versus worst‐case scenario
