B. Summary of cost-effectiveness of ranibizumab under alternative scenarios

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1 B. Summary of cost-effectiveness of ranibizumab under alternative scenarios In response to the Committee s concerns, a number of assumptions in the model base case have been revised (section 1): Mortality rate increased Treatment stopping rule removed Transition probability matrices reestimated based on RESTORE cohort with 75 letters or less BCVA at baseline Treatment duration extended The better-seeing eye (BSE) is treated; therefore the costs of blindness are applied only when BCVA in this eye falls below 36 letters New ranibizumab list price as of 1 st February 2011 introduced ( ). Base case estimates with xxxxxxxx and without the proposed Patient Access Scheme (PAS) are presented. In response to the Committee s queries about the utility data applied to the model, potential confounding factors were tested in the utility regression analysis. None, except gender, were found to be significant, and the original RESTORE utilities were therefore retained in the base case presented in section 1. The regression analysis and results using alternative utility sources are presented in section 2. A bottom up estimate of an intravitreal administration visit cost is presented in section 3.This suggests that the cost applied to the model is not significantly underestimated, and the base case has therefore not been amended. In response to comments from the clinical experts at the meeting, and the Committee s comments with regards to subgroups, we present the cost effectiveness of patients with >400 um central foveal thickness (section 4). As noted in the ACD, these are patients who are expected, and observed, to respond less favourably to laser. In section 5, the cost effectiveness of ranibizumab when some patients are treated in both eyes is estimated.

2 1. Alternative base case estimate Key parameters of the revised cost effectiveness analysis are presented in tables 1 and 2. The results of the revised base case analysis are presented in Table 3. Using a BSE analysis as a framework for decision making (as was the case for previous technology appraisals including TA155), ranibizumab has an ICER of 36,812 without the PAS and 30,277 when the PAS is included. Thus, even when applying more conservative assumptions, ranibizumab is cost effective when the PAS is included in the analysis. It is noteworthy that, should the mean age of initiation of treatment be lower than 63, cost effectiveness of ranibizumab improves (ICER 33,092 without the PAS and 27,016 with the PAS when mean age is 58). The mean age of the model cohort is based on RESTORE. In NHS clinical practice, one might expect patients with visual impairment due to DMO to present at an earlier age as they are identified predominantly through screening. Table 1: Key parameters of the revised cost effectiveness analysis Variable Value Notes Baseline age 63 Time horizon is unchanged at 15 years Baseline health state distribution (BCVA letter score) % Unchanged from original submission % % % % % % <25 0% Transition probabilities Year 1 RESTORE trial data (cohort adjusted for drop out rates as in trial) No treatment stopping rule is applied to ranibizumab treated patients

3 Transition probabilities Year 2 Worsening Calibration supported by 24 months follow up DRCR.net. No change Unchanged from previous submission. Improvement Transition probabilities Year 3 Worsening Calibration supported by 24 months follow up DRCR.net. No change Improvement Transition probabilities Year 4 Worsening Calibration supported by 24 months follow up DRCR.net. No change Improvement Transition probabilities Year 5 and beyond Worsening Calibration with long term observational data. Data is No change unchanged from previous submission, but applied to years 5 and beyond only. Improvement Utilities Unchanged from previous submission, as possible confounding factors were found to be insignificant and utilities are consistent with other BSE utilities (section 2) < Mortality in DMO population Relative risk of mortality 2.45 Increased in light of ERG and Committee s concerns, to incorporate excess mortality risk of diabetes. Estimates from Mulnier and Hirai combined. Table 2: Resource use assumptions (years 1 and 2 are unchanged from original submission) Time period Model Input Ranibizumab monotherapy Laser alone Year 1 Treatment frequency 7 injections 1 2 laser sessions Monitoring visits 12 4 Year 2 Treatment frequency 3 injections 2 1 laser session 2 Monitoring visits Year 3 Treatment frequency 2 injections 4 1 laser session Monitoring visits Year 4 Treatment frequency 1 injection 4 1 laser session Monitoring visits Year 5 Treatment frequency Laser maintenance as required 5 Monitoring visits 2 2 Laser maintenance as required 5 All years Cost of severe vision loss Applied to health states at 35 letters or less (all eyes are

4 Time Model Input Ranibizumab Laser alone period monotherapy BSE) 1. Withdrawals continue to laser 2. Assumption supported by treatment frequencies in year 2 in DRCR.network protocol I study 3. Assumption supported by lower monitoring frequency in 18 month extension of READ-2 4. Assumption supported by significant reduction in number of injections required in year 2 of treatment 5. Assumption supported by clinical advice to the Committee that a deferred laser regimen may be implemented in clinical practice. Resource use and costs are assumed to be equal in both arms and therefore are not included in the model

5 Table 3: Incremental cost effectiveness of ranibizumab treatment of the BSE Total costs ( ) Total LY Total QALYs Ranibizumab vs. laser monotherapy Incremental costs ( ) Incremental QALYs ICER ( ) versus baseline (QALYs) ICER ( ) incremental (QALYs) Laser 8, Ranibizumab 15, , ,812 Ranibizumab: With PAS xxxxxx xxxxx ,277 Table 4: Probability of cost effectiveness WTP= 0 WTP= 20,000 WTP= 30,000 Ranibizumab vs. Laser Ranibizumab vs. Laser: with PAS WTP: Willingness to pay threshold

6 2. Applying alternative utility estimates In response to the Committee s concerns about the utilities derived from RESTORE, age, blood pressure and HbA1c and other systemic characteristics were included as covariates in the regression model to explore the potential confounding effect of diabetic co morbidities on the relationship between BCVA and utility. 2.1 Background The submitted model is a Markov model with health states defined by visual acuity (VA) in the study (treated) eye. In the RESTORE study, patients were followed up over 12-months. Data on visual acuity and utility (EQ-5D) were recorded at baseline, 3 months, 6 months and 12 months for the treated eye. EQ-5D scores were converted to utility scores. In the original submission, average utility values were applied to each of the model s health states derived from a linear regression model using the utility value as dependent variable and the VA category as independent variable. The impact of other predictors (treatment group, visit and time as a continuous variable) was also tested to ensure that there was no bias in the estimation of the relationship between VA category and utility value. This demonstrated that neither treatment nor visit/time has a significant impact on the relationship between utility and VA category. It was therefore considered acceptable to derive the utility value for each VA category using the whole set of data, without any adjustment variable. The objective of this extended analysis was to test for additional confounding factors in the RESTORE population that may influence the relationship between VA category and utility value. 2.2 Methods The variables included in the analysis are presented in Table 5. Table 5 Confounder analyses Dependent variable Utility in study eye Independent variables VA categorized Treatment group Visit number/time, continuous Age (one year groups, continuous) Gender Duration of diabetes (year, continuous) Blood pressure group in baseline (controlled, uncontrolled) HbA1c in baseline (continuous) Treated eye better seeing or worse seeing (by comparison of the VA in baseline of the treated eye and the fellow eye) In the confounder analyses the health states letters and letters were collapsed into a single category. The reason was that the initial model estimated a utility of in letters and 0.86 in and letters, which suggests that the estimate in letters is unreliable (probably due to small n).

7 2.3 Results xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxx. Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxx Figure 1: STATA output Note: Model categories letters BCVA and letters BCVA were collapsed into one category. The regression baseline is category 1= letters BCVA, Gender =1 (males), blood pressure group =1 (controlled). Coefficient Ivacategory-2 expresses the difference in utility between the baseline and patients with a BCVA of letters. Variables used in the STATA analysis are described in Table 6 below. Table 6: STATA variables STATA name Explanation, values _Ivcatego~2,3,4,5,6,7 Health state categories (dummies for 2,3,4,5,6,7) Age Age in baseline in years, continuous _Isex1c_2 Gender, dichotomous _Ibp_2 Blood pressure states (dichotomous, controlled/uncontrolled) Hba1c HbA1c in baseline in %, continuous Dur_dia Duration of diabetes in years, continuous

8 Bse Cons Utilityuk Better seeing eye Constant in regression Visit number, months (baseline=2) Utility score 2.4 Conclusion The confounder analysis demonstrates that the utility function estimated from the RESTORE data is not confounded by factors relating to diabetic disease. Age, blood pressure, glycaemic control, nor length of diabetic disease were significantly correlated with the relationship of utility and BCVA. Whether the treated eye was better or worse seeing did not have a significant impact on the utility function. The limitations to this analysis remain as identified by the manufacturer, ERG and the Committee: The RESTORE EQ-5D dataset is small, and the analysis relies on pooling of observations across treatment arms and time periods The number of patients in some subgroups (eg BSE, HbA1c) is especially small There are no equivalent studies of EQ-5D utilities in a DMO population, or in a population with mixed better and worse seeing treated eyes, against which to validate these results. Given that the Committee expressed interest in understanding the impact of systemic characteristics of the RESTORE population on the utility estimates, both significant and insignificant variables relating to the baseline characteristics of the RESTORE patients were included in a model simulation of the adjusted utility function. This adjusted utility function is presented in appendix 1, with the results of a cost effectiveness analysis using these data discussed in section 2.5 below. 2.5 Discussion The confounder analysis suggests that markers of diabetic comorbidity do not influence the RESTORE utility function. However, reestimating the utility function including these covariates reduces the range of utilities applied to the model (reduces the difference in utility in the best BCVA health state and the worst BCVA health state). This reduces the cost effectiveness of ranibizumab compared to laser (Table 10). As noted in section 1, the revised base case is considered a BSE model to facilitate interpretation of results. This approach to estimating the cost effectiveness of ophthalmic interventions was used in previous NICE appraisals, including TA155. This allows us to explore the cost-effectiveness of ranibizumab when applying alternative utilities (Table 10): Consider the RESTORE utilities as BSE utilities Apply the BSE utilities reported by Lloyd et al in a diabetic retinopathy population (1) (Table 7) Apply the utilities preferred during the NICE appraisal of ranibizumab for the treatment of wet AMD, based on a utility study carried out by the School of Health and related research (ScHARR) (Brazier et al, University of Sheffield) (2) (Table 8)

9 Apply utilities derived from VA using the formula reported by Sharma et al. (3) (Table 9). Including utilities in the model, other than the RESTORE utilities, results in lower ICERs. Table 7: Utilities reported by Lloyd et al. and applied to the model Vision category Utility Model health states Modelled utility No retinopathy letters /6 6/ letters /12 6/ letters letters /24 6/ letters letters /60 6/ letters 0.53 CF-HM 0.34 <25 letters The utility reported by Lloyd et al for this health state may be erroneous, as this represents worse utility than reported for a health state with worse vision. This value was adjusted in the base case, resulting in bias against ranibizumab 2. The average value of the higher and lower BCVA health states was applied Table 8: Utilities for wet AMD patients and applied to the model Vision category Utility Model health states Modelled utility 6/15 ( 64) letters letters letters /60 to 3/60 (49-63) letters letters /38 to 6/48 (39-48) letters /60 to 3/60 (19-38) letters /60 (<19) <25 letters Table 9: Utilities derived from Sharma et al s formula Sharma univariate equation U = (0.374)(visual acuity in BSE) R 2 = 0.173; F = p < Sharma bivariate equation U = (0.362)(visual acuity in BSE) + (0.0346)(duration of visual loss) R 2 = 0.258; F =13.2. p < Model health states Modelled utility (univariate) letters letters letters letters letters letters letters <25 letters Modelled utility (bivariate)

10 Table 10: Cost effectiveness of ranibizumab treatment of the BSE using alternative utilities RESTORE utilities Total costs Total QALYs Incremental costs ( ) Laser Incremental QALYs ICER ( per QALY) Ranibizumab 15, , ,812 Ranibizumab: With PAS xxxxxx 7.76 xxxxx ,277 Adjusted RESTORE utilities Laser 8, Ranibizumab 15, , ,165 Ranibizumab: With PAS xxxxxx 7.49 xxxxx ,857 Lloyd utilities Laser 8, Ranibizumab 15, , ,127 Ranibizumab: With PAS xxxxxx 6.97 xxxxx ,779 Wet AMD utilities Laser 8, Ranibizumab 15, , ,637

11 Ranibizumab: With PAS xxxxxx 7.88 xxxxx ,843 Sharma utilities (univariate equation) Laser 8, Ranibizumab 15, , ,322 Ranibizumab: With PAS xxxxxx 6.83 xxxxx ,610 Sharma utilities (bivariate equation) Laser 8, Ranibizumab 15, , ,969 Ranibizumab: With PAS xxxxxx 5.82 xxxxx ,312

12 3. Administration costs for intravitreal procedures A bottom up approach to costing was used to estimate the unit cost of an intravitreal injection visit based on number of minutes of health professionals time and their hourly cost. The average time spent during each patient visit was taken from the wet AMD Project Practice Management resource utilisation study (Novartis UK 2010, data on file). Methods of the study are outlined in the appendix. Hourly costs of health professional time were taken from the Industry Costing Template for the National Institutes of Health Research Clinical Research Network (NIHR CRN); overhead and capacity building elements were included (available at Procedure costs (OCT) did not include this addition, in line with guidance in the NIHR CRN template. OCT was not listed as a procedure within the NIHR CRN template; the NHS Reference Cost was applied. Drugs and disposables were not included in the estimate. This approach suggests that the cost of 150 used in the original model does not underestimate the cost of an intravitreal injection visit, even when the costs of a full ophthalmology clinic team are considered individually. There is likely to be some additional cost for drugs and disposables that have not been captured. However, on a per patient basis, these are unlikely to be so significant as to result in an important change the result of the cost effectiveness analysis. Table 11: Bottom up estimate of intravitreal injection visit cost Activity Average time (mins) Minimum time (mins) Resources Hourly cost 1 Reception x x 1 receptionist Pre-exam xx x x 1 nurse/orthoptist Dilation time xx x x N/A OCT x x 1 technician/nurse OCT procedure Total cost ( )Total Assessment x x 1 consultant/doctor Injection preparation x x 1 nurse Injection procedure xx 1 Doctor nurses Intravitreal injection procedure Discharge/appointment booking ; x Receptionist/nurse Total Average time rounded up to the nearest 5 minutes. 1. Standardised staff grades and rates , inclusive of overhead and capacity building elements (rate: 70% and 20%, respectively) and NIC and NHS Superannuation Scheme. Administrative/data management staff: Band 3, Nurse staff: Band 7, Clinical staff: Top Consultant Band

13 2. Some units reported that these activities did not take place/were included alongside other activities 3. No staff resource required 4. NHS Reference Costs Evidence of subgroup effects We note the advice from clinical experts to the Committee that patients with thicker, more oedematous retina were more likely to lose vision despite treatment (paragraph 4.3 of the ACD). It is well recognised that patients with a thicker retina require a higher amount of laser energy to achieve a reaction at the level of the retinal pigment epithelium. This may result in suboptimal laser treatment being given, and damage due to absorption of the extra laser energy in other layers of the retina. Furthermore, as laser results in a slower reduction in retinal thickness, there is a longer period of time over which the tissues, including photoreceptors, may be undergoing damage caused by excess oedema. Ranibizumab rapidly reduces retinal thickness, enabling earlier resolution of normal or near-normal retinal architecture, thus a lower likelihood of long-lasting photoreceptor damage. Therefore, patients with a thicker retina form a clinically plausible subgroup of patients in whom laser is expected to be less effective in stabilising vision and ranibizumab has demonstrated significant clinical benefits. This expectation is confirmed by subgroup analysis of the RESTORE trial. Efficacy outcomes of patients defined by Central Foveal Thickness (CFT) at baseline are presented in Table 12 and Table 13. These results reflect those of subgroups defined by Central Subfield Retinal Thickness (CSRT) (presented in the original submission). CFT was preferred for this analysis as this is the measure of macular oedema that is considered more clinically relevant to NHS practice. CFT is measured by OCT. As presented in Table 13, a large proportion of patients with > 400 µm CFT lose 10 letters or more BCVA despite laser treatment. Only a small minority improve BCVA. The higher mean average change in the µm CFT subgroup may be explained by the slightly higher number of patients with improvement in vision, despite the majority of patients who experience a significant deterioration. It may be that patients in this subgroup have more focal macular oedema, which may be more responsive to treatment. This has not yet been explored. It is noted that there are small numbers of patients in this subgroup. Table 12: Mean average change in BCVA, by subgroups defined by central foveal thickness (CFT) (µm) (post-hoc analysis) Ranibizumab monotherapy Ranibizumab plus laser combination therapy Laser alone < >

14 Table 13: Proportion of patients with BCVA change, by CFT subgroup (post-hoc analysis) Ranibizumab monotherapy Proportion of patients with at least 10 letter improvement Ranibizumab plus laser combination therapy Laser alone CFT (µm) < % 25.9% 15.4% CFT (µm) % 43.8% 20.6% CFT (µm) > % 42.4% 10.0% Proportion of patients with at least 10 letter deterioration CFT (µm) < % 3.7% 69.2% CFT (µm) % 3.1% 76.5% CFT (µm) > % 5.1% 72.0% BCVA, best corrected visual acuity; CFT, central foveal thickness; It is important to note that the pre-specified subgroup analyses performed in RESTORE were exploratory in nature; designed to provide information regarding the consistency of ranibizumab efficacy across patients with differing characteristics. The subgroup analyses were not powered to detect significant differences, and as noted in table 1 the number of patients in each subgroup is is very small. Thus, no tests of statistical significance were planned. In light of the Committee s comments, significance testing of key subgroups (based on retinal thickness and BCVA at baseline) has been provided as academic in confidence data. The cost effectiveness of patients with > 400 µm CFT has is presented in Table 14. When the PAS is applied, an ICER of 21,418 for ranibizumab versus laser is estimated. If the utility values using the Sharma formula are used in the analysis, the cost effectiveness of ranibizumab improves to 12,000 per QALY.

15 Table 14: Incremental cost effectiveness of ranibizumab treatment of the BSE for patients with >400 µm CFT Total costs ( ) Total QALYs Ranibizumab vs. laser monotherapy Incremental costs ( ) Incremental QALYs ICER ( ) versus baseline (QALYs) ICER ( ) incremental (QALYs) Laser 9, Ranibizumab 15, , ,008 Ranibizumab: With PAS xxxxxx 7.74 xxxxx ,418

16 5. Bilateral treatment scenarios The scenarios presented in previous sections assume that only the BSE is treated with ranibizumab. These scenarios can be justified under two alternative assumptions: The precedent of TA155, where the BSE was modelled although the WSE was treated predominantly in the clinical trials. The Committee concluded that considerations of cost effectiveness should relate to the BSE, but recommendations should relate to the first affected eye. In DMO, patients may be treated in the WSE with laser in order to maintain vision in the WSE. Vision is improved with ranibizumab in the BSE, which is argued to have most impact on health related quality of life. To consider the cost-effectiveness of ranibizumab treatment in both eyes, where affected, we have conducted a simple extension of the approach suggested by the ERG. Simplifying assumptions are: Bilateral involvement is assumed at presentation in 35% of the DMO cohort Both eyes are treated and monitored at the same visit Ranibizumab drug and treatment costs are doubled in bilateral patients 35% of the costs of blindness are applied (assuming that this is the proportion of patients with a BSE) Utility gains of treating the second eye are assumed to be 25% of that of treating the first eye (incremental QALYs increased by 25%).

17 Table 15: Cost effectiveness of bilateral treatment (assumptions in section 1 are applied) Incremental costs ( ) Incremental QALYs ICER ( ) incremental (QALYs) Patients with >400 µm CFT Ranibizumab vs laser 12, ,699 With PAS xxxxxx ,719 All patients Ranibizumab vs laser 12, ,531 With PAS xxxxxx ,355

18 Appendix Adjusted utilities applied to the model State number State description Cycle Utility in state

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20 Methodology of Project Practice Management The overall project goal was to help hospitals to optimise the usage of hospital resources in delivering intravitreal injection (anti-vegf) clinics for wet AMD. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx

21 Reference List (1) Lloyd A, Nafees B, Gavriel S, Rousculp MD, Boye KS, Ahmad A. Health utility values associated with diabetic retinopathy. Diabet Med 2008 May;25(5): (2) NICE. Final Appraisal Determination: Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. England: National Institute for Health and Clinical Excellence; Report No.: TA155. (3) Sharma S, Brown GC, Brown MM, Shah GK, Snow K, Brown H, et al. Converting visual acuity to utilities. Can J Ophthalmol 2000 Aug;35(5):