3 The company's submission

The Appraisal Committee (section 7) considered evidence submitted by Allergan and a review of this submission by the Evidence Review Group (ERG), plus additional analysis (section 8). The company also received permission to submit new evidence in response to the appraisal consultation document.

Clinical effectiveness

3.1 The company identified 6 randomised controlled trials (RCTs) that compared dexamethasone intravitreal implant with a relevant comparator in adults with diabetic macular oedema (DMO; MEAD‑010, MEAD‑011, study 024, PLACID, NCT00035906 and BEVORDEX).

3.2 MEAD‑010 and MEAD‑011 were identical in design and provided the key data for dexamethasone intravitreal implant in the company submission. The trials compared dexamethasone 700 micrograms and dexamethasone 350 micrograms with sham procedure in adults who had been treated before with medical or laser photocoagulation therapy or if laser photocoagulation therapy was not suitable. MEAD‑010 included 494 patients and took place at 59 study centres in 10 countries, including countries in Australasia, North America, Europe, Asia, and Africa. MEAD‑011 included 554 patients and took place at 72 study centres in 14 countries, including countries in South America, Europe, Australasia, Asia and North America. Patients were included in the trials if they had a baseline best corrected visual acuity (BCVA) between 34 and 68 letters and a baseline central retinal thickness (CRT) of 300 micrometres or more. Both trials lasted between 36 and 39 months. In both trials, patients had the first treatment on the day of randomisation. They were evaluated for re‑treatment at 6 months and then every 3 months, although treatment was not given more often than every 6 months. Patients were eligible for re‑treatment if retinal thickness in the 1 mm central macular subfield was greater than 225 micrometres (until May 2010) or 175 micrometres (from May 2010), or if optical coherence tomography showed evidence of residual retinal oedema consisting of intraretinal cysts or any regions of increased retinal thickening. The primary outcome in both trials was mean BCVA average change from baseline which was performed using analysis of covariance (ANCOVA) with the treatment as a fixed effect and the baseline BCVA as a covariate. For patients with no post‑baseline BCVA assessment, the average change from baseline was 0.

3.3 Study 024 was an open‑label trial comparing dexamethasone 700 micrograms with ranibizumab 0.5 mg. Patients having dexamethasone intravitreal implant were treated at baseline, month 5 and month 10.

3.4 PLACID compared dexamethasone 700 micrograms plus laser photocoagulation with sham procedure plus laser photocoagulation in 253 patients. Patients had either dexamethasone intravitreal implant or sham procedure on the day of randomisation. At 1 month all patients had laser photocoagulation treatment. Patients could have up to 3 additional laser photocoagulation treatments (at months 4, 7 and 10) and 1 additional dexamethasone intravitreal implant treatment or sham procedure (at month 6 or 9).

3.5 NCT00035906 compared dexamethasone 700 micrograms and dexamethasone 350 micrograms with observation in 171 patients. The population included people with DMO and people with macular oedema associated with uveitis, retinal vein occlusion or Irvine–Gass syndrome, that persisted at least 90 days after laser photocoagulation or medical treatment. Patients had a single treatment at randomisation and were followed for 90 days.

3.6 BEVORDEX compared dexamethasone 700 micrograms with bevacizumab 1.25 mg in 88 eyes. Dexamethasone intravitreal implant was not given more than every 4 months.

3.7 For full details of the trials, please see the company's submission.

Outcomes of the trials

3.8 The outcomes from the trials were analysed using an intention‑to‑treat approach. Missing data were accounted for by using a last observation carried forward approach.

3.9 In the MEAD trials, the pooled results showed there was a statistically significant difference in the mean BCVA average change when dexamethasone intravitreal implant and sham procedure were compared in the general DMO population (3.5 letters with dexamethasone compared with 2.0 letters with sham, p=0.023) and in people with a pseudophakic lens (6.5 letters with dexamethasone compared with 1.7 letters with sham, p<0.001).

Health‑related quality of life

3.10 Health‑related quality of life and visual functioning were assessed in the MEAD trials. EQ‑5D, NEI‑VFQ 25 and SF‑36 were assessed at baseline and NEI‑VFQ 25 was also assessed at follow‑up. The NEI‑VFQ 25 is a vision‑specific quality‑of‑life measure that has been validated in a DMO population. It consists of 25 vision‑targeted questions that represent 11 vision‑related quality‑of‑life subscales and 1 general health item. SF‑36 and EQ‑5D were not assessed during follow‑up as they do not contain vision‑specific items.

3.11 There were no statistically significant differences in the mean average change in health‑related quality of life when comparing dexamethasone intravitreal implant with sham procedure in the MEAD trials (overall composite score: dexamethasone 1.9 versus sham 2.2, p=0.64; general vision: dexamethasone 4.5 versus sham 5.0, p=0.92; difficulty with near vision: dexamethasone 5.8 versus sham 4.3, p=0.25; difficulty with distance vision: dexamethasone 2.9 versus sham 2.7, p=0.70; mental health symptoms due to vision: dexamethasone 4.6 versus sham 4.8, p=0.89). The company stated that the health‑related quality of life of patients having dexamethasone intravitreal implants was negatively affected by lens opacification and primary cataract formation. A post‑hoc analysis done by the company showed that, after cataract surgery, the improvement in vision‑related quality of life associated with dexamethasone intravitreal implant use was greater than that before cataract formation and it was similar to the improvement reported in people with a pseudophakic lens.

Treatments and discontinuations

3.12 The mean number of dexamethasone intravitreal implant treatments per patient in the MEAD trials was 4.1. Less than 10% of patients had therapy every 6 months.

3.13 In the MEAD trials, 36% of patients in the dexamethasone 700 micrograms group and 57% of patients in the sham procedure group discontinued from the trial. Of the discontinuations in the dexamethasone intravitreal implant group, 36% were because of adverse events, 24% because of 'other' reasons, 18% because of a lack of efficacy, 11% withdrew for personal reasons, 9% were lost to follow‑up, and 2% were withdrawn because of protocol violations. Of the discontinuations in the sham group, 42% withdrew because of lack of efficacy, 20% withdrew because of adverse events, 15% withdrew for 'other' reasons, 13% withdrew for personal reasons, 9% were lost to follow up, and less than 1% were withdrawn because of protocol violation. 'Other' reasons included closure of the study site, patient withdrawal of consent, poor compliance from the patient, sponsor request, patient participation in another trial, and patient relocation. In NCT00035906, 7 (12%) of patients in the dexamethasone 700 micrograms group discontinued treatment and 8 (14%) of patients in the observation group discontinued from the trial.

Deaths and adverse events

3.14 There were 9 deaths in the dexamethasone intravitreal implant group and 5 deaths in the sham group in the MEAD trials. None of these deaths were related to treatment. There were 2 deaths in the group that had dexamethasone intravitreal implant in NCT00035906, although it is not reported whether these were treatment‑related deaths, and there were no deaths in the sham group. In the PLACID trial, there were 2 deaths in the dexamethasone intravitreal implant plus laser group and 4 deaths in the laser monotherapy group. None of the deaths were treatment‑related. The number of deaths in study 024 was reported as confidential and cannot be presented here. It was not reported whether the deaths were treatment‑related.

3.15 The most common ocular treatment‑related adverse events in the MEAD trials were cataract formation and raised intraocular pressure with dexamethasone intravitreal implant, and conjunctival haemorrhage with sham procedure. Treatment was discontinued because of adverse events in 45 (13.0%) patients having dexamethasone intravitreal implant and 40 (11.4%) patients having sham in the MEAD trials.

3.16 In study 024, the number of treatment‑related adverse events was reported as confidential and cannot be presented here.

3.17 In PLACID, treatment‑related adverse events were reported in 52 (41.6%) eyes treated with dexamethasone intravitreal implant plus laser photocoagulation and in 24 (18.9%) eyes treated with laser photocoagulation alone. There were no serious adverse events related to treatment. The number of treatment‑related adverse events in patients with a pseudophakic lens was not reported in the company's submission.

3.18 The number of treatment‑related adverse events was not reported for the BEVORDEX or NCT00035906 trials. There were no treatment‑related serious adverse events in the dexamethasone intravitreal implant group in NCT00035906.

Subgroup analyses

3.19 In patients with a pseudophakic lens, the mean BCVA change from baseline in the MEAD trials was statistically significantly greater with dexamethasone intravitreal implant compared with sham procedure. There were fewer ocular adverse events in the study eye in people with a pseudophakic lens in the MEAD trials than in the general DMO population. This is because people with a pseudophakic lens cannot develop cataracts.

Network meta‑analysis

3.20 Because the head‑to‑head trials did not compare dexamethasone intravitreal implant with all of the relevant comparators, the company carried out a network meta‑analysis. The network meta‑analysis included 5 of the 6 trials already identified (MEAD‑010, MEAD‑011, study 024, PLACID, and BEVORDEX) plus 6 other RCTs identified in a systematic review carried out specifically for the network meta‑analysis (BOLT, ETDRS, OLK, PROTOCOL I, RESTORE and REVEAL). NCT00035906 was not included in the base‑case network meta‑analysis because it did not report data at 12 months.

3.21 The network meta‑analysis included 2 trials that compared dexamethasone intravitreal implant with sham procedure or no treatment (MEAD‑010 and MEAD‑011). It included 3 trials that compared ranibizumab plus laser photocoagulation with ranibizumab alone and laser photocoagulation alone (PROTOCOL I, RESTORE, REVEAL) and 2 trials that compared laser photocoagulation with sham or no treatment (ETDRS and OLK). The network also included 1 trial for each of the following comparisons: dexamethasone intravitreal implant compared with ranibizumab (study 024), bevacizumab compared with laser photocoagulation (BOLT), dexamethasone intravitreal implant plus laser photocoagulation compared with laser photocoagulation alone (PLACID), and dexamethasone intravitreal implant compared with bevacizumab (BEVORDEX).

3.22 All trials included in the network meta‑analysis reported data for gaining and losing 10 letters at 12 months, except BOLT which only reported data for gaining letters. The network meta‑analysis included data for 10‑letter loss, a change of less than 10 letters and 10‑letter gain for the general DMO population of the trial and for the subgroup of patients who had a pseudophakic lens. The BCVA data from each of the trials were split into the following 3 categories: worsening, defined as a loss of 10 or more letters at 12 months; stable, defined as loss or gain of less than 10 letters at 12 months; and improvement, defined as gain of 10 or more letters at 12 months. The stable vision group for each trial was calculated by subtracting the total number of patients from the number of patients losing 10 or more letters and the number of patients gaining 10 or more letters.

3.23 The results of the network meta‑analysis for the general DMO population showed that dexamethasone intravitreal implant alone was not associated with a statistically significant benefit in gaining or losing 10 letters over sham or no treatment. The results showed that dexamethasone intravitreal implant plus laser, laser alone, ranibizumab plus laser, ranibizumab alone, and bevacizumab were associated with a statistically significantly higher risk of gaining at least 10 letters compared with sham or no treatment, and a statistically significantly lower risk of losing at least 10 letters compared with sham or no treatment. The company stated that all models fitted to the general DMO population resulted in mild to moderate heterogeneity between the trials. The company also noted that the 95% credible intervals around the estimated heterogeneity were wide, denoting uncertainty around the true amount of heterogeneity.

3.24 The company also created a separate network to assess the impact on the efficacy outcomes of patients with a pseudophakic lens at baseline. The network for patients with a pseudophakic lens included the same trials and pathways as the network for the general DMO population, but used data on patients with a pseudophakic lens if available. For trials where data on patients with a pseudophakic lens were not reported separately (OLK, ETDRS, BOLT, BEVORDEX, REVEAL or RESTORE), the company used general DMO population data. The results of the network meta‑analysis for people with a pseudophakic lens were similar to those for the general DMO population. However, dexamethasone intravitreal implant plus laser photocoagulation therapy was not associated with a statistically significantly higher risk of gaining or losing at least 10 letters compared with sham or no treatment (the numbers are reported as confidential and cannot be presented here).

3.25 Sensitivity analyses were conducted for the network meta‑analysis based on data from the FAME trial, which compared fluocinolone acetonide intravitreal implant with sham procedure. The company reported that the results for all interventions included in the base case remain largely unchanged when FAME trial data were included and when the outcome of gaining 15 or more letters was used. The results of the network meta‑analysis including the FAME trial are confidential and cannot be presented here.

Pairwise meta‑analysis of the MEAD trials

3.26 The company carried out a pairwise meta‑analysis of MEAD‑010 and MEAD‑011 and the results were then qualitatively compared with the results from the network meta‑analysis for dexamethasone intravitreal implant compared with sham procedure or no treatment. The results (corrected for an error during the factual error check stage of the appraisal – see ERG erratum) showed that the relative risk from the pairwise meta‑analysis of losing 10 or more letters was 0.72 (95% CrI 0.35 to 1.25) whereas the relative risk from the network meta‑analysis was 0.71 (95% CrI 0.41 to 1.08). The relative risk for gaining at least 10 letters at 12 months from the pairwise meta‑analysis was 1.35 (95% CrI 0.77 to 2.21) whereas the relative risk from the network meta‑analysis was 1.40 (95% CrI 0.92 to 2.14).

Cost effectiveness

3.27 The company submitted an economic evaluation that, in the base case, compared dexamethasone intravitreal implant with a watch‑and‑wait approach for patients with DMO that has not responded to non‑corticosteroid treatment or for whom such treatment is unsuitable, and compared dexamethasone intravitreal implant with ranibizumab for patients with DMO who have a pseudophakic lens. The company carried out additional analyses comparing dexamethasone intravitreal implant with fluocinolone acetonide intravitreal implant in people with disease that has not responded adequately to non‑corticosteroids, and with bevacizumab, watch‑and‑wait and laser photocoagulation in people with a pseudophakic lens.

3.28 For patients with DMO that is considered unsuitable for non‑corticosteroid therapy, dexamethasone intravitreal implant was considered as a first‑ or second‑line treatment option. For patients with DMO that has not responded adequately to non‑corticosteroid therapy (such as ranibizumab, bevacizumab and laser photocoagulation), dexamethasone intravitreal implant was considered as a second‑line treatment. The company considered watch‑and‑wait to be the most appropriate comparator for patients with disease that has not responded adequately to non‑corticosteroid therapy, and those for whom non‑corticosteroid therapy is not suitable. The company used data from the whole DMO population as a proxy for both populations because the available evidence did not suggest a differential efficacy between them and the general DMO population.

3.29 For patients with DMO who have a pseudophakic lens, dexamethasone intravitreal implant was considered as a first‑ or second‑line treatment. The company considered the most appropriate comparator to be ranibizumab, as this is the most common first‑line treatment for DMO. The analysis was based on the network meta‑analysis for patients with a pseudophakic lens. This included data from the subgroup of patients with a pseudophakic lens in the pooled MEAD trials and data for the subgroups of people with a pseudophakic lens in the other trials in the network if available. If data from people with a pseudophakic lens were not available in the trials, data for the whole DMO population were used instead to enable the network to be constructed.

3.30 The model had 3‑monthly cycles and a time horizon of 15 years. A half‑cycle correction and a discount rate of 3.5% for quality‑adjusted life‑years (QALYs) and costs were applied. An NHS and personal social services perspective was used.

3.31 There were 6 health states in the model defined by the BCVA changes in each eye, regardless of whether the eye was treated, in addition to the absorbing health state of death. Both eyes could transition independently between the 6 visual acuity states. The health states were defined by a 10‑letter range in BCVA:

  • health state 1: people with a BCVA of 35 letters or less

  • health state 2: people with a BCVA of 36–45 letters

  • health state 3: people with a BCVA of 46–55 letters

  • health state 4: people with a BCVA of 56–65 letters

  • health state 5: people with a BCVA of 66–75 letters

  • health state 6: people with a BCVA of 76 letters or more.

    Patients could move into an improved health state, remain in the same health state, or move into a worse health state. The probability of moving between visual acuity states in each cycle was modelled using transition probability matrices.

3.32 The model allowed BCVA changes in both eyes to be modelled independently, with the 'better‑seeing eye' (BSE) and 'worse‑seeing eye' (WSE) defined at baseline and fixed throughout the time horizon. The baseline distribution of vision across visual acuity states was reported as confidential and cannot be presented here. Patients entering the model could be affected by DMO in either their BSE or WSE (unilateral DMO), or both eyes (bilateral DMO), with the proportions determined by the pooled number of patients in these groups in the dexamethasone intravitreal implant treatment arms of the MEAD trials. The proportions are assumed to vary by population.

3.33 Patients with DMO in 1 eye at baseline could develop DMO in their other eye ('fellow eye involvement') and move to bilateral treatment. In the model, this could occur only at the end of year 1 or year 2. Patients with bilateral DMO were assumed to have the same treatment in both eyes. Patients could discontinue treatment because of adverse events or loss of efficacy of treatment.

3.34 Patients were at risk of death at all times during the model. The risk of all‑cause mortality was applied to all patients, adjusted for the additional mortality from diabetes and from DMO. The model assumed that mortality occurred equally across all visual acuity states. There was no additional mortality from blindness in the base case (although this was tested in sensitivity analyses).

3.35 For the baseline effect, the 3‑monthly probabilities of eyes treated with dexamethasone intravitreal implant transitioning between visual acuity states were based on the dexamethasone arm of the pooled MEAD trials. For the relative effect, the transition probabilities for watch‑and‑wait were calculated by applying the relative risks for sham procedure from the network meta‑analysis to the 3‑month transition probabilities for dexamethasone intravitreal implant (baseline treatment). For the relative effects of ranibizumab (and bevacizumab, laser photocoagulation and fluocinolone acetonide intravitreal implant in the sensitivity and scenario analyses) the transition probabilities were calculated by applying the relative risks from the network meta‑analysis to the 3‑month transition probabilities for dexamethasone intravitreal implant (baseline treatment). If treatment was discontinued, visual acuity was assumed to follow the natural history of vision in eyes with DMO based on Mitchell et al. (2012). Eyes without DMO were assumed to maintain constant vision.

3.36 The model included data for 5 adverse events: cataracts, raised IOP, retinal detachment, endophthalmitis and vitreous haemorrhage. Data were taken from the clinical trials included in the network meta‑analysis. Data for watch‑and‑wait were taken from a natural history study (the Blue Mountains study). The risk of adverse events was assumed to be equal for the general DMO population and the population with a pseudophakic lens, except that there was no risk of cataract in the population with a pseudophakic lens. Adverse effects did not have any effect on health‑related quality of life in the model.

3.37 The company concluded that the published utility values used in NICE technology appraisal guidance on ranibizumab for treating diabetic macular oedema and fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy were subject to a large number of limitations:

  • the published utility values corresponded to visual impairment resulting from causes other than DMO

  • the majority of utility values were based on vision in the BSE only, meaning assumptions were needed for the impact of vision resulting from treatment of the WSE or bilateral treatment

  • the health states for which utility values were available did not match the health states in the company's model, meaning adjustments or assumptions were needed to make the published utility data 'fit' within model structures.

3.38 Health‑related quality of life in the model was dependent on the patient's visual acuity. The company conducted its analyses using Visual Function Questionnaire Utility Index (VFQ‑UI) data, which were calculated from the 25‑item National Eye Institute Visual Function Questionnaire (NEI VFQ‑25) data collected in the MEAD clinical trials. These data related specifically to the DMO population. A regression model was used to estimate utility values for each patient, based on the BCVA of a patient's BSE and WSE. It included vision in the BSE and in the WSE separately as exploratory variables, allowing both eyes to contribute independently to the utility equation used in the economic modelling. The BCVA of the BSE had a higher impact on the estimated utility than the BCVA of the WSE. VFQ‑UI data calculated from the NEI VFQ‑25 data collected in the MEAD trials were used directly to estimate utilities in the model. EQ‑5D values obtained from the MEAD clinical trials were used in the sensitivity analyses. The company performed a systematic review for publications with additional health‑related quality‑of‑life data, but did not find any relevant studies. The utility values associated with the different visual acuity states are reported as confidential and cannot be presented here.

3.39 The company used NHS reference costs and the Monthly Index of Medical Specialities to cost the resources associated with treatment of DMO, including: intervention costs, monitoring and test costs, health state costs and adverse event costs. Treatments were costed as follows: dexamethasone intravitreal implant, £870.00; ranibizumab, £742.17; and fluocinolone acetonide intravitreal implant, £5500. Laser photocoagulation was assumed to have zero cost because all treatment centres were thought to have access to existing equipment. Watch‑and‑wait was also associated with zero cost. Bevacizumab was assumed to have an acquisition cost of £50.00 in line with the lower limit reported in the NICE Decision Support Unit report on bevacizumab in eye conditions: issues related to quality, use, efficacy and safety. Ranibizumab and fluocinolone acetonide intravitreal implant both have a confidential patient access scheme and scenario analyses varying the discount to the list price were provided by the company. The cost of laser photocoagulation administration was assumed to be £116.68. All intravitreal injections were assumed to be given in an outpatient setting at a cost of £116.68. If a day‑case procedure was used in the sensitivity analyses, the cost was assumed to be £356.35.

3.40 The assumed total costs per round of treatment were different for unilateral and bilateral disease, except for laser photocoagulation which was assumed to have the same cost for both (£116.68). Dexamethasone intravitreal implant was assumed to have a total cost of £986.68 for treating unilateral disease and £1944.19 for bilateral disease. For ranibizumab, the total cost based on its list price was £858.85 for unilateral disease and £1659.36 for bilateral disease. The total cost of bevacizumab was £166.68 for unilateral disease and £275.02 for bilateral disease. Fluocinolone acetonide intravitreal implant was assumed to have a total cost of £5616.68 for treating unilateral disease and £11,204.19 for bilateral disease (based on its list price).

3.41 The costs of monitoring and tests used were as follows (all sourced from NHS reference costs): routine monitoring visit, £80.04; optical coherence tomography, £18.06; fluorescein angiography, £116.68; and IOP check, £80.04. The costs of monitoring and treatment were assumed to be equal across all health states. In addition, if BCVA in the BSE fell below 35 letters (severe vision loss), there were a number of additional costs including community care, residential care, hip replacement and depression (total cost per patient per year for severe vision loss is £16,755.23).

3.42 The average number of monitoring visits used in the model was taken from the NICE technology appraisal guidance on fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy for watch‑and‑wait and fluocinolone acetonide intravitreal implant, NICE technology appraisal guidance on ranibizumab for treating diabetic macular oedema for ranibizumab, and the summary of product characteristics and clinical opinion for dexamethasone intravitreal implant. In the model it was assumed there would be 4 monitoring visits each year for watch‑and‑wait, dexamethasone intravitreal implant and laser photocoagulation. It was assumed there would be 12 visits in year 1, 10 visits in year 2, and 4 visits in year 3 for ranibizumab and bevacizumab.

3.43 The average number of treatments per year used in the model was taken from the MEAD trials (dexamethasone intravitreal implant), FAME (fluocinolone acetonide intravitreal implant), RESTORE (ranibizumab), BOLT (bevacizumab, trial data to year 2 and then assumed to be equal to ranibizumab), and PROTOCOL I (laser photocoagulation, trial data to year 2 and then the last observation was carried forward). The model assumed a maximum treatment duration of 3 years. The number of treatment visits for dexamethasone intravitreal implant and laser photocoagulation are reported as confidential and cannot be presented here. It was assumed that there would be 1 visit in year 1 and 0.26 visits in years 2 and 3 for fluocinolone acetonide intravitreal implant. The model assumed 7 treatment visits in year 1, 3.9 visits in year 2 and 2.9 visits in year 3 for ranibizumab, and 9 visits in year 1, 4 visits in year 2 and 2.9 visits in year 3 for bevacizumab. It was assumed that there were no treatment visits with watch‑and‑wait. The model allowed the use of rescue therapy with laser photocoagulation for some interventions, although not in the comparison of dexamethasone intravitreal implant with watch‑and‑wait.

3.44 Adverse events were associated with costs in the model, all taken from NHS reference costs. The cost of a cataract extraction procedure was assumed to be £865.56. The total average cost of treating raised IOP per patient was £262.40 for medical management and £1222.93 for surgical management (costs stated here are those used in the company model). The cost of re‑attachment of the retina following retinal detachment was £1685.00. The cost of vitreous biopsy following endophthalmitis was £1393.00. The cost of a vitrectomy procedure following vitreous haemorrhage was £1685.00.

3.45 In the company's base case, dexamethasone intravitreal implant dominated watch‑and‑wait for patients with DMO that does not respond adequately to non‑corticosteroid therapy, or for whom such treatment is unsuitable (incremental costs: −£1469; incremental QALYs 0.0656). In the full population of people with a pseudophakic lens, treatment with ranibizumab resulted in a deterministic incremental cost‑effectiveness ratio (ICER) of £50,905 per QALY gained (incremental costs £6004, incremental QALYs 0.1179) compared with dexamethasone intravitreal implant when the list price of ranibizumab was used. The corresponding probabilistic ICER was £89,531 per QALY gained (incremental costs £6710, incremental QALYs 0.0749). When a discount of 50% was applied to the list price of ranibizumab, ranibizumab dominated dexamethasone intravitreal implant in the deterministic analysis (incremental costs −£716, incremental QALYs 0 1179) and probabilistic analysis (incremental costs −£15, incremental QALYs 0.0749).

Company sensitivity analyses and scenarios

3.46 The company carried out 1‑way sensitivity analyses and scenario analyses to assess the impact on the deterministic results.

3.47 In the company's sensitivity analyses for patients with DMO that has not responded adequately to non‑corticosteroid therapy, or for whom such treatment is unsuitable, dexamethasone intravitreal implant remained cost‑effective compared with watch‑and‑wait. The ICERs were most sensitive to changes to the cost of residential care and the percentage of patients requiring residential care.

3.48 In the company's sensitivity analyses for people with a pseudophakic lens, dexamethasone intravitreal implant remained cost effective compared with ranibizumab at list price. The ICERs were most sensitive to changes to the relative risk of worsening vision from the network meta‑analysis and the proportion of outpatient procedures for ranibizumab.

3.49 The company performed 28 scenario analyses. The scenarios that had a significant impact on the ICER are reported in sections 3.50–3.54.

3.50 For patients with DMO that has not responded adequately to non‑corticosteroid therapy, or for whom such treatment is unsuitable, dexamethasone intravitreal implant continued to dominate in the majority of the scenarios. When 1‑year and 5‑year time horizons were used, dexamethasone intravitreal implant had an ICER of £1,822,946 and £127,034 per QALY gained compared with watch‑and‑wait. A 10‑year time horizon resulted in an ICER of £6365 per QALY gained with dexamethasone intravitreal implant compared with watch‑and‑wait. Assuming that the person had DMO in their WSE with no fellow eye involvement resulted in an ICER of £131,276 per QALY gained for dexamethasone intravitreal implant compared with watch‑and‑wait.

3.51 For patients with DMO that has not responded adequately to non‑corticosteroid therapy, the ICER for fluocinolone acetonide intravitreal implant at list price compared with dexamethasone intravitreal implant was £24,591 per QALY gained (incremental costs £1953; incremental QALYs 0.0794). When a discount of 10% was applied to the cost of fluocinolone acetonide intravitreal implant, the ICER decreased to £10,241 per QALY gained. When the discount was increased to 20% or more, fluocinolone acetonide intravitreal implant dominated dexamethasone intravitreal implant.

3.52 For people with a pseudophakic lens, dexamethasone intravitreal implant was dominated by both laser photocoagulation (incremental costs £7359; incremental QALYs −0.0482) and bevacizumab (incremental costs £6318; incremental QALYs −0.1491).

3.53 For people with a pseudophakic lens, the ICERs for ranibizumab compared with dexamethasone intravitreal implant with a 10% and 20% discount to the list price of ranibizumab were £39,510 and £28,116, respectively, per QALY gained. With a discount of 30% and 40% to the list price of ranibizumab, the ICERs were £16,721 and £5327, respectively, per QALY gained. Ranibizumab dominated dexamethasone intravitreal implant when a discount of 50% was applied to the list price of ranibizumab.

3.54 For the other scenarios for patients with a pseudophakic lens, a discount of 50% to the list price of ranibizumab was used. Ranibizumab dominated dexamethasone intravitreal implant in most of the scenario analyses. When stable vision after discontinuing treatment was assumed, the ICER was £1554 per QALY gained for ranibizumab. With a 1‑year, 5‑year and 10‑year time horizon the ICERs were £697,936, £47,729 and £7564 respectively per QALY gained. When it was assumed that there was unilateral DMO in the WSE with no fellow eye involvement, the ICER was £57,384 per QALY gained with ranibizumab. When it was assumed that all injections were given as day cases, the ICER was £16,323 per QALY gained, and when it was assumed that 50% of injections were day cases, the ICER was £5128 per QALY gained.

Company response to clarification

3.55 The company provided several additional analyses in response to clarification; the most important of these are described below.

3.56 In the first analysis, the baseline BCVA distribution in bilateral DMO was taken from the subgroup of patients with bilateral DMO, rather than from patients with unilateral DMO (as in the base case). In people with a pseudophakic lens, the cost effectiveness of dexamethasone intravitreal implant was improved, as it remained cost effective at higher discount to the price of ranibizumab (up to 39% of the list price). Ranibizumab at 50% discount price was not dominant anymore, although it was still cost effective compared with dexamethasone intravitreal implant at an ICER of £7208 per QALY gained.

3.57 In the third and fourth analyses, the company used 3‑month transition probabilities for both watch‑and‑wait and dexamethasone intravitreal implant directly from the pooled data from the MEAD trials rather than from the network meta‑analysis. The ERG argued that the results of the economic analysis between dexamethasone intravitreal implant and watch‑and‑wait should be the same, whether the relative effect is taken from the MEAD trials (as in analyses 3 and 4) or from the network meta‑analysis (as in the company's base case). However, this is not the case. The ERG argued that this may be because the company used relative risks derived from the network meta‑analysis with the assumption that the 12‑month relative risks remained constant to year 3. The ERG believed that this assumption was incorrect because the pooled data from the MEAD trials showed that the relative effect of dexamethasone intravitreal implant versus sham procedure is not stable over 3 years. The ERG also argued that the differences in the economic analyses may be a result of the company's normalisation of the transition probabilities which were done so that the probabilities summed up to 1. This may have introduced bias in the company's analysis, although it is not clear how much and in which direction. The company argued that the results of the network meta‑analysis were more appropriate to use than the pooled MEAD data because the sham arm of the MEAD trials was likely to overestimate the true efficacy of a watch‑and‑wait strategy. The ERG agreed that the use of the MEAD sham data is likely to have overestimated the true efficacy of watch‑and‑wait. However, it highlighted that the MEAD trials were the only ones in the network meta‑analysis that provide relative effects for dexamethasone intravitreal implant compared with sham, and so these relative effects are also present in the results from the network meta‑analysis. In the third analysis, the company restricted movements between health states to a maximum of 1 state (as in the company's base case). This resulted in watch‑and‑wait dominating dexamethasone intravitreal implant. In the fourth analysis, there was unrestricted movement between health states. This resulted in an ICER of £1,411,676 for dexamethasone intravitreal implant compared with watch‑and‑wait. The ERG argued that the fourth analysis, which uses data directly from the MEAD trials, appears to be more reflective of relative clinical effects between dexamethasone intravitreal implant versus watch‑and‑wait for patients with DMO that is unsuitable for or insufficiently responsive to non‑corticosteroid therapy.

New company evidence submitted at ACD comments stage

3.58 The company received permission from NICE to submit new analyses in response to the appraisal consultation document on patients who do not have a pseudophakic lens and with DMO that does not respond to non‑corticosteroid treatment, or for whom such treatment is unsuitable. The company's base‑case analyses including the new evidence used the head‑to‑head MEAD trial data, incorporated the corrections previously made by the ERG and included changes to 4 further areas:

  • Residential care costs.

  • Transition matrices.

  • Utility values.

  • Clinical continuation rule.

3.59 In its new analyses, the company considered the true cost of residential care was unlikely to be wholly in the private sector or local authority. Instead, it used a weighted cost that was 95% of the cost of private sector residential care and 5% of the cost of local authority residential care, giving an annual residential care cost of £28,985. Implementing this change, together with the assumptions preferred by the Committee in the appraisal consultation document (see section 4.19), gave an ICER of £1,170,914 per QALY gained (incremental costs £6753; incremental QALYs 0.0058) for dexamethasone intravitreal implant compared with watch‑and‑wait.

3.60 The company believed that the high discontinuation rates in the MEAD studies were a major source of uncertainty in its previous analyses. It considered that the natural history transition matrix from Mitchell et al. (2012) had likely overestimated BCVA in patients who discontinued because of a lack or loss of efficacy or who were censored from the study:

  • The natural history trajectory estimated by Mitchell et al. was based on a population of patients with diabetes who may or may not have had an associated eye condition (for example, diabetic retinopathy or DMO).

  • The estimate was based on a total population that may have had better vision than a population of patients who had discontinued treatment because of a lack or loss of efficacy.

  • The same probability of improving or worsening vision was applied irrespective of the starting health state.

3.61 In its new analyses, the company estimated the outcomes for patients who were censored from or who discontinued the studies in both treatment arms using a last transition carried forward (LTCF) approach. For these patients, the last observed transition (that is, the change in BCVA between the last 2 visits before discontinuation or censoring) was applied in every cycle after discontinuing until the end of the initial 3‑year treatment period. Transition matrices were generated for each 3‑month cycle then cumulative LTCF matrices were combined with the observed transition matrices to give an estimated matrix for the total population, assuming no discontinuation from treatment. This methodology was applied to both treatment arms and re‑treatment rates were adjusted to reflect the lack of discontinuation. Adding this change to the assumptions in section 3.59 caused the ICER for dexamethasone intravitreal implant compared with watch‑and‑wait to drop from £1,170,914 per QALY gained to £148,403 per QALY gained (incremental costs £5554; incremental QALYs 0.0374).

3.62 The company stated that there was no evidence to suggest that other model types would provide a better fit to the data derived from the MEAD trials than the linear regression approach. It noted that including an interaction term between BCVA in the BSE and BCVA in the WSE did not improve the model fit or provide a meaningful point estimate for the interaction. In its new base case, the company used published estimates of utility values from Czoski‑Murray et al. (2009) instead of those derived from the MEAD studies, which covered a narrower range. The company noted that in previous technology appraisals for DMO, the Committee had preferred these published values. The company included scenario analyses using utility values from Brown (1999) and Brown et al. (2000) because these have also been discussed in other technology appraisals in DMO. Because these 3 studies reported only BSE utility values, the company estimated the utility values in the WSE by assuming that the change in the WSE was 30% of that in the BSE, which it said was consistent with assumptions in previous technology appraisals. Adding this change to the assumptions in section 3.61 caused the ICER for dexamethasone intravitreal implant compared with watch‑and‑wait to drop further from £148,403 per QALY gained to £50,280 per QALY gained (incremental costs £5554; incremental QALYs 0.1105).

3.63 The company applied a clinical continuation rule for dexamethasone intravitreal implant in its economic model. It was assumed that treatment was not continued if patients did not gain at least 5 letters by month 6 after their first injection of dexamethasone intravitreal implant. Of the 338 patients remaining in the dexamethasone intravitreal implant arm at month 6 in the MEAD studies, 105 (31.1%) did not gain at least 5 letters by month 6. These patients were assigned transition probabilities associated with the natural history of vision (in line with Mitchell et al.). Applying only the continuation rule gave an ICER of £678,142 per QALY gained (incremental costs £5347; incremental QALYs 0.0079). Adding this change to the assumptions described in section 3.62 resulted in the company's base‑case ICER using the new evidence submitted in response to the appraisal consultation document (see below).

3.64 In its new analyses of patients who do not have a pseudophakic lens and with DMO that does not respond to non‑corticosteroid treatment, or for whom such treatment is unsuitable, the company's base‑case ICER for dexamethasone intravitreal implant was £14,978 per QALY gained (incremental costs £2523; incremental QALYs 0.1685). According to the company's probabilistic analyses, the probability of dexamethasone being cost effective compared with watch‑and‑wait was 54% at a maximum acceptable ICER of £20,000 and 58% at a maximum acceptable ICER of £30,000 per QALY gained.

ERG comments on the company's main submission

Clinical evidence

3.65 The ERG stated that none of the 6 RCTs of dexamethasone intravitreal implant directly addressed the populations covered by the marketing authorisation. All 6 RCTs included broader populations than those specified in the marketing authorisation.

3.66 The ERG stated that none of the RCTs presented in the company's submission directly assessed the efficacy of dexamethasone intravitreal implant in the populations outlined in the marketing authorisation (people with a pseudophakic lens, and people with DMO that has not responded to non‑corticosteroid treatment or for whom such treatment is unsuitable). Therefore the efficacy of dexamethasone intravitreal implant in these populations is uncertain, particularly in comparison to the other treatments listed in the final scope. The ERG stated that the whole trial population data should be interpreted with caution in relation to the decision problem. Furthermore, there is an absence of direct comparative data from RCTs comparing the licensed dosing regimen for dexamethasone intravitreal implant with any of the comparators specified by NICE in the decision problem.

3.67 The ERG highlighted that study 024 and BEVORDEX used a dosing regimen of dexamethasone intravitreal implant that is not covered in the EU marketing authorisation. The marketing authorisation requires a 6‑month waiting period between re‑treatments of dexamethasone intravitreal implant, but dexamethasone intravitreal implant was given more frequently than every 6 months in study 024 and BEVORDEX. The ERG argued that these studies are not relevant to the decision problem and did not consider them further in its report.

3.68 The ERG highlighted that the 2 MEAD trials and NCT00035906 were 3‑armed trials, with 1 of the treatment groups being a lower dose of dexamethasone intravitreal implant than that licensed for use in the UK (350 micrograms). The ERG did not consider data from the trial arm using a lower dose of dexamethasone intravitreal implant to be relevant to the decision problem.

3.69 The ERG stated that the treatment algorithms used in the PLACID trial used laser photocoagulation concomitantly with dexamethasone intravitreal implant, which the ERG did not consider to be in line with UK clinical practice.

3.70 The ERG noted that the company did not present data for fluocinolone acetonide intravitreal implant in combination with laser photocoagulation or data for bevacizumab in combination with laser photocoagulation.

3.71 The ERG highlighted that the company's submission only reported BCVA outcomes for the study eye, and not for both eyes as requested in the final NICE scope.

3.72 The ERG stated that the long‑term safety and clinical efficacy data for dexamethasone intravitreal implant is limited because the MEAD trials have a maximum follow‑up duration of 39 months.

3.73 The ERG stated that the results of the MEAD trials are potentially flawed because of high discontinuation rates across the trial arms (36% in the dexamethasone intravitreal implant arm and 57% in the sham arm) in combination with the use of a last observation carried forward analysis to account for the missing data. The ERG believed that a last observation carried forward approach would only be robust if the disease was stable before people discontinued treatment, and the ERG thought that this was unlikely to be the case in the MEAD trials. The ERG was unable to determine in which direction this bias might affect the results. The ERG was also concerned that the discontinuation rates in the dexamethasone intravitreal implant arm of the MEAD trials were higher than discontinuation rates seen with dexamethasone intravitreal implant in the other RCTs.

3.74 The ERG highlighted that the methods used in the network meta‑analyses were in line with the methodology recommended by NICE's Decision Support Unit. However, the ERG were concerned about the validity of the results of the network meta‑analyses for several reasons:

  • There were high levels of clinical and statistical heterogeneity in the network meta‑analyses, which were partly a result of differences in the baseline characteristics of the studies included in the networks.

  • The 95% credible intervals around a large number of the relative risk estimates from the network meta‑analyses and the sensitivity analyses were quite wide and thus there is a large amount of uncertainty around the efficacy estimates.

  • The frequency of dexamethasone treatments used in the ranibizumab and bevacizumab trials differs from that recommended in the European marketing authorisation.

  • The trials linking dexamethasone with the other treatments in the network were not considered comparable.

  • The models were a poor fit to the datasets (as indicated by the residual deviance).

    The ERG considered that the results reported from the network meta‑analyses should be interpreted with caution.

Cost‑effectiveness evidence

3.75 The ERG commented that modelling transitions in BCVA states independently for each eye was an improvement over previous economic models assessing treatment for DMO, because it considers the impact of each of the BSE and WSE on health‑related quality of life separately. This allows a more realistic representation of patient experience and a more accurate estimate of health‑related quality of life.

3.76 The ERG stated that the model structure appears to be consistent with the progression of the disease and reflective of patient presentation and treatment in clinical practice. The treatments and populations used in the model were appropriate to inform the decision problem.

3.77 The use of the VFQ‑UI is more relevant to people with DMO than the EQ‑5D because it contains vision‑specific items. In addition, the EQ‑5D is relatively insensitive to changes in visual functioning.

3.78 The ERG highlighted that the data presented by the company in relation to the impact of cataract on health‑related quality of life were from a post‑hoc analysis and were for near‑vision rather than for the overall composite NEI VFQ‑25 score, and therefore should be interpreted with caution.

Modelling assumptions and approach

3.79 The ERG stated that the economic analysis adopted a number of assumptions and approaches that may have biased the cost effectiveness results, including the following:

  • The assumption that the baseline distributions of BSE and WSE across BCVA states were independent from each other, which may have resulted in the WSE being in a better BCVA state than the BSE at baseline, and potentially throughout the duration of the model.

  • The assumption that the relative effects of all treatments considered in the network meta‑analysis remained stable from initiation of treatment up to 3 years of treatment duration. Evidence from the MEAD trials suggests that this assumption is not correct.

  • The 'normalisation' of transition probabilities in the economic model, in order to ensure that transition probabilities add up to 1, which resulted in the relative risks from the network meta‑analysis being consistently altered from their original values. The ERG argued that this would have introduced bias into the analysis, although the direction and magnitude of the bias was not clear.

  • The restriction of transitions between health states for each cycle, so that each patient could only move 1 BCVA health state per cycle. Further analyses requested by the ERG and undertaken by the company showed that this restriction did not reflect the trial evidence.

3.80 The ERG expressed concern that fluocinolone acetonide intravitreal implant was not included in the base‑case analysis for patients who have a pseudophakic lens and for patients with disease that has not had an adequate response to non‑corticosteroid therapy. The ERG was aware, however, that the data analysis needed to include fluocinolone acetonide intravitreal implant in the base case would have considerable limitations.

3.81 The ERG argued that laser photocoagulation should have been included in the base‑case analysis of patients who have a pseudophakic lens because it is routine clinical practice in patients with DMO and CRT less than 400 micrometres.

Costs

3.82 The ERG noted that the company may have overestimated the cost associated with severe vision loss (BCVA <35 letters) because of an overestimation of the cost of residential care. It noted that the company had used the unit cost of residential care provided by a local authority and that this was inconsistent with previous economic analyses in technology appraisals, which used the unit cost of private residential care. It highlighted views that the private sector is the main provider of residential care in the UK. The unit cost of private residential care is almost 50% lower than the unit cost of residential care provided by a local authority. If the private sector is the main provider of residential care, then use of the unit cost of local authority residential care by the company has greatly overestimated the cost associated with severe vision loss.

Sensitivity analyses

3.83 The ERG stated that the sensitivity analyses conducted by the company were comprehensive. However, the ERG highlighted that the FAME study, used in the company's sensitivity analysis for patients who have not had an adequate response to non‑corticosteroid therapy, had 2 major limitations. The study reported the probability of gaining at least 15 letters, meaning that the probability of gaining at least 10 letters had to be estimated for the model. Also, the study only reported 1 of the 3 outcomes of interest (gaining letters) and the remaining 2 outcomes needed to be estimated.

Scenario analyses

3.84 The ERG highlighted that increasing the duration of treatment from 3 to 5 years had no impact on the results in any population. However, they noted that this was because of limitations in the available data, as only 1 maintenance treatment per year (or a maximum of 1 additional fluocinolone acetonide intravitreal implant treatment) was allowed and extrapolation beyond 3 years was based on the LOCF and stable vision in scenarios 5 and 6 respectively. The ERG acknowledged that this was unlikely to reflect outcomes in DMO patients observed in clinical practice.

3.85 The ERG did not agree that the scenarios with a time horizon less than 10 years were appropriate, because a short time horizon would not allow the long‑term impact of treatment on outcomes to be taken into account. The ERG acknowledged that the company would have to make a number of assumptions to consider a time horizon of longer than 10 years, because the data were only available for up to 3 years. The ERG noted that increasing the time horizon to 20 years did not have any impact on the results.

3.86 The ERG did not believe that giving injections as day cases 100% or 50% of the time was relevant to UK clinical practice because their clinical expert informed them that the vast majority of dexamethasone intravitreal implant and anti‑vascular endothelial growth factor (VEGF) treatments, such as ranibizumab and bevacizumab, would be given in an outpatient setting.

ERG corrections to the model

3.87 The ERG identified and corrected the following errors in the company's model:

  • The annual probability of fellow eye involvement in the model was estimated from the 2‑year probability. This is an instantaneous rate and should have been converted to an annual probability.

  • The mean number of re‑treatments for fluocinolone acetonide intravitreal implant in year 3 in the model (0.26) was based on LOCF. However, cumulative data for year 3 are available. The number of re‑treatments in year 3 was estimated to be 0.036.

  • The probability of cataract for dexamethasone intravitreal implant in years 1, 2, and 3 in the model were 8.40%, 19.17% and 2.94% respectively. The ERG calculated these as 11.83%, 37.66% and 26.39% respectively. The annual probability of cataract in people in the watch‑and‑wait group and in people who discontinued dexamethasone intravitreal implant was also slightly amended from 2.34% to 2.32%.

  • The cost of fluorescein angiography in the model was £117, based on the price of a minor vitreous retinal outpatient procedure. The ERG argued this should have been £144 based on the cost of an outpatient ophthalmology contrast fluoroscopy procedure.

  • The cost of intermediate vitreous procedures used in the model was £1685. The ERG argued this should have been £989. The ERG argued that the total cost of retinal detachment should have been £1080, because they estimated that the management of retinal detachment was achieved by intermediate vitreous procedure (day case) in 80% of cases and by major vitreous procedure (day case) in 20% of cases.

3.88 The ERG also amended the number of monitoring and treatment visits in the model. As well as correcting the number of treatment visits for fluocinolone acetonide intravitreal implant in year 3 (see section 3.87), it assumed that monitoring visits could incorporate treatment visits for ranibizumab and bevacizumab. The ERG increased the number of treatment visits by 1 for dexamethasone intravitreal implant, fluocinolone acetonide intravitreal implant and laser photocoagulation.

3.89 The ERG's corrections to the model did not change the dominance of dexamethasone intravitreal implant compared with watch‑and‑wait for all patients with DMO. For people with a pseudophakic lens, ranibizumab remained dominant at a 50% discount to the list price. At list price the ICER for dexamethasone intravitreal implant compared with ranibizumab, when all of the errors were corrected, was £52,494 per QALY gained. Each of the individual corrections resulted in ICERs between £50,849 and £52,494 per QALY gained at the list price of ranibizumab.

ERG scenario analyses

3.90 For all patients with DMO, only the change to the unit cost of residential care from local authority price to private price changed the base‑case ICER. This changed it from dexamethasone intravitreal implant dominating to an ICER of £30,366 per QALY gained for dexamethasone intravitreal implant compared with watch‑and‑wait.

3.91 For people who have a pseudophakic lens, ranibizumab continued to dominate dexamethasone intravitreal implant with a 50% discount to the list price of ranibizumab in all but 2 scenarios – changing the overall mortality hazard ratio and changing the unit cost of residential care. Using an overall mortality hazard ratio of 3.5 for DMO compared with the general population resulted in an ICER of £197 per QALY gained for ranibizumab compared with dexamethasone intravitreal implant. Changing the unit cost of residential care from local authority price to private price resulted in an ICER of £12,889 per QALY gained. When the list price of ranibizumab was used for patients who have a pseudophakic lens, the ICERs for the scenarios ranged from £43,759 to £69,862 per QALY gained.

ERG exploratory ICERs

3.92 The ERG's base‑case ICER incorporated all corrections to errors in the model and included the following scenarios:

  • in people with a pseudophakic lens, anti‑VEGF treatment in both eyes was assumed to need 1 administration visit 75% of the time and 2 administration visits 25% of the time

  • the numbers of total visits associated with treatment and monitoring of each treatment each year were amended to take into account that some re‑treatment visits included monitoring visits

  • costs associated with IOP checks were removed from the analysis, because IOP checks are performed within monitoring visits

  • the unit cost of local authority residential care was replaced by the unit cost of private residential care

  • updated costs of depression associated with severe vision loss

  • the cost of medication for raised IOP was amended to take into account that generic prostaglandins comprise the more widely used pharmacological treatment for raised IOP

  • the cost of surgery for raised IOP was amended to take into account that trabeculectomy is the only surgical procedure relevant for raised IOP that is an adverse event of treatment in patients with DMO

  • 6 extra IOP visits were assumed for patients with DMO who were treated for raised IOP.

People with a pseudophakic lens with CRT of 400 micrometres or more

3.93 The ICER for patients with a pseudophakic lens was £63,609 per QALY gained (incremental costs £7378, incremental QALYs 0.1160) for ranibizumab compared with dexamethasone intravitreal implant, when the list price of ranibizumab was used.

3.94 A 10% and 20% discount in the list price of ranibizumab resulted in ICERs of £52,119 and £40,630, respectively, per QALY gained. A 30% and 40% discount resulted in ICERs of £29,141 and £17,651, respectively, per QALY gained. When a 50% discount to the list price of ranibizumab was used, the ICER was £6162 per QALY gained (incremental costs £715, incremental QALYs 0.1160) for ranibizumab compared with dexamethasone intravitreal implant.

People with a pseudophakic lens with CRT less than 400 micrometres

3.95 When laser photocoagulation and bevacizumab were included in the ICER calculation for patients with a pseudophakic lens, bevacizumab and laser photocoagulation both dominated dexamethasone intravitreal implant.

People who do not have a pseudophakic lens and with DMO that does not respond to non‑corticosteroid treatment or for whom such treatment is unsuitable

3.96 The ERG's deterministic ICER for dexamethasone intravitreal implant compared with watch‑and‑wait in patients with DMO that does not respond to non‑corticosteroid treatment, or for whom such treatment is unsuitable, became £22,049 per QALY gained (incremental costs £1428, incremental QALYs 0.0648) when network meta‑analysis outputs were utilised. It became £1,166,271 per QALY gained (incremental costs £6727, incremental QALYs 0.0058) when data from the MEAD trials for both dexamethasone intravitreal implant and watch‑and‑wait (sham) were utilised, without transitions being restricted by 1 health state up or down. The ERG emphasised that the results of the model based on the network meta‑analyses are characterised by severe flaws including the assumption that relative risks between all treatments of improving vision, stable vision and worsening vision are equal to the 12‑month relative risks and are stable over the whole 3‑year duration of treatment, and the use of a normalisation approach. The ERG therefore advised that the results obtained from these analyses should be interpreted with great caution.

People with a pseudophakic lens and with DMO that does not respond to non‑corticosteroid treatment or for whom such treatment is unsuitable

3.97 The ICER for fluocinolone acetonide intravitreal implant compared with dexamethasone intravitreal implant for patients with disease that does not respond adequately to non‑corticosteroid therapy, or for whom such treatment is not suitable, was £45,684 per QALY gained (incremental costs £3569, incremental QALYs 0.0781) when the list price of fluocinolone acetonide intravitreal implant was used. The ICER decreased to £33,047 per QALY gained with a 10% discount in the price of fluocinolone acetonide intravitreal implant, £20,411 per QALY gained with a 20% discount, and £7775 per QALY gained with a 30% discount. With a 40% and 50% discount in the price of fluocinolone acetonide intravitreal implant, it dominated dexamethasone intravitreal implant.

ERG comments on new company evidence submitted at ACD comments stage

3.98 The ERG provided comments on the company's new evidence:

  • It found the company's approach to modelling the costs for residential care to be reasonable.

  • Although the ERG agreed that using the utility values from Czoski‑Murray et al. was acceptable, it considered the company's implementation of the utility values for the WSE to be flawed because it could result in the WSE contributing a higher utility value than the BSE.

  • The ERG noted that the company had correctly implemented the clinical continuation rule in its economic model, but it was uncertain if it would be feasible to apply this rule in clinical practice.

3.99 The ERG reviewed how the company had modelled the transition probabilities for patients who had discontinued treatment or had been censored. It noted that using the company's new LTCF approach instead of the original transition matrices considerably reduced the ICER for dexamethasone intravitreal implant versus watch‑and‑wait (from £1,170,914 per QALY gained to £148,403 per QALY gained; see sections 3.60 and 3.61). In its critique, the ERG said that it was clinically implausible for patients who discontinued treatment to have stable disease (that is, to remain in their health state at discontinuation). At the Committee meeting, the company noted it appeared that the ERG had misinterpreted the company's approach. The company confirmed that patients did not remain in the same health state after discontinuing. Instead, the company assumed that no discontinuation or censoring occurred and used patient‑level data to anticipate what would happen in future cycles. The company confirmed it had modelled this by applying the last transition before discontinuing to the overall calculations of future movement between any 2 health states. The ERG agreed that this was an error in its report on the company's new evidence. Nevertheless, it considered the company's previous assumption (that patients who discontinued reverted to a natural history of vision decline) to be less biased.

ERG exploratory analyses

3.100 The ERG regarded some of the assumptions in the company's new analyses submitted in response to the appraisal consultation document to be reasonable (see section 3.98). However, it did not consider the company's alternative transition matrices to be clinically plausible and believed that the utility values based on Czoski‑Murray et al. had not been correctly implemented. The ERG conducted exploratory analyses using the original transition matrices (based on natural history data) and corrected the BSE and WSE utility values applied in the model. Based on the BSE values reported in Czoski‑Murray et al., the ERG calculated the overall utility value as being 10/13 BSE utility and 3/13 WSE utility.

3.101 In people who do not have a pseudophakic lens and with DMO that does not respond to non‑corticosteroid treatment, or for whom such treatment is unsuitable, the ERG's exploratory base‑case ICER for dexamethasone intravitreal implant compared with watch‑and‑wait was £127,645 per QALY gained (incremental costs £5347; incremental QALYs 0.0419).

3.102 Full details of all the evidence are available.

  • National Institute for Health and Care Excellence (NICE)