Effectiveness and Safety of Reference Infliximab and Biosimilar in Crohn Disease: A French Equivalence Study

Abstract

Infliximab is an antitumor necrosis factor (TNF) monoclonal antibody approved for the treatment of Crohn disease (CD), ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis. The TNF inhibitors, including infliximab, have improved the management of inflammatory bowel disease (1). The U.S. Food and Drug Administration defines biosimilars as highly similar to the reference product (RP) notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences between the biologic product and the reference product in terms of safety, purity, and potency of the product (2). The patent for the RP infliximab (Remicade [Janssen Biotech, Horsham, Pennsylvania]) expired in 2015 in Europe. Biosimilar infliximab CT-P13 was approved by the European Medicines Agency in 2013. The phase 1 PLANETAS study (3) and the phase 3 PLANETRA study (4) were conducted in infliximab-naive patients with ankylosing spondylitis and rheumatoid arthritis, respectively. CT-P13 has been approved for the treatment of these two diseases, and this approval has been extended to other diseases, including CD. The principle of extrapolation remains controversial (5, 6) because of minor structural differences between CT-P13 and RP and because of the possible differences in the mechanisms of action of infliximab across indications (7). The NOR-SWITCH randomized noninferiority trial (8) included 129 patients in the CD subgroup. Disease worsened more frequently in patients who switched to CT-P13 than in those who continued use of the RP (14.3%) and almost reached the prespecified noninferiority margin (15%). A 6-week randomized trial conducted in 220 patients with CD showed no difference between CT-P13 and RP in efficacy and safety (9). Other published prospective studies of CT-P13 have provided reassuring results but did not directly compare CT-P13 and RP (1015). In view of these results, larger and longer-term studies are needed. The study hypothesis was that CT-P13 and RP are equivalent. The European Medicines Agency and the U.S. Food and Drug Administration recommend equivalence trials to demonstrate biosimilarity (2, 16). Randomized controlled trials conducted with CT-P13 in rheumatoid arthritis and spondyloarthritis were equivalence trials (PLANETAS and PLANETRA [3, 4]); this is also the case for adalimumab (17). We aimed to compare the effectiveness and safety of CT-P13 and RP in a large nationwide observational equivalence cohort study of infliximab-naive patients with CD. Methods Data Source This study was conducted using the Systme National des Donnes de Sant (SNDS) French nationwide health administrative database (18). This database covers more than 99% of the French population (around 65million people). Each person is identified by a unique, anonymous number. The SNDS contains all outpatient (drugs, imaging, or endoscopic investigations) and inpatient information (diagnoses; procedures performed; and expensive drugs dispensed, including anti-TNF agents). Patients with long-term diseases (LTDs), such as CD, are reimbursed for their health expenditure, and their diagnosis is recorded. The SNDS also contains sociodemographic data and, when applicable, the date of death. Details are given in the Appendix. Study Population This study was designed as a real-life comparative equivalence cohort study. All patients diagnosed with CD before 31 December 2016 were identified in the SNDS. An individual was considered to have been diagnosed with CD when he or she was eligible as having an LTD (since 1 January 2006) or had a hospital discharge diagnosis of CD (since 1 January 2010) (19) (Appendix Table 1). Infliximab-naive patients with CD who received at least 1 infliximab infusion between 1 March 2015 and 30 November 2016 were included. An infliximab-naive patient was defined as a patient who had not been reimbursed for infliximab during the previous 12 months. A diagnosis of CD had to be reported within 30 days after initiation of infliximab, to take into account longer hospital stays or administrative delays related to LTD procedures. Appendix Table 1. Disease Identification Algorithms Patients younger than 15 years were excluded owing to the very small number of CT-P13 dispensings. Patients who did not receive outpatient health care during the 3 years before initiating infliximab therapy were excluded. These patients may have lived outside of France or may not have any outpatient data entered in the SNDS (<1% of the French population). Patients who received anti-TNF for diagnoses other than CD before the first infliximab infusion were also excluded (Appendix Table 1). Patients with a diagnosis of cancer during the previous 5 years were excluded from analysis of the secondary outcome of cancer. Exposure Definition The primary exposures of interest were infliximab: CT-P13 or RP. The other infliximab biosimilar, SB2, was not studied, because it has been marketed in France only since 2017. In France, infliximab is administered in either public or private hospitals. When the first infliximab reimbursement corresponded to the RP, the patient was included in the RP group, and when the first infliximab reimbursement corresponded to CT-P13, the patient was included in the CT-P13 group. Follow-up started 30 days after the first infusion. Patients were followed until onset of a predefined outcome or censoring. Patients were censored at study end (30 June 2017), switch from RP to CT-P13 (or vice versa) plus 30 days, or discontinuation of infliximab. In the secondary outcome cancer analysis, patients were censored at study end (30 June 2017) or switch from RP to CT-P13 (or vice versa) plus 30 days. Discontinuation of infliximab was defined as the absence of drug dispensing for 56 days (theoretical coverage) + 60 days= 116 days. Outcomes The primary outcome was a composite end point of death; CD-related surgery; all-cause hospitalization except childbirth (Appendix Table 1) for at least 1 night; or reimbursement of adalimumab, vedolizumab, or ustekinumab. Only the first event was considered. Crohn diseaserelated surgery included bowel resection, stricturoplasty, new intestinal stoma, and surgery for anorectal abscess or fistula (Appendix Table 2). Because adalimumab, vedolizumab, and ustekinumab are not coadministered with infliximab, use of these biologic therapies indicates failure or toxicity of infliximab therapy. This primary outcome assessed effectiveness because it includes all-cause hospitalization. Appendix Table 2. Procedure Identification Algorithms Secondary outcomes were CD-related hospitalization, CD-related surgery except for anorectal abscess or fistula surgery, or each individual item of the composite end point. Serious infection (defined as infection requiring hospitalization), except for intestinal or anorectal abscess or fistula (20), tuberculosis (21), and solid or hematologic cancer (22), were also assessed (Appendix Table 1). Covariates Covariates were time-fixed at cohort entry and included sociodemographic data: sex, age, complementary universal health insurance status (free access to health care for people with low income), and a deprivation index expressed in quintiles that was developed in France as the first component of a principal component analysis of 4 socioeconomic variables (23). The interval since CD-related LTD or hospitalization was used as a proxy for CD duration. The CD site was identified by the fourth character of the International Classification of Diseases, 10th Revision (ICD-10), code: small bowel, colon, both, or unspecified. Proxies for CD severity were defined during the 12 months before initiation of infliximab and consisted of abdominal or pelvic computed tomography or magnetic resonance imaging, anal ultrasonography, gastroscopy, colonoscopy, or capsule endoscopy; cumulative duration of CD-related overnight hospitalizations (excluding CD-related surgery); CD-related surgery (Appendix Table 2); and exposure to aminosalicylates, corticosteroids (cumulative prednisone equivalent dose), budesonide, thiopurines (azathioprine, 6-mercaptopurine), methotrexate, or another biologic therapy. Crohn diseaserelated surgery included colon/small-bowel surgery and anorectal abscess or fistula surgery. Prior thiopurine exposure was defined as dispensing of thiopurine during the 12 months before infliximab initiation except for the last month. Thiopurine combination therapy was defined as thiopurine dispensing between 1 month before and 1 month after infliximab initiation. The last exposure to other biologic therapies was based on dispensing of adalimumab, vedolizumab, and ustekinumab, because these drugs are usually used in this order. Cumulative duration of all-cause overnight hospitalizations without CD-related surgery was used as a proxy for general health condition during the 12 months before cohort entry. The type of hospital (university, general, or private) in which the first infliximab infusion was administered was also taken into account. Statistical Analysis Sample size was determined according to the formula proposed by Chow and colleagues (24), based on the therapeutic equivalence of CT-P13 and RP and an expected event rate of 40% in each group (25). A sample of 2173 patients was required for a 2-sided level of 0.05, a power of 90%, and a 2-sided equivalence margin of 0.80 to 1.25. In an equivalence trial, 2 treatments can be considered equivalent when the treatment hazard ratio (HR) and CI are situated within the predefined clinical equivalence margins: [ 1/]. Equivalence margins in biosimilar arthritis trials were an absolute difference of 15%, and the noninferiority margin in NOR-SWITCH was also 15% (4, 8, 26, 27). Equivalence margins of 10% were used in our study, because such margins can be considered to be more clinically relevant. These 10% margins correspond to relative margins of 0.80 to 1.25. The more s