Manufacturers' Submissions
Both manufacturers provided cost-utility models. Both models were Markov state transition models, with the states being different levels of visual acuity and death. Both models assumed that only the better-seeing eye is treated.
Ranibizumab
The manufacturer's submission compared the use of ranibizumab with best supportive care for patients with minimally classic or occult no classic lesions, and with both photodynamic therapy (PDT) with verteporfin and best supportive care for patients with predominantly classic lesions. The different types of wet age-related macular degeneration (AMD) were analysed separately based on results from randomised controlled trials (RCTs).
The model had five health states defined by declining visual acuity ranging from 6/15 or better (least severe) to less than 3/60 (most severe), and an additional absorbing state, death. In the base-case analysis for the model, 8 injections in the first year and 6 injections in the second year were used.
The base-case incremental cost-effectiveness ratios (ICERs) for predominantly classic lesions, assuming 1 year of treatment as per the ANCHOR RCT, were 4,489 pounds sterling per quality-adjusted life-year (QALY) gained for ranibizumab versus PDT, and 14,781 pounds sterling per QALY gained for ranibizumab versus best supportive care. For occult no classic lesions, assuming 2 years of treatment, the ICER was 26,454 pounds sterling per QALY gained for ranibizumab versus best supportive care. Likewise, for minimally classic lesions, the ICER was 25,796 pounds sterling per QALY gained. For all lesion types (PIER), assuming 1 year of treatment, the ICER was 12,050 pounds sterling per QALY gained.
Pegaptanib
The manufacturer's model for pegaptanib compared the cost effectiveness of pegaptanib with usual care in the NHS. Usual care was identified as the best supportive care (visual rehabilitation and provision of visual aids) for all patients, with the addition of PDT with verteporfin in patients with predominantly classic lesions. The base-case analysis is based on all lesion types. The analysis was based on patient-level data from the VISION study.
The model had 12 health states, defined by visual acuity ranging from 6/10 or better to less than 3/60, and an additional absorbing state, death. Treatment was assumed to be stopped if visual acuity dropped below 6/96 or by six or more lines from baseline at the end of a year. This is referred to as scenario A. The cost effectiveness of adopting an alternative stopping rule with a higher threshold of visual acuity (6/60) for stopping pegaptanib treatment, labelled scenario B, is also reported in the submission. Cycle length in the model is 6 weeks.
In the base case, the ICER was 15,819 pounds sterling per QALY gained for scenario A and 14,202 pounds sterling per QALY gained for scenario B. Results of sensitivity analyses carried out by the manufacturer showed that the costs and probabilities of receiving visual impairment services and the model time horizon had a significant effect on the ICERs.
The Assessment Group Model
The Assessment Group's model evaluated the cost effectiveness of ranibizumab and pegaptanib compared with current practice (PDT with verteporfin for classic no occult lesions or predominantly classic lesions, and best supportive care for all lesion types).
A six-state Markov model was developed and the rate of disease progression was modelled as the probability of progressing to a different level of visual acuity health state in each model cycle. The model extrapolated the effects of the 2-year trial period (or 1 year for ranibizumab in predominantly classic lesions) to 10 years in both arms of the model. Ranibizumab and pegaptanib treatments are assumed to have stopped at the end of year 2, and thereafter benefits were assumed to decline at the same rate as those for usual care, although from a higher level of visual acuity.
Resources and costs incorporated in the Assessment Group model included those for treatment, administration, monitoring, managing adverse events and blindness.
Ranibizumab
The Assessment Group's base-case ICERs over a 10-year time horizon for predominantly classic lesions assuming 1 year of treatment were 15,638 pounds sterling per QALY gained compared with PDT, and 11,412 pounds sterling per QALY gained compared with best supportive care. For minimally classic lesions and occult no classic lesions, assuming 2 years of treatment, they were 25,098 pounds sterling per QALY gained compared with best supportive care.
The Assessment Group carried out sensitivity analyses of different assumptions used in their model. The results for ranibizumab showed that as the time horizon decreased the ICERs increased.
Pegaptanib
The Assessment Group estimated the base-case ICER for pegaptanib (all lesion types) compared with usual care to be 30,986 pounds sterling per QALY gained over a 10-year time horizon.
The Assessment Group carried out sensitivity analyses of different assumptions used in their model. As with ranibizumab, the results for pegaptanib showed that decreasing the time horizon increased the ICERs. The ICER was also sensitive to the costs of blindness, in particular the uptake of services, estimated as the proportion of patients with visual acuity of less than 6/60 receiving services. Using high uptake and high unit-cost estimates resulted in pegaptanib being economically dominant (with a lower cost and better outcome) compared with usual care. However, when low costs and medium uptake assumptions were used, the ICER increased from the base case of 30,986 pounds sterling to 37,154 pounds sterling per QALY gained.
Further Analysis by the Assessment Group and the Decision Support Unit
The Committee requested additional analysis from the Assessment Group and the Decision Support Unit. The Assessment Group explored alternative assumptions for the main drivers of the economic model: namely the costs of blindness, the costs of administering the injections, the number of injections of ranibizumab, and the utility values used in the analysis. The Decision Support Unit provided similar analyses using the manufacturer's model for pegaptanib.
The Assessment Group explored the cost of treating the first eye to come to clinical attention rather than treating only the better-seeing eye. The analysis assumed an annual incidence of AMD in the second eye of 10% and explored a number of different scenarios. It found that for ranibizumab the additional cost of treating two eyes ranged from about 9,900 pounds sterling to about 28,600 pounds sterling, depending on the number of injections (9 to 24) over 2 years. For pegaptanib, the additional cost of treating two eyes ranged from about 9,100 pounds sterling to about 15,700 pounds sterling.
In addition to the cumulative assumptions described in sections 4.2.4.5 and 4.2.4.6 of the original guideline document, but instead assuming that only 14 injections would be required over two years to attain the same clinical benefit without reducing the frequency of monitoring costs, the ICER for ranibizumab for predominantly classic lesions further decreased from 37,489 pounds to 13,671 pounds per QALY gained compared with PDT, and from 23,887 pounds to 9,900 pounds per QALY gained compared with best supportive care. For minimally classic or classic no occult lesions the ICER decreased from 38,659 pounds to 19,904 pounds per QALY gained compared with best supportive care.
For pegaptanib, the Decision Support Unit used the manufacturer's model to reproduce the manufacturer's finding that the cost per QALY gained for pegaptanib treatment is lower in subgroups with better baseline visual acuity using all the Committee's preferred assumptions. The lowest cost per QALY gained was obtained in a subgroup of people with visual acuity between 6/12 and 6/24. When the inputs outlined in section 4.2.4.4 of the original guideline document were cumulatively considered in the manufacturer's model, the ICER was 23,124 pounds sterling per QALY gained in the 6/12 to 6/24 subgroup compared with best supportive care, 40,627 pounds sterling per QALY gained for the 6/24 to >6/60 subgroup, 115,244 pounds sterling per QALY gained for the 6/60 to >3/60 subgroup, and 34,602 pounds sterling per QALY gained for the whole cohort. Using the same set of assumptions, the ICER from the Assessment Group model was 44,259 pounds sterling per QALY gained for the whole group irrespective of visual acuity levels.
Consideration of the Evidence
The Committee concluded that treatment with ranibizumab would be cost effective if the manufacturer pays for the drug cost of ranibizumab beyond 14 injections in the treated eye. The Committee further concluded that treatment with pegaptanib for wet AMD is not a cost-effective use of national health Service (NHS) resources.
Refer to Sections 4.2 and 4.3 of the original guideline document for details of the economic analyses provided by the manufacturer, the Assessment Group comments, and the Appraisal Committee considerations.
