Celltrion finds fault with a critique of equivalence margins used to approve its infliximab biosimilar.
A new study critically evaluated the methodology used by Celltrion Healthcare and the FDA to determine whether Celltrion’s infliximab biosimilar CT-P13 (Remsima, Inflectra) was equivalent to the reference product Remicade for treating rheumatoid arthritis (RA) in the 2013 PLANETRA trial.
In 2016, CT-P13 became the first infliximab biosimilar approved by the FDA. By the second quarter of 2020, sales of CT-P13 achieved a 10.5% share of the US market for infliximab vs 84.1% for Remicade. In Europe, CT-P13 achieved a 57% market share vs 28% for the originator product.
The authors say their objective was to evaluate “if the equivalence margins chosen by Celltrion and the FDA for the first infliximab biosimilar CT-P13 were scientifically valid and clinically justifiable.”
They argued the appropriate equivalence margin for approval of infliximab biosimilars is 5.7 percentage points. Celltrion used an equivalence margin of 13 percentage points in their analysis, and the FDA used 12 percentage points in the approval process for CT-P13 and has recommended the same margin for the evaluation of other infliximab biosimilars.
The Test for Constancy
The authors used the same method the FDA recommends to determine the equivalence margin; however, they contended the clinical trials of the originator drug used to calculate the equivalence margin did not meet the test for constancy, or comparability. The principal of constancy requires that clinical trials being used to estimate an equivalence margin must be similar enough to be pooled together.
In reviewing Celltrion's application for approval, the FDA evaluated data from 5 historical clinical trials involving infliximab to calculate an equivalence margin. However, according to the authors, only 2 of these trials met the constancy assumption. The remaining 3 trials were included in the pooled PLANETRA trial.
The FDA declined a request to comment, saying it does not comment on third-party research, but Celltrion responded with a point-by-point critique of the study.
The authors claim 1 clinical trial violated the constancy assumption because it evaluated efficacy approximately 8 weeks earlier than the others. However, according to Celltrion, which cited the summary of product characteristics for Remicade, “Available data suggest that the clinical response is usually achieved within 12 weeks of treatment and is maintained….Therefore, it is clinically acceptable to use the results of earlier time points.”
In another of the pooled PLANETRA trials, the authors noted, the methotrexate (MTX) dose was only about half that used in the other trials. However, Celltrion responded that this study was conducted in Japan: “It is general practice to use a lower dose of MTX in Asian countries (because of a relatively lower body weight).” Furthermore, Celltrion noted a subgroup analysis of CT-P13 efficacy in the PLANETRA study “suggests no difference in efficacy by MTX dose.”
Celltrion also refuted the authors’ claim that this trial enrolled “milder” patients than the others, saying, “The average number of swollen joints in the Abe et al study [PLANETRA] was similar to the other trials and serum CRP [c-reactive protein] was the highest in the Abe et al study (4.2 vs 1.6-3.3). In addition, disease duration was the longest in the Abe et al study. Based on this, it is difficult to conclude that slightly milder patients were enrolled in the Abe et al study.”
For the third trial in the PLANETRA pooled trials, the authors reported that the severity of RA symptoms at baseline and the dose of MTX were unclear “solely based on the published information.” Celltrion responded that “the eligibility criteria were in line with other studies,” refuting the idea that this trial was different enough from the others to violate the standard of constancy.
The authors used 6 pooling scenarios to estimate what they considered an appropriate equivalence margin for CT-P13. Three of the 6 scenarios used all 5 trials, similar to the methodologies of Celltrion and the FDA. In these scenarios, equivalence margins ranged from 11.8 to 14.2 percentage points, similar to Celltrion’s 13 and the FDA’s 12 percentage point ranges.
A Conservative Equivalence Margin
In 3 scenarios, the equivalence margins were 10.5, 9.4, and 5.7 percentage points. The authors contend the equivalence margin of 5.7 percentage points is the most appropriate.
According to the authors, “The equivalence claim for CT-P13 to original infliximab in patients with rheumatoid arthritis did not appear to be supported when the constancy assumption was strictly assessed.”
They added, “The equivalence margin for biosimilars could be determined more conservatively.” The authors recommend the more conservative approach because of the complexity of biologic therapies and the novelty of biosimilars, saying, “This approach can guarantee that patients are protected from any remaining uncertainty or risks with the use of follow-on biological products.”
It is unclear based on the publication what prompted the authors to examine the FDA’s methodology for demonstrating equivalence of infliximab biosimilars. The authors claim no conflicts of interest and no specific funding from commercial or public sectors. The project was supported by the BK21 Plus Program of the National Research Foundation of Korea, which is a faculty-mentored talent development program. The article was peer reviewed.
Celltrion responded, “This study does not reflect the FDA review procedure and the principles of the regulatory guidelines. The constancy assumptions have been evaluated improperly, and the disease is also misrepresented within the evaluation.” Celltrion also pointed out “In addition, the equivalence margin used for PLANETRA study was endorsed by EMA (European Medicines Agency).”
Celltrion has a growing influence on the biosimilar scene. In June, the World Health Organization prequalified its rituxumab biosimilar (Truxima), promoting the use of this product among developing nations. In March, Celltrion and Teva Pharmaceuticals USA launched a trastuzumab biosimilar (Herzuma) on the US market.
Kim S, Kim S, Lee H. A critical review of the United States regulatory pathways for determining the equivalence of efficacy between CT-P13 and original infliximab (Remicade). Drug Des Devel Ther. 2020;14:2831-2840. doi:10.2147/DDDT.S254776