Cost-effectiveness of fluocinolone acetonide implant (ILUVIEN®) in UK patients with chronic diabetic macular oedema considered insufficiently responsive to available therapies

Diabetes is a common and chronic health condition with a global prevalence of 8.5% in the adult population [1]. In the UK, almost 3.6 million people are living with this disease [2]. Those suffering from diabetes may experience long-term complications impacting various parts of the body, including kidney failure, cardiovascular events, lower extremity amputations and loss of vision [1]. The latter is related to diabetic retinopathy, which affects approximately 35% of diabetics, threatening the vision of 7% [1]. However, certain populations, such as those with longer duration of diabetes or type 1 disease, are more frequently affected [1].

Diabetic macular oedema (DMO) is a complication of diabetic retinopathy characterised by increased vascular permeability, where leakage of fluid from blood vessels causes swelling of the retina, which may lead to visual loss and – eventually – blindness [3, 4]. DMO is the most common cause of moderate visual loss from diabetic retinopathy [4], with an estimated age-standardised prevalence of 6.81% amongst patients with diabetes [5]. However, DMO can be far more common in certain populations, with age-standardised prevalence approaching 15% in patients with type 1 diabetes and 20% in those who have had diabetes for ≥20 years [5]. Recent studies from the UK reported an estimated DMO prevalence of 7.12% amongst diabetics in England (with the condition affecting both eyes in 2.34% of diabetes patients) [6, 7].

A number of drugs used to treat DMO are available to UK patients on the National Health Service (NHS), following a positive recommendation from the National Institute for Health and Care Excellence (NICE). These include the anti-VEGFs aflibercept and ranibizumab, recommended in patients whose eye has a central retinal thickness of ≥400 μm at the start of treatment, and two steroid implants – a short-acting [8] one that uses dexamethasone, and a long-acting [9] fluocinolone acetonide (FAc) implant (ILUVIEN®) [10, 11]. The main mechanism of action is the induction of phospholipase A inhibitory proteins, collectively called lipocortins. These proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids have also been shown to reduce levels of vascular endothelial growth factor, a protein which increases vascular permeability and causes oedema.

There is a substantial body of evidence supporting the use of the FAc implant in DMO. Although, it is licensed for use in DMO patients regardless of their lens status [9]. NICE recommended restricting the use of the FAc implant on the NHS to pseudophakic eyes only. It is an eye in which the natural lens is replaced with an intraocular lens, since cost-effectiveness results in the full DMO population were associated with substantial uncertainty. However, the analysis in the full population was confounded by the formation of cataracts in phakic eyes, and the resulting uncertainty in BCVA gain extrapolations. Furthermore, recent evidence shows that the FAc 0.2 μg/day implant provides cost savings to the NHS versus continued ranibizumab therapy, irrespective of lens status [12]. This is of particular importance considering that in UK clinical practice many patients who insufficiently respond to anti-VEGFs continue to receive them. A recent post-hoc analysis of the Diabetic Retinopathy Clinical Research (DRCR) Network’s Protocol I study showed that approximately 40% of patients treated with ranibizumab responded to it insufficiently [13]. Consequently, patients are potentially exposed to burden some intravitreal injections, despite not experiencing sufficient benefits while the NHS incurs unnecessary costs of an intervention lacking real-world effectiveness. Thus, ensuring adequate treatment options are available to patients who do not sufficiently respond to anti-VEGFs is crucial, both from the clinical and health economics perspectives.

The objective of this study was therefore to assess the cost-effectiveness of the FAc 0.2 μg/day implant in patients insufficiently responsive to other therapies, compared with: 1) usual care, consisting of laser photocoagulation and anti-VEGFs, and 2) dexamethasone implant.

Our analysis investigated cost-effectiveness of the FAc 0.2 μg/day implant in patients who suffered from chronic DMO in at least one eye that was pseudophakic or phakic with a cataract, and did not respond sufficiently, or ceased to respond sufficiently, to anti-VEGF treatments. With a base-case ICER of £16,609 and £28,751 per QALY in pseudophakic and phakic patients, the FAc 0.2 μg/day implant was estimated to be cost-effective compared with usual care, considering that a cost-effectiveness threshold of £20,000–£30,000 per QALY is normally applied in the UK [27]. Thus, the FAc 0.2 μg/day implant can provide a cost-effective solution also for phakic patients, whose treatment options are currently quite limited. The results of sensitivity analyses were generally consistent with the base-case scenario. However, the ICER estimate was sensitive to the assumption that anti-VEGFs continue to be used in patients insufficiently responsive to these therapies, as seen in Scenario B, where patients were assumed to receive laser photocoagulation only and their vision neither improved nor deteriorated with this treatment. Nonetheless, the inclusion of anti-VEGFs in usual care of patients that do not respond to them sufficiently appears justified, as available clinical trial evidence suggest patients may continue treatment with anti-VEGFs despite insufficient response to the initial phase of treatment [13, 29, 30]. Further, with the dosing regimen of anti-VEGFs based on the real-world ICE-UK study, the assumptions used to model anti-VEGF treatment are more likely to accurately reflect the reality of using these treatments on the NHS.

The FAc 0.2 μg/day implant was estimated to be cost-effective compared with dexamethasone in patients who were pseudophakic at baseline, with a base-case ICER of £14,070. Furthermore, with a price reduction of £1210, the FAc 0.2 μg/day implant would dominate the dexamethasone implant. It is worth noting that this comparison against dexamethasone is likely to be highly conservative, as we assumed retreatment with the dexamethasone implant could be performed every six months in line with the approved indication [8], while its dosing in routine clinical practice is likely to be more frequent (i.e. every 3–4 months) [31], thus increasing the costs associated with this treatment option. This assumption was consistent with the efficacy data we used, which was derived from a clinical study of the dexamethasone implant [32], where treatment frequency was in line with the label.

Our model appeared to provide a reasonable approximation of the changes in visual acuity observed in the FAME trial, which provides reassurance on the validity of the modelling approach, inputs and assumptions. In the model, pseudophakic patients treated with the FAc 0.2 μg/day implant gained 10.9 ETDRS letters over 3 years, while phakic patients gained 11.5 letters – an overestimation of 3.3 and 3.9 letters, respectively, compared with the FAME trial, where the average number of ETDRS letters gained with the FAc 0.2 μg/day implant was 7.6 [17]. It is, however, worth noting that this improvement in visual acuity in the FAME trial was measured in a population with a mixed lens status – 54.5% of chronic DMO patients treated with the FAc implant and 58.9% of those treated with sham injection were phakic at baseline [17]. In the usual care group, the model predicted a gain of 6.8 ETDRS letters in pseudophakic patients and 8.5 ETDRS letters in phakic patients, compared with a gain of 1.8 letters reported in the sham arm of the FAME trial [17] – an overestimate of 6.7 letters. Although the model seems to overestimate gains in BCVA obtained with both treatments, it can be considered conservative, as the degree of overestimation was higher in the usual care arm, and the modelled benefit of the FAc implant (4.0 and 3.0 additional ETDRS letters gained with the FAc implant compared with usual care at 3 years in pseudophakic and phakic patients, respectively) was lower than that observed in the FAME trial (between-treatment difference of 6.1 letters at 3 years [17]). The difference between BCVA observed in the FAME trial and BCVA predicted in the model appears attributable to random variability – although probabilities of transition between BCVA categories estimated using a more complex multinomial model allowed for a better fit to the trial data, some factors were removed from the model since they were not statistically significant.

In terms of structure, the current model is similar to other UK models for DMO treatments – two such models were identified, one used in the dexamethasone implant Single Technology Appraisal (STA), the other in STA of aflibercept. In the model used within aflibercept STA, patients treated with laser photocoagulation accumulated 7.30 QALYs (11.34 life-years [LY]) over a lifetime horizon [14]. In order to compare our results with those presented in aflibercept STA submission, we performed an additional analysis extending the time horizon of the present model to 30 years. The analysis showed that patients treated with laser photocoagulation lived on average 9.66 years, corresponding to 6.05 QALYs. This difference between QALY estimates between the two models results from differences in mortality that was included. However, the ratio between generated QALYs and LYs is consistent between both models.

It is noteworthy that results of the comparison between dexamethasone implant and the FAc 0.2 μg/day implant were largely similar in the current model and the model used in the dexamethasone implant STA. Over a 15-year time horizon, the dexamethasone STA model estimated that total costs were £22,365 for the FAc implant compared with £20,413 for the dexamethasone implant [33]. In our model, the same comparison performed in the pseudophakic population resulted in total costs of £22,117and £20,340 for the two treatments, respectively. The results of both models were also comparable in terms of QALY estimates, with the model used in dexamethasone implant STA returning 5.82 QALYs with the FAc implant compared to 5.74 QALYs with the dexamethasone implant [33], and the current model estimating 5.78 and 5.65 QALYs, respectively.

The FAc 0.2 μg/day implant was estimated to be cost-effective compared to usual care in patients with chronic DMO who display an insufficient response to anti-VEGFs irrespective of the lens status. Further, the FAc 0.2 μg/day implant was cost-effective compared to dexamethasone implant in patients with pseudophakic eyes, for whom both of these treatments are currently recommended.