1 Appraisal Committee's preliminary recommendations

1.1 Ranibizumab is not recommended for the treatment of visual impairment caused by macular oedema secondary to central or branch retinal vein occlusion.

2 The technology

2.1 Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that block the action of vascular endothelial growth factor A (VEGF-A). Retinal vein occlusion (RVO) is a common cause of reduced vision as a result of retinal vascular disease. Thrombosis in the retinal veins causes an increase in retinal capillary pressure, resulting in increased capillary permeability and the discharge of blood and plasma into the retina. This leads to macular oedema and varying levels of ischaemia through reduced perfusion of capillaries. These changes trigger an increase in VEGF, which increases vascular permeability and new vessel proliferation. By inhibiting the action of VEGF-A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'. For more details, see the summary of product characteristics (SPC).

2.2 The SPC states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3 consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment should be resumed if monitoring indicates a loss of visual acuity caused by macular oedema secondary to RVO, and continued until visual acuity has remained stable for 3 consecutive months. The interval between doses should not be shorter than 1 month. For full details of the method of administration, see the SPC.

2.3 Contraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. Side effects of treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. For full details of side effects and contraindications, see the SPC.

2.4 Ranibizumab is administered as a single 0.5 mg intravitreal injection. Each vial of ranibizumab contains 2.3 mg in 0.23 ml. Ranibizumab costs £742.17 per vial (excluding VAT; this represents a recent reduction from the price of £761.20 listed on MIMS, August 2011 and in the 'British national formulary' [BNF] edition 61). The manufacturer of ranibizumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ranibizumab is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab versus grid laser photocoagulation in people with macular oedema secondary to branch retinal vein occlusion (BRVO) and for ranibizumab versus best supportive care in people with macular oedema secondary to central retinal vein occlusion (CRVO). The manufacturer stated that there was no direct evidence for ranibizumab compared with bevacizumab or dexamethasone intravitreal implant (which were defined as comparators in the scope) and therefore no formal indirect clinical effectiveness comparison was presented for dexamethasone or bevacizumab in either BRVO or CRVO (see section 3.10).

3.2 The main sources of evidence presented in the manufacturer’s submission came from the BRAVO and CRUISE randomised controlled trials (RCTs). These evaluated the efficacy of ranibizumab for the treatment of macular oedema secondary to branch retinal vein occlusion and to central retinal vein occlusion respectively. The BRAVO (n = 397) and CRUISE (n = 392) trials were both three-armed RCTs carried out at multiple centres in the USA. Patients were randomised equally to sham injection, monthly intraocular ranibizumab 0.3 mg or monthly intraocular ranibizumab 0.5 mg. Both trials included people with macular oedema that had been diagnosed in the 12 months before study initiation. Patients entered a 6-month treatment phase during which monthly injections were given, beginning on day zero. In BRAVO, patients in both sham injection and ranibizumab groups could receive grid laser photocoagulation for rescue treatment from 3 months. In both BRAVO and CRUISE, the treatment phase was followed by a 6‑month observation phase during which all groups (that is, the sham group and the two ranibizumab groups) could receive ranibizumab as needed. Patients in the observation phase of BRAVO (but not CRUISE) could receive grid laser photocoagulation for rescue treatment from 3 months (that is, at month 9 of the study). The final treatment in both BRAVO and CRUISE was given at month 11, with a final study visit at month 12. Patients who completed the 12-month BRAVO and CRUISE trials could enter an open-label extension study (HORIZON).

3.3 The primary outcome in both BRAVO and CRUISE was the mean change from baseline in best corrected visual acuity (BCVA) score in the study eye at 6 months. BCVA score was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity (‘20/20 vision’). Secondary outcomes reported in both BRAVO and CRUISE included mean change from baseline in BCVA score over time up to 6 and 12 months, and the proportion of patients gaining or losing more than 15 letters in BCVA score at 6 and 12 months compared with baseline. The trials also reported results for several exploratory outcomes, including the mean change from baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite score up to 6 months. The NEI VFQ-25 has 25 questions that are designed to measure the effect of visual impairment on daily functioning and quality of life.

3.4 This appraisal considered the 0.5 mg dose of ranibizumab, which is the only dose with a UK marketing authorisation. In BRAVO, 91.7% of patients in the sham group and 95.4% in the ranibizumab group were treated in the eye affected mostly by RVO (i.e. their ‘worse-seeing eye’). In CRUISE, 90.0% of patients in the sham group and 92.3% in the ranibizumab group were treated in their ‘worse-seeing eye’. The mean number of ranibizumab injections in the treatment phase was 5.7 (BRAVO) and 5.6 (CRUISE). The average number of ranibizumab injections in the observation phase was 2.7 (BRAVO) and 3.3 (CRUISE). More than 80% of patients from the sham injection group in both BRAVO and CRUISE received ranibizumab as needed during the observation phase. During the first 6 months of the BRAVO trial, grid laser photocoagulation was used in 57.6% of patients in the sham injection group and in 21.4% of the patients in the ranibizumab group. Over the 12-month study period in BRAVO, 61.4% of patients in the sham (plus ranibizumab) group and 34.4% of patients in the ranibizumab group received rescue treatment with grid laser photocoagulation. 

3.5 In BRAVO, at month 6, patients in the ranibizumab group had gained an average of 18.3 letters (95% confidence interval [CI] 16.0 to 20.6) from baseline BCVA score. This gain was statistically significant compared with the gain of 7.3 letters (95% CI 5.1 to 9.5) in the group receiving sham injection (p < 0.0001). At month 12 of the BRAVO trial (that is, at the end of the 6-month observation period, during which all patients could receive ranibizumab as needed), the 0.5 mg ranibizumab group reported an average gain in BCVA baseline score of 18.3 letters (95% CI 15.8 to 20.9) compared with the sham (plus ranibizumab) group that had gained 12.1 letters (95% CI 9.6 to 14.6, p value not reported). The observed improvement at month 6 from baseline in the NEI VFQ-25 composite score was statistically significantly greater in patients receiving ranibizumab (10.4 points, 95% CI 8.3 to 12.4) than in patients receiving sham injection (5.4 points, 95% CI 3.6 to 7.3; p < 0.005). The manufacturer reported that overall the BRAVO trial demonstrated a clinically meaningful and statistically significant effect of ranibizumab on visual acuity and patient-reported outcomes based on the NEI VFQ-25 at 6 months. The manufacturer carried out a post-hoc analysis stratified by rescue treatment with grid laser photocoagulation to investigate the effects of adding this treatment to ranibizumab. The manufacturer concluded that concomitant use of grid laser photocoagulation did not lead to an overestimation of the efficacy of ranibizumab.

3.6 At month 6 in the CRUISE trial, patients in the ranibizumab group achieved a statistically significant mean gain in BCVA score from baseline of 14.9 letters (95% CI 12.6 to 17.2) compared with the sham group who gained 0.8 letters (95% CI −2.0 to 3.6, p < 0.0001). The manufacturer reported that the improvements in visual acuity in the ranibizumab group at month 6 were generally maintained, through to month 12 with treatment as needed (13.9 letters [95% CI 11.5 to 16.4] for ranibizumab; 7.3 letters [95% CI 4.5 to 10.0] for sham (plus ranibizumab) group; p value not reported). Patients receiving ranibizumab 0.5 mg demonstrated statistically significantly greater improvements in patient-reported outcomes as measured by the NEI VFQ-25 (6.2 points, 95% CI 4.3 to 8.0) than patients receiving sham injection (2.8 points, 95% CI 0.8 to 4.7; p < 0.05).

3.7 For patients who entered the open-label extension study (HORIZON), ranibizumab 0.5mg was given at intervals of at least 30 days. Sixty-seven percent of patients from BRAVO and 60% of patients from CRUISE completed month 12 of HORIZON. The primary outcome for the HORIZON extension study was mean change from HORIZON baseline in BCVA score up to 24 months. The manufacturer presented results from the first 12 months. From the BRAVO trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 15.6 letters and 17.5 letters respectively. From the CRUISE trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 7.6 and 12.0 letters respectively (no confidence intervals reported).

3.8 Adverse events were reported at 6 months and 12 months in both BRAVO and CRUISE trials, and for a further 12 months’ follow-up in the HORIZON extension study. In BRAVO, at 6 months there were seven ocular adverse events (5.4%) in the ranibizumab group compared with 21 (16%) in the sham group, excluding occurrences of raised intraocular pressure. Non-ocular serious adverse events (potentially related to VEGF inhibition) at 6 months were higher in the ranibizumab group (five events [3.8%]) than the sham group (one event [0.8%]). In CRUISE, at 6 months there were 13 ocular adverse events (10.1%) in the ranibizumab group compared with 25 (19.4%) in the sham group, excluding occurrences of raised intraocular pressure. In CRUISE, non-ocular serious adverse events (potentially related to VEGF inhibition) were similar in both the ranibizumab and sham groups (three [2.3%] and two [1.6%] respectively). The most common adverse event reported in BRAVO and CRUISE at 12 months was cataract, with eight (6.2%) and nine (7%) instances associated with ranibizumab treatment respectively; in the sham (plus ranibizumab) group, three (2.3%) and two (1.8%) instances of cataract were reported. Instances of raised intraocular pressure were reported in both BRAVO and CRUISE at 6 months but were academic in confidence. In the HORIZON extension study, the incidence of any adverse event in the sham and ranibizumab groups was 2.2% and 5.8% respectively for the patients (with branch retinal vein occlusion) recruited from BRAVO, and 3% and 5.2% respectively for the patients (with central retinal vein occlusion) recruited from CRUISE.

3.9 A systematic review was undertaken to identify RCTs involving potential comparators for ranibizumab in the treatment of macular oedema secondary to RVO. The manufacturer discussed the feasibility of conducting a formal indirect comparison of ranibizumab with dexamethasone intravitreal implant or bevacizumab in CRVO, and an indirect comparison of ranibizumab with dexamethasone intravitreal implant, bevacizumab or grid laser photocoagulation in BRVO. For a comparison of ranibizumab and bevacizumab in CRVO, the manufacturer identified a study by Faghihi et al. (2008) and stated that there was inadequate information regarding the baseline characteristics of patients in the study. For a comparison with bevacizumab in BRVO, studies by Moradian et al. (2011) and Russo et al (2009) were identified. The manufacturer stated that because of differing durations of macular oedema from diagnosis between Moradian et al. (2011) and BRAVO and a difference in trial durations between all 3 studies, an indirect comparison could not be conducted without bias. In addition, the manufacturer considered that bevacizumab is not an appropriate comparator because its use in the NHS is not routine and not considered best practice. Therefore an indirect comparison of ranibizumab with bevacizumab was not included in their submission. The manufacturer stated that, because of the differences in trial populations between trials involving ranibizumab and those with dexamethasone intravitreal implant (patients had differing durations of macular oedema from diagnosis, different baseline ranges of BCVA and different retinal thickness in the BRAVO and CRUISE trials compared with GENEVA), an indirect comparison of these treatments could not be undertaken for CRVO or BRVO. In addition, the manufacturer stated that because of fundamental differences in trial design between BRAVO and the laser studies, BVOS (1984) and Battaglia et al. (1999) (BRAVO was sham-injection-controlled and the laser studies were not), ranibizumab could not be compared indirectly with grid laser photocoagulation.

3.10 Although no formal indirect comparison of ranibizumab with other drug treatments was performed, the relative systemic safety profiles of ranibizumab and bevacizumab were discussed in the manufacturer’s submission. The manufacturer stated that ranibizumab was associated with an improved safety profile compared with bevacizumab. The manufacturer provided data from three large retrospective studies by Carneiro et al. (2011), Curtis et al. (2010) and Gower et al. (2011) in support of this statement, but these studies compared bevacizumab with ranibizumab for the treatment of age-related macular degeneration rather than RVO. The manufacturer acknowledged that age-related macular degeneration manifests later in life than RVO, and so the average age of patients in the BRAVO and CRUISE trials was lower than in the studies of age-related macular degeneration.

3.11 For evidence of cost effectiveness, the manufacturer submitted a Markov state transition model that compares treatment with ranibizumab with grid laser photocoagulation (standard care) for macular oedema secondary to BRVO and with best supportive care for CRVO. Treatment was modelled over a 15-year time horizon for a hypothetical cohort of 1000 patients with visual impairment because of macular oedema secondary to RVO, with a starting age of around 66 years. Eight BCVA health states and death are included in the model structure, with each health state having an associated utility and mortality risk depending on whether the 'better-seeing eye' or 'worse-seeing eye' is treated. In the manufacturer's base-case analysis, it was assumed that all patients are treated in their 'better-seeing eye'. People move through the model in monthly cycles, accumulating the utility associated with each health state they enter, together with the costs of treatment and subsequent monitoring. People experiencing adverse events have an associated cost and disutility applied, and people considered to be blind accumulate the additional costs associated with blindness. Blindness is defined as a visual acuity equal to or less than 35 letters in the 'better-seeing eye'. An exploratory indirect comparison with dexamethasone intravitreal implant was conducted for both BRVO and CRVO, but no comparison with bevacizumab was made because the manufacturer considered that it was not an appropriate comparator.

3.12 Transition probabilities were determined monthly and subsequently used to calculate overall monthly transition probabilities for months 0 to 1, months 2 to 6 and months 7 to 12. For CRVO, the probabilities derived from the sham group of the CRUISE trial for months 2 to 6 were applied to months 2 to 6, 7 to 12 and 13 to 24 in the best supportive care arm of the model, because of the absence of any comparator data after month 6. For BRVO, the probabilities for months 7 to 12 were pooled from the sham and ranibizumab groups of BRAVO and applied to months 7 to 12 and months 13 to 24 in both arms of the model to account for the effect of using grid laser photocoagulation as rescue treatment in both arms. Dexamethasone intravitreal implant was incorporated into the model by applying relative risks from two trials (GENEVA studies) and assigning probabilities observed in the control groups of the BRAVO and CRUISE trials.

3.13 The manufacturer conducted a systematic review of the literature to identify utility values for populations with visual impairment because of RVO, with priority given to populations with macular oedema secondary to BRVO or CRVO. The manufacturer stated that consideration would have been given to patients with visual impairment related to diabetic macular oedema or age-related macular degeneration if utility values for RVO could not be identified. The manufacturer chose a study by Brown (1999) as the source of utilities because this was the only study which reported utility values related to visual acuity. This is a US study assessing preferences for different levels of visual acuity in patients with vision loss from various causes, 7% of whom had RVO. The manufacturer's model applies different utility values to each BCVA health state, depending on whether the 'better-seeing eye' or 'worse-seeing eye' is treated. Brown (1999) presented separate utility values for visual acuity in the 'better-seeing eye' and 'worse-seeing eye'; however, the manufacturer used different utility values for each BCVA health state only in the 'better-seeing eye' and assumed a value of 0.85 for all BCVA health states in the 'worse-seeing eye'. Utilities were not adjusted for age and the 'worse-seeing eye' was not considered in the base case.

3.14 Costs included intervention and comparator costs. The acquisition cost of ranibizumab was £742.17 (see section 2.4). Grid laser photocoagulation (BRVO only) was assumed to incur no cost but had an administration cost of £192.00. The acquisition cost of dexamethasone intravitreal implant was £870.00 with an administration cost of £295.25. The manufacturer applied a follow up visit cost of £151.00 for ranibizumab, grid laser photocoagulation (BRVO only), dexamethasone intrvitreal implant and observation (CRVO only). In addition, patients experiencing adverse events had an associated cost and disutility applied, and patients considered to be blind had the additional costs associated with blindness.

3.15 The manufacturer presented all of its base-case incremental cost-effectiveness ratios (ICERs) with the inclusion of the approved patient access scheme. Only the ICERs that include the patient access scheme are reported here. In the base case for BRVO, the ICER for ranibizumab compared with grid laser photocoagulation was £20,494 per QALY gained. In the base case for CRVO, the ICER for ranibizumab compared with best supportive care was £8643 per QALY gained. The manufacturer also presented incremental results for ranibizumab compared with dexamethasone intravitreal implant for BRVO and CRVO. The base-case ICERs for ranibizumab compared with dexamethasone for BRVO and CRVO were £5486 and £7174 per QALY gained respectively. Incremental costs and QALYs for the base case results were commercial in confidence and therefore cannot be presented here.

3.16 The manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow-up visits; for example, in BRVO increasing the number of injections in year 2 (from 2.5 to 6) increased the ICER for ranibizumab versus grid laser photocoagulation to £28,468 per QALY gained. The manufacturer performed scenario analyses to assess the impact of varying the proportion of people treated for macular oedema in the ‘worse-seeing eye’ and commented that this is a key driver of cost effectiveness. The manufacturer also presented probabilistic sensitivity analyses and concluded that based on base-case results the probability that ranibizumab is cost effective when compared with grid laser photocoagulation in BRVO is 45.5% at a threshold of £20,000 per QALY gained and 57.2% at a threshold of £30,000 per QALY gained. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 74.5% and 83.3% at thresholds of £20,000 and £30,000 per QALY gained respectively.

Evidence Review Group comments

3.17 The ERG noted that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because one of the exclusion criteria was brisk afferent pupillary defect which, as the manufacturer stated, equates to severe retinal ischaemia. Therefore the ERG considered that the results of any analyses could only be applied to people without retinal ischaemia.

3.18 The ERG considered that the concomitant use of grid laser photocoagulation from month 3 confounded the results of the BRAVO study and that definite conclusions could not be drawn about the effects of ranibizumab compared with sham injection or grid laser photocoagulation alone. The ERG noted that there was insufficient evidence to conclude that grid laser photocoagulation had no effect in the ranibizumab group. It also noted that the treatment period of the BRAVO trial was insufficient to capture any benefits of grid laser photocoagulation on patient outcomes, which may last longer than 3 years. Furthermore, clinical advice to the ERG suggested that concomitant use of ranibizumab and grid laser photocoagulation does not represent how ranibizumab would be used in clinical practice.

3.19 The ERG considered that the most relevant data for determining the comparative effectiveness of ranibizumab in treating macular oedema secondary to RVO are the data from the period when ranibizumab was given as needed (that is, from month 6). However, the ERG noted that this period may not be long enough to determine the long-term effects of ranibizumab.

3.20 The ERG questioned the manufacturer's view that an indirect estimate of the efficacy of ranibizumab compared with bevacizumab, dexamethasone and grid laser photocoagulation (for BRVO only) was not possible. Although the ERG accepted that there were differences in baseline characteristics between patients in the CRUISE, BRAVO and GENEVA trials (see section 3.9), it stated that this would not prevent an indirect comparison between ranibizumab and dexamethasone, and would likely favour ranibizumab. The ERG suggested that the impact of any bias could have been explored through critical assessment. The ERG agreed with the manufacturer that it was not possible to incorporate bevacizumab for people with CRVO in an adjusted indirect comparison based on the information in the manufacturer's submission. For BRVO, the ERG considered that studies of bevacizumab reported in the manufacturer's submission (see section 3.9 for more details) were suitable for inclusion in an indirect comparison with the first 3 months of data from BRAVO (that is, before rescue treatment with grid laser photocoagulation was permitted). Again, the ERG accepted that there would be some bias in this comparison, but overall the biases would likely favour ranibizumab and could be explored in critical assessment.

3.21 The ERG performed an exploratory indirect comparison of ranibizumab with dexamethasone intravitreal implant in BRVO and CRVO, using the direct comparisons with sham injection in the BRAVO and CRUISE trialsand the two dexamethasone intravitreal implant trials (GENEVA) as the common comparator. The ERG presented analyses that suggested a trend favouring ranibizumab over dexamethasone in macular oedema secondary to both BRVO and CRVO. Based on exploratory analyses of the proportion of people whose visual acuity improved by 10 or more ETDRS letters (considered to be clinically meaningful), the ERG found a relative risk of 0.40 (95% CI 0.24 to 0.66) in people with macular oedema secondary to CRVO for achieving this outcome at 6 months for ranibizumab compared with dexamethasone intravitreal implant (a relative risk of less than 1 favours ranibizumab). The relative risk of achieving a visual acuity improvement of 15 or more ETDRS letters at 3 months was 0.79 (95% CI 0.56 to 1.12) for patients with macular oedema secondary to BRVO, again favouring ranibizumab over dexamethasone intravitreal implant. However, the ERG commented that these results were exploratory and should therefore be interpreted with caution.

3.22 From the trials reported in the manufacturer's submission, the ERG was able to construct a linear network of trials using BRAVO (ranibizumab compared with sham), Moradian et al. 2011 (bevacizumab compared with sham) and Russo et al. 2009 (bevacizumab compared with grid laser photocoagulation). The ERG commented that although the results should be treated with caution because they are exploratory, they provide estimates of around a three-letter improvement in visual acuity with ranibizumab over bevacizumab and an eight-letter improvement with ranibizumab over grid laser photocoagulation at month 3. However, the ERG did not consider this difference between bevacizumab and ranibizumab to be clinically meaningful.

3.23 The ERG noted that in the base-case analysis the model assumes all patients are treated in the 'better-seeing eye', despite the fact that over 90% of patients in the BRAVO and CRUISE trials were treated in their 'worse-seeing eye'. The ERG considered that it was not reasonable to assume equivalent gains in utility and reductions in costs when treating a patient in their 'worse-seeing eye'. The ERG considered the manufacturer's use of a 'better-seeing eye' model to be inappropriate in macular oedema secondary to RVO because RVO is predominantly a unilateral condition, and therefore most patients will receive treatment in their 'worse-seeing eye' only.

3.24 The ERG considered the pooled transition probabilities for ranibizumab, which the manufacturer stated had been necessary to account for the effect of grid laser photocoagulation in people with BRVO. The ERG commented that pooling would lead to overestimation of the efficacy of ranibizumab because the benefit seen in patients in the sham group who received ranibizumab after the first 6 months would be added to the continued effect of ranibizumab in those patients initially randomised to receive ranibizumab. The ERG conducted sensitivity analyses using unpooled transition probabilities and noted that the ICER for ranibizumab compared with grid laser photocoagulation (for BRVO) increased to £52,004 per QALY gained for months 7 to 12, and ranibizumab was dominated (was less clinically effective and more expensive) for months 13 to 24, months 7 to 12 plus months 13 to 24 together. Incremental costs and QALYs for the base case results were commercial in confidence and therefore cannot be presented here.

3.25 The ERG considered the manufacturer's exploratory economic analysis that incorporated dexamethasone intravitreal implant. The ERG commented that there was a potential bias towards ranibizumab in the manufacturer’s approach (see section 3.20).  The ERG conducted an indirect comparison of ranibizumab with dexamethasone intravitreal implant, which provided relative risks of an improvement in visual acuity of 10 letters (two lines) or more for patients with macular oedema secondary to BRVO and CRVO. The relative risks increased from 0.55 to 0.79 for ranibizumab compared with dexamethasone in BRVO. For CRVO, the corresponding figures were 0.30 to 0.40. The ERG commented that the relative risks calculated from the manufacturer's model were more favourable to ranibizumab in both BRVO and CRVO. Moreover, because the ERG’s indirect comparison was known to be biased towards ranibizumab, the manufacturer’s approach to modelling dexamethasone was largely biased towards ranibizumab.

3.26 The ERG noted the manufacturer's assumption in the economic model that there is no mortality risk attributable to RVO. The ERG identified a UK-based study that concluded that patients with RVO were at a significantly greater risk of death from myocardial infarction than the general population. The ERG commented that the relative risk of 1.6 reported by Tsaloumas et al. (2000) is the most applicable to the UK and should be considered in their exploratory analyses. The ERG also noted the mortality risk associated with visual impairment reported by Christ et al. (2008) and commented that this should be applied in their exploratory analyses.

3.27 The ERG noted that the utility values for visual acuity in the 'better-seeing eye' were taken from Brown (1999) rather than Brazier et al. (2009), which was used for 'Ranibizumab and pegaptanib for the treatment of age-related macular degeneration' (NICE technology appraisal guidance 155). The ERG noted that the manufacturer's model assumes utilities are independent of age and that age adjustment is expected to have minimal impact on the ICERs. However, the ERG commented that age adjustment of the utilities presented by Brazier et al. (2009) was not necessary because age had already been adjusted for. The ERG commented that the study by Brazier et al. (2009) should therefore be used as the source for utility associated with visual acuity in the 'better-seeing eye' in this assessment.

3.28 The ERG undertook four exploratory analyses that examined:

• the effect of assumptions around treating the 'better-seeing' or 'worse-seeing eye' and incorporating Brazier utilities
• using the above scenario and adjusting for mortality and visual impairment in the ‘worse-seeing eye’
• immediate compared with delayed treatment in BRVO
• cost-minimisation analysis of bevacizumab.

The ERG amended the manufacturer's model to account for various assumptions that it considered to be more appropriate. The ERG carried out these amendments for the CRVO population only; it did not feel that the BRVO data could be used because of the issue of confounding from rescue treatment with grid laser photocoagulation. The first amendment was to the proportion of patients treated in their 'better-seeing eye' (10% instead of 100%). This increased the manufacturer's base-case ICER from £8643 to £92,047 per QALY gained for ranibizumab versus best supportive care. The ERG subsequently applied age-adjusted utilities derived from Brazier et al. (2009) and this increased the ICER further to £98,733 per QALY gained. By further applying the ERG’s assumption of a 0.1 overall benefit associated with treating the 'worse-seeing eye' the ICER decreased to £49,323 per QALY gained. The ERG also applied an additional assumption of an increased risk of mortality associated with RVO and this changed the ICER to £52,502 per QALY gained. The ERG noted that applying a mortality risk associated with visual impairment in the 'worse-seeing eye' decreased the ICER from £49,323 to £43,280 per QALY gained. Applying all of these assumptions together resulted in an ICER of £43,760 per QALY gained and this formed the ERG’s base-case estimate for ranibizumab versus best supportive care in CRVO.

3.29 The ERG also considered the impact of their preferred assumptions on comparisons of ranibizumab with dexamethasone intravitreal implant in both CRVO and BRVO. The ERG’s assumption that 10% of patients were treated in their 'better-seeing eye' and the age-adjusted utilities derived from Brazier et al. (2009) were included in the analyses detailed below, but not reported separately. For CRVO, assuming a benefit associated with treating the 'worse-seeing eye' increased the manufacturer's base-case ICER from £7174 to £42,147 per QALY gained; applying an increased risk of mortality further increased the ICER to £44,462 per QALY gained. However, applying a mortality risk associated with visual impairment in the 'worse-seeing eye' alone decreased the overall ICER, resulting in the ERG's base-case ICER for ranibizumab versus dexamethasone intravitreal implant in CRVO of £37,443 per QALY gained. For ranibizumab versus dexamethasone intravitreal implant in BRVO, assuming a benefit associated with treating the 'worse-seeing eye' increased the manufacturer’s base-case ICER from £5486 to £34,598 per QALY gained; applying an increased risk of mortality increased the ICER further to £36,498 per QALY gained. Applying a mortality risk associated with visual impairment in the 'worse-seeing eye' alone decreased the ERG’s base-case ICER from £36,498 to £31,122 per QALY gained. 

3.30 The ERG commented that its comparisons of ranibizumab with dexamethasone intravitreal implant for both BRVO and CRVO used relative risks derived from the manufacturer's model (0.55 for BRVO and 0.30 for CRVO) rather than those derived from the ERG's indirect comparison (0.79 and 0.40 respectively). The ERG commented that this would bias the results in favour of ranibizumab and if the ERG's suggested relative risks were applied, the ICER would increase further. The ERG also commented that the efficacy of dexamethasone is potentially underestimated because of differing patient characteristics in the trials that informed the comparison (patients had differing durations of macular oedema from diagnosis in the GENEVA trials compared with BRAVO and CRUISE). Hence the ICERs reported here may be underestimates. In addition, the ERG highlighted that the ICER generated for ranibizumab compared with dexamethasone from the BRAVO trial is derived using the pooled transition probabilities, meaning that there is uncertainty around the ERG's estimate of £31,122 per QALY gained. Using the unpooled transition probabilities would increase this ICER further.

3.31 The ERG conducted a cost-minimisation analysis for ranibizumab versus dexamethasone intravitreal implant assuming equivalent efficacy for the two treatments (in BRVO and CRVO) and an acquisition cost of £50 per month for bevacizumab, as used in Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal 229). The ERG presented data on incremental costs of ranibizumab compared with bevacizumab that included commercial-in-confidence information and cannot be presented here. The ERG’s analysis using the manufacturer’s model suggested that ranibizumab would need to generate 1.5 times more QALYs  than bevacizumab (each month between months 2 and 6) in macular oedema secondary to BRVO to give an ICER at the top end of the range usually considered cost effective. Ranibizumab would need to generate 1.7 times more QALYs than bevacizumab for macular oedema secondary to CRVO to give an ICER at the top end of the range usually considered cost effective.

3.32 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of visual impairment caused by macular oedema secondary to RVO and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. In addition, the patient experts stated that the condition impacts upon ability to work, hobbies such as reading and gardening. The patient experts acknowledged that although people may be worried about having an injection in the eye, they are willing to receive injections in order to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health-related quality of life.

4.3 The Committee heard from clinical specialists that, until recently, the current standard treatment for macular oedema secondary to BRVO was grid laser photocoagulation. However, the clinical specialists commented that this is now used less now that other treatments, such as dexamethasone or anti-VEGF drugs, are available. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with CRVO and the current standard treatment is dexamethasone or anti-VEGF drugs such as bevacizumab. Clinical specialists stated that bevacizumab is likely to be as effective as ranibizumab, but they highlighted that because a licence has not been sought for the use of bevacizumab in the eye, its safety in the eye is not assured. They stated that bevacizumab is used in much smaller doses in the eye than in its licensed indications. The Committee concluded that ranibizumab is one of a group of innovative anti-VEGF treatments, and does not stand alone in this therapeutic area and its benefits are appropriately captured in the QALY calculation.

Clinical effectiveness

4.4 The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. The Committee noted that the main sources of evidence came from the BRAVO and CRUISE RCTs, which included patients with macular oedema secondary to BRVO and CRVO respectively. It also noted the evidence from the 12-month open-label extension of both trials, the HORIZON study. The Committee noted that the scope included people with or without retinal ischaemia, however it was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, as a result of the exclusion of patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia). It heard from the clinical specialists and the manufacturer that this meant that there was no evidence on the treatment of RVO in patients with ischaemia, and concluded that it could consider evidence in this patient population.

4.5 The Committee noted that in both BRAVO and CRUISE, ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye (for non-ischaemic patients) compared with sham injection for the 6-month treatment phase. It also noted that ranibizumab provided sustained gains in BCVA at 12 months in both BRAVO and CRUISE, but that these were not statistically significant. The Committee was aware that ranibizumab could be used as needed in both arms of both trials from 6 months. In addition, the Committee was aware that in the BRAVO trial, grid laser photocoagulation was permitted after 3 months in both the sham group and the ranibizumab group, confounding the results of the treatment phase from month 3 onwards. The Committee was aware that both BRAVO and CRUISE trials only compared ranibizumab with sham injection rather than the treatments used in current clinical practice (bevacizumab and dexamethasone). Nevertheless the Committee concluded that ranibizumab is an effective treatment for non-ischaemic macular oedema secondary to BRVO and CRVO.

4.6 The Committee discussed the decision problem submitted by the manufacturer, in particular the manufacturer's view that indirect comparisons against dexamethasone and bevacizumab could not be undertaken for either BRVO or CRVO, despite being in the scope. The manufacturer incorporated an assessment of the relative benefit of ranibizumab and dexamethasone only, but not bevacizumab. The manufacturer's economic modelling on ranibizumab and dexamethasone used data taken from a study by Haller et al. (2010). The Committee was aware that dexamethasone intravitreal implant is currently recommended as a treatment option for BRVO when treatment with laser photocoagulation has not been beneficial (or is not considered suitable) and for CRVO (NICE technology appraisal guidance 229) and therefore concluded that dexamethasone is also a relevant comparator. 

4.7 The Committee noted that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about the use of any unlicensed treatments for which there was no formal post-marketing surveillance, particularly if there were alternatives that have a UK marketing authorisation. The Committee noted that licensing is not a prerequisite for consideration of a comparator in a NICE technology appraisal as long as it is in routine use or is considered to be best practice. The Committee heard from clinical specialists that bevacizumab is likely to be as effective as ranibizumab but there is uncertainty relating to its safety profile in eye conditions. The Committee heard from the clinical specialists that bevacizumab is currently reasonably widely used in the NHS. However, the extent of use varies between centres (with some using bevacizumab routinely for RVO, others only using it for some RVO cases and some not using it at all). All the clinical specialists said that they used bevacizumab. The Committee concluded that bevacizumab is in routine use to treat RVO in some parts of the UK. It therefore confirmed bevacizumab to be a relevant comparator for ranibizumab.

4.8 The Committee considered the comparative effectiveness of ranibizumab and dexamethasone intravitreal implant. The Committee agreed with the ERG’s view that an adjusted indirect comparison could have been carried out despite the differences between the BRAVO, CRUISE and GENEVA (dexamethasone) trials (see section 3.9). The Committee considered the evidence for the relative effectiveness of ranibizumab compared with dexamethasone. It first considered the ERG’s exploratory analyses involving adjusted comparisons of ranibizumab versus dexamethasone intravitreal implant for BRVO and CRVO. It noted that the ERG’s suggested relative risks from its indirect comparison were higher than those derived from the manufacturer’s model (0.79 compared with 0.55 at month 3 for BRVO and 0.40 compared with 0.30 at month 6 for CRVO). However, the Committee heard from the manufacturer that the relative risks calculated by the ERG for ranibizumab compared with dexamethasone intravitreal implant were calculated from the probability of gaining 10 letters (two lines) or more rather than 20 letters (four lines) or more. The Committee heard from the manufacturer that the relative risks for ranibizumab versus dexamethasone were in fact 0.70 for BRVO (no confidence intervals reported) and 0.51 for CRVO (no confidence intervals reported). The Committee therefore accepted the manufacturer’s relative risks of ranibizumab versus dexamethasone intravitreal implant.

4.9 The Committee noted the available evidence on bevacizumab and agreed with the ERG's view that an adjusted indirect comparison between ranibizumab and bevacizumab could have been performed and considered the ERG's exploratory analyses comparing ranibizumab with bevacizumab. The Committee noted that the ERG was able to construct a linear network of trials for BRVO using the BRAVO, Moradian et al. (2011) and Russo et al. (2009) studies, and noted that ranibizumab was associated with a three-letter improvement compared with bevacizumab (at month 3), although it was aware that this difference was not, in the ERG's view, clinically meaningful and that these are likely to be optimistic estimates of the efficacy of ranibizumab (see section 3.22). The Committee also heard from the clinical specialists that non RCT data and RCTs in other eye conditions did not indicate a significant difference in efficacy between bevacizumab and ranibizumab.

4.10 The Committee considered the manufacturer’s approach to conducting an indirect comparison of ranibizumab versus grid laser photocoagulation (BRVO only). The Committee noted the manufacturer’s view that an indirect comparison with grid laser photocoagulation for BRVO was difficult to justify because of differences in the relevant identified laser studies (Battaglia et al. 1999 and BVOS 1984). The Committee was aware of the ERG’s view that an adjusted indirect comparison was possible with grid laser photocoagulation but there are potential biases that are likely to favour ranibizumab (see section 3.9).

4.11 The Committee considered the evidence for adverse events associated with ranibizumab. It noted that the safety of ranibizumab had been demonstrated previously in patients with wet age-related macular degeneration. The Committee also noted that the overall frequency of adverse events in the BRAVO and CRUISE trials at month 6 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.

4.12 The Committee noted that the BRAVO and CRUISE trials collected data on the effect of visual impairment on quality of life using the NEI VFQ-25 questionnaire. It noted that both trials reported a statistically significant difference in NEI VFQ-25 score at month 6 between the ranibizumab and sham injection groups. The Committee concluded that administration of ranibizumab improved the quality of life of people with macular oedema secondary to RVO.

Cost effectiveness

4.13 The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee discussed the key parameters used in the model. It broadly accepted the model structure, but was aware of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer. 

4.14 The Committee noted the ERG's concerns that in the base-case analysis the model assumes that all patients are treated in the 'better-seeing eye' despite most patients being treated in their 'worse-seeing eye' in the trials. The clinical specialists confirmed that RVO is a unilateral disease in most patients (i.e. affects one eye more than the other and therefore the proportions treated in their 'worse-seeing eye' in the trials much better reflect clinical practice than those in the manufacturer's model. The Committee concluded on the basis of the trial data that most people are treated for BRVO or CRVO in their 'worse-seeing eye' and the assumption in the model of all people being treated in their 'better-seeing eye' was inappropriate because it does not reflect UK clinical practice.

4.15 The Committee discussed the utility values used in the model. It was aware that the utility values for visual acuity in the 'better-seeing eye' were taken from Brown (1999) rather than Brazier et al. (2009). The Committee noted that Brown (1999) included people with visual acuity loss rather than the general population. The Committee heard from the ERG that the utilities derived from Brown (1999) were not age adjusted, unlike the utility values presented by Brazier et al. (2009), and concluded that the manufacturer's base-case analysis had failed to account for age adjustments in the utility values, and accepted the ERG's approach for age adjustment.

4.16 The Committee discussed the manufacturer's approach of pooling transition probabilities during months 7–12 of the BRAVO trial to account for the effect of grid laser photocoagulation. The Committee considered that this would overestimate the efficacy of ranibizumab compared with sham injection because the unpooled estimates for ranibizumab were lower than the pooled estimates. Conversely, the unpooled estimates for the sham group were higher than the pooled estimates. The Committee noted the ERG’s exploratory analyses using unpooled transition probabilities and that these increased the manufacturer's base-case ICER for ranibizumab compared with grid laser photocoagulation from £20,494 to £52,004 per QALY gained. The Committee concluded that the pooling or unpooling of transition probabilities had a substantial impact on the overall ICER for ranibizumab versus grid laser photocoagulation in BRVO.

4.17 The Committee discussed the frequency of injections and the number of follow-up visits in the manufacturer's base case. The Committee also heard that people with CRVO might expect to receive between six and nine injections in the first year and three to four in the second year. The Committee noted from the clinical specialists that very few people would receive injections in the third year of treatment. The Committee heard from clinical specialists that the manufacturer's assumptions relating to treatment frequency and follow-up were reasonable. The Committee accepted this advice and concluded that the manufacturer's approach was reasonable.

4.18 The Committee considered the manufacturer's assumption in the economic model that there is no mortality risk associated with RVO or visual impairment in the 'worse-seeing eye'. It understood that including mortality risk may cause the ICER to increase because most benefit from ranibizumab was assumed to occur in the first year, and if more people were assumed to die within the first year, the benefit from ranibizumab would decrease. The Committee agreed that it was appropriate to include mortality risk associated with the condition and with visual impairment in the 'worse-seeing eye'.

4.19 The Committee discussed the cumulative impact on the ICER of its conclusions about each of the following assumptions in the model (previously discussed in sections 4.12 to 4.16):

• the effect of assumptions around treating the 'better-seeing' or 'worse-seeing eye' and incorporating Brazier utilities
• using the above scenario and adjusting for mortality and visual impairment in the 'worse-seeing eye'

First, the Committee considered the estimated ICERs for CRVO versus best supportive care, despite observing that comparisons with dexamethasone and bevacizumab were needed. The Committee noted the substantial impact of the manufacturer’s assumption that all patients were treated in their 'better-seeing eye', which was shown by the exploratory analysis carried out by the ERG in which the manufacturer’s base-case ICER increased to £92,000 per QALY gained (see section 3.28) when only 10% of patients were assumed to be treated in their 'better-seeing eye'. It further noted the additional impact of using the utilities from Brazier et al. (2009), which further increased the ICER from £92,000 to £98,700 per QALY gained. The Committee noted that the ICER decreased to £49,300 per QALY gained when the benefit of treating the 'worse-seeing eye' was incorporated into this analysis, and considered that this was to be expected because most people (90%) in the analysis would be treated in their 'worse-seeing eye' and could be expected to experience some benefit from ranibizumab. The Committee also accepted the impact on the ICER of incorporating an assumption of mortality risk from RVO and the impact of the mortality risk associated with visual impairment in the 'worse-seeing eye'. Together these assumptions reduced the ICER to £43,800 per QALY gained. The Committee did not accept the assumption in the manufacturer's base-case analysis that all patients would be treated in their ‘better-seeing eye’ and concluded that the ERG's base-case estimate of the ICER of £43,800 per QALY gained was the most plausible ICER for ranibizumab versus best supportive care in CRVO.

4.20 The Committee next discussed the impact of the ERG's assumptions on the ICER for ranibizumab versus dexamethasone intravitreal implant in CRVO. The Committee was aware of the manufacturer's base-case ICER of £7200 per QALY gained. The Committee noted the ERG’' exploratory analyses incorporating their assumptions of 10% of patients being treated in their 'better-seeing eye', the utilities of Brazier et al. (2009), the benefit associated with treating the 'worse-seeing eye', the excess mortality associated with RVO and visual impairment in the 'worse-seeing eye'. The Committee noted that by applying these assumptions together the ERG's exploratory analysis increased the manufacturer's base-case ICER from £7,200 to £37,400 per QALY gained. The Committee was also aware that there was additional bias because the efficacy estimates for dexamethasone could be underestimates as a result of patients in the dexamethasone trial having macular oedema for a different duration than in the CRUISE trial. The Committee agreed with the ERG's assumptions and concluded that the ICER for ranibizumab versus dexamethasone intravitreal implant in CRVO is likely to be in excess of £37,400 per QALY gained.

4.21 The Committee considered the ICER for ranibizumab versus bevacizumab in CRVO. It noted the ERG's exploratory cost-minimisation analysis, which resulted in the dominance of bevacizumab over ranibizumab. The Committee considered the ERG’s threshold analysis based on the manufacturer's model and noted that using ranibizumab would need to generate 1.7 times more QALYs than bevacizumab (each month between months 2 and 6) in macular oedema secondary to CRVO to give an ICER at the top end of the range usually considered cost effective. The Committee noted the comments from the clinical specialists who stated that ranibizumab is likely to be as equally effective as bevaciuzmab. The Committee agreed that ranibizumab and bevacizumab had approximately equal effectiveness.

4.22 For the cost effectiveness of ranibizumab in BRVO, the Committee noted that the ERG could not perform the same additional analyses for ranibizumab versus grid laser photocoagulation in BRVO because of data limitations. It noted that the manufacturer's base-case ICER was £20,500 per QALY gained, and was aware that using unpooled transition probabilities and accounting for the 3-year therapeutic effect of grid laser photocoagulation would substantially increase the manufacturer’s base-case ICER to £52,000 per QALY gained. The Committee further recognised that the ICER for BRVO was estimated by the manufacturer and ERG higher than that for CRVO. It considered that this was plausible, on account of the poorer clinical course of CRVO, and the potential for ranibizumab to have a more substantial impact on improving the vision of people with CRVO than of people with BRVO. On the basis of its previous conclusion regarding the most plausible ICER for ranibizumab compared with best supportive care for CRVO (£43,800 per QALY gained), the Committee concluded that, even if data not confounded by the use of grid laser photocoagulation were available, it would be very likely that the ICER for ranibizumab compared with standard care in BRVO would be significantly higher than the manufacturer's base-case ICER of £20,500 per QALY gained.

4.23 The Committee considered the cost effectiveness of ranibizumab versus dexamethasone in BRVO. The Committee noted the manufacturer’s base-case ICER of £5500 per QALY gained, and the ERG’s exploratory analyses incorporating the assumptions relating to 10% of patients being treated in their 'better-seeing eye', the utilities of Brazier et al. (2009) the benefit associated with treating the 'worse-seeing eye', the excess mortality associated with RVO and visual impairment in the 'worse-seeing eye'. The Committee noted that by applying these assumptions together the ERG's exploratory analysis increased the manufacturer’s base-case ICER from £5500 to £31,100 per QALY gained. The Committee were also aware that the ERG's analyses used pooled transition probabilities as in the manufacturer's analyses. The Committee heard from the ERG that it was able to subsequently assess the impact of using unpooling transition probabilities and that this increased the ICER further to approximately £47,000 per QALY gained. The Committee was also aware that there was uncertainty around this ICER because the efficacy estimates for dexamethasone could be underestimates as a result of patients in the dexamethasone trial having macular oedema for a different duration to patients in the BRAVO trial.

4.24 The Committee discussed the comparison of ranibizumab with bevacizumab in BRVO. It was aware of the ERG’s exploratory cost-minimisation analysis, which resulted in the dominance of bevacizumab over ranibizumab. The Committee considered the ERG's threshold analysis based on the manufacturer's model and noted that using ranibizumab would need to generate 1.5 times more QALYs than bevacizumab (each month between months 2 and 6) in macular oedema secondary to BRVO to give an ICER at the top end of the range usually considered cost effective. Again the Committee noted the comments from clinical specialists and agreed that ranibizumab and bevacizumab had approximately equal effectiveness.

4.25 The Committee discussed the issue of bevacizumab as a comparator for ranibizumab in the treatment of macular oedema secondary to RVO. The Committee noted that it would be desirable to collect data relating to the safety of bevacizumab for the treatment of macular oedema secondary to RVO. The Committee agreed with the clinical specialists' view that bevacizumab is likely to be as effective as ranibizumab and could be similar in terms of safety, and it noted the large price difference between the two treatments.

4.26 The Committee agreed that the most plausible ICERs for ranibizumab versus best supportive care and dexamethasone in CRVO were £43,800 and £37,400 per QALY gained respectively. It was aware that current standard treatment in the UK is dexamethasone or anti-VEGF drugs and therefore comparing ranibizumab with best supportive care in CRVO was not relevant to UK clinical practice.  The Committee agreed that the most plausible ICER for ranibizumab versus dexamethasone in BRVO was £31,100 per QALY gained while ranibizumab versus grid laser photocoagulation in BRVO was likely to be in excess of £20,500 per QALY gained. In summary, the Committee considered that the most plausible ICERs for ranibizumab for the treatment of macular oedema secondary to RVO were all above the ranges considered cost effective (i.e. £20,000 to £30,000 per QALY gained). The Committee therefore concluded that ranibizumab is not an effective use of NHS resources and is not recommended as a treatment for people with macular oedema secondary to RVO.

4.27 The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title:		Section
Key conclusion
Ranibizumab is not recommended for the treatment of visual impairment caused by macular oedema secondary to central or branch retinal vein occlusion.			1.1
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts acknowledged that although people may be worried about having an injection in the eye, they are willing to receive injections in order to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health-related quality of life. Until recently, standard treatment for macular oedema secondary to BRVO was grid laser photocoagulation. However, clinical specialists commented that this is now used less now that other treatments, such as dexamethasone or anti-VEGF drugs, are available. Grid laser photocoagulation is not an option for people with CRVO and the current standard treatment might be dexamethasone or anti-VEGF drugs such as ranibizumab and bevacizumab. Clinical specialists stated that bevacizumab is likely to be as effective as ranibizumab, but they highlighted that because a licence has not been sought for the use of bevacizumab in the eye, its safety in the eye is not assured.	4.2 4.3
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee concluded that ranibizumab is one of a group of innovative anti-VEGF treatments, and does not stand alone in this therapeutic area and its benefits are appropriately captured in the QALY calculation.	4.3
What is the position of the treatment in the pathway of care for the condition?		Ranibizumab has a marketing authorisation for ‘the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)’.	2.1
Adverse effects		The Committee noted that the safety of ranibizumab had been demonstrated previously in patients with wet age-related macular degeneration. It also noted that the overall frequency of adverse events in the BRAVO and CRUISE trials at month 6 was low. The Committee agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.	4.11
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, as a result of the exclusion of patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia). The Committee was aware that both BRAVO and CRUISE trials only compared ranibizumab with sham injection rather than the treatments used in current clinical practice (bevacizumab and dexamethasone). The Committee discussed the manufacturer’s position that indirect comparisons against dexamethasone and bevacizumab could not be undertaken for either BRVO or CRVO, despite being in the scope. The Committee agreed with the ERG’s view that an adjusted indirect comparison could have been carried out between ranobizumab and dexamethasone despite the differences between the BRAVO, CRUISE and GENEVA (dexamethasone) trials. The Committee noted the available evidence on bevacizumab and agreed with the ERG’s view that an adjusted indirect comparison between ranibizumab and bevacizumab could have been performed. The Committee was aware of the ERG’s view that an adjusted indirect comparison was possible with grid laser photocoagulation but there are potential biases that are likely to favour ranibizumab.	4.4 4.5 4.6 4.8 4.9 4.10
Relevance to general clinical practice in the NHS		Until recently, standard treatment for macular oedema secondary to BRVO was grid laser photocoagulation. However, clinical specialists commented that this is now used less now that other treatments, such as dexamethasone or anti-VEGF drugs, are available. Grid laser photocoagulation is not an option for people with CRVO and the current standard treatment might be dexamethasone or anti-VEGF drugs such as ranibizumab and bevacizumab. The Committee was aware that both BRAVO and CRUISE trials only compared ranibizumab with sham injection rather than the treatments used in current clinical practice (bevacizumab and dexamethasone).	4.3 4.5
Uncertainties generated by the evidence		The Committee was aware that ranibizumab could be used as needed in both arms of both trials from 6 months. In addition, the Committee was aware that in the BRAVO trial, grid laser photocoagulation could be used after 3 months in both the sham group and the ranibizumab group, confounding the results of the treatment phase from month 3 onwards. The Committee discussed the approaches taken by both the manufacturer and the ERG with regard to the comparative effectiveness of ranibizumab and dexamethasone intravitreal implant. The Committee accepted the manufacturer’s relative risks of ranibizumab versus dexamethasone intravitreal implant.	4.4 4.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee considered the evidence from BRAVO and CRUISE RCTs which included patients with macular oedema secondary to BRVO and CRVO respectively. The Committee concluded that ranibizumab is an effective treatment for non-ischaemic macular oedema secondary to BRVO and CRVO.	4.4 4.5
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that in both BRAVO and CRUISE, ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye (for non-ischaemic patients) compared with sham injection for the 6-month treatment phase. It also noted that ranibizumab provided sustained gains in BCVA at 12 months in both BRAVO and CRUISE, but that these were not statistically significant. The Committee was aware that both BRAVO and CRUISE trials only compared ranibizumab with sham injection rather than the treatments used in current clinical practice (bevacizumab and dexamethasone). Nevertheless the Committee concluded that ranibizumab is an effective treatment for non-ischaemic macular oedema secondary to BRVO and CRVO. The Committee considered the ERG’s exploratory analyses comparing ranibizumab with bevacizumab. The Committee noted that ranibizumab was associated with a three-letter improvement compared with bevacizumab (at month 3), although it was aware that this difference was not, in the ERG’s view, clinically meaningful and that these are likely to be optimistic estimates of the efficacy of ranibizumab.	4.5 4.9
Evidence for cost effectiveness
Availability and nature of evidence		The Committee discussed the key parameters used in the model. It broadly accepted the model structure, but was aware of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer.	4.13
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee concluded on the basis of the trial data that most people are treated for BRVO or CRVO in their ‘worse-seeing eye’ and the assumption in the model of all people being treated in their ‘better-seeing eye’ was inappropriate. The Committee discussed the utility values used in the model. It was aware that the utility values for visual acuity in the ‘better-seeing eye’ were taken from Brown (1999) rather than Brazier et al. (2009). The ERG stated that when utilities from Brown (1999) were age adjusted and then used in the model, the resulting ICER was higher than with utilities from Brazier et al. (2009). The Committee concluded that the manufacturer’s base-case analysis had failed to account for age adjustments in the utility values. The Committee noted the ERG’s additional analyses using unpooled transition probabilities and that these increased the manufacturer’s base-case ICER for ranibizumab compared with grid laser photocoagulation from £20,494 to £52,004 per QALY gained. The Committee concluded that the pooling or unpooling of transition probabilities had a substantial impact on the overall ICER for ranibizumab versus grid laser photocoagulation in BRVO. The Committee considered the manufacturer’s assumption in the economic model that there is no mortality risk associated with RVO or visual impairment in the ‘worse-seeing eye’. It understood that including mortality risk may cause the ICER to increase because most benefit from ranibizumab was assumed to occur in the first year, and if more people were assumed to die within the first year, the benefit from ranibizumab would decrease. The Committee agreed that it was appropriate to include mortality risk associated with the condition and with visual impairment in the ‘worse-seeing eye’.	4.14 4.15 4.16 4.18
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee noted that the BRAVO and CRUISE trials collected data on the effect of visual impairment on quality of life using the NEI VFQ-25 questionnaire. The Committee discussed the utility values used in the model. It was aware that the utility values for visual acuity in the ‘better-seeing eye’ were taken from Brown (1999) rather than Brazier et al. (2009). The Committee concluded that the manufacturer’s base-case analysis had failed to account for age adjustments in the utility values, and accepted the ERG’s approach for age adjustment..	4.12 4.15
Are there specific groups of people for whom the technology is particularly cost effective?		The Committee considered that the most plausible ICERs for ranibizumab for the treatment of macular oedema secondary to RVO were all well in above the ranges considered cost effective (i.e. £20,000 to £30,000 per QALY gained). The Committee therefore concluded that ranibizumab is not an effective use of NHS resources and is not recommended as a treatment for people with macular oedema secondary to RVO.	4.26
What are the key drivers of cost effectiveness?		The Committee noted the substantial impact of the manufacturer’s assumption that all patients were treated in their ‘better-seeing eye’. For example, in the exploratory analysis carried out by the ERG, the manufacturer’s base-case ICER (for CRVO) increased to £92,000 per QALY gained (see section 3.28) when only 10% of patients were assumed to be treated in their ‘better-seeing eye’.	4.19
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that the ERG’s base-case estimate of the ICER of £43,800 per QALY gained was the most plausible ICER for ranibizumab versus best supportive care in CRVO. The Committee concluded that the ICER for ranibizumab versus dexamethasone intravitreal implant in CRVO was likely to be in excess of £37,400 per QALY gained. The Committee concluded that, even if data not confounded by the use of grid laser photocoagulation were available, it would be very likely that the ICER for ranibizumab compared with standard care in BRVO would be significantly higher than the manufacturer’s base-case ICER of £20,500 per QALY gained.	4.19 4.20 4.22
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of ranibizumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ranibizumab is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.	2.4
End-of-life considerations		Not applicable.	-
Equalities considerations and social value judgements		The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.	4.25

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011). Available from www.nice.org.uk/TA229
• Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Available from www.nice.org.uk/guidance/TA155
• Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003). Available from www.nice.org.uk/guidance/TA68

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion. Technology appraisal in development
• Ranibizumab for the treatment of diabetic macular oedema. Technology appraisal in development

Suspended

• Pegaptanib sodium for the treatment of diabetic macular oedema. Technology appraisal suspended.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
September 2011

Appendix A: Appraisal Committee members, and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Dr Andrew Burnett
Director for Health Improvement and Medical Director, NHS Barnet, London

Dr Chris Cooper
General Practitioner, St John's Way Medical Centre, London

Professor Peter Crome
Consultant Geriatrician and Professor of Geriatric Medicine, Keele University

Dr Christine Davey
Research Adviser, North and East Yorkshire Alliance Research and Development Unit, York

Richard Devereaux-Phillips
Director, Public Policy and Advocacy NW Europe, BD, Oxford

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Professor Eugene Milne
Deputy Regional Director of Public Health, North East Strategic Health Authority, Newcastle upon Tyne

Dr Neil Myers
General Practitioner, Glasgow

Professor Katherine Payne
Professor of Health Economics, University of Manchester

Dr Danielle Preedy
Lay Member

Dr Martin Price
Head of Outcomes Research, Janssen-Cilag, Buckinghamshire

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team, Warrington

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr John Stevens
Lecturer in Bayesian Statistics in Health Economics, School of Health and Related Research, Sheffield

Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Professor Paul Trueman
Professor of Health Economics, Brunel University, London

Dr Judith Wardle
Lay Member

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Christian Griffiths
Technical Lead

Joanne Holden
Technical Adviser

Lori Farrar
Project Manager

 Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by BMJ-Technology Assessment Group (BMJ-TAG)

• Edwards SJ, Barton S, Trevor N et al. Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion (RVO),July 2011

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Novartis Pharmaceuticals

II Professional/specialist and patient/carer groups:

• Royal College of Nursing
• Royal College of Ophthalmologists
• Royal College of Physicians
• Royal National Institute of Blind People (RNIB)

III Other consultees:

• Department of Health
• Welsh Assembly Government
• Wirral PCT

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Allergan
• BMJ Group
• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• National Institute for Health Research Health Technology Assessment Programme
• NHS Quality Improvement Scotland
• Roche Products

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion (RVO) by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor Jonathan Gibson, Consultant Ophthalmologist, nominated by Royal National Institute of Blind People – clinical specialist
• Ian Pearce, Consultant Ophthalmologist, nominated by The Royal College of Ophthalmologists – clinical specialist
• Sobha Sivaprasad, Consultant Ophthalmologist, nominated by Novartis Pharmaceuticals – clinical specialist
• Rita Keeley, nominated by Royal National Institute of Blind People – patient expert
• Steve Winyard, nominated by Royal National Institute of Blind People – patient expert

D Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Novartis