Abstract
BACKGROUND:
Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness.
OBJECTIVE:
To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS.
METHODS:
A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state.
RESULTS:
A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX’s benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug’s positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching.
CONCLUSIONS:
The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.
Plain language summary
Rituximab is a medicine used to treat various illnesses for almost 3 decades. It has been tested in many settings in real life. We want to explore what we have learned from these real-life experiences with rituximab to help people who make decisions about health care. This will help us understand what we already know and what we still need to find out.
Implications for managed care pharmacy
Managed care pharmacists use and apply real-world evidence to support various activities such as pharmaceutical product contracting and monograph, clinical program, and policy development. Since 2010, the state of observational research on rituximab has largely focused on evaluating the effectiveness, safety, and utilization in cancer, rheumatoid arthritis, and multiple sclerosis. Real-world evidence can help managed care professionals with treatment and coverage decisions for rituximab, especially as rituximab biosimilars become available, providing more product options.
Rituximab (RTX) is an anti-CD20 monoclonal antibody first approved by the US Food and Drug Administration (FDA) in 1997 for treatment of non-Hodgkin lymphoma (NHL), followed by subsequent indications in diffuse large B-cell non-Hodgkin lymphoma (DLBCL; 2006), rheumatoid arthritis (RA; 2006), chronic lymphocytic leukemia (CLL; 2010), follicular lymphoma (FL; 2011), granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis (2011), and pemphigus (2018).1
RTX has demonstrated improved outcomes in nearly all DLBCL, CLL, and autoimmune diseases; however, despite its recommended use in CLL and NHL guidelines,2,3 many physicians choose not to treat or are unable to treat patients with RTX owing to insurance coverage, reimbursement, and high costs to the patient, even with increasing availability of RTX biosimilars, and there is a growing need for real-world evidence to guide treatment and coverage decisions.4-6
Prior to the approval of RTX for the treatment of DLBCL, standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy was poorly tolerated and demonstrated five-year survival rates as low as 26% with particularly worse outcomes in patients with aggressive NHL.7 Inclusion of RTX into the cyclophosphamide, doxorubicin hydrocholoride, vincristine sulfate, and prednisone (R-CHOP) regimen for aggressive forms of NHL such as DLBCL improved treatment outcomes and tolerability, demonstrating statistically significant improvements in both 5-year estimated progression-free survival (56% vs 44%; P = 0.002) and overall survival (69% vs 40%; P < 0.001) in phase 3 clinical trials.7-9 In addition to DLBCL, chemoimmunotherapy with RTX is considered the standard initial treatment for common indolent malignancies such as newly diagnosed or relapsed-refractory FL and CLL.10,11 The relatively well-tolerated side-effect profile of RTX compared with other chemotherapy agents favorably positions RTX as a desirable treatment option for older patients.
Despite RTX’s contribution in improving the prognosis for all B-cell NHL, 30%-50% of patients with DLBCL do not reach complete remission with R-CHOP therapy.12 Decisions made regarding when to initiate RTX therapy for indolent lymphomas vs implementing watchful waiting methods during asymptomatic periods following diagnosis vary among clinicians and have shown conflicting results in observational and randomized controlled trials.12 In particular, patients with FL who have achieved remission following chemoimmunotherapy treatment are at continued risk of relapse and are eligible for treatment with RTX on a maintenance regimen every 2-3 months as an attempt to prolong remission. However, disparate clinical practices have made the use of maintenance RTX controversial, particularly in older patients with significant comorbidities who are often excluded from clinical trials.13 Real-world evidence can help provide clarity in treatment decisions.
In 2006, RTX was approved for use in RA, an autoimmune disease characterized by chronic synovial inflammation, joint destruction, and functional disability.14 Treatment goals of RA focus on improving patient quality of life by reducing symptoms and impact on daily function, preventing progressive joint damage, and reducing associated complications.15 Early and aggressive intervention using disease-modifying antirheumatic drugs (DMARDs), including conventional DMARDs such as methotrexate, biologic DMARDS, and other small molecule agents, has been proved to slow disease progression and preserve joint functionality.16,17 Although the development of anti–tumor necrosis factor (anti-TNF) therapies have led to better clinical outcomes, up to 30%-40% of patients do not respond.18 RTX is approved for use in combination with methotrexate in patients with moderately or highly active RA who have not responded satisfactorily to anti-TNF therapies.19
RTX has long been used as an off-label medication for many neurological diseases including multiple sclerosis (MS), the most common neurological degenerative disease affecting the central nervous system.20,21 T cells and B cells have long been known to play a vital part in the pathogenesis of MS; thus, therapies targeting B cells have particularly gained traction as potential treatment options in more severe and resistant forms of MS.22,23
RTX is currently not FDA approved for the treatment of MS; however, several studies have shown its efficacy in reducing inflammatory activity in relapsing-remitting MS.24 Additionally, RTX serves as a potential off-label therapy option in the treatment of primary progressive MS where only one option exists (ocrelizumab).25 Although RTX has limited use in the treatment of MS in the United States, many other countries have regularly used this drug as an off-label disease-modifying therapy, which has shown positive outcomes.24,26 Studies highlighting the effectiveness of anti-CD20 monoclonal antibodies on B lymphocytes have become an area of focus for use in those with rare and treatment-resistant forms of MS.27
Although RTX has a well-established place within treatment guidelines for oncology and RA, as well as regular off-label use in MS, questions remain regarding its real-world utilization and effectiveness. As more than 95% of patients are treated outside of clinical trials, real-world evidence is especially critical in investigating the therapeutic effects and risk profile of RTX within a more heterogeneous sample generalizable to a wider patient population.5 In addition, questions surrounding the practice of watchful waiting in indolent lymphomas, timing to initiate RTX treatment across disease states, and the lack of effective biomarkers in predicting patient response to RTX demonstrates a need for health care providers to better understand the current treatment landscape and use of RTX. Real-world evidence can help support health care decisions and treatment using rituximab, particularly as more biosimilars become available and the treatment landscape evolves. We conducted this scoping review to describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS.
Methods
Literature indexed in MEDLINE (PubMed), Embase, and CINAHL was included in the search strategy, as was any gray literature identified via Google Scholar. Peer-reviewed articles published in English between January 1, 2010, and June 14, 2022, were included in this analysis to reflect the most likely dates of product utilization amid reasonably contemporary treatment strategies and observational research approaches. Studies must have been of an observational design, prospective or retrospective, including adult patients aged 18 years or older with NHL, DLBCL, CLL, RA, or MS treated with RTX. Although RTX is used off label for other indications, we focused on MS as more studies were likely to be available than for other more rare conditions. We also wanted to inform RTX use in the context of biosimilars and other products indicated for MS expected to come to the market. Articles were excluded if they included only patients treated with RTX for other conditions; were conducted in pediatric (aged younger than 18 years) populations; or were randomized controlled trials or other interventional studies, studies that focused on molecular pharmacology or pharmacokinetics/pharmacodynamics, and economic evaluations.
The initial search was left broad as the intent was to capture the breadth and extent of data sources, methods, outcomes, and study designs published in peer-reviewed literature. The search strategy was simply ((observational OR real-world)) AND rituximab). Filters for English language, studies in humans, and observational studies were applied when available.
Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. A data charting scheme was designed collectively by all reviewers to capture information of interest in support of the research goals of this study. Data were extracted independently by 2 reviewers from each included publication for each disease state, and the scheme was updated iteratively and by consensus. A third reviewer checked all extracted data for quality, consistency, and completeness for each disease state. Any discrepancies were discussed among all reviewers to achieve consensus.
Data were summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. The characteristics of included literature was described based on study design, number of centers involved, geographic or regional distribution, data sources used, sample size, study follow-up time, and type of funding involved. Specific to rituximab, variables such as primary diagnosis, treatment and comparators, outcomes measured, and general study results were evaluated. The strengths, weaknesses, and characteristics of the study design were qualitatively evaluated by deriving key similarities across studies and summarized to frame the current state of real-world research on this topic and identify gaps in available peer-reviewed literature. Quantitative assessment of study quality is considered optional according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Scoping Review Extension reporting guidelines and was considered out of scope for this analysis.28 Simple counts or proportions were used to describe patterns of consistency or inconsistency across studies, and narrative descriptions of study methods, data sources, and reported outcomes were included for completeness.
The protocol for this review was drafted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 standard and modified by the research team as appropriate and specific for a scoping review.29 The complete protocol is available on the Biologics and Biosimilars Collective Intelligence Consortium website (https://www.bbcic.org).
Results
After duplicates were removed, a total of 848 records were screened for inclusion (Figure 1). Disease-related exclusions varied slightly between cohorts at each step, but other exclusions applied across diseases. A total of 260 studies were included: 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Summary tables for all included studies are provided in Supplementary Table 1 (412.1KB, zip) (available in online article).
FIGURE 1.
PRISMA Diagram Describing Articles Included for Analysis
For all disease cohorts, most studies (n = 189; 72.7%) were retrospective (Table 1). Studies spanned globally, with the majority conducted in Europe (n = 137; 49.6%), followed by North America (n = 56; 22.0%) and Asia (n = 35; 13.8%), with the remainder conducted in the Middle East, India, South America, and Australia. Overall, 171 (65.8%) studies used hospital or electronic health record (EHR) data as their data source, 65 (23.2%) used registry databases, and 16 (6.2%) used insurance claims databases. Sample size varied widely across disease types, with a mean 757 (range 9-9,333) in cancer, 3,129 (range 12-100,921) in MS, and 11,291 (range 19-409,706) in RA studies. However, there is an opposite trend regarding study follow-up time, with the cancer studies having the greatest mean follow-up time of 44.6 months and RA studies having the least mean follow-up time of 24.8 months.
TABLE 1.
Characteristics of Sources of Evidence
| Characteristic | Cancer (n = 144) | MS (n = 37) | RA (n = 79) |
|---|---|---|---|
| Study design, n (%) | |||
| Prospective | 34 (23.6) | 5 (13.5) | 29 (36.7) |
| Retrospective | 109 (75.7) | 31 (83.8) | 49 (62.0) |
| Both | 1 (0.7) | 1 (2.7) | 1 (1.3) |
| Centers | |||
| Monocentric, n (%) | 51 (35.4) | 19 (51.4) | 29 (36.7) |
| Multicentric, n (%) | 93 (64.6) | 18 (48.6) | 50 (63.3) |
| Mean (range) | 24.8 (1-400) | 2.2 (1-9) | 19.8 (1-169) |
| Location, n (%)a | |||
| NA | 36 (25.0) | 10 (27.0) | 11 (13.9) |
| EMEA | 65 (45.1) | 28 (75.7) | 59 (74.7) |
| LATAM | 2 (1.4) | 0 | 2 (2.5) |
| APAC | 42 (29.2) | 1 (2.7) | 7 (8.9) |
| Data source, n (%)a | |||
| Hospital/EHR | 105 (72.9) | 25 (67.6) | 41 (51.9) |
| Registry | 24 (16.7) | 12 (32.4) | 29 (36.7) |
| Claims | 12 (8.3) | 0 | 4 (5.1) |
| Otherb | 3 (2.1) | 2 (5.4) | 5 (6.3) |
| Sample size, n | |||
| Mean (range) | 757 (7-9,333) | 3,129 (12-100,921) | 11,291 (19-409,706) |
| Study follow-up, months | |||
| Mean (range) | 44.6 (2.5-156) | 25.7 (9.6-40) | 24.8 (3-108) |
| Funding, n (%) | |||
| Grant | 41 (28.5) | 13 (35.1) | 24 (30.4) |
| Industry | 39 (27.1) | 0 | 18 (22.8) |
| Both | 6 (4.2) | 0 | 3 (3.8) |
| No funding | 23 (16.0) | 16 (43.2) | 21 (26.6) |
| Unspecified | 35 (24.3) | 8 (21.6) | 13 (16.5) |
a Studies may have been counted twice (eg, study conducted in multiple location or used multiple data sources).
b Other includes governmental databases (eg, Medicare and US Food and Drug Administration), which contribute to large sample sizes.
APAC = Asia Pacific; EHR = electronic health record; EMEA = Europe, Middle East, Africa; LATAM = Latin America; MS = multiple sclerosis; NA = North America; RA = rheumatoid arthritis.
Both single-arm and comparative studies with other conventional treatments were included in this analysis (Table 2). However, the main emphasis was exclusively on the outcomes of RTX. Overall, 122 (46.9%) studies included a comparator or evaluated RTX in parallel with other treatments vs 138 (53.1%) single-arm studies with no comparator or compared with watchful waiting. This varied across disease cohorts, with 60 (75.9%) comparative studies included for RA, 44 (30.6%) for cancer, and 60 (75.9%) for MS. The results also illustrated that RTX is primarily used as part of combination therapy for cancer indications and monotherapy for RA and MS. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Finally, conclusive statements on RTX’s benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug’s positive benefit. All papers discussed common strengths and limitations associated with observational research. Highlighted strengths include large sample size in some studies, length of follow-up period, real world, high external validity, and multiple study outcomes. Common limitations discussed include retrospective study design, small sample size, heterogeneous population, selection bias, and lack of direct comparators and control groups.
TABLE 2.
Characteristics and Trends of RTX Use in Cancer, MS, and RA
| Characteristic | Cancer (n = 144) | MS (n = 37) | RA (n = 79) |
|---|---|---|---|
| Primary diagnosis, n (%) | |||
| Lymphomas | 100 (69.4) | — | — |
| Leukemias | 27 (18.8) | — | — |
| Any hematologic cancersa | 10 (6.9) | — | — |
| Any cancer types | 7 (4.9) | — | — |
| RMS | — | 12 (32.4) | — |
| Non-RMS | — | 2 (5.4) | — |
| Any MS subtypes | — | 23 (62.2) | — |
| RA | — | — | 64 (81.0) |
| Any rheumatic disease | — | — | 15 (19.0) |
| Treatment, n (%) | |||
| Monotherapy | 11 (7.6) | 37 (100) | 78 (98.7) |
| Combination therapy | 133 (92.4) | 0 | 1 (1.3) |
| Comparator, n (%) | |||
| Yes | 44 (30.6) | 18 (48.6) | 60 (75.9) |
| No | 100 (69.4) | 19 (51.4) | 19 (24.1) |
| Primary outcome, n (%) | |||
| Effectiveness | 83 (57.6) | 27 (73.0) | 43 (54.4) |
| Safety | 25 (17.4) | 9 (24.3) | 26 (32.9) |
| Descriptive | 11 (7.6) | 0 | 5 (6.3) |
| Treatment patterns | 26 (18.1) | 1 (2.7) | 5 (6.3) |
| Safety measure, n (%) | |||
| Yes | 77 (53.5) | 21 (56.8) | 47 (59.5) |
| No | 67 (46.5) | 16 (43.2) | 32 (40.5) |
| Conclusion, n (%) | |||
| Positive benefit | 66 (45.8) | 30 (81.1) | 29 (36.7) |
| Neutral benefit | 17 (11.8) | 5 (13.5) | 10 (12.7) |
| Negative benefit | 6 (4.2) | 1 (2.7) | 11 (13.9) |
| Unspecified or no relation | 55 (38.2) | 1 (2.7) | 29 (36.7) |
| Study evaluation | |||
| Common strengths | Large sample size, length of follow-up period, real world, high external validity, and multiple study outcomes | ||
| Common limitations | Retrospective study design, small sample size, heterogeneous population, selection bias, and lack of direct comparators and control groups | ||
a Studies include patients with lymphoma and leukemia alongside other hematologic cancers.
MS = multiple sclerosis; RA = rheumatoid arthritis; RMS = relapsing multiple sclerosis.
RHEUMATOID ARTHRITIS
A total of 79 included studies evaluated the use of RTX in RA. The majority (n = 49; 62%) were retrospective, and most (n = 50; 63.3%) involved multiple centers, with one study spanning 169 centers. The multicentric studies often relied on registries such as the US CorEvitas RA Registry (n = 5), British Society for Rheumatology Biologics Register (n = 4), Danish DANBIO registry (n = 3), and French AIR, ORA, and REGATE registries (n = 2) as data sources. Notably, the CERERRA collaboration, an investigator-support, industry-led initiative, facilitated regional collaboration and data sharing among 12 European countries to evaluate the clinical aspects of RTX use in RA. EHR data from hospitals and outpatient rheumatology clinics were used in 41 (51.9%) studies. The use of claims databases (n = 4; 5.1%) and other governmental databases (n = 5; 6.3%) was limited. Funding for the studies was primarily derived from grants and industry sources.
Most studies focused exclusively on RA (n = 64; 81.0%); however, some studies (n = 15; 19.0%) examined a broader population with various rheumatic diseases (eg, systemic vasculitis, systemic lupus erythematosus, and Sjogren’s syndrome), with RA being a subgroup. All included studies except one assessed RTX as monotherapy, and the majority (n = 60; 75.9%) compared the effectiveness of RTX against a comparator (eg, anti-TNF therapies, DMARDs, and non-TNF biologic DMARDs). Effectiveness of RTX was measured by the European League Against Rheumatism response, disease activity score-28, clinical disease activity index, joint counts, erythrocyte sedimentation rate, disease flare, and patient-reported outcomes. Safety assessment of RTX considered parameters such as death, adverse event incidence, infection rate, and cancer risk. Only 3 studies evaluated the effectiveness and safety of rituximab biosimilars, with 2 studies having comparative analyses with a reference rituximab product. Although one study demonstrated no differences in safety or treatment effect, another showed 16.5% of patients discontinued the rituximab biosimilar because of loss of effectiveness after switching from the originator product. Although no consensus emerged regarding the benefit of RTX in RA, a plurality of studies (36.7%) indicated a positive benefit, 10 (12.7%) found neutral benefit, 11 (13.9%) showed a negative benefit, and the remaining 29 (36.7%) were unspecified.
CANCER
A total of 144 included studies examined the use of RTX in cancer treatment. The majority were retrospective analyses (n = 109; 75.7%), and on average, the studies involved 24.8 centers, with the largest study spanning 400 centers and using a Japanese claims database to assess the comparative effectiveness of RTX-based vs non-RTX-based therapies for FL (Sue 2021). The largest number of studies were conducted in the United States (n = 33; 22.9%), followed by Italy (n = 18; 12.5%) and China (n = 13; 9%). Hospital/EHR data (n = 105; 72.9%), sourced from 1 to 50 centers, served as the primary data source for most studies. Registries (n = 24; 16.7%) were mainly used in European countries and Asian countries. Of the 12 studies using health insurance claims as a data source, most analyses were conducted in the United States, with databases ranging from commercial sources (eg, IQVIA, Komodo Health, and Optum) to noncommercial ones (US Veterans Health Administration, Medicare). On average, the studies included a sample size of 757 (range 7-9,333) patients, with a mean follow-up time of 44.6 months. Funding for the studies primarily came from grants and industry sources.
Most studies assessed the use of RTX in lymphomas, with a particular emphasis on DLBCL (n = 34; 23.6%), followed by NHL (n = 18; 12.5%) and FL (n = 15; 10.4%). RTX was also explored in CLL in 18 (12.5%) studies. One hundred thirty-three (92.4%) studies evaluated RTX as part of combination therapy for cancer, and most of these studies (n = 100; 69.4%) did not include a comparator group. The primary endpoints used to evaluate effectiveness were overall survival, progression-free survival, and response rate. Safety considerations included the assessment of adverse events such as hepatitis B virus reactivation, infections, neutropenia, and mortality. Twenty-six studies (18.1%) focused on examining treatment patterns related to the use of RTX in cancer. Furthermore, there was notable attention given to biosimilar research for RTX in this disease area compared with that of RA and MS. Several studies investigated the effectiveness, safety, utilization, and health care economic burden associated with transitioning from the reference product to a biosimilar (Bankar 2020, McBride 2021, Mendes 2021, Shelbaya 2021, and Urru 2021). Only 4 studies evaluated the effectiveness and safety of rituximab biosimilars compared with the reference rituximab product. All 4 demonstrated no differences in safety or treatment effect. Overall, 45.8% of the studies concluded that RTX use provided a positive benefit, whereas 11.8% indicated a neutral benefit and 4.2% suggested a negative benefit. Approximately 38.2% of the studies had a nonspecific or unrelated conclusion.
MULTIPLE SCLEROSIS
A total of 37 included studies evaluated the use of RTX in MS. The majority were retrospective analyses (n = 31; 83.8%). Nineteen (51.4%) studies were conducted in a single center, with the largest study involving 9 tertiary MS centers in France (Alcala 2022). The EMEA region, particularly Sweden, featured predominantly, likely due to the availability of the national Swedish MS registry. Registries played a notable role, with 12 (32.4%) studies using registry data and the remaining studies primarily relying on hospital/EHR data, primarily from specialized MS clinics. Interestingly, we identified no real-world research using insurance claims data related to RTX use in MS. The mean sample size across all included studies was 3,129 (range 12-100,921), although it was largely influenced by 2 studies that used the FDA Adverse Event Reporting System database (Caldito 2021, Oshima 2019). The follow-up time across the studies ranged from 9.6 to 40 months, averaging 25.7 months. The studies were mostly funded through grants or had no funding at all, and there were no studies funded by industry.
All studies examined different subtypes of MS: relapsing-remitting MS, primary progressive MS, and secondary progressive MS. RTX was used exclusively as a monotherapy in all studies. Overall, 18 studies evaluated RTX against comparators including alemtuzumab, natalizumab, ocrelizumab, glatiramer acetate, interferon-β, fingolimod, and dimethyl fumarate. Most studies (n = 27; 73%) assessed the effectiveness of RTX using endpoints such as the expanded disability status scale, annualized relapse rate, and disease activity, including new gadolinium-enhancing lesion activity observed through magnetic resonance imaging. Safety evaluation primarily focused on adverse event rate, time to first cancer, development of progressive multifocal leukoencephalopathy, and incidence of infections. Only 1 study evaluated the effectiveness and safety of a rituximab biosimilar with no comparative analysis with a reference product. Overall, the majority of the studies (n = 30; 81.1%) reported positive benefits of RTX in MS.
Discussion
RTX has been extensively studied in cancer, RA, and MS using real-world data. Retrospective study designs are common, with multicentric studies using registries or EHR data. Effectiveness is typically assessed using disease-specific endpoints, whereas safety considerations focus on adverse events and relevant disease-specific risks. Although the conclusions vary across studies, a large proportion suggests a positive benefit of RTX in these disease states. Specifically, of the 175 studies that provided a qualifying positive, negative, and neutral conclusion on RTX, 71% concluded that RTX demonstrated favorable effectiveness and/or safety profiles and supported its use. On the other hand, 10% of studies did not support RTX use and 19% of studies determined a neutral benefit. These results may potentially serve as evidence to not only aid clinicians in therapy decision-making but also assist in managed care formulary decision-making and class reviews.
Although results suggest that RTX is likely beneficial for patients with cancer, MS, and RA, this scoping review simultaneously revealed a number of evidence gaps in real-world research on RTX. From a managed care perspective, it is imperative to understand treatment landscape and utilization in addition to effectiveness and safety data to best allocate health care resources. Studies assessing RTX use and its associated economic burden were scarce, most notably in MS and RA. For instance, no studies used a payer claims database to assess RTX use in MS, leaving a knowledge gap regarding the extent of off-label RTX usage in this context.
Furthermore, there was a lack of evidence regarding RTX biosimilar use and product switching, likely due to the relatively recent introduction of biosimilars at the time of this analysis and the time lag associated with using real-world data for observational research. Only 5 examined outcomes related to biosimilar switching and were limited to RTX use in oncology. Biosimilars, biologic agents highly similar to—and with no clinically meaningful differences from—the reference product, provide alternative treatment options for clinicians, payers, and policymakers. In the United States, use of biosimilars is expected to bring $9-12 billion in savings for Medicare within the next decade.30 Although biosimilars undergo strict regulatory approval to ensure no clinically meaningful differences in efficacy, safety, and purity compared with the originator product, uptake of biosimilars in the United States has lagged behind other countries because of barriers in the perceptions of patients and health care providers.6 Consequently, there is a need for real-world evidence to provide insight on the safety and effectiveness of biosimilars to aid in treatment and coverage decisions made by patients, providers, and payers.6
To date, 3 RTX biosimilars have been approved by the FDA and launched within the United States: Truxima (2018), Ruxience (2019), and Riabni (2020). Comparatively, rituximab biosimilars have lagged behind in uptake (67%) compared with other biosimilar launches such as bevacizumab (82%) and trastuzumab (80%) within the first 3 years.6 Various factors, involving all stakeholders from the choice of providers to insurance coverage, patent monopolies on original products, and patient out-of-pocket expenses, can contribute to the variation in uptake. With biosimilars seeing increasing acceptance in the United States and the scale of spending on medicines facing upcoming biosimilar competition increasing,31 a review of the current state of the literature surrounding real-world biosimilar utilization is needed to raise clinician, patient, and payer awareness regarding RTX biosimilar use and their comparative effectiveness to the originator product.
LIMITATIONS
Although this study does not have limitations that directly affect its validity, several considerations should be noted. Scoping reviews do not usually include a formal quality assessment of the studies, which may limit the reliability of the findings. However, for this study our focus was evaluating the state of observational research and real-world data assessment of RTX in several specific disease states to understand the literature landscape, identify gaps in knowledge, and inform future research. Owing to inconsistencies in literature database search functions, it is likely we missed some articles in our screening, particularly as the use of filters may provide variable results in different databases; furthermore, it is possible that some relevant articles were not identified in the original search without using controlled vocabulary.32 However, as we determined the optimal search strategy, which is admittedly subjective, when we compared using Medical Subject Headings terms to our keyword search, we decided the keyword search was in fact deliberately broad, and we believe we captured the majority of relevant articles. We also chose to limit the search to articles published after January 1, 2010, which may have excluded earlier articles that could be relevant; however, we wanted to maximize our focus on articles when the diseases of interest would most likely be studies (eg, after FDA approval for subsequent indications), and to most closely align with current treatment patterns. Also, the field of observational research and the available data sources have evolved rapidly in recent years, especially within the past decade, so we were most interested in articles that would inform our future research. Lastly, scoping reviews may be prone to publication bias, which might be present in this study as a greater number of RTX studies with positive benefits compared with negative benefits were identified across disease states. However, this does not affect the validity of this review as the aim of this study is to assess the published state of observational research on RTX.
Conclusions
Overall, this scoping review provides insights into the current landscape of observational research on RTX and identifies gaps in the available literature. The findings underscore the need for health care providers to better understand the treatment landscape and use of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence plays a crucial role in evaluating the therapeutic effects and risk profile of RTX in diverse patient populations outside of controlled clinical trials. Further research is needed to address the identified gaps and guide clinical decision-making regarding the optimal use of RTX in cancer, RA, and MS.
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