Outcomes of the use of infliximab biosimilars in rheumatology and gastroenterology clinics

Abstract

The originator infliximab product, Remicade, was approved by the US Food and Drug Administration in August 1998 for the management of Chron’s disease. Since this time, several infliximab biosimilar agents have entered the market to introduce competition and lower costs for patients as well as health care systems. Clinical trials comparing infliximab biosimilars with the originator product have consistently demonstrated noninferiority, along with similar adverse effect profiles, leading to the approval of 3 additional biosimilars: Renflexis (infliximab-abda), Avsola (infliximab-axxq), and Inflectra (infliximab-dyyb). In 2021, the University of North Carolina rheumatology and gastroenterology outpatient clinics began an initiative to convert patients from the originator infliximab product to biosimilar agents Renflexis or Avsola based on market costs. Subsequently, a retrospective evaluation was conducted to analyze the clinical outcomes of patients that were switched to a biosimilar agent compared with those that were only ever using either the originator or biosimilar agent. A total of 180 patients were analyzed, of which half were prescribed a biosimilar as a result of the conversion initiative. Of these 90 patients, 79 (87.8%) were maintained on a single biosimilar agent without requiring a switch to an alternative infliximab product. We conclude that the effort to convert clinically stable patients to a biosimilar product resulted in a significant increase in biosimilar use within the health system. This is thought to have resulted in significant financial advantages both to our institution as well as patients, without sacrificing overall clinical control.

Plain language summary

Patients and providers within gastroenterology and rheumatology clinics at the University of North Carolina Medical Center were encouraged to switch from their infliximab originator product to a biosimilar, if clinically and financially appropriate. This study analyzes the clinical implications associated with this effort, as well as current attitudes surrounding biosimilar use. This study found that infliximab biosimilar products appear to be safe and effective, similar to their originator counterparts.

Implications for managed care pharmacy

This study adds to the existing research concerning the safety and effectiveness of biosimilar products. Our aim is for these data to provide further confidence to both patients and providers as biosimilars increase in use because of financial considerations.

A Case for Biosimilar Use

Biosimilar medications first entered the United States market in 2015 with the US Food and Drug Administration (FDA) approval of filgrastim-sndz (Zarxio). The pathway for biosimilar approval, created by the Biologics Price Competition and Innovation Act of 2009, was introduced with the intention of lowering health care associated costs for both institutions and patients. A recent study from the American Journal of Managed Care estimates total savings of $38.4 billion from 2021 to 2025 under current projections for biosimilar market growth and development, with authors allowing for additional cost savings with increased use beyond current assumptions.¹ This potential for significant financial savings is not intended to come at the cost of quality care for patients; biosimilar products must demonstrate close similarities to an existing FDA-approved biologic product, or “originator.” These similarities must reflect a lack of clinical meaningful difference in relation to the originator, both in relation to effectiveness as well as safety. Although this standard is well known and well established, biosimilar use within certain areas and systems remains low. Attitudes of biosimilar inferiority are common among both patients and providers, which in turn may drive low rates of prescribing and limited adoption among health system formularies. Many of those with negative views toward biosimilars request additional evidence before considering the potential for benefit in biosimilar use.

In 2021, University of North Carolina (UNC) rheumatology and gastroenterology outpatient clinics began a formal effort to convert patients from the originator infliximab product (Remicade: a chimeric monoclonal antibody it’s mechanism of action involves the inhibition of tumor necrosis factor alpha) to 1 of 2 biosimilar agents based on market costs at the time of conversion: Renflexis (infliximab-abda) or Avsola (infliximab-axxq). Renflexis was approved by the FDA in April 2017 after results from multiple trials showed favorable outcomes compared with Remicade, including those seen in a study in which effectiveness, safety, and immunogenicity profiles remained comparable among the infliximab originator product and the infliximab-abda product, even after switching from the originator product to the biosimilar.² Avsola (infliximab-axxq) was approved by the FDA in December 2019 based partly on a study in which 558 patients with moderate to severe active rheumatoid arthritis, despite appropriate methotrexate use, were randomized to receive the originator infliximab product or the infliximab-axxq product. Noninferiority in the biosimilar product was achieved, and adverse effect profiles were similar between the 2 agents.³ Based on such data, many UNC physicians and pharmacists in their respective clinics felt confident with the recommended protocol to switch certain patients from infliximab originator to biosimilar.

The following analysis of UNC’s efforts to increase biosimilar use sought to investigate the clinical outcomes associated with a conversion from a monoclonal antibody originator to a biosimilar. By doing so, we aimed to provide further insight into the factors impacting a successful switch between biologic products as outcomes associated with such a process have not been previously reviewed. In addition, similar studies have not included patient perspectives and extended follow-up time as features of the trials.

The Biosimilar Conversion Initiative

The formal effort to switch patients from infliximab originator Remicade to a biosimilar (either Avsola or Renflexis) was developed collaboratively between rheumatology and gastroenterology clinic physicians, pharmacists, and department administrators. To begin, infliximab patients within each clinic were identified as candidates for a switch between infliximab products (from the originator to a biosimilar, if applicable) by physicians based on clinical stability and perceived openness to switching products. As such, many patients were preliminarily excluded based on frequent flares, recent disease concerns, or assumptions on behalf of providers regarding biosimilar attitudes. Uninsured, or, self-paying, patients were not included in the formal conversion attempts, as they commonly received financial assistance from the institution, manufacturer, or both. Once identified as a candidate, a clinic physician, nurse, or clinical pharmacist would recommend a biosimilar conversion to the patient. This recommendation was made preferentially in the clinic setting during appointments or over the phone. If unable to be reached in 3 attempts, a secure message was sent to the patient via electronic health record. Clinicians responsible for discussing biosimilars with patients were provided with information to share with patients and literature on biosimilars, whereas patients were provided with plain language resources in order to best make an educated decision.

A subsequent investigation into the success of the program was conducted with outcomes of the program largely evaluated based on the number of patients maintained on a single biosimilar following conversion and the adverse effect incidence of each infliximab product. Specifically, we sought to answer questions surrounding the clinical appropriateness of switching stable patients from an originator to its biosimilar. The investigation consisted of a retrospective chart review using electronic health record search features to document medication response, intolerances, adverse effects, and attitudes. Patients were overall eligible for analysis if they had received the infliximab originator product (Remicade) and/or infliximab biosimilars Renflexis (infliximab-abda) and Avsola (infliximab-axxq) from August 2019 to August 2022. Patients were also required to be aged 18 years or older, be seen by an institution-affiliated provider, and have received the initial prescribed product for at least 12 months prior to analysis. Patients were excluded if they had an allergy to any infliximab product identified prior to the study period, or if they were uninsured.

Initiative Outcomes

The patients receiving infliximab through UNC’s rheumatology and gastroenterology clinics represent a diverse population treated for a number of conditions including (but not limited to) Chron’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, sarcoidosis, and ankylosing spondylitis. Around half of all patients were privately insured, whereas the remaining half represented Medicare-, Medicaid-, and Tricare-insured patients. Out of the 180 total patients considered for evaluation, 85 (47.2%) were deemed appropriate candidates to switch from the infliximab originator to a biosimilar product based on physician determination of clinical stability at the time of identification. Of these, 54 patients (63.5%) successfully converted products. Of the 31 patients (36.5%) who did not successfully switch, the most commonly cited reason was patient preference (n = 11). Other reasons for switch denial included inability to reach the patient for discussion (n = 5), insurance or cost (n = 7), and intolerance (n = 6). The reason for denial was unknown in 2 cases (Figure 1).

FIGURE 1.

Success Rates Associated With Converting a Patient Population From the Infliximab Originator to a Biosimilar Product

Twenty-five (13.9%) patients were started and maintained on a biosimilar (biosimilar-only group) during the observation period, 54 (30.0%) were switched from the originator product to a biosimilar (biosimilar-switch), and 11 (6.1%) were switched from a biosimilar to the infliximab originator (originator-switch). Among the 90 patients who received a biosimilar at any time along the course of treatment, 79 (87.8%) were maintained on a single biosimilar agent without requiring a switch to an alternative infliximab product (either to another biosimilar or the originator).

Patients reported 35 total adverse effects attributed to infliximab therapy over the course of the study period. Of these, 18 (51.4%) adverse effects were attributed to the originator product, whereas 17 (48.6%) were attributed to biosimilars. In all, these 17 biosimilar-attributed adverse effects represented 9.4% of the total study population. Out of the 17, 7 patients reported worsened symptoms with the biosimilar compared with the originator product, representing 3.8% of the total study population, or, 12.9% of the biosimilar-switch population who were converted from the originator to a biosimilar during study period. Five out of these 7 cases were reported after a limited number of doses: 1 dose in 2 cases, 2 doses in 2 cases, and 4 doses in 1 case. The most commonly reported adverse effects included transaminitis, infusion reactions, fatigue, nausea, and dermatologic reactions.

Experiences and Conclusions

Through this initiative, a significant number of patients within UNC’s gastroenterology and rheumatology clinics were successfully converted from an infliximab originator product to a corresponding biosimilar. This resulted in cost savings, both for the health system and for patients. Most identified candidates for switching were successfully converted to a biosimilar from the originator without an appreciated change in disease stability or treatment satisfaction, demonstrating the overall success of the clinics’ efforts to convert patients for cost-savings reasons. Of the patients who were not successfully converted from the originator to a biosimilar at the suggestion of a clinic provider, the most commonly documented reason was patient preference. Although there was standardized information provided to each patient as part of presenting the option of switching, some patients still discussed hesitancy to change products. In addition, there were cases of clinic providers preferring not to switch patients based on personal and clinical reasoning. This suggests bias against biosimilar and similar generic products still exists among both patients and providers.

A small proportion of patients self-reported worsened symptoms after switching from the originator product to a biosimilar, despite relatively well-controlled clinical status at baseline. However, we theorize that patients did not receive adequate trials of the biosimilar in most cases, determined by the aforementioned few biosimilar doses received. It also is important to recognize the subjective reporting required with managing chronic, autoimmune disease states. Conditions, such as ulcerative colitis and rheumatoid arthritis, are characterized by frequent, ongoing periods of flares followed by remission brought on by numerous circumstances. Through retrospective review, it was difficult to determine if symptom worsening following product-switching may be attributed to the medication, or, rather, to alternative circumstances. Regardless, in each case, when a patient wished to switch to an alternative infliximab product on the basis of disease control, they were allowed to do so.

There were several limitations involved with this initiative, one being the retrospective design of outcome evaluations. As a retrospective review, there was an inherent reliance on patient reporting and provider documentation in the electronic health record to analyze patient outcomes, which could introduce possible recall bias. Along with this, many outcomes associated with the management of chronic, autoimmune conditions are subjective in nature and are hard to capture with quantifiable data. In addition, at the time of this study, the biosimilar product infliximab-dyyb (Inflectra) and unbranded infliximab product were not available for our patients, leaving a gap in knowledge regarding similar clinical outcomes related to these specific products.

We aim to add to the limited literature available regarding conversions between biologic products, particularly as it relates to the real-world clinical outcomes associated with a formal effort to convert patients from an originator product to a biosimilar. Each biosimilar product currently on the market is associated with multiple clinical studies demonstrating their overall similarity to originators in order to gain regulatory approval. The experiences with this initiative are consistent with this preexisting literature, suggesting the overall effectiveness and safety of biosimilar products, even in patients previously well-maintained on an alternative or originator product. With increasing use of biosimilar products in practice comes the increased opportunity for discussions with both patients and providers on the clinical expectations and economic implications associated with their use. Ultimately, more work is needed from pharmacists to provide education to both patients and providers on biologic biosimilar products, as this may lead to cost savings passed on to patients and the health care system if biosimilar use is increased.