CME Author: Zeena Nackerdien
Study Authors: Antoine Meyer, Jérémie Rudant, et al.
Target Audience and Goal Statement Gastroenterologists and Internists
The goal is to understand the analysis of French nationwide health administrative data comparing outcomes among patients with Crohn’s disease (CD) treated with the biosimilar drug CT-P13 or infliximab.
Complex processes are required to manufacture medicines from living cells under carefully monitored conditions. Biologics are approved for a range of chronic conditions and have revolutionized disease management. Until recently, biologics have lacked competition because there was no shortened pathway to bring generic versions of these agents to market under the Public Health Service Act (PHSA), similar to what was done for small-molecule drugs created under the 1984 Hatch Waxman amendments to the Federal Food, Drug, and Cosmetics Act (FD&C Act). Based on the U.S. approval pathway for biosimilars, i.e., a biologic that is “similar” to another biologic drug already approved by the U.S. Food and Drug Administration (FDA), enacted in 2010, an applicant is allowed “to rely on the FDA’s finding of safety and effectiveness for a biological reference product to support approval of a biosimilar and, therefore, develop the product at a potentially lower cost than the original reference product, provided the sponsor can demonstrate that the product meets the statutory standards for biosimilar approval.” Since the ever-increasing array of biologics are the main cost drivers in healthcare budgets, the European Union has also created a regulatory framework enabling the development of biosimilars after expiration of relevant patents in a way that is analogous to what has been done for generic drugs. Basically, large and expensive efficacy and safety studies become unnecessary, as this concept implies that, if two products are similar in terms of molecular structure and bioavailability, then the main findings from the reference product (RP) can be extrapolated to the biosimilar.
Approximately 3 million American adults have inflammatory bowel disease — either CD or ulcerative colitis (UC). These debilitating disorders are characterized by transmural inflammation of all or regions of the gastrointestinal tract that could lead to gastrointestinal obstruction. Immunomodulators such as the anti-tumor-necrosis-factor-α (TNFα), infliximab, have shifted the treatment paradigm from symptom control to the goals of healing the mucosa and preserving intestinal function, as outlined by Ole Haagen Nielsen, MD, DMSc and Mark Andrew Ainsworth, MD, PhD, DMSc in an accompanying editorial to the current study.
The current study employed CT-P13, a biosimilar of the RP, infliximab, which is approved for a range of inflammatory conditions, including ankylosing spondylitis, rheumatoid arthritis, and CD. It is worth noting that the concept of extrapolation is controversial because of minor molecular differences between CT-P13 and the RP. Separate studies either examining a switch from RP to CT-P13 (NOR-SWITCH trial) or performing a short-term comparison of the two products showed either worsening disease that did not quite reach the prespecified noninferiority margin or no difference between the two products. Taken together with other prospective studies of CT-P13 providing reassuring results, there was a clear need to clarify outcomes through direct comparisons in longer-term studies.
The authors hypothesized that CT-P13 and infliximab would be equivalent. Therefore, the main goal of the study was to compare the efficacy and safety of the two agents in a large nationwide observational equivalence cohort study of infliximab-naïve patients with CD.
Study Synopsis and Perspective
Antoine Meyer and colleagues from Caisse Nationale de I’Assurance Maladie performed a comparative equivalence cohort study using a French nationwide database (Système National des Données de Santé [SNDS]; 2015-2017) to compare the effectiveness and safety of CT-P13 and the RP (infliximab) in 5,050 infliximab-naïve patients (>15 years of age) with CD who started treatment with infliximab (n = 2,551) or CT-P13 (n = 2,499). Patient characteristics at cohort entry were well-balanced, but with a trend toward more severe CD in the CT-P13 group, the researchers said.
The primary outcome was a composite endpoint of death, CD-related surgery, all-cause hospitalization, and reimbursement for a different biologic. Equivalence was defined as a 95% confidence interval (CI) of the hazard ratio (HR) of CT-P13 vs infliximab in a multivariable marginal Cox model situated within prespecified margins (0.80-1.25).
A total of 1,147 patients in the infliximab group and 952 patients in the CT-P13 group met the composite endpoint. The two agents were equivalent in terms of efficacy (HR = 0.92; 95% CI, 0.85-0.99) and the safety outcomes did not differ between the CT-P13 and infliximab groups. The hazard ratios (HR) for serious infections, tuberculosis, and solid or hematologic cancer were (HR, 0.82 [CI, 0.61 to 1.11]), (HR, 1.10 [CI, 0.36 to 3.34]) and (HR, 0.66 [CI, 0.33 to 1.32]), respectively.
Study strengths include the comprehensive nature of the SNDS database (drug dispensing, hospitalizations, and surgery), the use of an unselected sample of patients with CD, and the fact that the equivalence limits were more stringent than those employed in clinical trials (10% vs 15% absolute difference). Finally, the two groups were well-balanced and the choice of CT-P13 or infliximab was made by the hospital pharmacy, not the doctor.
Regarding study limitations, Meyer and co-authors pointed to the absence of full clinical data allowing calculation of indices of disease severity such as the Harvey-Bradshaw Index or Crohn’s Disease Activity Index, which necessitated the use of proxies. Additionally, the study used an algorithm to identify CD patients based on the combination of hospitalization and long-term disease codes. Infliximab use was based on prescriptions dispensed, and only infliximab-naive patients were included in the cohort.
Source Reference: Annals of Internal Medicine, Dec. 11, 2018; DOI: 10.7326/M18-1512
Study Highlights: Explanation of Findings
The initial approval of CT-P13 was based on extrapolation of results observed in arthritis. Equivalent effectiveness of CT-P13 and infliximab-naïve patients with CD was demonstrated in the current study, i.e., HR and 95% CI (HR, 0.92 [CI, 0.85-0.99]) fell within the predefined equivalence range (0.80 to 1.25). All-cause and CD-related 12-month hospitalizations were 33.8% and 24.9%, respectively, in keeping with real-life study results after 1 year of follow-up (all-cause hospitalizations, 25% to 34%; CD-related hospitalizations, 19%). No anomalies were observed for the safety profiles of both agents.
With CT-P13 performing similarly to infliximab, the researchers suggested that in real-life practice the choice between the two products could safely be based on cost alone. “Studies such as ours assess real-life effectiveness by including all patients receiving treatment with long-term follow-up,” wrote Antoine Meyer, MD, of Caisse Nationale de I’Assurance Maladie in Paris, and colleagues in Annals of Internal Medicine.
An accompanying editorial by Danish researchers pointed out that while TNF inhibitors have revolutionized the management of CD, the gains made with these biologics have come at considerable cost to patients and the healthcare system, a burden that biosimilars can ease.
“The introduction of biosimilars has resulted in cost savings, and further economic benefits are anticipated as use of these products increases,” wrote Ole Nielsen, MD, of the University of Copenhagen Herlev Hospital, and Mark Ainsworth, MD, of the Odense University Hospital.
They said that while access to biosimilars will likely expand with positive impacts on worker absenteeism and productivity, the challenges must not be underestimated. Even with the strict requirements for documentation of similarity, pharmacovigilance systems must be able to distinguish between the original product and the biosimilar to allow rapid identification of any signal of impaired safety and efficacy, Nielsen and Ainsworth stated.
In addition, when a patient is switching to a biosimilar or starting therapy with a biosimilar, communication must be open and clear, and patient concerns must be addressed. “Most important, to alleviate concerns, healthcare professionals must be proactive in increasing patients’ confidence by providing evidence-based information from the growing experience with biosimilars,” the editorial notes.
According to the Center for Biosimilars, the European Medicines Agency (EMA) has accepted for review an extension marketing authorization application for a subcutaneous formulation of the company’s biosimilar infliximab, CT-P13 (sold in Europe as Remsima and in the U.S. as Inflectra). A decision regarding the proposed subcutaneous formulation is anticipated in 2019.
Diana Swift wrote the original story for MedPage Today.