CADTH conducted a critical appraisal of the clinical studies for infliximab SC based on the summary of the evidence provided by the sponsor.
Internal Validity
The 2 parts of this study (CT-P13 3.5, parts 1 and 2) compared the PK, safety, and efficacy for the SC and IV doses of infliximab in patients with active RA who are not adequately responding to MTX administration over at least 3 months.
Part 1
Part 1 includes a study (CT-P13 3.5, part 1) conducted at 15 centres in 7 countries (none in Canada) that, over 30 weeks, aimed to find the optimal dose of infliximab SC by analyzing the AUCτ and efficacy, PK, and overall safety end points for the SC formulation compared with the IV formulation.
Overall, the study has a detailed description of the screening period, drug administration, preparation, doses, route, and validation of quantitative bioanalytic methods, as well as a proper description of the PK modelling methods. The formulas for calculated variables and the specific body weights used in drug dosing and PK calculations are well described. After the dose-finding evaluation, CT-P13 SC 120 mg every 2 weeks was the optimal dose recommended by the data safety monitoring board. The randomization in this phase of the study was adequately performed for the objectives of the study. No patients were lost to follow-up at week 30. The study properly reports the PK values of the 2 formulations (AUCτ and coefficient of variation), the safety results, and the secondary efficacy results according to pre-specified criteria of evaluation with no loss to follow-up information. Although the sample size was not specifically calculated, the precision of the results seems appropriate for the primary objectives of the study.
Part 2
Part 2 of the study (CT-P13 3.5, part 2) aimed to demonstrate the noninferiority of the SC formulation compared with the IV formulation at week 22 in terms of efficacy, as determined by clinical response — i.e., the change from baseline in disease activity as measured by the DAS28-CRP. Patients were followed to week 54 of the study.
The patients in the noninferiority trial could be considered similar to those in previous trials in which the efficacy of infliximab was established.5,6 Although the original superiority studies of (original) infliximab IV were published more than 20 years ago and, furthermore, that some differences in the inclusion criteria can be observed (for instance, the original studies considered a threshold of CRP concentration greater than 2 mg/dL for inclusion of patients, while the current study uses a threshold of greater than 0.6 mg/dL at screening), the differences are small and unlikely to bias the overall conclusions. This observation is related to the key constancy assumption required for valid inference to be drawn in noninferiority trials, which requires that the effect in the IV arm be the same as the effect observed in the previous superiority trials. In this case, CT-P13 IV was approved by Health Canada on the basis of the totality of the evidence and with no concerns about those definitions. The remaining patient characteristics, including age, proportion of female population, MTX use, and disease duration and characteristics, are similar in the noninferiority and superiority. Whether constancy assumption still holds is unknown, given the decades that have elapsed since the superiority trials were conducted, during which clinical practice has evolved dramatically.
The sample size was calculated using a noninferiority margin of −0.6 of the DAS28-CRP. The margin was acceptable based on a review of the literature and input from clinical experts consulted by CADTH.
The efficacy population consisted of the portion of the all-randomized population who received at least 1 full dose of study drug (IV, SC) at week 6 or thereafter and who had at least 1 efficacy evaluation result after week 6 or treatment thereafter. The ITT population was described and assessed for the sensitivity analysis, but not used for the primary outcome analysis, as is commonly done in noninferiority trials.
The primary outcome of efficacy was measured using the DAS28-CRP difference, similar to the measurements used in the key (first) trials evaluating the use of infliximab IV in patients with RA.7
No subgroup analyses were pre-specified, but post hoc subgroup analyses were conducted based on disease severity, mean change in DAS 28 score from baseline, and baseline characteristics such as region, age, race, and patient body weight. Although no significant effects were identified in the subgroups, the post hoc analyses were not meant to be used in this review by CADTH.
To assess the robustness of the results, sensitivity analyses were performed on the multiple imputation under the missing-at-random assumption. This method was used to reinforce the confidence in the results. Such an approach is particularly relevant when the early discontinuations in both formulation arms were a little disproportional, patients in the SC arm being more likely to discontinue by withdrawal of consent (7.2%) and those in the IV arm being more likely to discontinue because of AEs (6.3%).
Overall, a substantial proportion of patients discontinued the study (15.6% in the SC arm and 17.6% in the IV arm); however, the difference was similar to that in other studies of infliximab IV, and based on the results of sensitivity analyses, there seem to be no significant impacts on the primary analyses.
External Validity
Based on eligibility criteria for the studies, patients in the noninferiority trial could be considered similar to those in previous trials in which the efficacy of infliximab was established.5,6 Even when the original studies were published more than 20 years ago, and some differences can be observed (for instance, authors of the original studies considered a threshold of CRP concentration greater than 2 mg/dL for inclusion of patients, while the current study uses a threshold of greater than 0.6 mg/dL at screening), those issues have been reviewed by regulatory agencies and are unlikely to cause concerns about external validity. The remaining patient characteristics, including age, proportion of female population, MTX use, and disease duration and characteristics, are similar in the noninferiority and superiority trials.
Sponsor-Submitted Cost Comparison Table
Infliximab SC (Remsima SC) is a SEB product with a new mode of administration (SC injection)3,8 that is being compared with IV infusion in both branded and SEB products.9–11 The sponsor submitted a cost comparison of treatments available for RA,12 in which infliximab SC was compared with other infliximab products and with other bDMARDs. Only drug acquisition costs were considered, under the assumption that administration costs for IV infusion are funded by the respective manufacturers rather than by public plans. Costs were reported for both the initial year, which included induction with an IV infliximab product for infliximab SC, and years thereafter. The submitted price of infliximab SC is $646.57 per pre-filled syringe or pen.
For the treatment of RA, the recommended dose of infliximab SC in the infliximab-naïve setting is induction with 2 infliximab IV infusions of 3 mg/kg given 2 weeks apart, followed by a maintenance dose of 120 mg every 2 weeks starting 4 weeks after induction. For patients already using infliximab, the recommended maintenance dose is 120 mg every 2 weeks starting 8 weeks after the last infusion. The sponsor’s analysis indicated that, at a cost of $17,875 to $20,779 in the first year, depending on the infliximab IV product used during induction, and $16,857 per patient per year thereafter, the cost of infliximab SC was less than that of branded infliximab IV (Remicade), but more than for the other SEB infliximab. Infliximab SC was also less expensive than all other relevant biologic comparators with the exception of the SEB etanercept SC and tofacitinib. The latter drug was more expensive only during the initial year of therapy.
Critical Appraisal of Cost Information
Comparative efficacy of infliximab SC with respect to non-infliximab comparators is uncertain: The sponsor’s submitted clinical data compared infliximab SC only with infliximab IV; no direct or indirect evidence for infliximab SC compared with non-infliximab biologic options is available. The clinical review concluded that, based on the DAS28-CRP for patients with RA, infliximab SC is noninferior to the infliximab IV formulation. Given the lack of clinical evidence, no conclusions can be drawn with respect to clinical effects for infliximab SC compared with non-infliximab biologic options. If infliximab SC is considered to have differential clinical efficacy and/or safety when compared with non-infliximab comparators, comparisons beyond treatment costs may be warranted.
Miscalculation of infliximab IV costs: The sponsor-submitted revised cost comparison information (January 2021), in which the annual costs in the first year of use for the infliximab IV products were corrected by assuming a 6-week induction period, followed by 46 weeks as the maintenance period. However, the new method fails to account for the 8-week delay in the start of maintenance therapy after the induction injections at weeks 0, 2, and 6, thus overestimating the costs of those products in their induction year. The same error was not made when calculating the first-year costs of infliximab SC or non-infliximab comparators.
CADTH reverted to the sponsor’s calculations and results as submitted in December 2020.
CADTH Re-Analyses
CADTH used the version of the sponsor’s cost comparison submitted on December 2, 2020, for RA, which correctly estimated the cost of infliximab IV comparators in year 1, . Non-infliximab comparators are as described in , earlier.
CADTH Re-Analysis of Drug Cost Comparisons in RA.
Sponsor’s Drug Acquisition Cost Comparison for RA.
Price Reduction Analyses
CADTH conducted price reduction analyses estimating the percentage reduction to the sponsor’s submitted price that would make infliximab SC cost-neutral (equivalent) to the least expensive comparators available (). These price reductions assume induction with Renflexis, the least expensive infliximab IV product currently available. The submitted price of infliximab SC would have to be reduced by 43% for the annual cost of treatment acquisition to be equivalent to that of the least expensive SEB infliximab IV (Renflexis). Similarly, the submitted price of infliximab SC would have to be reduced by 36% or 26% (year 1 and maintenance years respectively) to be equivalent to the treatment acquisition costs of any SEB etanercept, the least expensive SC comparator.
CADTH Price Reduction Analyses.
Issues for Consideration
Weight-based dosing: Dosing for some comparators is based on patient weight. Treatment costs relative to infliximab SC for such comparators would differ for patients weighing substantially more or less than 75 kg. Considering the mean patient weight observed in the submitted clinical study (72.87 kg), the costs of weight-based comparators reported in the sponsor’s analysis do not change if wastage of excess medication in vials is considered.
8 Increases in dosing would affect the drug cost comparison: The clinical experts consulted by CADTH said that, in the case of partial or decreasing clinical response, infliximab and other comparators might be administered at higher doses or greater frequencies than recommended in the product monographs. These higher or more frequent doses would increase the annual costs of infliximab and other comparators relative to the costs reported here based on recommended dosing. Thus, the incremental costs for infliximab SC and its biologic comparators could change depending on how their doses or frequencies are increased.
Impact of IV administration on total costs: These analyses assume that the costs of IV infusion administration are incurred by product manufacturers rather than by public health care payers.
12,14 In situations in which the administration of infusions is reimbursed by public payers, the overall cost of all IV products would increase, and those of SC products such as infliximab SC would be unchanged.
Impact on health care resource utilization: Depending on the frequency at which infliximab SC is dispensed, it is possible that small incremental costs (if dispensed every 4 weeks) or savings (if dispensed every 12 weeks) related to dispensing fees may be realized relative to the fees associated with other biologics (e.g., every 8 weeks for infliximab IV products).
Additional SEB infliximab IV product available: According to the Health Canada Drug Product Database,
15 an additional SEB infliximab IV product, Avsola, has been marketed since June 2020 and is indicated for RA.
16 The IQVIA Delta PA database lists the wholesale price of Avsola as identical to the formulary list price of Renflexis, the least expensive infliximab product currently reimbursed.
17 The incremental costs of infliximab SC relative to the list price of Avsola are thus identical to those of Renflexis as reported in .
Analysis based on publicly available list prices: The sponsor’s and CADTH’s analyses are both based on publicly available list prices for all comparators. Actual costs paid by public drug plans are unknown.
