Diabetic macular oedema - fluocinolone acetonide intravitreal implant: appraisal consultation document

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using fluocinolone acetonide intravitreal implant 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 race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

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 fluocinolone acetonide intravitreal implant 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: 30 August 2012

Second Appraisal Committee meeting: 11 September 2012

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  Fluocinolone acetonide intravitreal implant is not recommended for the treatment of chronic diabetic macular oedema.

2  The technology

2.1  Fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) is a corticosteroid which has anti-inflammatory and anti-vascular endothelial growth factor (anti-VEGF) properties. It is administered by intravitreal injection. Each implant contains 190 micrograms of fluocinolone acetonide, releasing 0.2 micrograms/day for up to 36 months. Fluocinolone acetonide intravitreal implant has a marketing authorisation for the treatment of vision impairment associated with chronic diabetic macular oedema considered insufficiently responsive to available therapies.

2.2  The summary of product characteristics states that the recommended dose of fluocinolone acetonide is 1 implant in the affected eye every 3 years. Only patients whose disease has been insufficiently responsive to treatment with laser photocoagulation or other available therapies for diabetic macular oedema should be treated. Administration in both eyes concurrently is not recommended. An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema.

2.3  The summary of product characteristics lists the following adverse reactions for fluocinolone acetonide intravitreal implant: cataract, increased intraocular pressure, floaters (myodesopsia), retinal detachments, vitreous haemorrhages or detachments, glaucoma and endophthalmitis. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.4  The manufacturer’s submission states that the acquisition cost of a fluocinolone acetonide intravitreal implant is 5500 (excluding VAT) per 190-microgram implant (source: Alimera Sciences). 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 fluocinolone acetonide intravitreal implant and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1  The manufacturer submitted evidence on the clinical and cost effectiveness of fluocinolone acetonide intravitreal implant compared with optimised standard of care and laser photocoagulation monotherapy. The manufacturer did not provide any specific analyses comparing fluocinolone acetonide intravitreal implant with triamcinolone or the anti-VEGF treatments, bevacizumab and ranibizumab. The manufacturer explained that this was because fluocinolone intravitreal implant is not indicated as first-line therapy in the context of the clinical pathway in the UK.

Clinical effectiveness

3.2  The main source of evidence in the manufacturer’s submission was a preplanned analysis of data from the FAME A and B randomised controlled trials that evaluated the safety and efficacy of fluocinolone acetonide intravitreal implant for treating diabetic macular oedema. The preplanned analysis focused on duration of diabetic macular oedema, analysing patients who had had the condition for durations above and below the median separately. When the trial was unblinded the median duration was determined to be 3 years. The subgroup in the submission was those patients with duration of diabetic macular oedema above the median, that is, over 3 years.

3.3  FAME A and B were 2 identical randomised, double-blinded, sham injection-controlled multicentre trials conducted over 36 months. The results of the trials were combined and presented in the submission as a single analysis. Patients were randomised 1:2:2 to sham injection, 0.2 micrograms/day (low-dose) or 0.5 micrograms/day (high-dose) fluocinolone acetonide intravitreal implant. Participants in the trials were adults with diabetic macular oedema who were aged between 18 and 85, who had received at least 1 previous laser treatment, whose best corrected visual acuity (BCVA) was ≥19 to ≤68 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, and whose central retinal thickness was ≥250 microns at baseline. Exclusion criteria were intraocular pressure >21 mmHg, and systolic blood pressure >180 mmHg or diastolic blood pressure >105 mmHg.

3.4  In both groups (sham injection and low- or high-dose implant) additional treatment with laser photocoagulation was given as needed after week 6. Approximately 61% of the sham injection group and 41% of the fluocinolone acetonide intravitreal implant group received treatment with laser photocoagulation during the study. The mean number of laser treatments was 1.4 and 0.8 in the sham injection and fluocinolone acetonide intravitreal implant groups respectively. Retreatment with fluocinolone acetonide intravitreal implant was offered at any time after the month 12 assessments if patients experienced vision loss (5 letters or more) or retinal thickening of 50 microns or more compared with their best status in the previous 12 months.

3.5  Patients in both groups also received a range of therapies not allowed in the study protocol. These included intravitreal steroids (triamcinolone and dexamethasone), anti-VEGF therapy, vitrectomies and posterior sub-Tenon steroids. The number of off-protocol treatments was higher in the sham injection group than in the fluocinolone acetonide intravitreal implant group (117 compared with 48); approximately 35% of patients in the sham injection group and 13% of patients in the fluocinolone acetonide intravitreal implant group received at least 1 off-protocol treatment. Data from these patients were included in the analysis population.

3.6  The primary outcome reported in the FAME trials was the proportion of people with an improvement of 15 or more letters from baseline BCVA at month 24. Secondary outcomes included:

  • mean change in BCVA
  • mean change in excess retinal thickness
  • percentage with 3-step(15 letters or more) worsening of ETDRS
  • percentage requiring laser photocoagulation.

3.7  There were 956 patients enrolled in the FAME trials. Of these, 536 had had diabetic macular oedema for longer than 3 years and formed the subgroup of patients with chronic diabetic macular oedema identified for analysis. Of this subgroup of patients comprehensive data were presented by the manufacturer for the 0.2 micrograms/day implant group only, because only the low dose has been licensed. The resulting number of patients with chronic diabetic macular oedema in the analysis that formed the basis of the manufacturer’s submission was 321 (209 in the 0.2 micrograms/day implant group and 112 in the sham injection group).

3.8  The average age of the 321 patients included in the manufacturer’s analysis was 62.9 years in the sham injection group and 63.7 years in the 0.2 micrograms/day implant group. In the trials, the majority of patients had chronic diabetic macular oedema in both eyes at baseline (these data are marked by the manufacturer of fluocinolone acetonide intravitreal implant as academic in confidence and therefore are not presented here), but only 1 eye was treated. In most cases, the worse-seeing eye was treated.

3.9  At month 24, the proportions of patients with chronic diabetic macular oedema who had a ≥15 letter increase from baseline BCVA were 13.4% and 34.4% in the sham injection and 0.2 micrograms/day implant groups respectively (p<0.001). The proportions of patients who had a ≥15 letter improvement in BCVA at month 36 (13.4% and 34.0% respectively [p<0.001]) were comparable to those observed in month 24. Results were also presented for the proportion of patients who had an improvement of between 10 and 14 letters but these data are marked by the manufacturer as academic in confidence and therefore are not presented here. There were numerical increases in mean change in BCVA from baseline in the 0.2 micrograms/day implant group compared with sham injection group at all evaluations (12 through to 36 months); this was statistically significant at months 30 (p value academic in confidence) and 36 (p<0.004). At month 36, there was a mean improvement of 7.6 letters in the 0.2 micrograms/day implant treatment group compared with 1.8 letters in the sham injection group (95% confidence interval [CI] –10.2 to –2.0).

3.10  The FAME trials included an assessment of health-related quality of life using the Visual Function Questionnaire-25 (VFQ-25) at baseline and months 24 and 36. These data were provided in the clinical study reports of the FAME trials. The manufacturer stated that the VFQ-25 was not used in the economic model because it measures overall visual function which is driven by vision in the better-seeing eye, whereas in the FAME trials, the majority of patients had their worse-seeing eye treated. The results of the VFQ-25 are marked by the manufacturer as academic in confidence and therefore are not presented here.

3.11  The manufacturer also included laser photocoagulation monotherapy as a relevant comparator for fluocinolone acetonide intravitreal implant. The manufacturer conducted a literature search and identified 1 relevant study: DRCR Protocol B (2008). This study was a phase 3, multicentre, randomised clinical trial conducted in the USA to compare intravitreal triamcinolone with focal/grid laser photocoagulation in patients with diabetic macular oedema. The manufacturer noted that the severity of diabetic macular oedema in the DRCR study was not as great as in the FAME trials. Of the DRCR population approximately 40% of people who were laser-naive and randomisation was not done according to duration of diabetic macular oedema. A comparison of outcomes data as reported in the DRCR and FAME clinical trials was presented. The manufacturer did not use any statistical methods to compare the data indirectly. The manufacturer noted that the proportion of people with a ≥15 letter improvement in BCVA in the FAME trials at month 36 demonstrated a numerical difference in favour of fluocinolone intravitreal implant (34.0% compared with 18% for laser photocoagulation at 24 months in the DRCR protocol B study).

3.12  The manufacturer’s submission included data from the FAME trials for ocular adverse events in people with chronic diabetic macular oedema (duration of 3 years or longer). The data suggested that fluocinolone acetonide intravitreal implant is associated with the formation or progression of cataract and increased intraocular pressure. In the FAME trials, 34.4% (72/209) of patients in the fluocinolone acetonide intravitreal implant group experienced increased intraocular pressure or ocular hypertension compared with 14.3% (16/112) in the sham injection group. At baseline, 58.9% (66/112) of people in the shaminjection group and 54.5% (114/209) in the fluocinolone intravitreal implant group were phakic (still had their natural lens). Of those who were phakic at baseline, 77.9% of the fluocinolone acetonide intravitreal implant group and 77.0% of the sham injection group had a pre-existing cataract. Cataract surgery was needed by 85.1% (97/114) of the fluocinolone acetonide intravitreal implant group and 36.4% (24/66) of the sham injection group who were phakic at baseline. However, 45.5% of people in the fluocinolone acetonide intravitreal implant group and 41.1% in the sham injection group were pseudophakic at baseline (that is, they had already had an operation for cataract removal and had been fitted with an intraocular lens to replace the natural crystalline lens).

Cost effectiveness

3.13  The economic evidence provided by the manufacturer in its submission comprised a literature review (identifying no relevant published cost-effectiveness studies) and a de-novo cost–utility analysis. The manufacturer’s economic evaluation compared the fluocinolone acetonide intravitreal implant group with the comparator group (‘optimised standard of care’) of the FAME trials for a cohort of patients with chronic diabetic macular oedema. The model also included a comparison of fluocinolone acetonide intravitreal implant with laser photocoagulation using data from the DRCR Protocol B study.

3.14  The manufacturer’s model included14 health states (13 BCVA health states and death) which were defined by bands of 5 ETDRS letters in the treated eye. Utility values associated with the 13 BCVA-related health states captured the effect of varying degrees of visual gain or loss on patients’ quality of life. The model structure made no distinction between treatment on the better-seeing eye and the worse-seeing eye. The model had a 15-year time horizon and a quarterly cycle length, with costs and benefits both being discounted at 3.5%. For the first 3 years, the distribution of patients across health states was drawn directly from the FAME trial data. Beyond 3 years, a Markov model structure was adopted with transition probabilities being applied.

3.15  The base-case analysis assumed that 1 fluocinolone implant is needed every 3 years. To qualify for retreatment at the end of the first 3 years, patients needed to have gained 5 or more ETDRS letters of visual acuity between baseline and month 36. In addition, using data from the FAME trials the manufacturer applied a drop-out rate (for those who: withdrew consent; were lost to follow-up; or died) to the patients receiving fluocinolone acetonide intravitreal implant who qualified for retreatment at the end of the first 36 months (these details are marked by the manufacturer as commercial in confidence and therefore are not presented here). This adjusted retreatment rate was applied equally to each health state. Patients in both the fluocinolone groups and the optimised standard of care group also received laser treatments as described in the FAME trials, and in the first 3 years could receive other therapies including triamcinolone, ranibizumab, bevacizumab and dexamethasone, again based on rates in the FAME trials.

3.16  The model applied a diabetic macular oedema age-specific mortality rate derived from all-cause mortality data together with a 2.45 relative risk of death among patients with diabetic macular oedema.

3.17  In the base-case analysis, it was assumed that 35% of patients would receive bilateral treatment in the optimised standard of care group. The manufacturer assumed that patients treated in the first eye with fluocinolone who had a subsequent rise in intraocular pressure greater than 30 mmHg would not be eligible for bilateral treatment. Because some patients in the FAME trial experienced raised intraocular pressure (these data are marked by the manufacturer as academic in confidence and therefore are not presented here), the bilateral treatment rate in the fluocinolone group was reduced (these details are marked by the manufacturer as commercial in confidence and therefore not presented here). In response to a clarification request by the ERG the manufacturer submitted additional data that reviewed the FAME trial data and reported that a higher proportion of patients had chronic diabetic macular oedema in both eyes (these details are marked by the manufacturer as academic in confidence and therefore not presented here). On this basis, the manufacturer suggested that the model should assume that revised values should apply for those patientsreceivingbilateral treatment in both the comparator and the fluocinolone groups.

3.18  The clinical efficacy data from the FAME trials were used directly to calculate the number of patients in each of the model health states in each quarter for the first 3 years. Changes after 3 years were extrapolated from the FAME trial data. The FAME data were divided into patients who were responders and non-responders based on the ETDRS 5-letter criteria. Data were then analysed to determine the numbers of patients whose vision improved or worsened by at least 5 letters each quarter. The quarterly averages were then averaged over the period of the trial and for the last 4 quarters of the trials. The average changes in the last 4 quarters of the FAME trials were used in the model to extrapolate improvements in vision beyond 3 years. For people remaining on fluocinolone beyond 36 months, the model assumed that 5% who are responders at month 36 will improve by 5 letters every quarter. For those considered to be non-responders after retreatment with fluocinolone, 3% will experience a transition to a lower health state every quarter. In the optimised standard of care group and laser group, the model assumedthat 3% of patients in each health state will have a worsening in vision of 5 letters and therefore move to a worse health state every quarter.

3.19  The manufacturer did not consider it appropriate to include the VFQ-25 in the economic model because VFQ-25 is driven by vision in the better-seeing eye, whereas in the FAME trials, the majority of patients had their worse-seeing eye treated (these details are marked by the manufacturer as academic in confidence and therefore not presented here). Furthermore, the manufacturer stated that a mapping exercise was not considered because there was not a universally accepted mapping process to convert VFQ-25 data to utility scores.

3.20  The manufacturer conducted a systematic review to identify utility values reported in the literature for populations with visual impairment. The review of the articles included diabetic macular oedema and other disorders affecting visual acuity (such as age-related macular degeneration). Based on the data available, the manufacturer chose to use time trade-off data from Brown et al. (2000) as the source of utility values for its submission. Brown et al. (2000) is a US study that measured utility values in 5 groups according to visual acuity in the better-seeing eye in a population of patients with age-related macular degeneration. The values estimated by Brown et al. (2000) and the values used within the model range from 0.40 in the lowest health state (<20 ETDRS letters) to 0.89 in the highest health state (≥75 ETDRS letters). The Brown study did not report utility weights in patients with BCVAs between 35 and 50, and therefore the unweighted averages of the utility weights above and below this range were assumed.

3.21  For patients who received treatment in both eyes, a 25% bilateral treatment QALY uplift was also applied to the aggregate QALYs.

3.22  The model did not consider utility decrements due to adverse events or procedures and interventions for the adverse events. The manufacturer stated that because the utility values for the model were obtained directly from the quarterly BCVA values, the impact on patient vision of adverse events such as cataract formation was reflected in the BCVA of the treated eye.

3.23  The model included the costs of fluocinolone as well as laser and other therapies as observed in the FAME trials. Adverse events costs were also included. The manufacturer applied an annual cost of blindness of 6298 to the proportion of patients whose treated-eye BCVA fell below 35 letters.

3.24  In its deterministic base case, based on an incremental cost of 11,330 and an incremental QALY value of 0.500, the manufacturer estimated an incremental cost-effectiveness ratio (ICER) of 22,655 per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care.

3.25  The manufacturer presented a range of sensitivity analyses varying parameters such as the extrapolation assumptions relating to changing the percentage of people whose disease will improve or worsen by 1 health state each quarter year, the drop-out rate, health-related quality of life values and the number of fluocinolone treatments in the first 3 years. Varying the extrapolation assumptions resulted in ICERs between 18,090 and 46,192 per QALY gained for fluocinolone intravitreal implant compared with optimised standard of care. The details of the extrapolation assumptions are marked by the manufacturer as commercial in confidence and therefore not presented here. Varying the health-related quality of life values by using the lower and higher end of the confidence intervals for all utility weights resulted in ICERs of 18,883 and 28,387 per QALY gained respectively. Varying the number of treatments in the first 3 years increased the ICER to 26,809 per QALY gained.

3.26 Following the request for clarification from the ERG the manufacturer provided a revised analysis using alternative assumptions and including some changes to the model structure. The manufacturer acknowledged that the health-related quality of life values from Brown et al. (2000) may not apply to patients having their worse-seeing eye treated. The manufacturer therefore used revised health-related quality of life values to reflect a weighted average of values for people having their worse- and better-seeing eyes treated, taken from a study by Heintz et al. (2012). The adjusted Heintz EQ-5D values used in the manufacturer’s revised analysis ranged from 0.638, spanning health states 9 to 13 (that is, those with BCVA less than 40 ETDRS letters) to 0.848 (those with BCVA more than 60 ETDRS letters).

3.27  As well as changing health-related quality of life values, the manufacturer’s revised analysis also amended:

  • male and female mortality rates to revise the pooled annual all-cause mortality risk at baseline from 0.77% to 1.09%
  • the proportion of patients with bilateral chronic diabetic macular oedema needing bilateral treatment from 35% to a higher value (commercial-in-confidence)
  • the percentage of those needing bilateral treatment receiving bilateral fluocinolone treatment because of raised intraocular pressure in the originally treated eye from 82.9% to 85.3%
  • the quality of life uplift from bilateral treatment from 25% to 10%
  • the unadjusted response rate in the fluocinolone group from a rate based upon a 5-letter retreatment criterion to a different rate based upon a 10-letter retreatment criterion (the rates have been marked by the manufacturer as commercial in confidence and therefore are not presented here)

3.28  The manufacturer’s amendments reduced the estimate of cost effectiveness for fluocinolone compared with optimised standard of care from 22,655 to 19,268 per QALY gained, based on an incremental cost of 11,927 and an incremental QALY value of 0.619, and increased the estimate for fluocinolone compared with laser photocoagulation from 16,463 to 17,171 per QALY gained, based on an incremental cost of 11,698 and an incremental QALY value of 0.681.

ERG comments on the manufacturer’s submission

3.29  The ERG commented that the 3-year data used to inform the first 3 years of the economic model were robust, although the more usual modelling approach would have been to use transition probability matrices. The structure of the model means it cannot be manipulated during this 3-year period to explore different scenarios.

3.30  The ERG commented that it would have been more appropriate for the manufacturer to use a model structure that modelled patients as having 2 eyes, rather than undertaking an ad hoc adjustment to the output of a model in which patients only had 1 eye. The ERG noted that the FAME trials had a reasonable proportion of patients who had their better-seeing eye treated, and that the rate of chronic diabetic macular oedema in the other eye was high.

3.31  The ERG also noted that the distribution between health states for both fluocinolone responders and non-responders at 36 months was modelled as being a constant percentage of the overall patient distribution at 36 months. The ERG commented that this approach was not justified and might lead to bias against fluocinolone.

3.32  The ERG noted that the manufacturer’s base-case model applied a responder rule of a minimum 5-letter improvement between baseline and 36 months. The ERG commented that a more realistic rule might be a minimum 10-letter improvement between baseline and 36 months, which the manufacturer applied in response to the clarification request from the ERG. However, the ERG commented that this only changes the overall population of patients discontinuing fluocinolone treatment at year 3 and does not affect the health states distribution among the fluocinolone responders. The ERG commented that taking this into account might significantly improve the cost effectiveness for fluocinolone compared with optimised standard of care.

3.33  In the manufacturer’s submission clinical effectiveness beyond 3 years was extrapolated from the FAME trial data. The ERG commented that rather than including the proportions of patients improving or worsening each quarter of a year, the proportions were netted. The ERG considered that the reasons for analysing the data in this way were unclear.

3.34   The ERG commented that because in the FAME trial patients had only 1 eye treated, assumptions were required about rates of bilateral treatment. In the base-case analysis, it was assumed that 35% of patients would require bilateral treatment; this percentage was increased in the revised analysis (these details are marked by the manufacturer as academic in confidence and therefore are not presented here). The ERG considered that the manufacturer’s revision was too high because a proportion of patients would not have visual impairment in both eyes because of diabetic macular oedema, and a proportion would not be able to have both eyes treated because of raised intraocular pressure or other reasons.

3.35  The ERG commented that there was considerable uncertainty about the appropriateness of the utility values used in the model. The original submission used utility values that related to sight in the better-seeing eye. The ERG considered there were limitations in the data used in the revised analysis, as these provided only 3 quality of life values over 13 health states.

3.36  The ERG noted that the manufacturer’s revised analysis removed the bilateral treatment QALY uplift from the optimised standard of care group. The ERG commented that this conferred a large benefit upon the cost-effectiveness estimate for the fluocinolone intravitreal implant group and that the manufacturer did not explain this structural change.

Exploratory analyses by the ERG

3.37  The ERG conducted some additional exploratory analysesand then made a series of revisions to address what it considered to be possible errors in the model. These were:

  • a change to the formulae for averaging mortality between male and female rates
  • a change to the formulae for applying the yearly natural discontinuation rate (the detail of which is commercial-in-confidence) in the cohort flow cells
  • a change to the formula for the percentage of patients remaining on fluocinolone after year 9.

The cumulative impact of correcting the 3 errors was to increase the ICER from 22,655 to 26,526 per QALY gained for fluocinolone compared with optimised standard of care.

3.38  The ERG noted that the model anticipated large cost offsets from the fluorescein angiography costs of laser photocoagulation treatment, with all patients in the optimised standard of care group requiring fluorescein angiography 3 times during the first 3 years. The ERG noted expert opinion that these costs should be applied per laser administration regardless of the treatment group. The ERG therefore amended the model so that the 250 cost of fluorescein angiography needed before each laser administration was applied in both the fluocinolone group and the optimised standard of care group. The 250 costs were subsequently revised to 150 based on information provided by a clinical specialist to the ERG.

3.39  The ERG noted that there was a difference between the data inputs reported in the manufacturer’s submission and the electronic model for the number of laser administrations per patient. The ERG corrected the formula in the model for the rate of laser administration in the optimised standard of care group for year 1 to be in line with the raw data from the FAME trials (these data are marked by the manufacturer as academic in confidence and therefore are not presented here).

3.40  The ERG was unable to reconcile the unit costs for adverse event procedures used in the manufacturer’s model with NHS reference costs. The ERG changed the costs for glaucoma from 1128 to 1151, for vitrectomy from 1261 to 1938, for retinal detachment from 1339 to 1938 and for endophthalmitis from 1783 to 2244.

3.41  The ERG changed the way in which the proportions of responders and non-responders were handled in the model after 36 months. Instead of a net figure the proportions of people improving and worsening were included. The ERG also explored changes to the quarterly extrapolation percentages, with the following results:

  • Revising the quarterly extrapolation percentages for people improving and worsening for fluocinolone patients satisfying the 5-letter responder rule (the changes to the percentages are marked by the manufacturer as academic in confidence and therefore are not presented here) changed the ICER from 22,655 to 25,524 per QALY gained.
  • Revising the quarterly extrapolation percentages for people improving and worsening for optimised standard of care (the changes to the percentages are marked by the manufacturer as academic in confidence and therefore are not presented here) changed the ICER from 22,655 to 27,733 per QALY gained.

These 2 changes together increased the ICER from 22,655 to 32,148 per QALY gained.

3.42  The ERG amended the way in whichbilateral treatment was handled in the model. The ERG applied a preferred rate of bilateral treatment of 40% in the optimised standard of care group, and adjusted the treatment rate for fluocinolone to be 85.2% of the treatment rate in the optimised standard of care group. The quality of life uplift was reduced from 25% to 10% as had been done by the manufacturer in their revised analysis. In addition, the ERG applied a cost and quality of life uplift for those in the fluocinolone group who required bilateral treatment but were not suitable for bilateral treatment with fluocinolone to reflect the uplift applied in the standard of care group.

3.43  The final amendment was made to the cost of blindness. The cost was applied when only the treated eye fell to a BCVA of below 35 letters, rather than both eyes. The ERG applied the bilateral treatment rate of 40% in the optimised standard of care group to a cost of blindness of 5794, resulting in an annual average cost of blindness of 2318.

3.44  The ERG presented its baseline cost-effectiveness estimates for fluocinolone intravitreal implant compared with optimised standard of care; the estimates incorporated the cumulative impact of their changes described above. For the 5-letter responder rule, the ERG’s baseline ICER was 37,740 per QALY gained while that for the 10-letter responder rule was 35,940 per QALY gained for fluocinolone intravitreal implant compared with optimised standard of care. The ERG also conducted further exploratory sensitivity analyses with a particular focus on the source of utility values. These additional analyses modelled the impact of changes in the BCVA of the better-seeing eye using Brown et al. (1999) which suggests health-related quality of life values of 0.890 to 0.540, giving a range of 0.350 across the health states of the model. The ERG commented that if its suggested base-case cost-effectiveness estimates for fluocinolone compared with optimised standard of care were used as a starting point (37,740 per QALY gained for the 5-letter responder rule and 35,940 per QALY gained for the 10-letter responder rule), applying the health-related quality of life values taken from Brown et al (1999) would suggest cost-effectiveness estimates of 66,744 per QALY gained (5-letter responder rule) and 64,249 per QALY gained (10-letter responder rule).

3.45  The ERG explored the effect of using health-related quality of life values from Brazier et al. (as used in the manufacturer’s submission in TA 237), Brown et al. (1999) and Brown et al. (2000). The ERG noted that there is uncertainty around the health-related quality of life impact resulting from changes in the BCVA of the worse-seeing eye, and presented 6 scenario analyses to take this into account in conjunction with the 3 different sources of utility values:

  • Scenario analysis 1: A flat health-related quality of life function where changes in the BCVA of the worse-seeing eye have no impact.
  • Scenario analysis 2: A health-related quality of life function where changes in the BCVA of the worse-seeing eye have 15% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of (15%of 0.350) = 0.053.
  • Scenario analysis 3: A health-related quality of life function where changes in the BCVA of the worse-seeing eye have 30% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of (30%of 0.350) = 0.105.
  • Scenario analysis 4: A health-related quality of life function where changes in the BCVA of the worse-seeing eye have 50% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of (50%of 0.350) = 0.175.
  • Scenario analysis 5: A health-related quality of life function where changes in the BCVA of the worse-seeing eye have 70% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of (70%of 0.350) = 0.245.
  • Scenario analysis 6: A health-related quality of life function where changes in the BCVA of the worse-seeing eye have 100% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of 0.350.

3.46  The ERG also assumed 20% and 40% of people received unilateral treatment in their better-seeing eye and worse-seeing eye respectively. For the fluocinolone group it was also assumed that 34% of people received bilateral treatment with fluocinolone in both eyes, while 6% received treatment with fluocinolone in the first eye and sham injection in the second eye. In the optimised standard of care group, the ERG similarly assumed that 20% and 40% of people received unilateral treatment in their better-seeing and worse-seeing eye respectively; whereas 40% of people were assumed to receive treatment with sham injection in both eyes.

3.47  In the sensitivity analyses using Brown et al (1999), the ICERs (based on a 10-letter responder rule and including a bilateral benefit) ranged from 48,533 per QALY gained (scenario analysis 6, where changes in the BCVA of the worse-seeing eye have 100% of the range of changes in the BCVA of the better-seeing eye: i.e. a range of 0.350) to 110,730 per QALY gained (scenario analysis 1 where changes in the BCVA of the worse-seeing eye were assumed to have no impact). Using Brown et al. (2000) the equivalent ICERs ranged between 35,321 and 82,618 per QALY gained for fluocinolone compared with optimised standard of care. Using the utility values derived from Brazier et al., based upon the 10-letter responder rule and including a bilateral benefit, the ICERs ranged from 58,143 (scenario analysis 6) to 146,071 per QALY gained (scenario analysis 1).

3.48  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 fluocinolone acetonide intravitreal implant, having considered evidence on the nature of chronic diabetic macular oedema and the value placed on the benefits of fluocinolone acetonide intravitreal implant 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 was aware of comments from patient experts describing the significant negative impact that visual impairment has on physical and emotional wellbeing of people with diabetic macular oedema. The Committee noted that people with diabetes  manage some aspects of their own condition and that visual impairment can affect an individual’s ability to do this. This in turn could increase the risk of long-term disease complications such as kidney disease, cardiovascular disease and amputations. The Committee also heard from clinical specialists that chronic diabetic macular oedema tends to be a bilateral condition (that is, affecting both eyes) with the potential risk of losing sight in both eyes. The clinical specialists stated that the condition therefore impacts on the quality of life of people with visual impairment and also that of their carers because of loss of independence. The Committee noted comments from clinical specialists which highlighted that several studies have reported increased rates of depression in people with chronic diabetic macular oedema.

4.3   The clinical specialists stated that for diabetic macular oedema, standard treatment in some centres is anti-VEGF therapies, with or without laser photocoagulation, however the availability of anti VEGF therapies is subject to regional variation. The Committee heard that when anti-VEGF therapies are not readily available, standard treatment would be “optimised standard of care” including laser therapy. The Committee noted that there are currently no standard third-line or subsequent treatments for people with chronic diabetic macular oedema. The Committee recognised the importance of the good control of blood glucose, blood pressure and blood lipids in reducing the risk of diabetic macular oedema and other complications of diabetes.

4.4   The Committee noted current NICE guidance relating to the treatment of diabetic macular oedema. It was aware that ranibizumab is not recommended for the treatment of diabetic macular oedema (NICE technology appraisal guidance 237) and that there is currently no other NICE guidance relating specifically to treating chronic diabetic macular oedema.

4.5   The Committee heard from the clinical specialists’ that as fluocinolone intravitreal implant is a sustained-release low-dose long-acting steroid, it has clear advantages over other steroid implants, which the Committee was aware are not licensed for the treatment of diabetic macular oedema.

4.6   However, the Committee noted that the significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract and increased rates of raised intraocular pressure, still occur with fluocinolone. The Committee also heard from clinical specialists that there is a spectrum of severity of diabetic macular oedema and steroid treatment might be useful in those with more severe diabetic macular oedema where other treatments (including laser photocoagulation) have failed and where cataract removal surgery has already happened. The Committee agreed that the patient population considered as part of this appraisal would not receive laser photocoagulation in clinical practice. The Committee noted that this is recognised in the marketing authorisation of fluocinolone intravitreal implant, and concluded that it is only suitable when available therapies have been insufficiently responsive.

  Clinical effectiveness

4.7   The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fluocinolone intravitreal implant. The Committee noted that the main source of evidence came from the FAME A and B randomised controlled trials, which included people with diabetic macular oedema and a pre-defined subgroup of people with chronic diabetic macular oedema (that is, of more than 3 years’ duration). It noted that in the FAME trials, the majority of patients were treated in their worse-seeing eye. The Committee noted that fluocinolone intravitreal implant was associated with statistically significant gains in the proportion of patients with chronic diabetic macular oedema who had a more than 15-letter increase in BCVA from baseline compared with the sham injection group. It also noted that mean change in BCVA from baseline at month 36 of the FAME trials was statistically significantly higher in the fluocinolone intravitreal implant group compared with the sham injection group. The Committee concluded that fluocinolone intravitreal implant showed greater efficacy than sham injection in people with chronic diabetic macular oedema.

4.8   The Committee considered the patient population in the FAME trials relevant to the decision problem submitted by the manufacturer. It noted that some patients included in the trials received additional treatments such as laser photocoagulation and anti-VEGF injections. The Committee discussed the concerns raised by the ERG that this implied that fluocinolone intravitreal implant was not being used when available therapies have been insufficiently responsive, as specified in the marketing authorisation, and that therefore the results from the sham group of the FAME trials might be better than would be seen in clinical practice. The Committee concluded that the people included in the FAME trials may not have been as severely affected as patients who would receive fluocinolone intravitreal implant in routine clinical practice.

4.9   The Committee considered the manufacturer’s approach to conducting an indirect comparison of fluocinolone intravitreal implant compared with laser photocoagulation using the FAME trials and the DRCR Protocol B study (2008). The Committee was aware of the ERG’s concerns over the value of the indirect comparison given the absence of a common comparator to link the FAME study with the identified DRCR Protocol B study and its further concerns over methods used by the manufacturer. It also noted that: the retinopathy in patients included in the DRCR study was not as severe as in the FAME trials; that 40% of the DRCR population was laser-naive; and that randomisation was not done according to duration of diabetic macular oedema. The Committee concluded that the indirect comparison could not be interpreted with any confidence and in any case was inappropriate to the scope for this appraisal which considers fluocinolone when available therapies have been insufficiently responsive.

4.10   The Committee considered the evidence for adverse events associated with fluocinolone intravitreal implant. It noted that fluocinolone intravitreal implant was associated with the formation or progression of cataract but was aware that people who were phakic at baseline (still had their natural lens) had similar rates of pre-existing cataract between the 2 trial groups (77.9% and 77.0%); however cataract surgery was needed by a greater percentage (85.1% and 36.4%) of patients who were phakic at baseline in the fluocinolone intravitreal implant group than in the sham injection group. The Committee heard from clinical specialists that the majority of people with chronic diabetic macular oedema would be likely to develop cataracts at some stage but that fluocinolone intravitreal implant might accelerate its progression. The Committee also noted that administration of fluocinolone intravitreal implant was associated with increased intraocular pressure: 5.3% of people in the fluocinolone intravitreal implant group required intraocular pressure-lowering surgery compared with 0% in the sham injection group. The Committee heard from clinical specialists that intraocular pressure-lowering surgery was a particular concern and for this reason, in addition to the associated acceleration of cataracts, clinicians would be reluctant to use fluocinolone too early in the treatment pathway. The Committee concluded that fluocinolone intravitreal implant would only be considered after available therapies had been insufficiently responsive..

 Cost effectiveness

4.11   The Committee considered the manufacturer’s economic model and sensitivity analyses. The Committee discussed the key parameters used in the model. It noted that the manufacturer’s base-case analysis was based on 5 ETDRS letter bands across 13 treated eye health states and death; for the first 3 years of the model, the distribution of patients in the health states was drawn directly from the FAME trial data but subsequently extrapolated beyond the 3 years by applying transition probabilities conditioned by certain retreatment criteria and a bilateral treatment rate of 35%. The Committee noted the manufacturer’s base-case deterministic ICER for fluocinolone intravitreal implant compared with standard of care of 22,600 per QALY gained. The Committee also noted the sensitivity analyses presented by the manufacturer. The Committee concluded that the cost-effectiveness estimates were most sensitive to the assumption that a person’s overall visual acuity related only to the their treated eye, the number of fluocinolone treatments in the first 3 years, extrapolation assumptions relating to varying the percentage of people whose disease will improve or worsen by 1 health state each quarter year, the drop-out rate and health-related quality of life values.

4.12   The Committee considered the ERG’s critique of the manufacturer’s base-case model. The Committee noted that the manufacturer had only provided deterministic cost-effectiveness estimates and had not provided any probabilistic sensitivity analyses. It was aware that the ERG had made a series of revisions to address what it considered to be possible errors in the model using the manufacturer’s base-case ICER of 22,600 per QALY gained as a starting point. The Committee noted that by correcting an error relating to application of annual discontinuation rates in the model, and by changing the formulae for averaging male and female mortality rates and for calculating the percentage of patients remaining on fluocinolone beyond 9 years, the ERG’s analysis increased the manufacturer’s base-case ICER from 22,700 to 26,500 per QALY gained for fluocinolone compared with optimised standard of care. The Committee agreed that these ERG’s initial error corrections to the manufacturer’s model were appropriate.

4.13   Following on from the amendments described in section 4.12, the Committee went on to consider the following further adjustments to the manufacturer’s model by the ERG:

  • aligning assumptions regarding the rate of laser administrations per patient in the optimised standard of care group for year 1 of the model with the trial data
  • applying corrected unit costs for some adverse events
  • revising the quarterly extrapolation percentages through which the proportions of responders and non-responders are modelled beyond 3 years in the model
  • applying a bilateral treatment rate of 40% in the optimised standard of care group
  • applying an adjusted bilateral treatment rate in the fluocinolone acetonide intravitreal implant group (these data were marked by the manufacturer as academic in confidence and are therefore not presented here)
  • applying a quality of life uplift of 10% in both groups
  • applying a cost and quality of life uplift for those requiring bilateral fluocinolone treatment but ineligible for treatment as a result of contraindication
  • applying the cost of blindness when only the treated eye fell below a BCVA of 35 letters rather than both eyes.

The Committee noted that the ERG presented their preferred base-case ICERs for those satisfying the 5-letter and 10-letter responder rules. It noted that the cumulative impact of the ERG’s amendments resulted in ICERs for those satisfying the 5-letter and 10-letter responder rules of 37,700 and 35,900 per QALY gained respectively, for fluocinolone intravitreal implant compared with optimised standard of care. The Committee heard from the clinical specialists that a 10-letter responder rule was clinically meaningful and therefore the Committee accepted that using the 10-letter responder rule was appropriate. The Committee concluded that the amendments made to the manufacturer’s model did not correct all the issues identified by the ERG and accepted the ERG’s baseline ICERs as only a starting point for exploring the effect of other parameters.

4.14   The Committee next considered the manufacturer’s revised model submitted as part of the clarification process. The Committee noted the ERG’s view that the utility valuations from Brown et al. (2000) do not apply to patients having their ‘worse-seeing eye’ treated. It noted that the manufacturer’s attempt to correct for this by applying a weighted average of health-related quality of life values for people having their ‘worse-‘ and ‘better-seeing eyes’ treated using adjusted EQ-5D values from Heintz et al. (2012) increased the manufacturer base-case ICER from 22,600 to 32,600 per QALY gained for fluocinolone intravitreal implant compared with optimised standard of care. However the Committee considered that the very slight differences between Heintz utlities for the loss of ‘better-seeing eye’ vision to ‘worse-seeing eye’ vision lacked face validity. The Committee also noted the other changes applied by the manufacturer to address some of the ERG’s concerns relating to mortality, the percentage of patients having bilateral treatment, adjusting the percentage of people meeting the 5-letter retreatment criteria, and structural changes to the model of only applying the QALY uplift for bilateral treatment within the fluocinolone group. The Committee noted that applying all of these assumptions resulted in the manufacturer’s base-case ICER of 19,300 per QALY gained for fluocinolone intravitreal implant compared with optimised standard of care. It noted that the biggest impact on the base-case ICER arose from applying the QALY uplift only to the fluocinolone treatment group, mainly because the benefit of bilateral treatment is removed from the optimised standard of care group while the costs of bilateral treatment still apply. The Committee noted that removing this assumption, and so treating the groups in a similar way, was more plausible and increased the base-case ICER to 57,400 per QALY gained. The Committee concluded that it could not accept the manufacturer’s assumption relating to QALY uplift being applied only to the fluocinolone group in the model.

4.15   The Committee discussed the utility values first for the ‘better-seeing eye’ used in the model and then with adjustments for the ‘worse-seeing eye’. For the ‘better-seeing eye’, it was aware that the ERG’s revisions to the manufacturer’s original model retained the quality of life values used in the manufacturer’s original model (taken from Brown et al. 2000). The Committee noted that the ERG explored the effect of applying utility values from Brown et al. (1999), Brown et al. (2000) or Brazier et al. The Committee noted that when the ERG applied these utility values, without changing assumptions (see section 3.44-3.46) relating to the ‘worse-seeing eye’ or to bilateral treatment, this changed the ERG’s baseline ICER of 35,900 per QALY gained to 48,400, 35,300, and 58,100 per QALY gained respectively for fluocinolone intravitreal implant compared with optimised standard of care using the 10-letter responder rule. The Committee agreed that the validity of the sources of the utility values may vary in their appropriateness in being applied to this patient group, that is, people with chronic diabetic macular oedema. It accepted that the utility values from Brazier et al. were relatively insensitive to changes in visual acuity and therefore the ICER could be  lower, but that the study by Brown et al. (1999) included newer patients (that is people with a shorter duration of visual impairment) and therefore the ICER estimates could be higher using these utility values .

4.16   The Committee then considered the 6 scenario analyses carried out by the ERG, using the manufacturer’s model, using each of the different sources of utility and adjustments to the costs and QALYs associated with unilateral treatment in the ‘worse-seeing eye’ as well as the ‘better-seeing eye’ and with bilateral treatment. The Committee noted that the 6 scenario analyses varied the impact of changes in the BCVA of the ‘worse-seeing eye’ but considered scenario analysis 3 to be consistent with previous appraisals in that improvements for people treated in their ‘worse-seeing eye’ of 30% of the range of BCVA changes in the ‘better-seeing eye’ can be considered a reasonable reflection of the clinical situation. The ERG’s ICER calculations using utility values from Brown et al. (2000) was 58,900 per QALY gained for fluocinolone compared with optimised standard of care, whereas using values from either Brown et al. (1999) or Brazier et al. resulted in ICERs of 80,000 and 100,500 per QALY gained respectively using the 10-letter responder rule. The Committee further noted that the FAME trials collected data on the effect of visual impairment on quality of life using the VFQ-25 questionnaire which, as a direct measure of quality of life, avoided the need for assumptions of the proportions and differential benefits for patients receiving treatment in their better or worse seeing eye. The trial reported no significant differences at baseline, month 24 and month 36 between the fluocinolone intravitreal implant group and the optimised standard of care group. The Committee considered that mapping from the VFQ-25 health-related quality of life values collected in the FAME trials was possible, and that if VFQ-25 values had been used the ICERs would have been even higher than those using values from Brown et al. (1999), Brown et al. (2000) or Brazier et al. (2006). Therefore although there was no definitive proof as to which utility data were most appropriate to include in the model the Committee concluded that the most plausible ICER for flucinolone acetonide intravitreal implant would be at least 58,900 per QALY gained and possibly even higher.

4.17   The Committee discussed additional concerns of the ERG regarding the manufacturer’s original model. It noted that the model did not apply quality of life detriments to adverse events such as cataracts, glaucoma or raised intraocular pressure. The Committee noted the manufacturer’s rationale that the impact of adverse events such as cataract formation on visual acuity was incorporated in the overall utility measures. The Committee concluded that this did not take into account the disutilities associated with operations, procedures and hospital attendances (such as, cataract removal, glaucoma surgery, retinal detachment surgery, vitrectomy and treatment of endophthalmitis) which if taken into account would increase the ICER further.

4.18   The Committee discussed what outcomes might have resulted if there had been trial data that more accurately captured only those patients whose condition was insufficiently responsive to available therapies. They recognised that the fluocinolone acetonide intravitreal implant may be more cost-effective if the trial population was more aligned with the patients that are stated in the marketing authorisation. However even after taking into account that the ICER might decrease if used in the licensed population only, the Committee considered given the ICERs modelled that fluocinolone acetonide intravitreal implant is not an effective use of NHS resources and could not be recommended as a treatment for people with chronic diabetic macular oedema.

4.19   The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. The Committee considered any impact of its preliminary recommendations for fluocinolone intravitreal implant on otential inconsistency of access for people residing in care homes and also on the potential of unequal access to fluocinolone acetonide intravitreal implant due to ethnic family origin. The Committee concluded that the preliminary recommendations do not differentiate between any groups of people, therefore there were no issues directly relating to the equalities legislation and there was no need to alter or add to its preliminary recommendations.

Summary of Appraisal Committee’s key conclusions

TAXXX Appraisal title: Section
Key conclusion
Fluocinolone acetonide intravitreal implant is not recommended for the treatment of chronic diabetic macular oedema. 1.1
Current practice
Clinical need of patients, including the availability of alternative treatments

The Committee was aware of comments from patient experts describing the significant negative impact that visual impairment has on physical and emotional wellbeing of people with diabetic macular oedema.

The Committee noted that there are currently no standard third-line or subsequent treatments for people with chronic diabetic macular oedema.

4.2

4.3

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 Committee heard from the clinical specialists’ view that as fluocinolone intravitreal implant is a sustained-release low-dose long-acting steroid, it has clear advantages over other steroid implants, which are not licensed for the treatment of diabetic macular oedema.  4.5
What is the position of the treatment in the pathway of -care for the condition? The Committee concluded that because of the indication stated in the marketing authorisation, fluocinolone intravitreal implant is only suitable when other therapies have been insufficiently responsive. 4.6
Adverse reactions The Committee noted that the significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract and increased rates of raised intraocular pressure still occur with fluocinolone. 4.6
Evidence for clinical effectiveness
Availability, nature and quality of evidence

The Committee noted that the evidence came from the FAME A and B randomised controlled trials. The Committee concluded that the people in the FAME trials may not have been as severely affected as patients who would receive fluocinolone intravitreal implant in routine clinical practice.

The Committee noted the DRCR Protocol B study used by the manufacturer in its indirect comparison but noted the ERG’s concerns with this study.

4.7, 4.8

4.9

Relevance to general clinical practice in the NHS The Committee concluded that the people included in the FAME trials may not have been as severely affected as patients who would receive fluocinolone intravitreal implant in routine clinical practice. 4.8
Uncertainties generated by the evidence The Committee discussed the concerns raised by the ERG that this implied that fluocinolone intravitreal implant was not being used as a treatment when available therapies have been insufficiently responsive, as specified in the marketing authorisation, and that therefore the results from the sham group of the FAME trials might be better than would be seen in clinical practice. 4.8
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No clinically relevant subgroups were identified for which there was differential effectiveness.  
Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that fluocinolone intravitreal implant showed greater efficacy compared with sham injection in people with chronic diabetic macular oedema. 4.7
Evidence for cost effectiveness
Availability and nature of evidence

The manufacturer’s economic evaluation compared the fluocinolone acetonide intravitreal implant group with the comparator group (‘optimised standard of care’) of the FAME trials for a cohort of patients with chronic diabetic macular oedema. For the first 3 years, the distribution of patients across health states was drawn directly from the FAME trial data. Beyond 3 years, a Markov model structure was adopted with transition probabilities being applied.

The Committee was aware that the ERG had made a series of revisions to address what it considered to be possible errors in the model and a number of further adjustments.

3.13, 3.14

4.12, 4.13

Uncertainties around and plausibility of assumptions and inputs in the economic model

7              The Committee concluded that the amendments made to the manufacturer’s model did not correct all the issues identified by the ERG and accepted the ERG’s baseline ICERs as only a starting point for exploring the effect of other parameters.

The Committee concluded that it could not accept the manufacturer’s assumption relating to QALY uplift being applied only to the fluocinolone group in the model.

There was no definitive proof as to which utility data were most appropriate to include in the model

The Committee concluded that the manufacturer’s model did not take into account the disutilities associated with operations, procedures and hospital attendances which if taken into account would cause the ICER to be even higher.

4.13

4.14

4.16

4.17

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 Committee noted that the ERG explored the effect of applying utility values from Brown et al. (1999), Brown et al. (2000) or Brazier et al. The Committee agreed that the validity of the sources of the utility values may vary in their appropriateness in being applied to this patient group, that is, people with chronic diabetic macular oedema. It accepted that the utility values from Brazier et al. were relatively insensitive to changes in visual acuity and therefore the ICER could be  lower, but that the study by Brown et al. (1999) included newer patients (that is people with a shorter duration of visual impairment) and therefore the ICER estimates could be higher using these utility values .

The Committee considered that mapping from the VFQ-25 health-related quality of life values collected in the FAME trials was possible, and that if VFQ-25 values had been used the ICERs would have been even higher than those using values from Brown et al. (1999), Brown et al. (2000) or Brazier et al..

4.15

4.16

Are there specific groups of people for whom the technology is particularly cost effective? The Committee did not identify a specific group of people for whom fluocinolone acetonide intravitreal implant would be particularly cost effective.  
What are the key drivers of cost effectiveness? The Committee concluded that the cost-effectiveness estimates were most sensitive to the assumption that a person’s overall visual acuity related only to the their treated eye, the number of fluocinolone treatments in the first 3 years, extrapolation assumptions relating to varying the percentage of people whose disease will improve or worsen by 1 health state each quarter year, the drop-out rate and health-related quality of life values. 4.11
Most likely cost-effectiveness estimate (given as an ICER) Although there was no definitive proof as to which utility data were most appropriate to include in the model the Committee concluded that the most plausible ICER for flucinolone acetonide intravitreal implant would be at least 58,900 per QALY gained and possibly even higher. 4.16
Additional factors taken into account
Patient access schemes (PPRS) Not applicable  
End-of-life considerations Not applicable  
Equalities considerations and social value judgements The Committee concluded that the preliminary recommendations do not differentiate between any groups of people, therefore there were no issues directly relating to the equalities legislation and there was no need to alter or add to its preliminary recommendations. 4.19

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   The technology in this appraisal may not be the only treatment for chronic diabetic macular oedema. If a NICE technology appraisal recommends use of a technology, it is as an option for the treatment of a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes and the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3   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.

6 Related NICE guidance

Published

  • Ranibizumab for the treatment of diabetic macular oedema. NICE technology appraisal guidance 237 (2011). Available from www.nice.org.uk/guidance/TA237
  • Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011). Available from www.nice.org.uk/guidance/TA229
  • Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Available from http://nice.org.uk/guidance/TA155
  • Type 2 diabetes – newer agents (partial update of CG66). NICE clinical guideline 87 (2008). Available from www.nice.org.uk/guidance/CG87
  • Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults. NICE clinical guideline 15 (2004). Available from www.nice.org.uk/guidance/CG15

Under development

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

  • Aflibercept solution for injection for the treatment of wet age-related macular degeneration. NICE technology appraisal guidance (publication expected August 2013).
  • Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion. NICE technology appraisal guidance (publication date to be confirmed).

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 November 2015. 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
July 2012

Appendix A: Appraisal Committee members 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 4 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.

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

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

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 Mary Cooke
Lecturer, School of Nursing, Midwifery and Social Work, University of Manchester

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

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

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

Dr Greg Fell
Consultant in Public Health, Bradford and Airedale Primary Care Trust

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

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Dr Janice Kohler
Senior Lecturer and Consultant in Pediatric Oncology, Southampton University Hospital Trust

Dr Andrea Manca
Health Economist and Senior Research Fellow, University of York  

Professor Katherine Payne
Professor of Health Economics, University of Manchester

Alan Rigby
Senior Lecturer and Chartered Statistician, University of Hull

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

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

Professor Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle
Lay Member

B NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Christian Griffiths
Technical Lead

Joanna Richardson
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 Warwick Evidence:

  • Cummins E, Shyangdan D, Royle P et al. Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema: a single technology appraisal, June 2012

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:

  • Alimera Sciences, Inc.

II           Professional/specialist and patient/carer groups:

  • Diabetes UK
  • Fight for Sight
  • Organisation of Blind African Caribbeans
  • Royal College of Nursing
  • Royal College of Ophthalmologists
  • Royal College of Physicians
  • Royal National Institute of Blind People (RNIB)

III          Other consultees:

  • Department of Health
  • Welsh Government

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

  • Commissioning Support Appraisals Service
  • Department of Health, Social Services and Public Safety for Northern Ireland
  • Healthcare Improvement Scotland
  • Novartis Pharmaceuticals
  • Pfizer
  • Roche Products

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 fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Clare Bailey, Consultant Ophthalmologist, nominated by Alimera Sciences Inc – clinical specialist
  • Professor Yit Yang, Consultant Ophthalmologist, nominated by Royal College of Ophthalmologists – clinical specialist
  • Clara Eaglen, Policy and Campagins manager, 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.

  • Alimera Sciences, Inc.

This page was last updated: 31 August 2012

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Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.