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Abstract OBJECTIVES: Anti-vascular endothelial growth factor (VEGF) therapy restores retinal architecture and enhances vision in diabetic macular edema (DME). Bevacizumab is an off-label anti-VEGF drug that effectively treats DME. The safety and efficacy of bevacizumab biosimilars, which are more affordable than the original medication, still need to be established. This study aimed to assess the cost-effectiveness, efficacy, and safety of biosimilars for treating patients with naïve DME across various price ranges that are accessible in the Indian market. MATERIALS AND METHODS: Two biosimilars, BevaciRelTM (Reliance Life Sciences Pvt. Ltd.) and ZyBev (Cadila Healthcare Limited), were compared to their original, Avastin (Roche Products [India] Pvt. Ltd.), in a randomized, control study. Three end-notes were used to assess safety and efficacy: persistence, improvement, and adverse events. Cost-effective analysis was carried out using a decision-tree analysis model. RESULTS: This study included 69 (59%) men and 54 (41%) women with naïve DME. The cohort had an average log MAR visual acuity of 0.87 ± 0.22, and the central retinal thickness at baseline on OCT was 398.5 ± 37.61 μm. The visual acuity showed a similar improvement, and there was a decrease in central retinal thickness as observed on OCT across the groups. The incremental cost-effectiveness ratio was 10.8. CONCLUSIONS: The biosimilars of bevacizumab are safe and efficacious in treating DME in a cost-effective manner.

Background Bevacizumab shows superior efficacy in cerebral radiation necrosis (CRN) therapy, but its economic burden remains heavy due to the high drug price. This study aims to evaluate the cost-effectiveness of bevacizumab for CRN treatment from the Chinese payers’ perspective. Methods A decision tree model was developed to compare the costs and health outcomes of bevacizumab and corticosteroids for CRN therapy. Efficacy and safety data were derived from the NCT01621880 trial, which compared the effectiveness and safety of bevacizumab monotherapy with corticosteroids for CRN in nasopharyngeal cancer patients, and demonstrated that bevacizumab invoked a significantly higher response than corticosteroids (65.5% vs. 31.5%, P  < 0.001) with no significant differences in adverse events between two groups. The utility value of the “non-recurrence” status was derived from real-world data. Costs and other utility values were collected from an authoritative Chinese network database and published literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was evaluated via one-way and probabilistic sensitivity analyses. Results Bevacizumab treatment added 0.12 (0.48 vs. 0.36) QALYs compared to corticosteroid therapy, along with incremental costs of $ 2010 ($ 4260 vs. $ 2160). The resultant ICER was $ 16,866/QALY, which was lower than the willingness-to-pay threshold of $ 38,223/QALY in China. The price of bevacizumab, body weight, and the utility value of recurrence status were the key influential parameters for ICER. Probabilistic sensitivity analysis revealed that the probability of bevacizumab being cost-effectiveness was 84.9%. Conclusion Compared with corticosteroids, bevacizumab is an economical option for CRN treatment in China.

Background Age-related macular degeneration (AMD) is a blinding disease placing considerable burden on society due to blindness-associated costs. Intravitreal anti—vascular endothelial growth factors (anti-VEGFs) are effective in reducing the incidence of blindness, but at potentially high costs, depending on the cost of the drug used. Aflibercept has been introduced as an anti-VEGF equally effective to ranibizumab, but less costly. For this new drug, new cost-effectiveness analyses are needed, and AMD models used today give biased results. We investigated the cost-effectiveness of aflibercept compared to bevacizumab, ranibizumab, and no treatment and studied the influence of commonly used model parameters. Methods A patient-level, visual acuity-based, 2-eye model was developed. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of aflibercept, bevacizumab, and ranibizumab. Utility and resource utilization were assessed in interviews with AMD patients. Costs were based on standard health care cost prices. Time horizons were two and five years. A societal perspective was employed. Results Over five years, costs associated with aflibercept treatment were €36,030, with 2.15 QALYs. Costs associated with the bevacizumab regimens, ABC study as-needed (PRN); CATT study PRN; and CATT study 1×/month, were €19,367; €26,746; and €30,520, with 2.16; 2.17; and 2.15 QALYs, respectively. Costs associated with ranibizumab PRN and 1×/month were €45,491 and €74,837 with 2.16 and 2.15 QALYs, respectively. ‘No treatment’ was associated with €9530 and 1.96 QALYs. The incremental cost-effectiveness ratios versus ‘no treatment’ were: aflibercept—€140,274; bevacizumab—€51,062 (ABC PRN), €83,256 (CATT PRN) and €110,361 (1×/month); ranibizumab—€181,667 (PRN) and €349,773 (1×/month). Results were highly dependent on whether only one or both eyes were included, length of time horizon, and whether the costs of blindness and low-vision were included in the analysis. Conclusions Aflibercept is a cost-effective treatment for AMD over ranibizumab. However, aflibercept is not a cost-effective treatment when compared to bevacizumab. Application of inappropriate model assumptions leads to a biased cost-saving estimate of the cost-effectiveness of aflibercept. Therefore, cost-effectiveness analyses should be conducted with appropriate models.

Background and Objective The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data. Methods A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective. Results The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib. Conclusion When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of bevacizumab (Roche Products) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with metastatic colorectal cancer (mCRC), as part of the Institute’s Single Technology Appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE’s subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology provided within the manufacturer’s submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer’s decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a phase III, multicentre, multinational, two-arm, randomized, open-label study with the primary objective of confirming the non-inferiority of oxaliplatin plus capecitabine (XELOX) compared with oxaliplatin plus 5-fluorouracil and folinic acid (FOLFOX-4) in adult patients with histologically confirmed mCRC who had not previously been treated. The ERG considered that the NO 16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free and overall survival when bevacizumab is added to either XELOX or FOLFOX-4. The ERG considered that the size of the actual treatment effect of bevacizumab was uncertain due to trial design limitations, imbalance of a known prognostic factor, relatively short treatment duration compared with that allowed within the trial protocol, and interpretation of the statistical analyses. The manufacturer’s submission included a de novo economic evaluation using a cost-effectiveness model built in Microsoft® Excel. The ERG believed that the modelling structure employed was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratios (ICERs). The areas of uncertainty identified by the ERG included whether chemotherapy would be administered continuously or intermittently, patient access scheme (PAS) costs and uptake, survival that was dependent on the statistical analyses used, and the likely duration of continued treatment with bevacizumab after cessation of oxaliplatin and the efficacy associated with continuation. The STA described here highlighted the challenges in appraising interventions with a complex PAS. Based on the analyses that include a discount to the list price of oxaliplatin, the ERG concluded that the ICERs for the addition of bevacizumab to XELOX or FOLFOX were both over £50 000. The NICE Appraisal Committee concluded that bevacizumab in combination with oxaliplatin and either 5-fluorouracil plus folinic acid or capecitabine (i.e. FOLFOX or XELOX) was not recommended for the treatment of mCRC.

Background Bevacizumab (Avastin®) is as effective as ranibizumab (Lucentis®) in the treatment of neovascular age-related macular degeneration (nAMD). However it has two important structural differences. First, it has two active sites instead of one; second, it retains the Fc portion of the antibody which would be expected to confer a significantly longer half-life. These agents have been associated with systemic complications including strokes, so it is desirable to use the smallest effective dose. Furthermore, the standard dosing regimen requires monthly hospital visits, which present a significant challenge both to the hospital services and to the patients (who are elderly). Methods/Design Patients ≥50 years who are eligible for anti-vascular endothelial growth factor (VEGF) treatment of nAMD in the NHS, who are either newly referred for treatment or have reactivation of nAMD and who have not received treatment to either eye for the previous six months. We have designed a factorial multi-centre masked randomised controlled trial using bevacizumab as the intervention, with patients randomised to one of four arms: to standard or low dose and to monthly or two-monthly patient review. The aim is to recruit sufficient patients (around 1,000) to obtain 304 patients meeting the endpoint over a four-year period. The primary endpoint is time to treatment failure to be analysed using Cox regression. Discussion This randomised control trial will show if half dose and two monthly as required is as effective as full dose and monthly regimes. A two monthly as required regimen of Bevacizumab would significantly reduce both the cost and the service delivery burden for the treatment of nAMD while a reduced dose would be expected to enhance the safety profile of this treatment regime. Trial registration International Standard Randomised Controlled Trial Number: ISRCTN95654194 , registered on 22 September 2009.

Objective To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective. Design A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial. Setting 23 hospital ophthalmology clinics. Participants 610 patients aged ≥50 years with untreated nAMD in the study eye. Interventions 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years. Main outcome measures Quality-adjusted life-years (QALYs). Results Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI −0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab. Conclusions Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective. Trial registration number ISRCTN92166560.

Background The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. Aim To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. Design This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. Outcomes The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments.

Objective To assess the cost-effectiveness of ranibizumab compared with pegaptanib in the treatment of patients with minimally classic/occult neovascular age-related macular degeneration (AMD), from a societal perspective in Spain. Methods We constructed a Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale): VA >20/40, ≤20/40 to >20/80, ≤20/80 to >20/200, ≤20/200 to >20/400, ≤20/400, and an additional death state. Two cohorts of patients were distributed along the VA states, and treated with either ranibizumab or pegaptanib. Transition probabilities assigned for movement between these states with both drugs were obtained from published randomized clinical trials. Medical costs related to AMD treatment and follow-up, medical costs related to AMD comorbidities, and non-medical-related costs were taken into account. Costs (2008 Euro), health outcomes (Quality-adjusted life years—QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: €/QALY), were determined for a lifetime horizon in the base case analysis. Sensitivity analyses were conducted to explore different scenarios and assumptions in the model. Results Treating patients with varying degrees of visual impairment with monthly ranibizumab instead of pegaptanib was €71,206 more costly and provided 2.437 additional QALYs (€29,224/QALY). When administered on an as-needed basis, as in the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PrONTO) trial, the cost per QALY gained with ranibizumab was reduced to €4,623. Conclusions The cost per QALY gained with monthly ranibizumab compared with pegaptanib in the minimally classic/occult neovascular AMD population is just below the €30,000 threshold below which new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon and the chosen extrapolation method, the source for data on pegaptanib efficacy and the number of ranibizumab injections. When administered on an as-needed basis, ranibizumab was a cost-effective strategy compared to pegaptanib in this population.

There is an active and controversial debate about the role of intravitreal bevacizumab versus approved drugs in the treatment of neovascular age-related macular degeneration (AMD). Because bevacizumab was available prior to the launch of ranibizumab, off-label use of the former became widespread and the cancer drug bevacizumab is the most commonly used medication in ophthalmology nowadays. This review considers every publication identified in MEDLINE using the keywords ‘bevacizumab’ and ‘Avastin’ between 1 June 2005 and 31 July 2008. The search identified 511 papers that were evaluated. In 33 studies, there was consistent and clear evidence for the efficacy of bevacizumab in neovascular AMD. However, the highest grade studies (three prospective, randomized, controlled trials) did not attain better than grade 2b level of evidence, and objective evaluation of the benefit of bevacizumab relative to representative controls was therefore not possible. Certainly, the available evidence is inferior to that obtained from the approval studies of ranibizumab and this should influence treatment selection and guidance of patients. These considerations indicate that important quality criteria need to be included in future studies to ensure more meaningful conclusions can be drawn. These include clearly defined inclusion criteria, information about the recruitment procedure (including data on withdrawals, excluded patients, concealed treatment allocation, use of intention-to-treat analyses and blinded assessment procedures). Although preclinical studies have almost exclusively found bevacizumab to be safe, the design utilized in clinical case series cannot rule out a possible increase in adverse events, which already show a high spontaneous incidence in elderly AMD patients. The superior evidence level for ranibizumab and the limited safety data for bevacizumab must be taken into consideration when evaluating the costs that a healthcare system is willing to spend. However, the superior grade of evidence for ranibizumab should not be confused with the (still missing) evidence for superior efficacy. The results of ongoing randomized, controlled, comparative trials will provide further data on the efficacy and cost effectiveness of bevacizumab and ranibizumab in the treatment of AMD. In the meantime, patients should be informed about the alternatives, the price differences and the restricted liability issue when off-label use of bevacizumab is offered.