Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using dexamethasone in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using dexamethasone in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 1 March 2011
Second Appraisal Committee meeting: 9 March 2011

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1. Appraisal Committee's preliminary recommendations

1.1 The Committee is minded not to recommend dexamethasone intravitreal implant for the treatment of macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

1.2 The Committee recommends that NICE requests further clarification from the manufacturer. The following information should be made available for the next Appraisal Committee meeting:

• The clinical and cost effectiveness of dexamethasone intravitreal implant compared with bevacizumab. The cost-effectiveness analysis should include varying vial sharing assumptions for treatment with bevacizumab.
• A revised base case for the cost effectiveness of dexamethasone intravitreal implant, incorporating the following assumptions:
  • the costs of dexamethasone treatment based on a day case, with outpatient appointment costs as a sensitivity analysis
  • the extrapolation of data from the observation arm of the model based on all of the 0- to 6-month data from the randomised controlled trial
  • modelling of the fellow eye involvement, ensuring that costs of blindness are applied only to patients in whom both eyes fall into the worst health state (severe visual impairment).
• Alternative scenario analyses for the re-treatment rate that reflects clinical practice in the UK, including:
  • an analysis in which proportions re-treated are as at day 180 for the five injections after the first injection in people with CRVO
  • an analysis in which proportions re-treated are as at day 180 for the four injections after the first injection in people with BRVO
  • alternative analyses in which proportions re-treated are varied between the two extremes of the base case and the randomised controlled trial.

1.3 The Committee requires further clarification of the location and extent of macular haemorrhage for the subgroup of patients for whom laser treatment was not considered appropriate because of macular haemorrhage.

2. The technology

2.1 Dexamethasone intravitreal implant (Ozurdex, Allergan) is a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration. Corticosteroids inhibit the expression of vascular endothelial growth factor (VEGF), a cytokine that is expressed at increased concentrations in macular oedema and is a potent promoter of vascular permeability. Corticosteroids also prevent the release of prostaglandins, some of which are mediators of cystoid macular oedema.

2.2 Dexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

2.3 The most common adverse reactions are increased intraocular pressure and conjunctival haemorrhage. Conjunctival haemorrhage is related to the intravitreous injection procedure rather than the dexamethasone implant. Other common adverse events include ocular hypertension, vitreous detachment, cataract, subcapsular cataract, vitreous haemorrhage, visual disturbance, vitreous opacities, eye pain, photopsia, conjunctival oedema, anterior chamber cell and conjunctival hyperaemia. For full details of side effects and contraindications, see the summary of product characteristics.

2.4 The cost of a 700-microgram implant and applicator is £870.00 (MIMS, December 2010), excluding VAT. One dexamethasone intravitreal implant is administered usually every 6 months in the affected eye and up to six implants may be given. Costs may vary in different settings because of negotiated procurement discounts.

3. The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dexamethasone and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer submitted evidence of clinical and cost effectiveness for dexamethasone versus best supportive care (observation). No comparison was made with bevacizumab or triamcinolone (Kenalog formulation), which were defined in the scope as comparators for the treatment of macular oedema following both BRVO and CRVO. Similarly, dexamethasone was not compared with grid laser photocoagulation for non-ischaemic BRVO.

3.2 In the manufacturer’s submission, evidence of clinical effectiveness was based on two identical randomised, sham-controlled, three-arm parallel-group studies of dexamethasone intravitreal implant in people with macular oedema secondary to BRVO or CRVO. Both studies (GENEVA 008 and GENEVA 009) had an initial 6-month treatment period followed by a 6-month open-label extension in which all patients in both arms of the study who met the re-treatment criteria received a dexamethasone implant. Patients were re-treated if best corrected visual acuity (BCVA) was less than 84 letters or the retinal thickness by optical coherence tomography was more than 250 µm in the central 1 mm macular subfield and, in the investigators' opinion, the procedure would not put the patient at significant risk. All participants had macular oedema for 6 weeks to 12 months before study entry. Participants were allocated in a 1:1:1 ratio to receive a 700-microgram dexamethasone intravitreal implant (n = 427), a sham implant (n = 426) or a 350-microgram dexamethasone implant (n = 414). This appraisal considered the 700-microgram dose which is the only dose which has a UK marketing authorisation. The sham group had a needleless applicator pressed against the conjunctiva actuated with a click. Investigators were masked to study treatment. The results were presented separately for people with retinal vein occlusion (RVO) and the subgroups of people with macular oedema secondary to CRVO, BRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment. The results from the two studies (GENEVA 008 and GENEVA 009) were pooled and this formed the basis of the evidence considered by the Committee, although the data were also available separately for each study in the manufacturer's submission.

3.3 The results of the pooled analysis showed that for the total RVO population 21.3% of the 427 patients in the intention-to-treat population receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group. This rose to 29.3% at day 60 (compared with 11.3% in the sham group) but returned to 21.8% and 21.5% at day 90 and day 180 respectively (compared with 13.1% and 17.6% in the sham group). The differences were statistically significant at day 30 (p < 0.001), 60 (p < 0.001) and 90 (p = 0.008) but not at day 180 (p > 0.05). The results for patients who were re-treated at day 180 were presented as academic-in-confidence information and are therefore not presented here.

3.4 For the CRVO subgroup 21.3% of patients in the dexamethasone group had an improvement in BCVA from baseline of at least 15 letters compared with 6.8% in the sham group at day 30 (p < 0.001). At day 60, 28.7% in the dexamethasone group had an improvement in BCVA of at least 15 letters compared with 8.8% in the sham group (p < 0.001). There was no statistically significant difference between the groups at days 90 and 180.

3.5 In the subgroup with BRVO, 21.3% of patients receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.9% in the sham group (p < 0.001). The corresponding figures for the subgroup with BRVO with macular haemorrhage were 22.0 % and 8.8 % respectively (p ≤ 0.001). Both subgroups had statistically significant differences between patients treated with dexamethasone and the sham group at days 60 and 90, but not at day 180. In the subgroup with BRVO and previous laser therapy 22.2% had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 2.8% in the sham group (p = 0.028). Differences between the dexamethasone and sham groups were also statistically significant at days 60 (p < 0.001), 90 (p = 0.011) and 180 (p = 0.022).

3.6 The cumulative response rate for time to achieve an improvement in BCVA of at least 15 letters from baseline in the study eye was statistically significant for dexamethasone versus sham. The difference in mean change from baseline BCVA, the categorical change from baseline BCVA and proportion of patients with an improvement in BCVA of at least 10 letters from baseline in the study eye were statistically significantly higher for dexamethasone versus sham at days 30, 60, 90 and 180 in the pooled analysis.

3.7 For all RVO at 180 days, the most common adverse events were raised intraocular pressure, eye pain and ocular hypertension. Intraocular pressure was raised in 25.2 % of patients treated with dexamethasone compared with 1.2 % in the sham group. Of patients treated with dexamethasone, 7.4% had eye pain compared with 3.8% in the sham group. Ocular hypertension was experienced by 4% of patients in the treated group compared with 0.7% in the sham group. Anterior chamber cells and retinal neovascularisation were also reported. Other reported adverse events were retinal detachment, retinal tears and cataract.  Safety data for the re-treated population were presented as academic-in-confidence information.

3.8 For evidence of cost effectiveness, the manufacturer submitted a de novo Markov model that compared treatment with dexamethasone with sham injection in people with macular oedema and vision loss following CRVO or BRVO. Treatment was modelled over a lifetime horizon based on the transition of people between five health states based on the Early Treatment Diabetic Retinopathy Study (EDTRS) measurement of BCVA in the affected eye and death. The worst health state represented visual acuity less than or equal to 38 letters, which equated to severe visual impairment. The best health state was visual acuity of 69 letters or over. The mean BCVA of people in the model was 54 letters, which equates to the second best health state. The patient population was based on data from the GENEVA trials. The model assumed that 90% of people would present with macular oedema in the 'worse-seeing' eye. The model had a cycle length of 1 month for the first 3 months following presentation with RVO, followed by a 3-month cycle in months 4–6 and 6-monthly cycles thereafter. Patients entering the model received dexamethasone or observation. Up to 12 months, transition probabilities were based on pooled patient-level data from the GENEVA studies, including the open-label extension. Beyond 12 months, data were extrapolated from 6- to 12-month data for treatment and re-treatment and 3- to 6-month data for sham. Health effects were assumed to last for 2.5 years in people with BRVO and 3 years in people with CRVO; thereafter visual acuity was assumed to be stable.

3.9 The data inputs for the manufacturer’s model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population. Resource use was identified from a systematic review of the literature and input from clinical specialists. Costs included drug cost and medical resource use (hospital visits, monitoring, costs associated with blindness and the cost of treating adverse events, including raised intraocular pressure, cataracts, retinal tears/detachment). Costs associated with treating adverse events were assumed to increase with the third and fourth treatment.

3.10 Key assumptions of the economic model included:

• 90% of people treated would have macular oedema in the 'worse-seeing' eye
• the stabilisation of visual acuity for 2.5 years in people with BRVO and 3 years in people with CRVO
• re-treatment at 6-monthly intervals with a maximum of five injections for BRVO and six injections for CRVO (with assumptions over the number of treatments received)
• extrapolation beyond the trial duration
• transition probabilities
• a risk of involvement of the other eye of 6.5% in the first year (for those with initial RVO in their 'worse-seeing' eye)
• blindness and an excess mortality hazard of 1.54 associated with a BCVA in the 'better-seeing' eye of 38 or fewer letters (measured by the Early Treatment Diabetic Retinopathy Study [EDTRS]).

Sensitivity analyses included varying utility estimates, costs, stabilisation of visual acuity at day 360, extrapolation assumptions, mortality, involvement of the other eye, discounting, re-treatment, and people with a worse BVCA on entering the model. Results were presented for the entire RVO population and the subgroups of CRVO, BRVO with macular haemorrhage, BRVO with previous laser therapy, BRVO with a diagnosis of 90 days or less at the time of treatment, and BRVO with a diagnosis of more than 90 days at the time of treatment.

3.11 In the base case for all RVO, the total incremental cost was £1667 for dexamethasone compared with observation and the incremental QALYs were 0.23. The incremental cost-effectiveness ratio (ICER) was £7368 per QALY gained for dexamethasone intravitreal implant compared with observation in all RVO. In the base case for CRVO, the total incremental cost was £1836 and the incremental QALYs were 0.31. The cost per QALY gained was £6008 for dexamethasone compared with observation. In the base case for BRVO with macular haemorrhage, the total incremental cost was £1510 and the incremental QALYs were 0.19. The incremental cost per QALY gained was £7953. In the base case for BRVO with previous laser therapy, the total incremental cost was −£1218 (a saving) and the incremental QALYs were 0.31. Dexamethasone was dominant when compared with observation for BRVO with previous laser therapy. In the base case for BRVO with macular oedema for 90 days or less, the total incremental total cost over a patient’s lifetime was £10,993 and the incremental QALYs were 11.75. The corresponding figures were £10,699 and 11.72 respectively for BRVO with macular oedema for more than 90 days. Dexamethasone was dominant for the group treated within 90 days and had an ICER of £11,418 per QALY gained for people treated after 90 days of diagnosis.

3.12 In the sensitivity analysis, the factors having the largest impact on estimates of cost effectiveness for the total population were costs associated with vision loss (costs of residential care and the uptake of residential care), affected eye (proportion of people treated for macular oedema in the 'worse-seeing' eye) and rates of discount. When the annual cost of residential care was reduced from £23,972 to £16,999, the ICER increased from £7368 to £20,288 per QALY gained; all other one-way sensitivity analyses were associated with ICERs below £20,000 per QALY gained.

3.13 The ERG noted the lack of head-to-head or indirect comparisons with other treatments. The ERG highlighted several studies of triamcinolone and bevacizumab that were excluded by the manufacturer. These included case series, prospective and retrospective studies. The ERG considered that an indirect comparison with bevacizumab could have been conducted. The Royal College of Ophthalmologists also submitted interim guidelines that indicated the availability of data on bevacizumab.

3.14 The ERG considered the GENEVA trials to be of high quality. Although there was a statistically significant increase in the BCVA based on the mean letter score with the dexamethasone implant, the ERG did not consider this to be clinically significant because most patients did not achieve a 15-letter improvement from baseline. However, a higher proportion had an improvement of at least 10 letters. The effectiveness of the dexamethasone implant appeared to peak at around 60 days. The ERG highlighted that the trial protocol did not allow for early re-treatment and during the trial and open-label follow-on patients received only two injections of dexamethasone. The ERG noted that the main benefit from re-treatment was in patients whose condition had responded during the initial 180-day trial period. The ERG also commented that the number of treatments needed in practice is not known and that clinical opinion estimated a maximum of six.

3.15 The ERG also highlighted that because the trial included a maximum of two dexamethasone treatments, the impact of up to six treatments on the incidence of adverse events was not known. The ERG also expressed concern over the size of the implantation needle which is larger for dexamethasone than for other treatments. The ERG stated that the main weaknesses in the evidence were lack of long-term follow-up data and data on earlier re-treatment before 180 days.

3.16 The ERG considered the robustness of the manufacturer's model to cost inputs (particularly the cost of dexamethasone administration and the cost of severe visual impairment), structural assumptions in the model (such as the duration of trial data on which to base extrapolation of health states in the treatment and observation arms, assumptions related to the stability of visual acuity in ‘resolved’ patients, the proportion of people who will present with RVO in their 'worse-seeing' eye and the modelling of fellow eye involvement).

3.17 The ERG considered that a number of the unit costs applied in the corrected model had been overestimated. For example, the cost of administering the dexamethasone intravitreal implant might have been overestimated because the implant could be given on an outpatient basis (£150) but costs were based on day-case (£648) care in the manufacturer’s submission. The ERG also estimated that the cost of residential care was £16,999 instead of £23,972 as used in the base case, and the cost of cataract extraction was £789 rather than £965 as in the base-case model.

3.18 The ERG conducted a sensitivity analysis on the unit costs applied in the corrected manufacturer’s model and other assumptions related to the extrapolation of effectiveness data beyond the trial. According to the ERG, key uncertainties related to the extrapolation of data remain in the evaluation of cost effectiveness. The likely maximum number of dexamethasone administrations and frequency of re-treatment, the likelihood of resolution, the likelihood of cataract development and extraction, the likelihood of involvement of the other eye and the likelihood of the RVO leading to macular oedema are all important aspects of this uncertainty.

3.19 The ERG highlighted factors in the manufacturer's sensitivity analyses that appeared to have a particular impact on cost effectiveness. When visual acuity was assumed to be stable after a year with no further dexamethasone treatments (rather than at 2.5 years with BRVO and to 3 years with CRVO) the base-case ICER increased from £7368 to £10,764 per QALY gained for the RVO population.  When those not treated were all assumed to have the observation transition probabilities applied up to 2.5 years for BRVO and 3 years for CRVO (rather than transition probabilities weighted by proportion of people who were not treated who resolved at day 180 and those who discontinued treatment for other reasons), the base-case ICER increased from £7368 to £24,924 per QALY gained for the RVO population. When the proportions re-treated were based on the re-treatment rate in the trial (day 180) for the five injections after the first in CRVO (85.7%) and the four injections after the first in BRVO (78.8%), this increased the base-case ICER from £7368 to £19,100 per QALY gained for the RVO population. When there was a decline in vision in 1.5% of patients in each health state, worsening by one health state every 6 months was assumed (compared with visual stability from 2.5 years for BRVO and 3 years for CRVO in the base case). This had a small effect on the base-case ICER which increased from £7368 to £7685 per QALY gained for the RVO population.

3.20 The ERG also conducted its own additional exploratory analyses on the manufacturer's updated economic model of the 23rd November 2010 which updated the modelling of fellow eye involvement. The ERG  compared the manufacturer's model, which included the Weibull function for fellow eye involvement, with the same model with no fellow eye involvement. At the same time, the ERG also varied the proportion of people entering the model with macular oedema in the 'worse-seeing' eye from 90% (as in the manufacturer's model) to 97% (based on the proportion treated in the 'worse-seeing' eye in the trials). The revised assumption of no fellow eye involvement changed the base-case ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £17,279, £34,277 and £11,905 per QALY gained respectively. The revised assumption of 97% 'worse-seeing' eye changed the base case ICER for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £15,800, £10,206 and dominant per QALY gained respectively.

3.21 In addition, the ERG questioned the way in which 6-month data from the open-label phase were used for the extrapolation of results with dexamethasone treatment and the use of 3- to 6-month data from the trial phase for extrapolation in the observation arm of the model. When extrapolation was based on 6- to 12-month data from the open-label phase of the trial for dexamethasone treatment and 0- to 6-month data for the observation arm (with 90% of people being treated in the 'worse-seeing' eye) the base-case ICER increased from £6041 to £15,395 per QALY gained for the RVO population.

3.22 According to the ERG, the evidence was also limited by a lack of evidence examining the cost effectiveness of re-treating only those with a good response and a lack of comparisons with unlicensed comparators (when RCT and non-RCT evidence was available and could have been used in an indirect comparison).

3.23 In response to the ERG, the manufacturer submitted two additional base-case models: one which involved structural changes in the modelling of fellow eye involvement and included a half cycle correction, and another which also included lower costs of dexamethasone administration. The revised modelling of fellow eye involvement took account of age with differential survival by collapsing the model into two health states. Without inclusion of lower costs for dexamethasone administration, the revised model resulted in higher ICERs for dexamethasone versus observation of £10,271 per QALY gained for all RVO, £8165 for CRVO, £11,403 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment. With revised cost assumptions (outpatient appointments rather than day-case costs, reduced costs of residential care and reduced costs of cataract removal) ICERs were reduced to £7616 per QALY gained for all RVO, £6221 for CRVO, £8848 for all BRVO, £8313 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment.

3.24 The ERG noted that the manufacturer's model applied the cost associated with severe visual impairment to people with visual acuity less than or equal to 38 letters in the 'worse-seeing' eye. The ERG noted that the cost of severe visual impairment should only be applied when both eyes have visual acuity less than 38 letters. The ERG conducted a sensitivity analysis in which the cost of severe visual impairment was applied when both eyes entered the worse state (visual acuity less than 38 letters) and assumed perfect correlation in the BCVA of both eyes and no correlation between the eyes. This increased the base-case ICER for CRVO from £6221 to £15,956 per QALY gained when there was perfect correlation and to £18,091 per QALY gained when there was no correlation between eyes. The corresponding base-case ICERs for BRVO with macular haemorrhage increased from £8313 to £9674 and £21,443 per QALY gained respectively.

3.25 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4. Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dexamethasone, having considered evidence on the nature of macular oedema secondary to RVO and the value placed on the benefits of dexamethasone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee noted the comparators included in the scope of the appraisal and evidence on their regulatory status and availability in clinical practice in the UK. The Committee noted that the manufacturer’s submission compared dexamethasone with best supportive care (observation) alone. This was not consistent with the scope, which defined the comparators for both BRVO and CRVO as triamcinolone acetonide (IVTA; Kenalog formulation or equivalent), bevacizumab and best supportive care, and for non-ischaemic BRVO only as grid pattern photocoagulation.

4.3 The Committee noted that ranibizumab does not currently have a UK marketing authorisation for the treatment of RVO, although updated guidelines from the Royal College of Ophthalmologists (December 2010) recommend both ranibizumab and dexamethasone as treatment options. However, currently ranibizumab is not widely used and will be appraised once licensed.

4.4 The Committee heard from the clinical specialists that the triamcinolone formulation available in the UK is contraindicated for ocular use; it also heard from the manufacturer of the intraocular formulation of triamcinolone (Trivaris) that it is not available in the UK and would not be marketed anywhere in the world.

4.5 The Committee noted that bevacizumab does not have a UK marketing authorisation for the treatment of RVO but heard from clinical specialists that it is currently widely used in the NHS. The Committee heard from patient experts that they were concerned about the use of any unlicensed treatments for which there was no formal post-market surveillance, particularly if there were alternatives that had a UK marketing authorisation.

4.6 The Committee noted that manufacturer restricted the analysed population with ischaemic BRVO to people who cannot receive or have already tried and not benefitted from laser photocoagulation.

4.7 The Committee considered these points and accepted that ranibizumab, triamcinolone acetonide and laser (grid pattern photocoagulation) were appropriately excluded from the analysis. The Committee concluded that bevacizumab is the most clinically relevant comparator because of its widespread use and accepted effectiveness. The Committee further considered that an indirect comparison of dexamethasone and bevacizumab should have been included to appropriately assess the relative effectiveness of these treatments. It noted that licensing is not prerequisite for a comparator in reasonably wide use. It also noted that the ERG had identified a number of clinical trials investigating the effectiveness of bevacizumab and that an indirect comparison could have been performed. The Committee concluded that bevacizumab is a clinically relevant comparator for dexamethasone and that the manufacturer should have included an analysis of clinical and cost effectiveness for dexamethasone with bevacizumab as comparator.

4.8 The Committee considered the relevance of the subgroups presented in the manufacturer’s submission: CRVO, BRVO, BRVO with macular haemorrhage, BRVO that has not responded to previous laser treatment, and early treatment (within 90 days of diagnosis of macular oedema). The Committee heard from the clinical specialists that CRVO and BRVO have different natural histories and are treated differently. They also heard that macular haemorrhage occurs in all cases of macular oedema secondary to RVO, although the location and extent of macular oedema determines the extent of macular damage and the suitability of laser treatment for BRVO. The Committee concluded that all of the subgroups were appropriate, but more information was needed on the nature of the BRVO with macular haemorrhage for which laser treatment was not appropriate in the clinical trials.

4.9 The Committee considered the impact of macular oedema on the everyday life of patients. It heard from patient experts about the problems associated with macular oedema and related vision loss, including difficulties with driving in the dark, taking part in hobbies such as craftwork, picking up small things, reading, using computers and distinguishing objects in crowded places. The patient experts also noted the negative impact of macular oedema on social activities. The patient experts acknowledged that although people may be worried about having an injection in the eye, this is preferable to loss of vision. They also noted that the injections were administered from the side and so could not be seen. The Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment.

Clinical effectiveness

4.10 The Committee considered evidence from the clinical specialists on the availability and effectiveness of current treatment options for the management of macular oedema secondary to RVO.

4.11 The clinical specialists and patient experts confirmed that bevacizumab is currently widely in the NHS and that it is considered by most ophthalmologists to be efficacious and safe, although there is some uncertainty as to the optimal dosing schedule and frequency of treatments. The Committee heard of the importance of laser treatment for BRVO but agreed that the population who would benefit would have been treated before considering dexamethasone. The Committee heard that triamcinolone acetonide is used less frequently because only the Kenalog formulation, which has contraindications for intravitreous use, is available in the UK. The Committee heard that ranibizumab is recommended as a treatment option in the recent Royal College of Ophthalmologists guidelines, but it is not currently widely used for the treatment of RVO in the UK.

4.12 The Committee also heard from the clinical specialist that there is variation in practice (according to local funding, the number of treatments used and the duration of use) with regard to current treatments that do not have a UK marketing authorisation. This particularly applies to bevacizumab because some clinicians and patients want more information about its long-term efficacy and safety. Clinical specialists and patient experts emphasised that dexamethasone was a valuable and licensed new option for the treatment of macular oedema.

4.13 The Committee considered the mode of delivery and adverse events associated with dexamethasone and bevacizumab, including infection and needle phobia. The clinical specialist noted that dexamethasone was administered with a larger needle than existing treatments and that dexamethasone was associated with increased intraocular pressure and cataracts. They also noted that more injections of bevacizumab were needed and this presented a greater infection risk. The clinical specialist pointed out that with bevacizumab, which had no agreed protocol for use, sterile endophthalmitis had been reported. Although with dexamethasone the cumulative risk of infection was rare (1 in a 1000), cataracts and raised intraocular pressure were more common, but were more easily treatable.

4.14 The Committee considered whether early treatment with dexamethasone compared with a 3- to 6-month delay in treatment was relevant to clinical practice. The clinical specialist confirmed that vision loss mostly occurred as a definitive event and that vision did not progressively deteriorate after that. The clinical specialist noted that in BRVO, ophthalmologists typically wait for 3 months before offering treatment because of the potential for spontaneous resolution. The Committee heard there was a 20% spontaneous resolution rate in BRVO and resolution rates tended to be higher in those younger than 50 but that the prognosis associated with CRVO was poor, with a lower rate of spontaneous resolution. The Committee heard from the clinical specialist that early treatment, soon after 3 months, is associated with better visual outcome, but that even at 12 months there can be a valuable response depending on the extent of damage.

4.15 The Committee noted that in the GENEVA trials, 97% of patients were initially treated for their 'worse-seeing' eye, and that according to the literature and the application of a survival function, 6.5% then need treatment for the other eye ('fellow eye involvement') in the first year, with a continued risk of fellow eye involvement (according a Weibull function) over the following  6 years. However the manufacturer’s model was based on 90% of people being initially treated for the 'worse-seeing' eye. The Committee considered whether treating 90% of people for macular oedema in their 'worse-seeing' eye was representative of clinical practice. It heard from the manufacturer that the GENEVA trials had a higher proportion of people with macular oedema in their 'worse-seeing' eye because people with a visual acuity of less than 34 letters in the fellow eye were excluded from the study. The manufacturer stated that the 90% estimate was based on the literature and was representative of clinical practice.

4.16 The clinical specialist advised the Committee that the proportion of people with macular oedema in their 'worse-seeing' eye would be between 90% and 97%. The Committee also heard from the clinical specialist that the estimates of 6.5% fellow eye involvement in the first year and the cumulative probability in the subsequent 6 years (according a Weibull function) was plausible and gave an estimated lifetime risk of 10% overall. It also heard that the risk of fellow eye involvement was higher at the time of onset of macular oedema secondary to RVO and diminished after lifestyle changes to reduce the risk of a subsequent RVO.

4.17 Patient experts also highlighted the importance of treating the first eye affected, even though overall acuity depends mostly on the 'better-seeing' eye, because RVO and other eye conditions may later affect the critical second eye. The Committee concluded that it was appropriate to treat the first eye affected.

4.18 The Committee considered the potential of dexamethasone to offer additional health-related benefits compared with currently available treatment options. It heard from the patient experts about the impact of dexamethasone on their quality of life. Patients advised that after the administration of dexamethasone their sight improved and they were able to resume normal daily activities.

4.19 The Committee noted that the manufacturer had not identified data from RCTs comparing dexamethasone with bevacizumab or triamcinolone and had not conducted an indirect comparison. The Committee was aware that there was limited evidence for the efficacy and safety of dexamethasone when more than two sequential implants were administered, but that in clinical practice more than two implants, possibly given more frequently than every 6 months, were inevitable. The Committee concluded that the evaluation of clinical effectiveness was limited by the evidence presented, which excluded several comparators and was based on two sham-controlled RCTs of short duration with only one re-treatment at 6 months. The Committee was therefore unable to assess the relative effectiveness of dexamethasone compared with active treatment in the management of macular oedema secondary to RVO and requested that more evidence be provided by the manufacturer.

4.20 The Committee considered the relative importance of the different outcome measures reported in the pivotal GENEVA trials. The Committee noted that the primary outcome was percentage of patients with an improvement of BCVA of 15 letters or more, which represented a gain of three lines on the EDTRS chart (this enables patients to see letters half the height of those they could see before). The Committee heard from clinical specialists that this represented the gold standard for assessing the effect of treatment on visual acuity, although a gain of 10 letters is also considered to be clinically significant.

4.21 The Committee considered the pooled primary outcome data from the GENEVA trials for the entire population with macular oedema following RVO. The Committee noted that dexamethasone is associated with a statistically significant improvement in visual acuity (based on percentage of patients with an improvement of BCVA of 15 letters or more) compared with sham treatment at day 30, 60 and 90 (of 180) but was not statistically significant at day 180. The Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BVCA at day 30, 60, 90 and 180 for all people with macular oedema following RVO. For time to an improvement in BCVA of at least 15 letters, the Committee noted that the cumulative response rate was higher with dexamethasone than with sham treatment, but cumulative response appeared to level out after day 90 in both of these groups. 

4.22 The Committee considered that the data from the GENEVA trials gave the best estimate of clinical effectiveness versus best supportive care. The Committee considered the subgroup data from the GENEVA trials. The Committee noted that dexamethasone was associated with a statistically significantly higher proportion of people gaining BCVA of 15 letters or more compared with sham treatment for CRVO (day 30 and 60), BRVO (day 30, 60 and 90), BRVO with macular haemorrhage (day 30, 60 and 90) and at all time points for BRVO with previous laser treatment. These results for the subgroups were similar to those obtained for the combined population with RVO. The Committee concluded that dexamethasone offered short-term improvement in visual acuity with one treatment of dexamethasone compared with sham in all subgroups, although the duration of benefit following CRVO was shorter.

4.23 The Committee considered the evidence for re-treatment from the open-label extension of the GENEVA trials (which was submitted as academic-in-confidence information). The Committee noted that for the whole population the proportion of patients with an improvement in BCVA of at least 15 letters was higher in the group that received dexamethasone at day 0 and day 180 compared with those who received sham at day 0 and dexamethasone at day 180. The Committee also considered the expected frequency of treatment with dexamethasone at day 180. The Committee heard from the clinical specialist that the criteria for re-treatment were based on the patient's experience with previous treatment (whether their vision had initially improved on treatment and had started to deteriorate), deterioration in visual acuity as assessed by BCVA and the persistence of macular oedema. The Committee was further advised that it is difficult to use a cut-off value for visual acuity which would indicate re-treatment, but that with a loss of five letters it would be appropriate to consider re-treatment. The clinical specialist noted that although the safety data relate to 6-monthly treatment, clinicians may wish to re-treat at 4 months, but should not treat more frequently because of the risk of adverse events from the accumulation of dexamethasone in the eye.

4.24 The Committee considered the evidence for adverse events associated with dexamethasone. These included cataracts, raised intraocular pressure and infection. The Committee noted that evidence was limited to adverse events after two treatments with data up to 360 days. The Committee discussed the impact of dexamethasone in causing cataracts and the potential issues for diabetic patients, for whom there is a higher risk of developing glaucoma and cataracts. The Committee heard from clinicians that there is not likely to be any difference in the incidence of cataracts in people with diabetes, and that people with diabetes will be treated in the same way. The Committee noted the results of the GENEVA trials and also heard from the clinical specialist that, despite lack of clinical experience with this product, a similar infection risk to that of other current treatments would be expected. It also heard that there was a 20–25% risk of raised intraocular pressure but that this is usually well managed with eye drops. There is a 1% risk of needing treatment for glaucoma when dexamethasone is used. The Committee concluded that there were some concerns about the safety profile of dexamethasone treatment (given that the marketing authorisation is based two re-treatments but the manufacturer assumed that up to six treatments would be given) which was limited by the absence of comparative evidence and data on long-term treatment and multiple re-treatment.

Cost effectiveness

4.25 The Committee considered the evidence for the comparators listed in the scope and noted that the manufacturer had not included any evidence comparing the cost effectiveness of dexamethasone with any other active treatment for RVO, including bevacizumab. The Committee noted that the ERG and the Royal College of Ophthalmologists had identified prospective and retrospective studies and case series for bevacizumab in the treatment of macular oedema secondary to RVO. The Committee noted that the NICE 'Guide to the methods of technology appraisal' states that comparators should be current or best practice in the NHS and may include unlicensed treatments. The Committee concluded that a comparison of dexamethasone with bevacizumab in the economic model was required to address the decision problem of most relevance to the NHS. 

4.26 The Committee considered the manufacturer’s most recent update of its economic model (in which the modelling of fellow eye involvement was appropriately age adjusted) and the sensitivity analyses conducted by the manufacturer and critiqued by the ERG. The Committee noted that health-related quality-of-life benefits and utility values had been incorporated into the economic model and differentiated utilities for the 'worse-' and 'better-seeing' eye. The Committee also noted that several key model parameters (for example, the proportion of people presenting with the 'worse-seeing' eye and resource use) were based on the opinion of clinical specialists on an expert panel organised by the manufacturer. The Committee noted that the base-case ICERs were between £7500and £8500 per QALY gained depending on the patient population. It also noted the sensitivity analysis provided by the manufacturer and the exploratory analysis by the ERG of the robustness of the ICERs to various assumptions.

4.27 The Committee considered the plausibility of assumptions and inputs in the economic model. It noted that the main factors affecting cost effectiveness were the cost of the intervention (including drug and administration costs), savings associated with the prevention of severely impaired vision, the number of treatments needed, extrapolation of data on treatment benefits beyond trial data, the extrapolation of health-state data in the intervention arm, the proportion of patients presenting with macular oedema in the 'worse-seeing' eye, the degree of fellow eye involvement, and the utility estimates used.

4.28 The Committee considered the costs for dexamethasone used in the economic model. The Committee noted that some resource use data came from experts rather than the literature and it was uncertain how representative these would be. The Committee discussed whether the administration costs of dexamethasone should be based on a day-case (£648) or an outpatient appointment (£150). The Committee heard from clinical specialists that administration might initially be done in theatre, but that over time arrangements might be made for the implant to be administered as an outpatient procedure. However, the clinical specialists also emphasised that the cost of dexamethasone administration would be higher than the current outpatient tariff used in the model because the additional cost of the sterile room, nurse and assistant’s time had not been included in the tariff. The Committee concluded that the costs of treatment based on an outpatient appointment had been underestimated in the model and that the base-case model should include day-case costs, with outpatient costs included in a sensitivity analysis.

4.29 The Committee noted that the model’s costs of dexamethasone treatment (approximately £6000) were mostly offset by the considerable savings (approximately £4500) associated with preventing severely impaired vision (blindness). Although the Committee agreed that this was correct in principle, it noted that the manufacturer had applied the cost savings associated with preventing severe visual impairment based on only one eye with a visual acuity of less than 38 letters (EDTRS). The Committee considered additional exploratory analyses conducted by the ERG, which included applying savings from preventing severe visual impairment only when both eyes were affected. This increased the ICER to nearly £16,000 or £18,000 per QALY gained for CRVO depending on whether there was perfect or imperfect correlation between the BCVA in both affected eyes. The ICER in BRVO increased to nearly £10,000 or £21,500 per QALY gained depending on whether there was perfect or imperfect correlation between the BCVA in both affected eyes. The Committee concluded that the manufacturer should have applied the cost savings associated with preventing severely impaired vision only when both eyes had visual acuity of less than 38 letters, as presented in the ERG's exploratory analyses.

4.30 The Committee considered the number of treatments needed in clinical practice and whether the assumptions in the economic model were justified. The Committee noted that the modelled re-treatment rate at day 180 (86% for CRVO and 79% for BRVO) was based on the RCT, and the drop off in re-treatment beyond the trial of up to 2.5 years for BRVO and 3 years for CRVO was based on expert opinion. However, the Committee noted that the re-treatment rate was dependent on the proportion of patients who had resolution at day 180 and who were assumed not to need further treatment, and the proportion of patients who were not re-treated for other reasons (for example, because of discontinuation due to adverse events). The Committee heard from the clinical specialist that the assumption that a person who has resolution at day 180 would not need treatment does not reflect clinical practice where patients are quite likely to receive re-treatment at a subsequent follow-up appointment. The Committee considered that the modelled re-treatment rate drops off faster than in practice. It also noted that in clinical practice, initial re-treatment may occur at 4–6 months for up to 2 years rather than only at 6 months, but it acknowledged that efficacy and safety data for this were not available. The Committee further noted that although the manufacturer had modelled up to five to six dexamethasone treatments, clinical trial data were only available for two treatments. The Committee concluded that the re-treatment rate in the model was too low and that in practice the re-treatment rate is likely to be between that of the trial and the re-treatment rates assumed by the clinical advisers to the manufacturer. The Committee concluded that the manufacturer should conduct a sensitivity analysis with a range of re-treatment scenarios that are likely to reflect clinical practice in the UK. These should include an analysis in which proportions re-treated are as at day 180 for the five injections after the first injection in CRVO and the four injections after the first injection in BRVO, with alternative scenarios for the proportion of people re-treated at 6 months and re-treated at 6-monthly intervals thereafter.

4.31 The Committee considered the extrapolation of health state beyond the trial data. The Committee noted that the model extrapolated data from 3–6 months for the sham arm and 6–12 months for the treatment arm in order to obtain transition probabilities. The Committee noted the impact of using different trial periods on which to base transition probabilities as demonstrated in the ERG report: progression through health states stabilises in the treatment arm, but deteriorates rapidly in the observation arm. The Committee heard from the clinical specialist that the condition naturally stabilises whereas in the model it deteriorated continually because of the use of only the 3- to 6-month data. The Committee considered that the deterioration in the observation group was more extreme than that seen in clinical practice. The Committee concluded that the manufacturer should have included all available (0–6 months) trial data in their economic model because there was no evidence to suggest that only the second half of the trial was relevant to the transition probabilities. The Committee therefore requested that all available trial data should be included in a new base-case model.

4.32 The Committee considered the extrapolation of health-state data in the intervention arm of the model. The Committee noted that at 12 months, patients from the dexamethasone arm who did not receive re-treatment were either assumed to have resolved with stable visual acuity or to follow the same progression as the observation arm. The Committee heard from the manufacturer that in the trial, patients who had resolved at day 180 remained stable. This was validated by an expert panel. However, the Committee noted from the clinical specialist that the assumption of stable visual acuity in patients with resolution was too optimistic because it was unlikely that all patients whose macular oedema had resolved at day 180 would remain stable for up to 2 years without needing re-treatment.

4.33 The Committee considered the assumptions used in the economic model relating to the proportion of patients presenting with macular oedema in the 'worse-seeing' eye. This was 90% in the model but 97% in the clinical trial. The Committee accepted the ERG’s comments that the proportion of people treated for macular oedema in the 'worse-seeing' eye at baseline had a large impact on the ICER. In the partially updated manufacturer's model, which included fellow eye involvement, the ICER for all RVO was £11,700 per QALY gained when it was assumed that 90% of people present with macular oedema in the 'worse-seeing' eye compared with £21,400 per QALY gained for 97% presenting with macular oedema in the 'worse-seeing' eye. The Committee was advised that the proportion of people presenting with the 'worse-seeing' eye was likely to be between 90% and 97%. After discussion the Committee considered the assumption of 90% to be acceptable. The Committee considered the assumptions and inputs associated with modelling the degree of fellow eye involvement. The Committee was aware that this was an important factor in assessing the cost effectiveness because most people presented with macular oedema in the 'worse-seeing' eye and the utility gains were higher with treatment of the 'better-seeing' eye. The Committee heard from the clinical specialist that fellow eye involvement may be less pronounced in clinical practice (10% overall lifetime risk compared with 6.5% in the first year). However, patient experts highlighted that people may develop other eye conditions. The Committee concluded that the assumptions in the base case were acceptable and that the inclusion of fellow eye involvement was plausible, but that the sensitivity analyses were needed to show the robustness of the model to this assumption.

4.34 The Committee considered the revised estimates of cost effectiveness associated with amendments to the way age and mortality were modelled in relation to fellow eye involvement. The Committee noted that amending the way in which fellow eye involvement was modelled increased the ICER from £7370 in the base case to £10,300 per QALY gained for all people with macular oedema secondary to RVO.

4.35 In summary, the Appraisal Committee could not assess whether dexamethasone is a cost-effective option for the treatment of macular oedema secondary to RVO because it did not have evidence of the clinical and cost effectiveness of dexamethasone relative to bevacizumab. Furthermore, the Committee considered that several key assumptions in the model relating to the cost of treatment and extrapolation beyond the trial data in the treatment and observation arms were not plausible and did not reflect clinical practice in the UK. The Committee is minded not to recommend dexamethasone for the treatment of macular oedema secondary to RVO. It recommends that the manufacturer is asked to submit a revised base-case model in which the costs of dexamethasone treatment are based on a day-case appointment with outpatient costs as a sensitivity analysis, the cost saving associated with preventing severe visual impairment is based on two eyes, and the extrapolation of health states in the observation arm is based on 0-to 6-month data from the RCT. The model should also compare dexamethasone with bevacizumab and should include varying vial sharing assumptions for treatment with bevacizumab. The Committee also requests clarification of the location and extent of macular haemorrhage in the subgroup of patients for whom laser treatment was not considered appropriate in the pivotal trial.

4.36 The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion		Section
Key conclusion
The Committee is minded not to recommend dexamethasone intravitreal implant for the treatment of macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). The Committee recommends that NICE requests further clarification from the manufacturer. The following information should be made available for the next Appraisal Committee meeting: The clinical and cost effectiveness of dexamethasone intravitreal implant compared with bevacizumab. The cost-effectiveness analysis should include varying vial sharing assumptions for treatment with bevacizumab. A revised base case for the cost effectiveness of dexamethasone intravitreal implant, incorporating the following assumptions: the costs of dexamethasone treatment based on a day case, with outpatient appointment costs as a sensitivity analysis the extrapolation of data from the observation arm of the model based on all of the 0- to 6-month data from the randomised controlled trial modelling of the fellow eye involvement, ensuring that costs of blindness are applied only to patients in whom both eyes fall into the worst health state (severe visual impairment). Alternative scenarios analyses for the re-treatment rate that reflect clinical practice in the UK, including: an analysis in which proportions re-treated are as at day 180 for the five injections after the first injection in people with CRVO an analysis in which proportions re-treated are as at day 180 for the four injections after the first injection in people with BRVO alternative analyses in which proportions re-treated are varied between the two extremes of the base case and the randomised controlled trial. The Committee requires further clarification of the location and extent of macular haemorrhage for the subgroup of patients for whom laser treatment was not considered appropriate because of macular haemorrhage.			1.1 1.2 1.3
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from patient experts about the problems associated with macular oedema and related vision loss, including difficulties with driving in the dark, taking part in hobbies such as craftwork, picking up small things, reading, using computers and distinguishing objects in crowded places. The Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment. The Committee noted the comparators included in the scope which included triamcinolone acetonide (IVTA; Kenalog formulation or equivalent), bevacizumab and best supportive care as comparators for CRVO and BRVO, and grid pattern photocoagulation as an additional comparator for non-ischaemic BRVO. IVTA was not considered  to be a relevant comparator because the Kenalog formulation available in the UK is contraindicated for ocular use.   Ranibizumab was not considered to be a relevant comparator because it does not have a UK marketing authorisation and is not widely used in the NHS. Although bevacizumab does not have a UK marketing authorisation for the treatment of RVO, clinical specialists advised that it is currently widely used in the NHS. The Committee noted that the manufacturer restricted the analysed population with ischaemic BRVO to people who cannot receive or have already tried and not benefitted from laser photocoagulation. The Committee considered bevacizumab to be the most relevant comparator for this appraisal.	4.9 4.2 4.3 4.4 4.5 4.6
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The dexamethasone intravitreal implant is a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration.	2.1 2.2
What is the position of the treatment in the pathway of care for the condition?		Dexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either BRVO or CRVO.Clinical specialists and patient experts emphasised that dexamethasone was a valuable and licensed new option for the treatment of macular oedema.	2.2 4.12
Adverse effects		The Committee concluded that there were some concerns about the safety profile of dexamethasone treatment (given that the marketing authorisation is based two re-treatments but the manufacturer assumed that up to six treatments would be given) which was limited by the absence of comparative evidence and data on long-term treatment and multiple re-treatment.	4.24
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The ERG considered the GENEVA trials to be of high quality. The Committee noted that the manufacturer’s submission compared dexamethasone with best supportive care (observation) alone and did not include an indirect comparison with other treatments including bevacizumab. The Committee was therefore unable to assess the relative effectiveness of dexamethasone compared with active treatment in the management of macular oedema secondary to RVO. The Committee noted that the ERG and the Royal College of Ophthalmologists had identified prospective and retrospective studies and case series for bevacizumab in the treatment of macular oedema secondary to RVO. The Committee requested that the clinical and cost effectiveness of dexamethasone intravitreal implant compared with bevacizumab be provided by the manufacturer.The manufacturer restricted the analysed population with ischaemic BRVO to people who cannot receive or have already tried and not benefitted from laser photocoagulation	3.14 4.6 4.2 4.25
Relevance to general clinical practice in the NHS		The Committee considered the relevance of the manufacturer's economic model. The Committee heard from clinical specialists that the proportion of people with macular oedemain their 'worse-seeing' eye would be between 90% (in the manufacturer's model) and 97% (as in the clinical trial).	4.16
Uncertainties generated by the evidence		In the absence of any indirect comparison the Committee was not able to assess the clinical effectiveness of dexamethasone relative to other active treatments. An indirect comparison of dexamethasone with bevacizumab was considered to be most relevant and has been requested.	4.7
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee considered the effectiveness of dexamethasone for the subgroups CRVO, BRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment. The Committee concluded that dexamethasone offered short-term improvement in visual acuity with one treatment of dexamethasone compared with sham in all subgroups, although the duration of benefit following CRVO was shorter.	4.22
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The results of the pooled analysis from GENEVA 008 and GENEVA 009 trials showed that for the total RVO population 21.3% of the 427 patients in the intention-to-treat population receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group. The Committee considered the pooled primary outcome data from the GENEVA trials for the entire population with macular oedema following RVO. The Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BVCA at day 30, 60, 90 and 180 for all people with macular oedema following RVO. For time to an improvement in BCVA of at least 15 letters, the Committee noted that the cumulative response rate was higher with dexamethasone than with sham treatment, but cumulative response appeared to level out after day 90 in both of these groups.	3.3 4.21
Evidence for cost effectiveness
Availability and nature of evidence		The Committee noted that the manufacturer had not included any evidence comparing the cost effectiveness of dexamethasone with any other active treatment for RVO, including bevacizumab. The Committee noted that the ERG and the Royal College of Ophthalmologists had identified prospective and retrospective studies and case series for bevacizumab in the treatment of macular oedema secondary to RVO. The Committee requested that the manufacturer compare the clinical and cost effectiveness of dexamethasone and bevacizumab to include different vial sharing options for bevacizumab.	4.25 4.35
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee considered the appropriateness of key assumptions of the economic model. The Committee considered the proportion of people presenting with macular oedema in the 'worse-seeing' eye (90% in the model compared with 97% in the clinical trials). The Committee considered cost inputs (including treatment as a day case compared with outpatient as used in the base case of the updated model). The Committee concluded that the costs of treatment based on an outpatient appointment had been underestimated in the model and that the base-case model should include day-case costs, with outpatient costs included in a sensitivity analysis. The Committee considered the application of the cost of severe visual impairment to people in whom the 'worse-seeing' eye fell in a health state where visual acuity was less than 38 letters in the manufacturer's model. The Committee concluded that the manufacturer should have applied the cost savings associated with preventing severely impaired vision only when both eyes had visual acuity less than 38 letters, as presented in the ERG's exploratory analyses. The Committee considered the re-treatment rate which was based on the trial data at day 180 and advice from clinical advisers to the manufacturer about extrapolated re-treatment rates. The Committee concluded that the re-treatment rate in the model was too low and that in practice the re-treatment rate is likely to be between that of the trial and the re-treatment rates assumed by the clinical advisers to the manufacturer. The Committee concluded that the manufacturer should conduct a sensitivity analysis with a range of re-treatment scenarios that are likely to reflect clinical practice in the UK. These should include an analysis in which proportions re-treated are as at day 180 for the five injections after the first injection in CRVO and the four injections after the first injection in BRVO, with alternative scenarios for the proportion of people re-treated at 6 months and re-treated at 6-monthly intervals thereafter. The Committee considered the extrapolation of health state beyond the trial data in the base-case model (3–6 months for the sham arm and 6–12 months for the treatment arm). The Committee concluded that the manufacturer should have included all available (0–6 months) trial data in their economic model because there was no evidence to suggest that only the second half of the trial was relevant to the transition probabilities. The Committee therefore requested that all available trial data should be included in a new base-case model.	4.27 4.28 4.29 4.31 4.31
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The data inputs for the manufacturer’s model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population. The Committee noted that health-related quality-of-life benefits and utility values had been incorporated into the economic model and differentiated utilities for the 'worse-' and 'better-seeing' eye.	3.9 4.26???
Are there specific groups of people for whom the technology is particularly cost effective?		The Committee concluded that all of the subgroups identified by the manufacturer were appropriate, but more information was needed on the nature of the BRVO with macular haemorrhage for which laser treatment was not appropriate in the clinical trials. The ICERs of dexamethasone compared with sham were lower (and in most scenarios dexamethasone treatment dominated sham) for the population with BRVO and previous laser treatment.	4.8 3.11
What are the key drivers of cost effectiveness?		The key drivers of cost effectiveness are the proportion of people with macular oedema in the 'worse-seeing' eye, the cost of severe visual impairment implemented in the model when both eyes fall into a health state with a visual acuity of less than 38 letters, and the extrapolation of benefits in the treatment compared with the observation arm	4.33, 4.29
Most likely cost-effectiveness estimate (given as an ICER)		The Appraisal Committee could not assess whether dexamethasone is a cost-effective option for the treatment of macular oedema secondary to RVO because it did not have evidence of the clinical and cost effectiveness of dexamethasone relative to bevacizumab. Furthermore, the Committee considered that several key assumptions in the model relating to the cost of treatment and extrapolation beyond the trial data in the treatment and observation arms were not plausible and did not reflect clinical practice in the UK. The Committee were therefore unable to estimate the most plausible ICER.	4.35
Additional factors taken into account
Patient access schemes (PPRS)		None
End-of-life considerations		None
Equalities considerations and social value judgements		The Committee concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.	4.36

5. Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6. Related NICE guidance

Published

• Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Available from www.nice.org.uk/guidance/TA155
• Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003). Available from www.nice.org.uk/guidance/TA68

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion. Technology appraisal in development
• Ranibizumab for the treatment of diabetic macular oedema. Technology appraisal in development

7. Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
February 2011

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A. Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Dr Daniele Bryden
Consultant in Intensive Care Medicine and Anaesthesia, Sheffield Teaching Hospitals NHS Trust

Dr Andrew Burnett
Director for Health Improvement and Medical Director, NHS Barnet, London

David Chandler
Lay Member

Dr Chris Cooper
General Practitioner, St John’s Way Medical Centre, London

Professor Peter Crome
Consultant Geriatrician and Professor of Geriatric Medicine, Keele University

Richard Devereaux-Phillips
Public Affairs and Reimbursement Manager UK and Ireland, Medtronic, Watford

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Wasim Hanif
Consultant Physician and Honorary Senior Lecturer, University Hospital Birmingham

Professor Cathy Jackson
Professor of Primary Care Medicine, University of St Andrews

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Henry Marsh
Consultant Neurosurgeon, St George's Hospital, London

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Eugene Milne
Deputy Regional Director of Public Health, North East Strategic Health Authority, Newcastle upon Tyne

Dr Neil Myers
General Practitioner, Glasgow

Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Dr Danielle Preedy
Lay Member

Dr Martin Price
Head of Outcomes Research, Janssen-Cilag, Buckinghamshire

Ellen Rule
Programme Director, NHS Bristol

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team, Warrington

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr John Stevens
Lecturer in Bayesian Statistics in Health Economics, School of Health and Related Research, Sheffield

Dr Matt Stevenson
Reader in Health Technology Assessment, School of Health and Related Research, University of Sheffield

Professor Paul Trueman
Professor of Health Economics, Brunel University, London

Dr Judith Wardle
Lay Member

B. NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Jennifer Priaulx
Technical Lead

Eleanor Donegan
Technical Adviser

Lori Farrar
Project Manager

Appendix B: Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Aberdeen Health Technology Assessment Group (AbHTAG):

• Shyangdan D, Cummins E, Lois N, et al. Dexamethasone implants in the treatment of macular oedema due to retinal vein occlusion: a single technology appraisal. [Month] 2010

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Allergan Ltd UK

II Professional/specialist and patient/carer groups:

• Royal National Institute of Blind People (RNIB)
• Royal College of Nursing
• Royal College of Ophthalmologists
• Royal College of Physicians

III Other consultees:

• Department of Health
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Bristol Myers Squibb (triamcinolone)
• Roche Products (bevacizumab)
• Aberdeen HTA Group
• National Institute for Health Research Health Technology Assessment Programme

C. The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on dexamethasone intravitreal implant for the treatment of macular oedema caused by retinal vein occlusion by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Ian Pearce, Consultant Ophthalmologist, nominated by The Royal College of Ophthalmologists – clinical specialist
• Lady Sandra Taylor, Lead Ophthalomologist research Nurse Manager, nominated by Royal College of Nurses Ophthalmic Nurse Forum – clinical specialist
• Barbara McLaughlan, Campaigns Manager, nominated by Royal National Institute of Blind people – patient expert
• Carol Read, nominated by Royal National Institute of Blind people – patient expert

D. Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Allergan Ltd UK