Summary Basis of Decision for Inflectra

 

The Inflectra New Drug Submission (NDS) was filed as a Subsequent Entry Biologic (SEB) product to the Canadian authorized product, Remicade (active ingredient infliximab, marketed by Janssen Inc.). An SEB product is a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. In consideration of supporting information generated using the reference biologic drug, an SEB approval may be granted based on a reduced amount of original non-clinical and clinical information tailored to a particular class of products or a specific case.

In this NDS, Inflectra (active ingredient infliximab) was submitted as a similar biological medicinal product to the reference biologic drug, Remicade. Remicade is authorized for use in nine indications and uses in patients with inflammatory diseases. The specific diseases for which Remicade is authorized include rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, and ulcerative colitis. Remicade is also authorized for pediatric use in Crohn's disease and ulcerative colitis. On the basis of a reduced non-clinical and clinical data package, the sponsor requested market authorization, for Inflectra, for all of the indications and uses currently authorized for the reference product, Remicade.

Clinical Pharmacology

Inflectra was developed as a Subsequent Entry Biologic to the infliximab product, Remicade. Therefore, the biological activity of Remicade is considered to be representative of the mechanism of action and pharmacological effect of Inflectra.

A comparative pharmacokinetic (PK) analysis was conducted between Inflectra and the reference drug, Remicade, in a pivotal, parallel group study (CT-P13 1.1) in 250 patients with ankylosing spondylitis. Patients were randomized 1:1 to receive either Inflectra or Remicade. The PK parameters, area under the concentration-time curve over the dosing interval (AUC_tau) and maximum serum concentration (C_max) at steady state were the primary endpoints, but in the context of an intravenous infusion, their conventional interpretation as surrogates to estimate relative bioavailability was considered to be insufficient. Multiple discriminant analyses resulted in classification accuracy that was less than 14% over what would be expected if the observations were randomly assigned to the test or reference categories. This level of accuracy suggested that Inflectra could not be distinguished from the reference product, Remicade, based on the seven PK parameters (estimated at steady-state using a non-compartmental analysis) that were incorporated into the discriminant analysis.

For further details, please refer to the Inflectra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The NDS for Inflectra was filed with a reduced clinical package, based on the sponsor's claimed comparability in quality and manufacturing data between Inflectra and the Canadian authorized product, Remicade. The sponsor submitted one pivotal clinical safety and efficacy study (Study CT-P13 3.1) and one pivotal PK study (Study CT-P13 1.1) to support a conclusion of no meaningful clinical difference between Inflectra and Remicade. The pivotal efficacy and safety study was conducted in patients with active rheumatoid arthritis. The pivotal PK study was conducted in patients with active ankylosing spondylitis. No clinical studies were conducted in patients with psoriatic arthritis, plaque psoriasis, Crohn's disease, or ulcerative colitis. Therefore, authorization of these remaining indications and uses would require extrapolation from the submitted clinical studies.

Rheumatoid Arthritis

Study CT-P13 3.1 was a pivotal trial designed as a randomized, double-blind, multicentre, parallel-group, clinical equivalence study that compared the efficacy and safety of Inflectra with the reference product, Remicade, in adult patients with active rheumatoid arthritis who did not respond adequately to methotrexate (MTX) alone. A total of 606 patients were randomized to receive Inflectra or Remicade (3 mg/kg body weight) administered as 2-hour intravenous infusions at Weeks 0, 2, 6, then every 8 weeks up to 54 weeks, co-administered with MTX and folic acid.

Treatment with Inflectra or Remicade resulted in comparable rates of response. The improvement in rheumatoid arthritis patients was determined according to American College of Rheumatology (ACR) criteria, with ACR20 indicating an improvement of at least 20%. The primary endpoint compared the proportions of ACR20 responders at Week 30 using the all-randomized population. Patients with missing data were considered non-responders. The analysis found that 60.9% and 58.6% of the patients in the Inflectra and Remicade groups, respectively, achieved an ACR20 response. These percentages resulted in an estimated treatment difference of 2% [95% confidence interval (CI): -6%, 10%]. The result was entirely contained within the pre-defined comparability margins of -15% to 15%. Analysis of the ACR20 endpoint using the per-protocol population also indicated that the two treatments were comparable. Additional analyses of the ACR20 at Weeks 14 and 54, and of the ACR50/70 at Weeks 14, 30 and 54, supported the ACR20 findings of comparable efficacy. All ACR comparisons resulted in minimal treatment differences with 95% CIs falling within the pre-defined ACR20 (Week 30) comparability margins of -15% to 15%.

Additional secondary endpoints were investigated using the all-randomized and per protocol populations. These included the Hybrid ACR, Disease Activity Score in 28 joints (DAS28), European League Against Rheumatism (EULAR) response, Clinical Disease Activity Index (CDAI) score, Simplified Disease Activity Index (SDAI) score and assessments using Health Assessment Questionnaires and Short Form 36 (SF-36) questionnaires. Review of these endpoints did not identify any clinically concerning differences between the two products, Inflectra and Remicade.

Joint damage progression (JDP) was assessed by X-rays taken at baseline and Week 54. Radiographs were scored using the van der Heijde modified Sharp scoring method. Although, the analysis of JDP excluded a large number of patients, the complete case analysis did not identify clinically meaningful differences between the two products. To provide further reassurance that the two products were comparable in this respect, a subset of 20 patients was selected and their radiographs were requested by the reviewer. In-house scoring of these radiographs indicated that this subset of patients, who received either Inflectra or Remicade, achieved comparable JDP scores and that these scores were consistent with what has been observed historically in patients receiving Remicade or other anti-tumour necrosis factor agents.

For more information, refer to the Inflectra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Ankylosing Spondylitis

Study CT-P13 1.1, a randomized, double-blind, multicentre, parallel-group, comparative PK study also compared the efficacy and safety of Inflectra with the reference product, Remicade, in patients with active ankylosing spondylitis. A total of 250 patients were randomized 1:1 to receive Inflectra or Remicade (5 mg/kg body weight) administered as a 2-hour intravenous infusion at Weeks 0, 2, 6, then every 8 weeks up to 54 weeks.

Although the assessment of efficacy was secondary to the assessment of pharmacokinetics, no clinically meaningful differences were identified in the assessment of efficacy. The all-randomized population was assessed for clinical response according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. Patients with missing data were considered non-responders. The proportions of patients achieving an ASAS20 response (an improvement of ≥20%) at Week 30 in the Inflectra and Remicade treatment groups were 63% and 67%, respectively. This resulted in an estimated treatment difference of 4% (95% CI: -16%, 8%), which was considered to support the clinical comparability of the two products. Analyses of the treatment difference at Weeks 14 and 54 provided results similar to that obtained at Week 30. Evaluation of ASAS40 responses also indicated that the products elicited comparable levels of response. Importantly, the level of response elicited by both Remicade and Inflectra were in line with what has been reported previously for ankylosing spondylitis patients receiving Remicade. The results of the all-randomized analyses of ASAS20/40 were supported by results obtained for the per protocol population.

Other secondary endpoints that were investigated included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, and an assessment using the SF-36 questionnaire. These assessments were supportive of product comparability with both products eliciting improvements in clinical response.

Crohn's Disease, Ulcerative Colitis, Psoriatic Arthritis, and Plaque Psoriasis

As noted in the document Guidance for Industry: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), extrapolation may be possible where rationales are sufficiently persuasive. The decision to extrapolate should be based on:

• the demonstration of product similarity through a detailed and comprehensive comparative product characterization.
• A thorough understanding of the mechanism(s) of action and the similarities and differences in the mechanism(s) of action that play a role in each of the indicated conditions for which a sponsor applies.
• an understanding of the pathophysiological mechanism(s) of the indicated diseases and the differences and similarities between them.
• the safety profile in the respective conditions and/or populations.
• clinical experience with the reference drug.

In addition to these principles, comparative clinical studies should be performed in a population that is sensitive to product changes using a clinical endpoint that is capable of detecting such changes. This sensitivity may depend on a number of factors such as the magnitude of clinical effect over placebo, the use of concomitant therapies, the immmunocompetence of study participants, and the nature of the clinical endpoint under study. Furthermore, differences in other aspects such as route of administration, posology and pharmacokinetic/pharmacodynamic (PK/PD) profile of the therapeutic in each of the proposed indications, should be considered.

Extensive rationales were provided to support the extrapolation of clinical data from the settings of active rheumatoid arthritis and active ankylosing spondylitis to the remaining indications and uses that are authorized for the reference drug. The principles for extrapolation discussed above, and outlined in the SEB guidance document, were taken into account in the review of this submission, and extrapolation of data from the settings of rheumatoid arthritis and AS to adult and pediatric inflammatory bowel diseases (Crohn's disease, ulcerative colitis) was not recommended. This arose from the observed differences in the level of afucosylation, FcγRIIIa receptor binding, and some in vitro Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) assays. The Chemistry and Manufacturing review team concluded that differences in the ability of the two products to induce ADCC could not be ruled out. The sponsor provided rationale to support their position that ADCC is not an important mediator of the efficacy of their product (or of Remicade); however, after review of the sponsor's rationale for extrapolation and of literature regarding this mechanism of action, it was concluded that ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases (IBD). This position is supported by the observation that certolizumab pegol, another anti-TNF that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn's patients compared to other anti-TNFs, namely infliximab. Therefore, since differences in ADCC have been observed between the two products and because ADCC may be an active mechanism of action for infliximab in the setting of IBD, but not in the setting of rheumatic disease (the studied populations), extrapolation from the settings of rheumatoid arthritis and ankylosing spondylitis to IBD cannot be recommended due to the absence of clinical studies in IBD.

The differences observed in the FcγRIIIa binding and, subsequently, ADCC, do not preclude extrapolation from the settings of rheumatoid arthritis and AS to the other requested indications of psoriatic arthritis and plaque psoriasis. In these diseases, it is likely that ADCC is not an important mechanism for generating a response to infliximab. This is supported by the observation that certolizumab pegol is capable of producing clinical responses of the same order as infliximab in patients with psoriatic arthritis and plaque psoriasis despite its inability to induce ADCC. Further, the extrapolation to psoriatic arthritis and plaque psoriasis is supported by pathophysiology, PK profiles, dosage administered and routes of administration that are similar to those found in patients with rheumatoid arthritis and/or ankylosing spondylitis.

In addition to quality differences that may impact on the safety and efficacy of Inflectra in comparison to Remicade, it is also noted that pathophysiological differences exist between the rheumatic diseases and the IBDs making a direct extrapolation between the two groups challenging without clinical or PK/PD bridging data.

The safety profile of infliximab is also different between the rheumatic and inflammatory bowel diseases. In particular, the risk of hepatosplenic T-cell lymphoma appears to be uniquely associated with the inflammatory bowel diseases occurring in adolescents and young adults. It is unclear how physical, chemical and/or biological differences between the SEB and the reference product may affect this risk. Currently, no clinical study has been conducted in the setting of Crohn's disease or ulcerative colitis to show that the differences discussed above will not have an impact on the safety and efficacy in these conditions.

Clinical Safety

The safety database for Inflectra included 302 patients with rheumatoid arthritis (Study CT-P13 3.1) and 128 patients with ankylosing spondylitis (Study CT-P13 1.1). Both studies are described in the Clinical Efficacy section. An additional 9 patients with rheumatoid arthritis (Study CT-P13 1.2) were exposed as part of a pilot study to investigate the initial PK, safety, and efficacy of Inflectra in comparison to Remicade. Furthermore, the safety database of the reference product, Remicade, is considered relevant to the assessment of safety for Inflectra due to the similarity of the products. All three clinical studies were comparative studies to the reference product, Remicade. Patients who were administered Inflectra in Study CT-P13 3.1 received a mean of 8.0 doses [Standard Deviation (SD) 2.07] while patients who were administered Remicade received a mean of 7.9 doses (SD 2.08); with 77% and 73% of patients in the Inflectra group and Remicade group completing treatment, respectively. Exposure was similar in Study CT-P13 1.1. Patients with ankylosing spondylitis received a mean of 8.4 doses (SD 1.69) and 8.5 doses (SD 1.51) in the Inflectra and Remicade groups, respectively. Eighty-five (85%) percent of ankylosing spondylitis patients completed treatment with Inflectra while 83% of ankylosing spondylitis patients completed treatment with Remicade. Overall, the extent of exposure was similar between the two treatment groups in both the rheumatoid arthritis and ankylosing spondylitis studies.

No new significant safety signals, which had not been observed previously with Remicade, were observed in Study CT-P13 3.1 and Study CT-P13 1.1. Safety findings from both studies have been included in the Inflectra Product Monograph and reflect all treatment emergent adverse events (TEAEs) observed in at least 1% of patients in each of the treatment groups. A summary of the safety findings for each of these studies follows.

Study CT-P13 3.1 - Rheumatoid Arthritis Patients

In Study CT-P13 3.1, TEAEs were experienced by 70.2% of patients treated with Inflectra and 70.3% of patients treated with Remicade. The most commonly observed adverse events (AEs) in patients receiving Inflectra were latent tuberculosis and upper respiratory tract infection [27 (8.9%) patients each], nasopharyngitis [24 (7.9%) patients), and urinary tract infection [18 (6.0%) patients]. The TEAEs most frequently reported for patients in the Remicade treatment group were latent tuberculosis [25 (8.3%) patients]; urinary tract infection [21 (7.0%) patients]; bronchitis, increased alanine transaminase (ALT), and nasopharyngitis [17 (5.7%) patients each]; and upper respiratory tract infection and headache [16 (5.3%) patients each). Serious adverse events (SAEs) occurred in 42 (13.9%) Inflectra patients and 30 (10.0%) Remicade patients. The only SAEs occurring in more than one patient in either group were uveitis (2 Inflectra patients; 0 Remicade patients) and deep vein thrombosis (DVT) (2 Inflectra patients; 0 Remicade patients). Of the two DVTs, one was considered to be due to contraceptive medication and therefore was likely not related to treatment with Inflectra. All other SAEs occurred in 1 patient only. Uveitis is a common occurrence in patients with systemic inflammatory disease and, therefore, the relationship to study drug is uncertain.

Study CT-P13-1.1- Ankylosing Spondylitis Patients

In Study CT-P13 1.1, TEAEs were experienced by 72.7% of patients treated with Inflectra patients and 67.2% of patients treated with Remicade. The most commonly reported AEs in patients receiving either Inflectra or Remicade were increased ALT [14.8% of Inflectra patients versus (vs.) 15.6% Remicade patients], increased aspartate aminotransferase (AST) (12.5% vs. 10.7%), increased gamma-glutamyltransferase (GGT) (3.1% vs. 5.7%), neutropenia (3.1% vs. 4.1%), diarrhea (4.7% vs. 0.8%), headache (7.8% vs. 5.7%), rash (0.8% vs. 4.1%), nasopharyngitis (9.4% vs. 8.2%), increased blood creatine phosphokinase (CPK) (6.3% vs. 4.1%), urinary tract infection (6.3% vs. 0.8%), upper respiratory tract infection (7.8% vs. 10.7%), and influenza (1.6% vs. 4.9%). Serious adverse events occurred in 8 patients in each treatment group (6.3% Inflectra; 6.6% Remicade). The most frequently reported SAEs in the Remicade group were infusion-related reactions [3 patients (2.5%)]. No SAEs occurred in more than one patient in the Inflectra group.

The overall safety profiles obtained for Inflectra in studies performed in patients with rheumatoid arthritis and ankylosing spondylitis are considered acceptable and are consistent with the known safety profile of Remicade and with the safety profile observed for Remicade in these comparative safety and efficacy studies. The known risks of infliximab treatment are conveyed in the Warnings and Precautions section of the approved Inflectra Product Monograph.

For more information, refer to the Inflectra Product Monograph, approved by Health Canada and available through the Drug Product Database.