Aflibercept solution for injection for treating wet age‑related macular degeneration

Clinical effectiveness

4.5 The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of aflibercept. The Committee noted that the main sources of evidence came from the VIEW 1 and 2 trials which compared aflibercept (2 mg every 8 weeks) with ranibizumab (0.5 mg every 4 weeks) in people with wet age‑related macular degeneration and that both studies were considered to be of high quality by the Evidence Review Group (ERG). It also noted that aflibercept at its licensed dose was shown to be clinically non‑inferior to ranibizumab in terms of visual acuity outcomes at 96 weeks. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by wet age‑related macular degeneration.

4.6 The Committee considered the network meta‑analyses and indirect comparisons submitted by the manufacturer, which estimated the clinical effectiveness of aflibercept at its licensed dose compared with ranibizumab in a 'treatment as needed' regimen at 12 and 24 months. The Committee accepted the concerns highlighted by the manufacturer and the ERG about the validity of these analyses because of the heterogeneity of the included studies. It was also aware that, although the point estimates for visual acuity outcomes favoured aflibercept, no statistically significant differences compared with ranibizumab were reported. The Committee concluded that, in the absence of stronger evidence, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab in a 'treatment as needed' regimen.

4.7 The Committee considered the evidence for adverse events associated with aflibercept. The Committee noted that the frequency of adverse events in both treatment groups in the VIEW 1 and 2 trials was low. The Committee noted that the manufacturer had not provided a formal statistical analysis comparing adverse events between the 2 treatment groups. However, it also noted that no clinically meaningful differences in adverse events were reported by the manufacturer or the ERG. The Committee concluded that aflibercept was safe and well tolerated in patients with wet age‑related macular degeneration.

Cost effectiveness

4.8 The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analyses. The Committee noted that the model structure accounted for different levels of visual acuity in both eyes rather than the first eye to come to clinical attention. The Committee also noted the ERG's concerns about the manufacturer's approach to modelling second‑eye involvement. The Committee agreed with the ERG that it was unrealistic to assume no second‑eye involvement in the first 2 years of the model because a large proportion of patients in the VIEW 1 and 2 trials had visual impairment in their second eye at the start of treatment. It also agreed that the manufacturer did not give appropriate consideration to the timing of second‑eye involvement because the effect of treatment on visual acuity in the second eye and any associated costs were limited to years 3 to 5 in the model. The Committee concluded that the ERG's exploratory approach, which involved separate analyses depending on whether the study eye was a better‑seeing eye or worse‑seeing eye, was more reasonable.

4.9 The Committee discussed the clinical‑effectiveness data that were used in the economic model. The Committee noted that clinical‑effectiveness data for aflibercept were derived from the VIEW 2 study only rather than from a pooled analysis of the VIEW 1 and 2 studies. The Committee heard from the manufacturer that this was because VIEW 2 was conducted across multiple centres including the UK and therefore was more relevant to UK clinical practice than the VIEW 1 study, and also because the EQ‑5D utility values used in the model were collected in the VIEW 2 study. The Committee agreed that using clinical-effectiveness data from VIEW 1 only was unlikely to introduce any additional bias because results were similar between VIEW 1 and 2 and a pooled analysis of both studies. The Committee also noted the ERG's comments that the manufacturer had applied comparative clinical‑effectiveness data in terms of visual acuity from its network meta‑analyses and indirect comparisons between baseline and 12 months and between 12 months and 24 months rather than between baseline and 12 months and between baseline and 24 months. It noted that this resulted in aflibercept having better visual acuity than ranibizumab at 24 months in the model although the point estimates from the indirect comparison showed that aflibercept resulted in slightly worse outcomes. The Committee agreed with the ERG that the results of the manufacturer's indirect comparison at 24 months provided comparative clinical‑effectiveness data between baseline and 24 months, and it concluded that the ERG's exploratory analysis that incorporated this data was the preferred approach.

4.10 The Committee discussed the manufacturer's assumptions about the number of treatment and monitoring visits people in both treatment groups needed in the model. The Committee considered that, in the absence of any longer‑term data, it was reasonable for the manufacturer to assume that both treatment groups would have the same number of treatment and monitoring visits in years 3 to 5 of the model. The Committee noted that the manufacturer assumed that people receiving aflibercept had 7 treatment visits in the first year based on the summary of product characteristics. However, the Committee agreed with the ERG that it was more likely that people treated with aflibercept would need 8 treatment visits in the first year of the model on the basis of the average number of injections that patients received in the VIEW 2 study. It also noted that the ERG had corrected for this in its exploratory analyses. The Committee was aware that there are data from UK clinical practice on the treatment and monitoring frequency of ranibizumab but that no such data on the use of aflibercept currently exist. For this reason, the Committee considered that it would be fairer to use the same data that were used to estimate the relative clinical effectiveness of aflibercept and ranibizumab to inform assumptions about the number of treatment and monitoring visits in the model. Therefore, the Committee concluded that it was reasonable to assume that people in both treatment groups would need 8 treatment visits in the first year of the model in line with the approach taken by the ERG in its exploratory analyses.

4.11 The Committee discussed the manufacturer's assumptions about whether treatment administration and monitoring occurred at the same visit. The Committee noted that the manufacturer had assumed that, in the first year of the model, people in the aflibercept group had their treatment administration and monitoring at the same visit in a one‑stop model but 50% of people in the ranibizumab group had separate monitoring visits in a two‑stop model. The Committee heard from the clinical specialists that, in future clinical practice, it is expected that fewer people treated with anti‑VEGF therapies would need separate treatment and monitoring visits. The Committee noted that, if a higher proportion of people in both treatment groups had their treatment administration and monitoring at the same visit, this would reduce the total incremental costs of ranibizumab compared with aflibercept because of the higher number of monitoring visits needed by people treated with ranibizumab in the first 2 years of the manufacturer's model. However, the Committee agreed that, for people who had their treatment and monitoring at the same visit in a one-stop model, the aflibercept group had no separate monitoring visits in the first year and 2 separate visits in the second year and the ranibizumab group had 4 separate monitoring visits in the first year and 6 separate visits in the second year. The Committee also agreed that, for people who had their treatment and monitoring at separate visits in a two-stop model, the aflibercept group had 7 separate monitoring visits in the first year and 6 separate monitoring visits in the second year and the ranibizumab group had 12 separate monitoring visits in the first 2 years. The Committee concluded that, based on current clinical practice, it was reasonable to assume that 50% of people in both treatment groups would need separate monitoring visits in line with the approach taken by the ERG in its exploratory analyses.

4.12 The Committee discussed the manufacturer's assumptions about the costs of treatment and monitoring visits. The Committee noted that the manufacturer's estimated cost per treatment visit was higher than the cost used in the appraisal of ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 274) and that the ERG also estimated a lower average cost per treatment visit of £129. However, the Committee heard from the clinical specialists that the ERG's lower estimate was likely to be an underestimate of the true costs of a treatment visit. The Committee also heard from the clinical specialists that the ERG's estimated cost for optical coherence tomography of £51 as part of a monitoring visit was probably too low. Overall, the Committee concluded that although some uncertainty remained about the true costs involved in treatment and monitoring visits for people with wet age‑related macular degeneration, the estimates used in the ERG's exploratory analyses were a fair reflection of the costs involved.

4.13 The Committee considered the incremental cost‑effectiveness ratios (ICERs) estimated by the manufacturer and the ERG, which incorporated the confidential discounts applied to the list prices of aflibercept and ranibizumab agreed under the respective patient access schemes. The Committee noted that, in the manufacturer's base‑case analysis, aflibercept dominated (that is, was less expensive and more effective than) ranibizumab. The Committee also considered its preferred analyses based on the ERG's exploratory approach, which incorporated separate analyses depending on whether the study eye was a better‑seeing eye or a worse‑seeing eye, and its preferred assumptions about the frequency of injections, monitoring visits and clinical‑effectiveness data (see sections 4.8 to 4.11). It noted that these exploratory analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. The Committee also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models (see section 3.39). However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. The Committee therefore concluded that aflibercept could be recommended as a cost‑effective use of NHS resources if ranibizumab would otherwise be the treatment used.

4.14 The Committee discussed whether aflibercept solution for injection should be recommended within the terms of its UK marketing authorisation, that is, for the treatment of neovascular (wet) age‑related macular degeneration, or whether a more restrictive set of criteria was necessary. The Committee noted that guidance on the use of ranibizumab outlined in NICE technology appraisal guidance 155 was based on a more restrictive set of criteria than described in the terms of its UK marketing authorisation and that these criteria were set out in the clinical trials for ranibizumab for treating wet age‑related macular degeneration. It also noted that these criteria were very similar to those set out in the VIEW 1 and 2 studies. The Committee also heard from the clinical specialists that they would prefer that the use of aflibercept should not be restricted to people with a best‑corrected visual acuity between 6/12 and 6/96, as is the case with ranibizumab in NICE technology appraisal guidance 155. However, the Committee concluded that it would be appropriate to recommend aflibercept as a treatment option for people with wet age‑related macular degeneration if it is used according to the same criteria as described for the use of ranibizumab in NICE technology appraisal guidance 155 until both technologies could be appraised simultaneously in the context of a multiple technology appraisal.

4.15 The Committee discussed how innovative aflibercept is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the development of anti‑VEGF treatments, not the act of licensing. In addition the Committee was not aware of any substantial benefits of aflibercept compared with ranibizumab that had not already been captured in the manufacturer's economic model.

4.16 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 in the guidance.

Summary of Appraisal Committee's key conclusions