Assessing the Need for a Biosimilar: A Systematic Literature Review of the Treatment Burden of Rituximab in Hematological Malignancies
Authors: James Elizabeth , Trautman Holly , Hoehn Gerard , Szabo Erika , Tang Boxiong 
Published: October 2019

Abstract
BACKGROUND: Advanced targeted therapies have improved survivals and efficacies in patients with certain hematology conditions. However, the treatment costs and safety are some concerns among healthcare providers, patients, and payers.
OBJECTIVES: To identify and characterize the treatment burden of rituximab, focusing on drug cost, toxicity, and other treatment-related costs in hematological malignancies, given the anticipated market entry of biosimilar products.[1]
METHODS: We conducted a systematic literature review (SLR) using the online version of Index Medicus identified relevant publications using pertinent search terms (see Table) to capture treatment-related cost and non-cost burden publications in English language, publication dates 01/01/2010 to 01/24/2018.
RESULTS: Of the 704 publications returned in the search, a total of 28 US and ex-US treatment burden studies (9 cost, 16 non-cost, and 3 drug route comparison studies) were included in the review. US (4) and ex-US (5) treatment cost studies found that direct medical costs of care were dramatically increased with the addition of rituximab or that rituximab represented a large proportion of total costs of care. For publications with calculated benefits associated with treatment, the addition of rituximab to CT was coupled with life-year gains and lower mortality. A large observational study found no difference in all-cause hospitalization rates in the 12 months following rituximab treatment. While studies designed to evaluate rituximab toxicity have found the addition of rituximab to CT to be associated with a general increase in incidence of adverse events (AEs) overall, 1 prospective study found no subsequent decline in quality of life (QOL), and another prospective study observed a significant increase in time without disease symptoms or toxicity (8.33 months) and less time spent in relapse. Both rituximab maintenance (after successful induction) and retreatment at progression were associated with a decline in illness-related anxiety (1randomized, Phase III trial in indolent non-Hodgkin lymphoma), while rituximab maintenance was associated with significantly decreased pain and other illness-related symptoms vs observation (2 studies). Five studies (3 US; 2 ex-US) analyzed infusion-related reactions (IRRs) and/or rapid infusion use. Overall, IRRs, especially with first infusions, were common (40%-63%), but primarily low-grade (I-II), and rituximab was usually well-tolerated on same-day rechallenge. Marked patient time was saved with rapid infusion. An SLR and meta-analysis of rapid rituximab infusion further characterized rapid infusion, identifying all IRRs as Grade I or II with a pooled incidence of 2.6%. Three ex-US studies evaluated economic endpoints comparing intravenous and subcutaneous (SC) preparation and administration of rituximab. One study calculated higher labor costs for SC rituximab, while 2 studies calculated lower staff time for SC rituximab; all studies identified shorter patient treatment/chair time for SC rituximab.
CONCLUSIONS: We found that the treatment-related cost burden of rituximab in malignant conditions is substantial, while its associated toxicity is relatively low, and patient QOL is maintained or improved. Incident and increased toxicities associated with rituximab added to CT may or may not be exclusively attributable to rituximab. Administration rate and route influence economic endpoints with rituximab use. These findings highlight the potential economic benefit of lower-cost biosimilar rituximab products for patients, health care systems, and payers.
[1] This Abstract is not intended to refer to any particular biosimilar product or use thereof.

Disclosures
James: Teva: Consultancy; Roche: Consultancy. Trautman:Teva: Consultancy; Roche: Consultancy. Hoehn:Teva: Employment. Szabo:Teva: Employment. Tang:Teva: Employment.