Ranibizumab for treating choroidal neovascularisation associated with pathological myopia

Evidence-based recommendations on ranibizumab (Lucentis) for treating choroidal neovascularisation associated with pathological myopia in adults.

# Guidance
Ranibizumab is recommended as an option for treating visual impairment due to choroidal neovascularisation secondary to pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.# The technology 
Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that blocks the action of vascular endothelial growth factor (VEGF)A. By blocking the action of VEGFA, ranibizumab prevents abnormal blood vessels developing, thereby limiting visual loss and improving vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to choroidal neovascularisation secondary to pathologic myopia'.
Ranibizumab is administered as a single 0.5 mg intravitreal injection. Each vial of ranibizumab contains 2.3 mg in 0.23 ml; overfilling is considered necessary to achieve an injectable dose of 0.5 mg. The summary of product characteristics states that monitoring is recommended monthly for the first 2 months and at least every 3 months thereafter during the first year. If monitoring reveals signs of disease activity, for example, reduced visual acuity and/or signs of lesion activity, further treatment is recommended.
Adverse reactions to 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. 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. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The list price of ranibizumab 10 mg/ml is 742.17 per 0.23ml vial (excluding VAT; 'British national formulary'  edition 66). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274), which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercialinconfidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section 9).

# Clinical effectiveness
The manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with verteporfin photodynamic therapy (vPDT) in people with choroidal neovascularisation associated with pathological myopia. Pathological myopia is a chronic condition characterised by excessive lengthening of the eye and degenerative changes at the back of the eye. These changes to the eye can cause blood vessels to leak or bleed into the retina in a process known as choroidal neovascularisation. This can result in visual impairment, in particular a loss of central vision. The manufacturer did not provide a comparison with bevacizumab, which is listed as a comparator in the scope for this appraisal. It did not consider bevacizumab to be a valid comparator because it is unlicensed for this condition and not routinely used.
The main sources of evidence presented in the manufacturer's submission came from a Novartis phase III trial (RADIANCE) and 2 other randomised trials (Gharbiya 2010; Iacono 2012). Gharbiya (2010) and Iacono (2012) compared ranibizumab with bevacizumab. However, the manufacturer did not present data from the bevacizumab arm of these trials.
RADIANCE compared ranibizumab with vPDT in people with visual impairment caused by choroidal neovascularisation secondary to pathological myopia. The trial was a randomised, doubleblind, multicentre study conducted in 20 countries, which compared 2 groups of patients using ranibizumab (n=222) with 1 group using vPDT (n=55). On day 1 of treatment, patients in the ranibizumab groups received 0.5 mg of ranibizumab and patients in the vPDT group were given 6 mg/m2 of verteporfin intravenously, followed by a light dose of 50 J/cm2 at an intensity of 600 mW/cm2 for 83 seconds. In the ranibizumab disease activity group (n=116) and the vPDT group, patients were retreated if visual impairment caused by intra or subretinal fluid, or active leakage secondary to pathological myopia, was seen. Treatment was continued until these effects were no longer seen. In the ranibizumab disease stabilisation group (n=106), patients were retreated if there was a loss of best corrected visual acuity (BCVA) because of disease activity. Treatment was continued until BCVA was stable for 3 consecutive monthly assessments.
The primary end point of RADIANCE was the mean average change in BCVA between baseline and months 13, measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity. Gains in BCVA (reported as meanstandard deviation ) were statistically significantly greater in both ranibizumab groups (disease activity group; 10.67.3 letters, p<0.0001 compared with vPDT, disease stabilisation group; 10.58.2 letters, p<0.0001 compared with vPDT) than in the vPDT group (2.29.5 letters). The secondary end points included the proportion of patients gaining 10 or more or 15 or more letters, mean change in BCVA, and changes in central retinal thickness from baseline. Both of the ranibizumab groups had statistically significantly more patients gaining 10 or more letters or 15 or more letters than the vPDT group. There was no statistically significant difference between either of the ranibizumab groups compared with the vPDT group in mean change in BCVA or in mean change in central retinal thickness. The length of followup was 12 months for the 2 ranibizumab groups. After 3 months, 72% of the patients in the vPDT group received ranibizumab. Therefore, the manufacturer did not compare the results of the vPDT group with the results of the ranibizumab groups after the initial 3month period.
The 2 other randomised trials (Gharbiya 2010; Iacono 2012) were singlecentre trials conducted in Italy comparing ranibizumab with bevacizumab. The manufacturer did not present the data for the bevacizumab arm for either trial. The Iacono (2012) study was a doubleblind clinical trial in people with subfoveal choroidal neovascularisation secondary to pathological myopia (55 eyes; ranibizumab=27, bevacizumab=28) with a followup period of 18 months. Gharbiya (2010) was an interventional study in people with subfoveal or juxtafoveal choroidal neovascularisation secondary to pathological myopia and evidence of leakage from the choroidal neovascularisation lesion (32 eyes; ranibizumab=16, bevacizumab=16) with a followup period of 6 months. The mean (SD) change in BCVA was 9NR (not reported) letters in the ranibizumab arm of the Iacono (2012) study and 17.311.1 letters in the ranibizumab arm of the Gharbiya (2010) study. It was not reported how many patients gained 10 or more letters in the Iacono study, although 7 (30%) gained 15 or more letters in the ranibizumab arm. In the ranibizumab arm of the Gharbiya (2010) study, 12 (75%) patients gained 10 letters or more and 9 (56%) gained 15 letters or more. The mean change in retinal thickness was not reported in the Iacono (2012) study. In the ranibizumab arm of the Gharbiya (2010) study, the mean change in retinal thickness was 45NR micrometers.
The manufacturer identified 6 nonrandomised studies relevant to the decision problem. All 6 studies investigated the use of ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia, with followup times ranging from a mean of 8 months to a median of 17 months. One study was a multicentre phase II study (the REPAIR study) and the other 5 studies were prospective caseseries (CalvoGonzalez 2011; Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011). A statistically significant change in BCVA from baseline to time of assessment was shown in 4 of the 6 studies. The number of patients who gained 15 or more letters at followup ranged from 2447%.
Adverse effects of ranibizumab were reported in RADIANCE. Ocular adverse events in the ranibizumab disease activity group were 16 (14%, 0 severe), 31 (26%, 1 severe), and 44 (37%, 1 severe) and in the ranibizumab disease stabilisation group were 29 (27%, 0 severe), 38 (36%, 0 severe), and 46 (43%, 1 severe) by 3, 6, and 12 months respectively. There were 5 (9%) ocular adverse events in the vPDT group by 3 months, of which none were severe. Nonocular adverse events in the ranibizumab disease activity group were 30 (25%, 1 severe), 42 (36%, 3 severe), and 51 (43%, 6 severe) and in the ranibizumab disease stabilisation group were 27 (26%, 0 severe), 38 (36%, 1 severe), and 48 (45%, 3 severe) by 3, 6, and 12 months respectively. There were 6 (11%) nonocular adverse events in the vPDT group by 3 months, of which none were severe. There were no systemic or significant ocular adverse events in the Iacono (2012) or Gharbiya (2010) trials. REPAIR reported adverse events that occurred in 2 or more patients. Ocular adverse events occurred in 29 (45%) patients and nonocular adverse events in 39 (60%) patients over 12 months. CalvoGonzalez (2011) reported that 2 eyes developed anterior uveitis over a mean followup of 16 months. The other 4 nonrandomised studies (Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011) reported that no systemic or ocular adverse events were observed, with the mean followup ranging from 8 to 17 months.
Impact on healthrelated quality of life was measured in RADIANCE. The change in National Eye Institute Visual Functioning Questionnaire 25 item (NEI VFQ25) composite score from baseline to 3 months (reported as meanSD) was statistically significantly higher for the 2 ranibizumab groups (disease activity group; 4.310.1, p<0.05 compared with vPDT, disease stabilisation group; 5.314.0, p<0.05 compared with vPDT) compared with the vPDT group (0.312.6). The mean (SD) change in the EQ5D questionnaire from baseline to 3 months was 2.355.0, 4.2NR, and 2.1NR for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The mean (SD) reduction in Work Productivity and Activity Impairment Questionnaire: General Health (WPAIGH) score from baseline to 3 months was 22.055.0, 21.975.2, and 10.259.9 for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The statistical significance of the differences between the groups for the EQ5D and WPAIGH scores were not reported.

# Cost effectiveness
The manufacturer developed a costutility Markov model that evaluated the cost effectiveness of ranibizumab compared with vPDT in people with choroidal neovascularisation associated with pathological myopia. There were 8 health states in the model, defined by the BCVA in the treated eye in addition to the absorbing health state of death. The health states were defined by a 10letter range in BCVA. The model had 3monthly cycles and a lifetime time horizon.
The transition probabilities for the first cycle of the model (baseline to month 3) for both ranibizumab and vPDT were based on RADIANCE. For the next 3 cycles (months 4 to 12), the transition probabilities between health states were derived from RADIANCE for ranibizumab and from the Verteporfin in Photodynamic Therapy (VIP) trial for vPDT. VIP compared vPDT with photodynamic therapy in 120 patients with subfoveal choroidal neovascularisation secondary to pathological myopia. For cycles 5 onwards (1 year onwards), a slow worsening of visual acuity was assumed, based on natural disease progression reported in Yoshida (2002) for the base case and an additional 6 natural history studies for the other transition probabilities. The model included crossover from the betterseeing eye to the worseseeing eye and vice versa as patients changed health states.
A baseline rate of bilateral involvement (that is, both eyes affected by choroidal neovascularisation) of 15% was derived from 2 published studies (Cohen 1996; Hampton 1983) and the model assumed no incidence of choroidal neovascularisation secondary to pathological myopia after baseline measurement. Based on expert opinion, the manufacturer estimated a recurrence of choroidal neovascularisation in 6% of patients each year after the first 2 years of modelling. The manufacturer assumed an indefinite duration of treatment benefit, based on the treatment benefit seen at year 1.
Basecase utility values for the betterseeing eye were taken from a published study of the UK general population in which BCVA health states were simulated with contact lenses that created the effects of agerelated macular degeneration (CzoskiMurray et al. 2009). They ranged from 0.850 in patients with a BCVA of 86 to 100 letters to 0.353 for those with a BCVA of less than 25 letters. Basecase utility values for the worseseeing eye were calculated from the values for the betterseeing eye, with the assumption that the maximum utility gain in the worseseeing eye was 0.1. These utilities therefore ranged from 0.850 for a BCVA of 86 to 100 letters, to 0.750 for a BCVA of less than 25 letters.
Disutilities were defined as adverse events that occurred in more than 5 patients and were suspected to be related to the study drug or ocular injection in RADIANCE (for ranibizumab) or VIP (for vPDT). Disutilities were conjunctival haemorrhage (ranibizumab; 8.5%, vPDT; 0%), increased intraocular pressure (ranibizumab; 4.2%, vPDT; 0%), visual disturbance (ranibizumab; 0%, vPDT; 14.8%), and injection site adverse events (ranibizumab; 0%, vPDT; 9.9%).
Total costs for treatment were calculated from the unit costs, administration costs, and the cost of a monitoring visit multiplied by the total number of treatment visits and monitoring visits needed. The cost of blindness was calculated as 17,326 in the first year and 17,245 in each year after.
The manufacturer's basecase deterministic costeffectiveness analysis results showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (9694 compared with 12,455). The manufacturer similarly presented basecase probabilistic results which showed that ranibizumab dominated vPDT.
The manufacturer conducted oneway sensitivity analyses using a net monetary benefit approach (calculated by multiplying the incremental QALYs by 20,000 and then subtracting the incremental costs) because ranibizumab dominated vPDT in the basecase analysis. The sensitivity analysis showed that the model was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worseseeing eye. The results of the manufacturer's sensitivity analysis showed that ranibizumab remained dominant up to a unit cost of 783 (range 03750) and when up to 12 injections were needed in either year 1 or year 2 (range 012, with vPDT given 3.4 times per year). Scenario analyses showed that ranibizumab remained dominant when other methods for calculating transition probabilities, such as keeping transition probabilities constant across all visual acuity levels, and other sources of natural history data (Bottoni et al. 2001; Hampton et al. 1983; Hotchkiss et al. 1981; Kojima et al. 2006; Secretan et al. 1997; Tabandeh et al. 1999; Yoshida et al. 2002), were used, and when the maximum gain in utility for the worseseeing eye is 0.2 or 0.3. The sensitivity analysis showed that there was a 100% probability of ranibizumab being cost effective if the maximum acceptable ICER was 20,000 or 30,000 per QALY gained.
The manufacturer conducted 3 scenario analyses. The first scenario analysis involved calculating the transition probabilities from patientlevel data using 3 different methods. The basecase method used probabilities that were dependent on the current BCVA level and assumed the patient could move from any health state to any other health state in each cycle. The second method used probabilities that were dependent on the patients' current BCVA level for the top 2 health states only, so that a patient could only gain or lose up to 2 health states in each cycle. The third method used a constant probability across all BCVA levels, regardless of the patient's current BCVA level, and assumed that patients could only gain or lose up to 2 health states each cycle. The second scenario analysis involved using different sources for calculating transition probabilities beyond year 1. The third scenario analysis involved using different values for the maximum utility gains for the worseseeing eye. Ranibizumab continued to dominate vPDT in all of the scenario analyses.

# ERG critique of the manufacturer's submission
The ERG commented that the manufacturer did not include bevacizumab as a comparator even though it was included in the NICE appraisal scope. The ERG noted that the manufacturer stated that bevacizumab is unlicensed for use in the UK for choroidal neovascularisation associated with pathological myopia and that use of bevacizumab is not established practice in the UK for this indication. The ERG stated that although vPDT has a UK marketing authorisation for treatment of choroidal neovascularisation, it is rarely used in clinical practice.
The ERG found 2 headtohead trials of bevacizumab and ranibizumab. The ERG noted that the manufacturer had included these 2 trials in their submission, but had only presented data from the ranibizumab arms. The ERG stated that neither of these studies showed statistically significant differences between the ranibizumab and bevacizumab arms in mean change from baseline in BCVA, mean change in central retinal thickness, or in the number of patients gaining 10 or more or 15 or more letters.
The ERG noted that in RADIANCE the primary end point was at 3 months, and the ERG's clinical specialist thought that 12 months should be the minimum to assess longer term efficacy of treatment. The ERG stated that in VIP, the statistically significant difference between the vPDT and photodynamic therapy groups in the primary end point at 3 months was no longer seen at 24 months, and that this could also be true for ranibizumab. The ERG believed that it was unlikely that a 3month followup period would provide adequate information about potential adverse effects of the antiVEGF treatment.
The ERG noted that geographic atrophy, which is an advanced form of dry agerelated macular degeneration in which the rods and cones of the retina degenerate, is a common feature in patients with pathological myopia. It stated that the development of geographic atrophy or extension of preexisting geographic atrophy has been recognised as a potential side effect in patients with agerelated macular degeneration having antiVEGF treatment. The ERG was concerned that geographic atrophy was not assessed in RADIANCE because it can affect longterm visual outcomes.
The ERG noted that there was a difference between the patient populations in the RADIANCE and VIP trials. It was concerned that RADIANCE included a greater proportion of patients with nonsubfoveal involvement. The ERG stated that this may affect the comparability of the trials, because patients with subfoveal involvement tend to have a worse prognosis. The ERG suggested that the difference in the number of patients with subfoveal involvement in the 2 trials may overestimate the benefit of ranibizumab.
The ERG noted that the model accounted for the possibility of the betterseeing eye becoming the worseseeing eye, and vice versa, as patients change health states. The ERG stated that the method used by the manufacturer may underestimate the net qualityadjusted life year (QALY) gains and costs of blindness that may arise from the more effective treatment.
The ERG questioned whether an appropriate source had been used for the healthrelated quality of life data in the model. The ERG identified the Brown et al. (1999) study, which measured healthrelated quality of life directly from patients with impaired vision in at least 1 eye, producing a narrower range of utility values than the study by CzoskiMurray et al. (2009).
The ERG noted that the number of ranibizumab injections needed in years 2 and 3 may have been underestimated. It described a study by Franqueira et al. (2012) that reported results of a 3year retrospective study of 40 eyes with choroidal neovascularisation associated with pathological myopia. The mean number of injections in the study was 2.4 in year 2. The ERG suggested that 1.7 injections in year 2 would be a more reasonable assumption than the 1 injection in year 2 assumed in the manufacturer's model.
The ERG commented that the costs of blindness may have been overestimated. This was driven by the different costs of residential care calculated by the ERG and the manufacturer. The ERG suggested that a cost of blindness of 7510 in the first year and 7429 in each subsequent year, based on 2011 Personal and Social Services Research Unit costs and 30% of people being privately funded, was a more reasonable assumption.
The ERG noted that there were health state probabilities included in the manufacturer's model that were populated by relatively few patients. It was unsure whether the trials provided sufficient patientlevel data to be able to sensibly populate a model with 8 health states and a 64 cell transition probability matrix. Therefore the ERG was concerned about the reliability of the manufacturer's probability modelling.
The ERG noted some uncertainty about the use of mortality multipliers in the manufacturer's model. It stated that the definition of visual impairment in Christ et al. (2008), which was used by the manufacturer as a source of the multipliers, was ambiguous.
The ERG noted that EQ5D data were collected in RADIANCE but were not included in the manufacturer's submission. The ERG requested the EQ5D data during the clarification process and these were provided by the manufacturer. The ERG commented that the data indicated that changes in the BCVA of the worseseeing eye had no impact on patients' healthrelated quality of life.
The ERG stated that the manufacturer's assumption that treatment benefit would continue indefinitely was optimistic. The ERG performed exploratory analyses that incorporated alternative durations of treatment benefit of 1, 5, 10 and 20 years. This caused the net savings, QALYs and health benefits to decrease compared with those in the manufacturer's model. Ranibizumab remained dominant compared with vPDT even for a 1 year duration of treatment benefit.
The ERG highlighted minor errors in the manufacturer's model, in the calculation of the quarterly proportion of patients worsening, derived from natural history data. These errors were acknowledged in the manufacturer's clarification responses. The ERG corrected the errors in their exploratory analysis of the manufacturer's model.
The ERG conducted an exploratory analysis which involved the following modifications to the manufacturer's model:
Brown et al. (1999) as a source of utility values in addition to CzoskiMurray et al. (2009)
changed the dose of ranibizumab in year 2 from 1 to 1.7
changed the costs of blindness from 17,326 in year 1 and 17,245 in each subsequent year to 7510 and 7429 respectively
changed the mortality multiplier for blindness (BCVA of 35 letters or less) from 1.54 to 1.48
corrected the calculation of the quarterly proportion of patients worsening.
In the ERG's exploratory analysis, ranibizumab dominated vPDT. The total cost of ranibizumab was 10,055 and of vPDT was 12,529 (incremental cost 2474). Using utility values from Brown et al. (1999), the total QALYs were 14.514 for ranibizumab and 14.170 for vPDT (incremental QALYs 0.344). Using utility values from CzoskiMurray et al. (2009), the total QALYs were 13.105 for ranibizumab and 12.838 for vPDT (incremental QALYs 0.266).
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of choroidal neovascularisation associated with pathological myopia 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.
The Committee considered the current management of visual impairment caused by choroidal neovascularisation associated with pathological myopia. The clinical specialist stated that verteporfin photodynamic therapy (vPDT) has been used since 2005, and before this, no treatment was available. It heard from the clinical specialist that vPDT is not effective in most patients. The Committee discussed the use of vPDT and noted that its use is now diminishing because of the antivascular endothelial growth factor (antiVEGF) treatments, such as ranibizumab and bevacizumab. It noted that bevacizumab is used outside of its marketing authorisation and has to be formulated under a 'specials' licence. It concluded that a licensed alternative treatment to vPDT for visual impairment caused by choroidal neovascularisation with pathological myopia would be welcomed by clinicians and patients.
The Committee considered the impact of visual impairment caused by choroidal neovascularisation with pathological myopia on the everyday life of patients. The Committee understood from the patient expert that the condition affects a younger group of patients compared with other eye conditions and so affects the ability to work, drive, and care for children or other dependents. It heard from the patient expert that loss of vision has a significant effect on the independence of people with the condition and can lead to depression. The Committee agreed that loss of vision caused by choroidal neovascularisation seriously impairs quality of life.
The Committee considered the comparators for this appraisal. The Committee expressed concern that the manufacturer had not included bevacizumab as a comparator. It noted that the scope listed vPDT and bevacizumab as comparators, although it was aware that bevacizumab does not have a marketing authorisation for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee noted that appropriate comparators should be established practice in England. This is not intended to be restrictive, but to emphasise the need for comparison with all relevant comparators; any drug in routine use or considered to be best practice should be considered a potential comparator. The Committee heard from the manufacturer that it considered that bevacizumab was not an appropriate comparator because its use in the NHS is not routine or best practice. The Committee heard from the patient expert and clinical specialist that bevacizumab is used in some patients, but only after some delay to agreement for funding. The Committee noted that the written statements submitted by the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication. The Committee also noted that there are 2 trials (see section 4.7) that compared ranibizumab with bevacizumab in choroidal neovascularisation associated with pathological myopia. However, both of these had a small number of patients. The Committee heard from the clinical specialist that there are some residual safety concerns with the use of bevacizumab, but considered these to be minor. It was aware of the conclusions of the Decision Support Unit report (Bevacizumab in eye conditions: Issues related to quality, use, efficacy and safety), which stated that adverse event rates were low in all bevacizumab and comparator groups. However, the Committee also noted that the use of bevacizumab in the eye had not been assessed by the regulatory agencies. It agreed that bevacizumab was a legitimate potential comparator with respect to its use in the NHS. The Committee concluded that because the available evidence for bevacizumab in this indication was limited to 2 small trials, there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and costeffectiveness analysis, but it did not rule out the possibility of future evidence providing that confidence.

# Clinical effectiveness
The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. The Committee acknowledged that the evidence was primarily from RADIANCE, which compared ranibizumab with vPDT, and was complemented by evidence from 2 other randomised trials that compared ranibizumab with bevacizumab, even though the manufacturer did not present the data for the bevacizumab arms of these trials in its submission. The Committee noted that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity (BCVA) between baseline and months 13. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.
The Committee discussed the primary end point of RADIANCE, which was the mean average change in BCVA between baseline and months 13. The Committee heard from the clinical specialist that 3 months was not a long time period to assess the longer term benefits of ranibizumab. However, the other studies of ranibizumab and the longterm followup of its use in other eye conditions suggest a sustained effect. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months in RADIANCE, there is uncertainty about the longterm efficacy of ranibizumab for visual impairment caused by choroidal neovascularisation associated with pathological myopia.
The Committee considered the 2 trials presented in the manufacturer's submission that compared the use of ranibizumab and bevacizumab in choroidal neovascularisation associated with pathological myopia. The Committee noted that this was in line with the scope, in which bevacizumab was included as a comparator. The Committee heard from the clinical specialist that the 2 trials, although small, showed ranibizumab and bevacizumab to be equally effective. It was aware that the manufacturer presented only the results from the ranibizumab arms of these trials in their submission and that the Evidence Review Group (ERG) had presented the results from the bevacizumab arms in their report (see section 3.19). The Committee concluded that ranibizumab is likely to be as clinically effective as bevacizumab in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.
The Committee considered the trial evidence for adverse events associated with ranibizumab. The Committee discussed whether geographic atrophy was underreported because markers of this effect were not measured in RADIANCE. The clinical specialist argued that there was no particular reason to expect geographic atrophy as a side effect of ranibizumab treatment. The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.

# Cost effectiveness
The Committee considered the costeffectiveness evidence presented in the manufacturer's submission, including the basecase results, the sensitivity and scenario analyses and the ERG's critique of the manufacturer's evidence. It noted that the manufacturer had not included bevacizumab as a comparator in its economic model. The Committee understood that the manufacturer's basecase analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more qualityadjusted life years (QALYs; 13.18 compared with 12.75) and lower costs (9694 compared with 12,455).
The Committee accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. In particular, the Committee queried:
the larger proportion of patients with subfoveal involvement at baseline in the VIP trial than in the RADIANCE trial
the assumption of an indefinite duration of benefit of ranibizumab treatment
the low number of ranibizumab injections needed in year 2 of treatment
the high estimated costs of blindness
the low estimated costs of ranibizumab and vPDT administration
the lack of clarity about the source of the mortality multipliers used in the model
the underestimated changes in net QALY gains and the cost of blindness resulting from the method used to account for the possibility of the treated eye changing from being the betterseeing eye to being the worseseeing eye
the use of CzoskiMurray et al. (2009) as a source of utility values, rather than the EQ5D data collected in RADIANCE.The Committee considered each of these issues in turn, as detailed below.
The Committee considered the clinicaleffectiveness data that were used in the manufacturer's economic model. It recognised that the clinicaleffectiveness data for ranibizumab were derived from RADIANCE and the data for vPDT after 3 months were derived from the VIP trial. The Committee noted that there was a larger proportion of patients at baseline with subfoveal involvement in VIP compared with RADIANCE and it was concerned that this might have had an impact on the model. The Committee heard from the clinical specialist that an imbalance would only be clinically relevant if it was in the number of patients with extrafoveal involvement, and that this did not appear to be the case. The Committee concluded that the imbalance in the number of patients with subfoveal involvement in RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.
The Committee discussed the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. The Committee heard from the clinical specialist that data collected at the 3 time points in RADIANCE showed that the benefit of ranibizumab was maintained for at least 12 months. The Committee noted that the ERG's sensitivity analyses included different durations of treatment benefit, and that ranibizumab dominated vPDT even when the duration of treatment benefit was reduced to 1 year. The Committee concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, and that ranibizumab dominated vPDT when the duration of effect was reduced.
The Committee discussed the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice. The Committee heard from the clinical specialist that, on average, patients only need ranibizumab injections in the first 3 months of their first year of treatment. The clinical specialist also stated that patients in the REPAIR trial had well preserved eyesight after 18 months and did not need further treatment. The Committee noted that the ERG had increased the number of ranibizumab injections in the second year of ranibizumab treatment from 1.0 to 1.7 in its exploratory analysis. Based on experience with patients using ranibizumab, the clinical specialist felt that this number could be too high. The Committee concluded that the number of injections included in the manufacturer's base case could be an underestimate and that even if the number of injections was increased, ranibizumab would continue to dominate vPDT.
The Committee considered the costs of blindness used in the manufacturer's economic model. It noted that the ERG presented lower costs of blindness in their report. The Committee heard from the ERG that the difference in the costs of blindness was mainly related to the way the costs for private residential care were calculated. The Committee noted that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the costs of blindness. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that if the ERG's assumptions had been used, ranibizumab would continue to dominate vPDT.
The Committee discussed the administration costs of ranibizumab used in the manufacturer's economic model. It noted that these costs were likely to be an underestimate of the true costs incurred in the NHS. The Committee recognised that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the administration costs. The Committee concluded that although some uncertainty remained about the NHS costs involved in the administration of ranibizumab, the uncertainty was not great enough to affect the dominance of ranibizumab over vPDT.
The Committee discussed the mortality multipliers that the manufacturer had used in its economic model. It heard from the ERG that the source of some of the mortality multipliers was unclear. The ERG also stated that changing the mortality multipliers to alternative values had little impact on the cost savings or QALYs for ranibizumab. The Committee concluded that the manufacturer's rationale for some of the mortality multipliers used in their model was unclear, and that any changes to them were unlikely to change the dominance of ranibizumab over vPDT.
The Committee considered the method used in the manufacturer's economic model to account for the possibility of the treated eye changing from being the betterseeing eye to being the worseseeing eye as patients changed health states. The Committee understood that the way the manufacturer had modelled this seemed to underestimate the changes in net QALY gains and costs of blindness that may arise from the more effective treatment. The Committee noted that it was not possible to quantify the size of the effect on the basecase analysis. The Committee concluded that the modelling of the treated eye changing from being the betterseeing eye to being the worseseeing eye as patients changed health states may have had an impact on the basecase analysis, which showed that ranibizumab dominated vPDT, although the level of impact remained unclear.
The Committee discussed the utility values used in the manufacturer's economic model. The Committee noted that the source of utility data used in the basecase analysis (CzoskiMurray et al. 2009) was used in Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 274), Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 283), and Aflibercept solution for injection for treating wet age-related macular degeneration (NICE technology appraisal guidance 294). It was aware that EQ5D data were also collected in RADIANCE, but these data were not used in the model. The Committee heard from the manufacturer that the EQ5D data from RADIANCE were not included because the EQ5D is widely recognised as not being sensitive in studies of eye conditions. The Committee heard from the ERG that using the EQ5D data collected in RADIANCE did not have a large effect on the model, although the effect for the worseseeing eye was not clear. The Committee concluded that using the EQ5D data from RADIANCE was unlikely to change the overall results of the basecase analysis and that ranibizumab would continue to dominate vPDT.
The Committee noted that the manufacturer's model had not included bevacizumab as a comparator and so the basecase analysis was limited to a comparison of ranibizumab with vPDT. However, because the available evidence for bevacizumab in this indication was limited to 2 small trials (see section 4.4), there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and costeffectiveness analysis. The Committee considered the uncertainties in the manufacturer's model and noted that they did not have an effect on the overall results of the basecase analysis, which showed that ranibizumab dominated vPDT. The Committee concluded that ranibizumab was a costeffective use of NHS resources for treating people with visual impairment caused by choroidal neovascularisation associated with pathological myopia when vPDT was the comparator.
The Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on healthrelated benefits. It agreed that antiVEGF treatments, such as ranibizumab, were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was a step forward in providing healthrelated patient benefits, not the act of licensing. In addition there were no substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.
The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed.

# Summary of Appraisal Committee's key conclusions
TA298
Appraisal title: Ranibizumab for treating choroidal neovascularisation associated with pathological myopia
Section
Key conclusion
Ranibizumab is recommended as an option for treating choroidal neovascularisation associated with pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.
The clinical evidence from RADIANCE, which compared ranibizumab with vPDT, showed that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity between baseline and months 13, although there is uncertainty about the efficacy after 3 months. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.
The key drivers of the costeffectiveness analysis included the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worseseeing eye. The manufacturer's basecase costeffectiveness analysis showed that ranibizumab dominated vPDT, resulting in more QALYs and lower costs. The Committee concluded that the uncertainties associated with the key drivers in the model were unlikely to have an effect on the overall costeffectiveness results. The Committee therefore recommended ranibizumab as a costeffective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard that visual impairment caused by choroidal neovascularisation seriously impairs quality of life.
The Committee heard that the current standard treatment for choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of antiVEGF treatments.
The Committee heard from a clinical specialist that the nonlicensed use of bevacizumab in the NHS is not routine or best practice. However, written statements from the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication.
The Committee heard from the patient expert and the clinical specialist that there are often delays in agreements to fund ranibizumab or bevacizumab.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee agreed that antiVEGF treatments (such as ranibizumab) were a substantial improvement over previous treatments.
It was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.
What is the position of the treatment in the pathway of care for the condition?
The Committee assessed the clinical effectiveness of ranibizumab compared with vPDT for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia.
Adverse reactions
The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee acknowledged that the evidence presented by the manufacturer was primarily from RADIANCE, which compared ranibizumab with vPDT. This evidence was complemented by data from the ranibizumab arm of 2 other randomised trials.
The Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the ERG identified only 2 small trials that compared ranibizumab and bevacizumab. The Committee concluded that there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and costeffectiveness analysis.
Relevance to general clinical practice in the NHS
The Committee heard that the current standard treatment for visual impairment caused by choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of antiVEGF treatments, such as ranibizumab and bevacizumab.
Uncertainties generated by the evidence
The Committee noted that the primary end point of RADIANCE was the mean average change in BCVA between baseline and months 13. The Committee heard from a clinical specialist that 3 months was not a long time period to assess the longer term benefits of ranibizumab. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months, there is uncertainty about the longterm efficacy of ranibizumab for choroidal neovascularisation associated with pathological myopia.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that ranibizumab was associated with a greater improvement than vPDT in BCVA between baseline and months 13. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer.
The Committee noted that the manufacturer had not included bevacizumab as a comparator in its economic model.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered the larger proportion of patients with subfoveal involvement in the VIP trial, which provided the vPDT data after 3 months. However, it concluded that the imbalance between RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.
The Committee considered the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. It concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, but that ranibizumab dominated vPDT when the duration of effect was reduced.
The Committee discussed whether the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice was too low. It concluded that the number of injections included in the manufacturer's base case could be an underestimate, and that even if the number of injections was increased, the basecase analysis would not be affected.
The Committee discussed whether the costs of blindness used in the manufacturer's model were too high. The Committee noted that the ERG presented lower costs of blindness in their report. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that any changes were unlikely to have a large impact on the basecase analysis.
The Committee discussed whether the administration costs of ranibizumab used in the manufacturer's model were an underestimate. It concluded that the NHS costs were uncertain, but the uncertainty was not great enough to affect the basecase analysis.
The Committee discussed whether the mortality multipliers used in the manufacturer's economic model were appropriate. It concluded that the manufacturer's rationale for some of the mortality multipliers in the model was unclear, and that any changes to them were unlikely to change the basecase analysis.
The Committee discussed whether the method used in the manufacturer's model to account for the possibility of the treated eye changing from being the betterseeing eye to the worseseeing eye as patients change health states was appropriate. It concluded that the modelling may have had an impact on the basecase analysis, but the level of impact was unclear.
The Committee considered that EQ5D data were collected in RADIANCE, but were not used in the manufacturer's economic model. It concluded that using the EQ5D data from RADIANCE was unlikely to change the overall results of the basecase analysis.
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the EQ5D data collected in RADIANCE was not used in the model and the manufacturer used utility values from CzoskiMurray et al. (2009), in line with previous appraisals of drugs for eye conditions. The Committee heard from the ERG that using the EQ5D data from RADIANCE did not have had a large effect on the model, although the effect for the worseseeing eye was not clear. The Committee concluded that using the EQ5D data from RADIANCE was unlikely to change the overall results of the basecase analysis.
The Committee was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.
Are there specific groups of people for whom the technology is particularly cost effective?
None
What are the key drivers of cost effectiveness?
The manufacturer's sensitivity analyses showed that the cost effectiveness of ranibizumab was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits, and the maximum utility gain in the worseseeing eye.
Most likely costeffectiveness estimate (given as an ICER)
The Committee noted that manufacturer's basecase analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (9694 compared with 12,455). The Committee considered the uncertainties in the manufacturer's model and noted that they were unlikely to have an effect on the overall results of the basecase analysis, which showed that ranibizumab dominated vPDT.
Additional factors taken into account
Patient access schemes (PPRS)
The Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of discount is commercial in confidence.
Endoflife considerations
Not applicable
Equalities considerations and social value judgements
No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed.

# Related NICE guidance 
Details are correct at the time of publication. Further information is available on the NICE website.
Aflibercept solution for injection for treating wet age-related macular degeneration. NICE technology appraisal guidance 294 (2013).
Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283 (2013).
Ranibizumab for the treatment of diabetic macular oedema (rapid review of TA237). NICE technology appraisal guidance 274 (2013).
Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013).
Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011).
Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008).
Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003).# Review of guidance
The guidance on this technology will be considered for review in March 2016. 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 DillonChief ExecutiveNovember 2013# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
It has been incorporated into the NICE pathway on eye conditions along with other related guidance and products.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
Copyright National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and notforprofit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
ISBN: 978-1-4731-0362-7