The Rituximab Biosimilar CT-P10 in Rheumatology and Cancer: A Budget Impact Analysis in 28 European Countries

Our BIA model demonstrated that introduction of the rituximab biosimilar CT-P10 into the EU would save €90.04 million in the first year (assuming 30% market share), which could be reallocated to allow 7531 additional patients (including 2857 patients with RA, 2263 patients with NHL, 1624 patients with CLL, and 787 patients with other diagnoses) to access rituximab treatment. This was equivalent to a 6.4% increase in patients with access to rituximab. If CT-P10 market share was assumed to be 50%, budget savings rise to €150.10, with a total of 12,551 additional patients now able to access rituximab. Over a 3-year time horizon, projected budget savings total approximately €570 million, equating to 47,695 additional patients able to access this potentially life-changing treatment. These data clearly represent a substantial societal health gain and it can be concluded from our findings that, with some assumptions as defined in the model, use of CT-P10 will present significant savings for healthcare systems, in accordance with our stated hypothesis. Although we assumed the price of CT-P10 to be up to 30% lower than that of RTX, expert opinion suggests that the actual difference could be as much as 60–70%. Thus, our projections on the number of additional patients able to access treatment might be considered conservative estimates, and actual figures may prove to be notably higher.

As with all BIA models, assumptions were applied that create some uncertainty with respect to the inputted data. For example, as a result of a lack of literature evidence, we estimated the number of RTX-treated patients from IMS utilization data. We also applied some estimates to the calculation of RTX distribution across diagnoses, again because of a lack of literature data. Finally, list prices may differ from actual purchasing prices (which are not publicly available), and an assumption was made with respect to the price of CT-P10 as a proportion of RTX list price. Several other factors outside the scope of this model may influence the budget impact of CT-P10, such as the emergence of other biosimilars and originator products, and price reductions of the reference product. However, no other rituximab biosimilars are currently available for use in the indications assessed in this study, and new originator biologicals are either under regulatory review or only recently approved. Given the time horizon of our model these factors, and potential RTX price reductions, are unlikely to impact our findings.

In addition to these methodological limitations, it should be remembered that inequities in access to rituximab are not solely linked to national income [28, 57]; for example, country- and healthcare system-specific factors also influence uptake of biosimilars [58‐60]. It is important to understand that the availability of CT-P10 at a lower cost than RTX will not in itself automatically increase patient access to rituximab. Payer, healthcare professional, and patient perceptions regarding the use of biosimilars also play an important role in determining uptake.

There are two broad potential patient populations who may be treated with CT-P10: RTX-naïve patients and those already receiving RTX who could be switched to CT-P10. The clinical uptake of CT-P10 will therefore be dependent on both these populations. Clinical evidence from other EMA-approved second-generation biosimilars suggests that switching does not result in decreased efficacy or new safety concerns. For example, a large phase 4 randomized controlled trial funded by the Norwegian government (NOR-SWITCH) assessed the switch from reference infliximab to CT-P13 in six immune-mediated inflammatory diseases including RA [61] and found that switching to the biosimilar was not inferior to continued treatment with the reference product [62]. However, physicians may have reservations regarding switching to a biosimilar and, in general, seem to be less willing to switch patients already receiving treatment with an innovator or reference product than to prescribe a biosimilar to a biological-naïve patient [63]. This “ambiguity or uncertainty aversion” may be reduced when healthcare professionals are able to reallocate budget themselves [64]. Healthcare professionals may choose, for example, to use financial savings to enable more patients to access treatment, for patients to access treatment at an earlier stage of disease, or to benefit patients being treated for other diseases.

Uptake of biosimilars may also be affected by physician views on the process of “extrapolation”. The EMA and US Food and Drug Administration consider that once a biosimilar demonstrates comparability to its reference product in one indication, extrapolation of data can permit approval in other indications held by the reference product, as long as this is scientifically justified [4, 65]. For example, use of biosimilar epoetins in chemotherapy-induced anemia was originally permitted owing in part to extrapolation from studies in renal anemia [66, 67]. Despite the stringent regulatory requirements for extrapolation, concern can still exist among physicians regarding this process, as was initially the case for some inflammatory bowel disease (IBD) specialists after approval of CT-P13 in IBD [68]. In the case of CT-P13 (clinical trials of which were performed in RA and ankylosing spondylitis), initial concerns about extrapolation centered around possible differences in the mechanisms of action of infliximab in IBD versus rheumatology indications, although these were subsequently proved unfounded [69]. Post-approval data on the real-world use of CT-P13 in IBD has since provided reassurance on its efficacy and safety in this setting, as evidenced in a recent statement from the European Crohn’s and Colitis Organisation which asserts that switching from an originator or reference product to a biosimilar in IBD patients is acceptable [70]. In line with regulatory requirements, approval of CT-P10 in some indications of RTX was based in part on the extrapolation of clinical data collected in other indications [36‐45], plus a scientific justification based on the consistency of rituximab mechanisms of action across indications.

BIA analyses are limited in the literature, both in general [34] and with respect to second-generation biosimilars [12]; therefore, the present study represents a valuable addition to the current knowledge base. In 2014, a systematic literature review identified a total of 17 EU BIA publications across all therapy areas [71]. A 2015 review [12] of the budget impact of the introduction of biosimilars in rheumatology found three BIA studies [72‐74], two studies that reported data in six indications (RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and psoriasis) [75, 76], and a further two studies in IBD [77, 78]. To our knowledge, a further two studies have estimated the potential cost savings of biosimilar infliximab in IBD and of biosimilar etanercept in all indications [79, 80]. Thus there are a total of nine BIA studies of second-generation biosimilars in rheumatology, gastroenterology, and dermatology, with substantial budget savings presented in all papers [72‐80]. For example, the introduction of CT-P13 in Central and Eastern Europe was estimated to result in €15.3–20.8 million budget savings over 3 years in RA, enabling 1200–1800 extra patients to be treated [73], and savings of €8.0–16.9 million in Crohn’s disease, enabling 722–1530 extra patients to be treated [77]. Annual savings in the treatment of inflammatory autoimmune diseases in Belgium, Germany, the Netherlands, and the UK and due to CT-P13 were estimated to be €2.89–33.80 million, enabling 250–2602 additional patients to be treated [76]. Predicted savings with CT-P13 over 5 years in RA in France, Germany, Italy, and the UK totaled €96–433 million [72]. Savings were also predicted with the introduction of an etanercept biosimilar in the treatment of inflammatory autoimmune diseases in France Germany, Italy, Spain, and the UK. Over 5 years, these savings totaled €35–284 million, resulting in an additional 3100–17,130 patients able to access treatment [80]. In the area of supportive cancer care, budget impact and cost-effectiveness analyses of first-generation biosimilars in supportive care have also demonstrated the cost savings of biosimilars. For example, a BIA model of biosimilar erythropoiesis-stimulating agent usage in the EU G5 (France, Germany, Italy, Spain, and UK) calculated that €111–146 million could be saved if all patients converted to biosimilar erythropoiesis-stimulating agent, potentially freeing up budget from supportive care for reallocation to increase patient access to anticancer treatments [81]. Analyses in the EU G5 illustrate cost savings associated with biosimilar filgrastim, estimated at between €32.70 (1-day regimen) to €2747 (14-day regimen) per treatment, compared with the reference product [82, 83].

Realizing the benefits of biosimilars in clinical practice is a major challenge for the coming years. For RTX biosimilars, the most evident benefit is the potential to cut the ever-growing healthcare costs associated with the treatment of RA and cancer and thus potentially help to maintain or increase patient access. The budget savings achieved via the use of biosimilars can be reinvested into the treatment of additional patients, as proposed in our study (Table 3) and two multi-country BIAs [76, 77]. In this respect, some countries have already demonstrated an intention to benefit from using biosimilars in their healthcare system. The lower cost of CT-P13 has driven uptake in Europe, with market share reaching 73% in the UK by mid-2016 [84]. In South Korea, 15 months from the introduction of biosimilar infliximab, approximately 20% of all patients treated with infliximab received the biosimilar. At the same time, the use of biological therapy increased [85]. Such findings provide real-world evidence that budget savings are being spent on the reimbursement of biosimilar therapy for additional patients.

Aggregated health gains at a societal level can also be estimated in terms of quality-adjusted life year (QALY) gains. In virtually all European countries, health technology assessment guidelines require the reporting of QALY gains at a patient and societal level, as well as cost-effectiveness and budget impact. These data form part of a product’s economic dossier and are required by public bodies for reimbursement. In this study, we report BIA data. By comparing our data on the numbers of additional patients that could access treatment as a result of budget savings to literature data on the relationship between numbers of additional patients and associated average QALY gains, estimates of expected QALY gains due to the introduction of CT-P10 can be made (assuming budget savings are reallocated to treat new patients within the same diagnosis). As calculated QALY gains are based on patient-reported outcome measures, such as the EQ-5D questionnaire [86, 87], this measure gives some indication of patient-level health gains, and is of increasing importance in determining the overall value of a therapeutic intervention.

Some evidence already exists regarding QALY gains with the use of biological therapies, including RTX. In RA, the mean QALY gain during 1 year of biological therapy is 0.14 [88]. In DLBCL, various groups report that R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) results in a QALY gain of between 0.82 and 1.07 QALYs compared with CHOP alone, over a 15-year time horizon [89‐91]. In CLL, when RTX is added to fludarabine and cyclophosphamide (FC), QALYs increase to 1.127 (assuming an effect for 5.9 years) and to 1.459 (assuming an effect for 10 years) compared with FC alone [92]. Another study found the addition of RTX to FC led to an incremental gain of 0.94 QALYs in a 15-year horizon [93]. In a lifetime horizon study in advanced FL, the addition of RTX to chemotherapy increased QALY by 0.458–1.184 [94, 95]. Wisløff et al. recently conducted a review of cost-utility studies and evaluated expected incremental QALY gains [87]. In the 333 studies identified, the median incremental QALY gain across a range of indications was 0.06. The authors noted a number of methodological limitations that affected the determination of QALY gains in individual studies. Using the data collected in the present study, the projected societal QALY gains for RA in the EU are 400 and 667 QALYs per year in the base case scenario and scenario 2, respectively. In NHL, the QALY gain is estimated at 133 in the base case scenario and 221 in scenario 2, while in CLL the QALY gain per year would be 95–310 and 159–517 in the base case scenario and scenario 2, respectively.