Health Policy Advisory Committee on Technology
Transcription
Health Policy Advisory Committee on Technology
Health Policy Advisory Committee on Technology Technology Brief Intravitreal corticosteroid implant for the treatment of diabetic macular oedema August 2012 © State of Queensland (Queensland Health) 2012 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 2.5 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/2.5/au/. For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Access Improvement Service, Centre for Healthcare Improvement, Queensland Health Lobby 2, Level 2, Citilink Business Centre 153 Campbell Street, Bowen Hills QLD 4006 Postal Address: GPO Box 48, Brisbane Qld 4001 Email: [email protected] Telephone: (07). 3131 6969 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Queensland Health, GPO Box 48, Brisbane Qld 4001, email [email protected], phone (07) 3234 1479. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact DISCLAIMER: This brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health (“Queensland Health”) does not guarantee the accuracy, currency or completeness of the information in this brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a subcommittee of the Australian Health Ministers’ Advisory Council (AHMAC), reporting to AHMAC’s Hospital Principal Committee (HPC). AHMAC supports HealthPACT through funding. This brief was prepared by Heath White and Stefanie Gurgacz from the Australian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S). TECHNOLOGY BRIEF Register ID WP108 Name of technology Intravitreal corticosteroid implant Purpose and target group Patients with diabetic macular oedema Stage of development in Australia : Yet to emerge Established Experimental Established but changed indication or modification of technique Investigational Should be taken out of use Nearly established Australian Therapeutic Goods Administration approval Yes : No Not applicable ARTG number International utilisation Country Level of use Trials underway or completed United States 9 United Kingdom 9 Spain 9 India 9 Canada 9 Poland 9 Germany 9 Italy 9 France 9 Limited use Widely diffused Impact summary Chronic hyperglycaemia associated with diabetes mellitus is damaging to the microvasculature of the eye, leading to diabetic macular oedema (DMO). DMO results in visual disturbances due to retinal thickening and enlargement of the foveal avascular zone (FAZ), and affects approximately 67,500 Australians. Laser Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 19 photocoagulation, the gold standard treatment, is usually effective, but can result in loss of visual acuity and laser burns to the fovea. Current corticosteroids used to treat DMO are limited by either the short duration of sustained drug release, or the invasive nature of the insertion. Fluocinolone acetonide implants are either injected or surgically implanted into the intravitreal space, releasing a sustained dose over three years with the primary objective of improving visual acuity and decreasing foveal thickness. One device of this injectable formulation is currently available, namely, the Iluvien® device manufactured by Alimera Inc.™. Effectiveness results indicated that whilst short-term improvements in visual acuity and central macular thickness may be achieved (via either injection or implantation) these are not maintained at one to two years. Background Diabetic retinopathy is defined as the presence of typical retinal microvascular lesions in persons with diabetes mellitus. A specific form of diabetic retinopathy, DMO, is usually defined as a retinal thickening within two disc diameters of the macula (Table 1).1 DMO is primarily associated with damage to the microvasculature, including retinal haemorrhages, exudates, micro-aneurysms, microvascular abnormalities and areas of capillary closure; leading to the accumulation of fluid and serum macromolecules in the intercellular space.2, 3 As a result, thickening of the retina and fovea can occur, leading to disturbances in visual acuity (Figure 1). In addition, hypoxia associated with vascular damage leads to an increase in the production of vascular endothelial growth factor (VEGF) and inflammatory cytokines such as interleukin-6. A strong association between systolic blood pressure and persistent hyperglycaemia and DMO has been identified, and evidence exists to suggest that diabetic nephropathy, smoking and hyperlipidaemia may contribute to the development of DMO.4 Table 1 ETDRS definition of clinically significant macular oedema 4 x Thickening of the retina at or within 500 μm of the centre of the macula x Hard exudates at or within 500 μm of the centre of the macula, if associated with thickening of adjacent retina x A zone or zones of retinal thickening at least one disk area in extent, any part of which is within one disk diameter of the centre of the macula ETDRS: Early Treatment Diabetic Retinopathy Study Research Group, 1985 Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 20 Figure 1 Anatomical structures of the eye (http://www.vision-training.com/) Although DMO can occur at any stage of diabetic retinopathy, it occurs more frequently as the duration of diabetes mellitus and severity of diabetic retinopathy increase. DMO is the most common cause of vision impairment in patients with diabetes mellitus, affecting approximately 14 per cent of people with diabetes mellitus. Approximately three quarters of all cases of vision loss in this patient population is caused by DMO.4 There are four main types of DMO, namely, focal, diffuse, cystoid and ischemic macular oedema, outlined in Table 2.4 Table 2 The four main types of DMO Type of DMO Pathophysiology Focal Localised areas of retinal thickening, resulting from localised leakage of individual or clusters of microaneurysms (Figure 2). Diffuse Widespread thickening of the macula secondary to generalised abnormal permeability of the retinal capillary bed; which appears to be diffusely dilated (Figure 3). Cystoid Associated with diffuse DMO and results from generalised breakdown of the blood retinal barrier. Fluid accumulates in a petaloid pattern, primarily in the outer plexiform and inner nuclear layers. Ischemic Characterised by the presence of rarefaction and occlusion of the perifoveal capillary network, with doubling of the extension of FAZ (Figure 4). DMO: diabetic macular oedema; FAZ: foveal avascular zone Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 21 Figure 2 Focal DMO4. Left: red-free photograph shows circinate ring of hard exudates surrounding micro-aneurysms. Right: fluorescein angiograhpy reveals leakage from hyperfluorescent punctate lesions corresponding to microaneurysms Figure 3 Diffuse DMO4. Fluorescein angiography (left: early phase; right: late phase) shows leakage throughout the posterior pole with late dye pooling at the macula in a petaloid pattern Figure 4 Ischemic DMO4 Fluoroscein angiography shows extensive non-perfusion at the macula with enlargement and irregularity at the FAZ Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 22 There are several methods of treating DMO, including laser photocoagulation (the present gold standard), surgical vitrectomy, corticosteroids and VEGF antagonists. Corticosteroids may improve the pathological processes associated with DMO via inhibition of leukostasis and by decreasing the expression of VEGF and inflammatory cytokines. Studies have demonstrated short-term improvement in DMO following injection with corticosteroids; however, the clinical benefit is limited by the drug dissolution rate. As a result, there is a greater need for more frequent reimplantation of the drug, or for the use of surgical implantation, as opposed to injection.4 Iluvien® (pSivida Corp, MA, USA) is a slow-release injectable intravitreal fluocinolone acetonide implant used for the treatment of DMO. Designed to be injected using a 25-gauge needle (creating a self-sealing hole)5, Iluvien® delivers a very low dose of fluocinolone acetonide to the retina for up to three years. Clinical need and burden of disease According to the Australian Institute of Health and Welfare (AIHW) report, ‘Diabetes prevalence in Australia – Detailed estimates for 2007-08’, almost 900,000 Australians were diagnosed with diabetes mellitus during this period, 90 per cent of whom were diagnosed with type 2 diabetes mellitus.6 Due to the diet and inactivity associated with modern lifestyles, diabetes mellitus is on the increase. The rate of new cases of insulin-treated type 2 diabetes mellitus in those aged 10 years and above increased from 74 per 100,000 population per year in 2000, to 117 per 100,000 in 2009 (a 63% increase).7 A recent report by the Meta-Analysis for Eye Disease (META-EYE) group pooled the results of 35 studies in order to assess the incidence of diabetic retinopathy and DMO in patients with diabetes mellitus, producing a cohort of over 22,000 patients. The authors concluded that, on a global scale, approximately 35 per cent of individuals with diabetes mellitus have diabetic retinopathy, and 7.5 per cent have DMO. Applying these prevalence rates to the world diabetes population as of 2010 would suggest that, on a global scale, 20.6 million individuals have DMO.8 Applying this to the estimated number of Australians with diabetes mellitus (900,000) translates into an estimated 67,500 Australians with DMO. Diffusion of technology in Australia Iluvien® does not have TGA approval for use in Australia. The Medicines and Healthcare products Regulatory Agency (MHRA; UK), along with six Concerned Member States (CMS; Austria, France, Germany, Italy, Spain and Portugal) recently delivered marketing approval for Iluvien® for the treatment of vision impairment Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 23 associated with chronic DMO when other available treatments are not sufficient. Market authorisation has subsequently been granted in Austria and the UK, and it is anticipated that other CMS states will follow.9 On 11 November 2011, the FDA provided Alimera Inc. ™ (the US licensee of Iluvien® from parent company pSivida) with a complete response letter (CRL), stating that it was unable to approve Iluvien® because there was insufficient data supporting its safe and effective use in patients with DMO. The FDA stated that the risks of adverse reactions, as demonstrated in the FAME study (Fluocinolone Acetonide in Diabetic Macular Edema), were significant and were not offset by the benefits demonstrated in clinical trials. The FDA indicated that Alimera Inc.™ will need to conduct two additional clinical trials prior to reconsideration.10 Comparators The gold standard treatment for DMO is laser photocoagulation, which has demonstrated superior effectiveness at improving visual acuity, reducing the visual angle and the incidence of legal blindness compared to placebo. However, photocoagulation can result in an enlargement of the FAZ, resulting in loss of visual acuity. In addition, small involuntary eye movements (microsaccades) during treatment may result in laser burns to the fovea and there is evidence that laser treatment of microaneurysms does not necessarily result in their closure.11 Vitrectomy, the removal of part or all of the vitreous humor from the eye (with or without peeling of the inner limiting membrane), was first performed in 1992 following the observation that resolution of DMO could occur following posterior vitreous detachment.11 Improvements in visual acuity and decreased retinal thickness have been observed following this technique; however, both tractional and chemical damage can occur to the retina during surgery. Vitrectomy is generally indicated in patients who are resistant to laser photocoagulation or steroid injection.12 Corticosteroids represent a promising pharmaceutical treatment for DMO, having demonstrated inhibitory effects on the expression of VEGF and key pro-inflammatory genes.4 Promising results have been obtained following the intravitreal and peribulbar injection of triamcinolone acetonide (TA); however, this exposes the patient to the risk of developing acute infections, endophthalmitis, pseudoendophthalmitis and iatrogenic retinal breaks. In addition, increased intraocular pressure (IOP) and increased incidence of cataract have been reported in patients treated with TA compared with photocoagulation.4 Several glucocorticoid implants are available; however, those that are injectable have short durations (3-4 Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 24 months), and those with longer durations (2-2.5 years) require implantation through incision and suture/scleral procedures. VEGF is involved in mediating the vasculogenesis and angiogenesis processes within human tissues. The regulation of VEGF expression is often lost in patients suffering from diabetic retinopathy. Consequently, VEGF is overexpressed, and the subsequent increase in angiogenesis results in proliferative retinopathy which contributes to the deterioration of the retina. VEGF inhibitors are competitive inhibitors consisting of recombinant humanised monoclonal antibodies; and interfere with VEGF binding to VEGF receptors (VEGF-A and VEGF-B receptors). The three primary VEGF inhibitors for the treatment of DMO are pegaptanib sodium (Macugen, Eyetech Pfizer), ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech). Both ranibizumab and bevacizumab are currently listed on the PBS; however, the TGA and PBS approved indication of bevacizumab use is for the treatment of metastatic colorectal cancer, not for DMO. While bevacizumab has proven success in the ‘off-label’ treatment of DMO, since listing on the PBS, ranibizumab has largely replaced bevacizumab use; at a significantly greater cost to the PBS per injection of $1,967 (compared to approximately $50 per dose of bevacizumab).13 Studies suggest that VEGF inhibitors are at least as effective as laser photocoagulation in achieving improvements in visual acuity and decreases in retinal thickness, with no major safety issues identified.14 Safety and effectiveness Three studies assessed the safety and effectiveness of intravitreal corticosteroid implants for the treatment of DMO. The primary effectiveness outcome of interest was improvements in visual acuity, while the incidence of adverse events was reported in all studies. Secondary outcomes included fluorescein leakage in the treated eye, reductions in clinical grading of macular oedema and mean reduction in retinal thickness from baseline. Pearson et al (2011)15 Study description The authors published 3-year results from an industry-funded, 4-year prospective, multi-centre, randomised controlled trial (RCT; n=196) comparing safety and effectiveness outcomes in patients treated with either 0.59 μg/day fluocinolone acetonide implants (n=127) or standard of care (n=69), which consisted of either focal/grid laser photocoagulation, or observation (at the investigator’s discretion). All patients were enrolled between September 2001 and 2003. Outcome assessors were Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 25 blinded to the treatment used (both surgeon and patient were aware of the treatment). Follow-up visits were scheduled on day two, weeks one, three, six, 12, 26, 39 and 52, and every 13 weeks thereafter for three years. Eligible patients required a visual acuity of between 20 letters (20/400 vision) and 68 letters (20/50 vision), a retinal thickening of more than one disc area in size, and were required to have undergone macular laser treatment at least 12 weeks earlier. Safety High rates of ocular adverse events were observed in both treatment groups, affecting 100 per cent of patients who received fluocinolone acetonide implants and 88 per cent of patients who received standard of care (Table 3). Implant patients experienced a higher incidence of adverse events for the majority of the 14 adverse events reported, resulting in an average of 4.6 per patient in the implant group and 2.5 per patient in the standard of care group. Forty-three patients (34%) in the implant group required one or more surgical interventions to relieve elevated IOP. Table 3 Ocular treatment-emergent adverse events over 3 years15 Adverse event FA implant (n=127) n (%) SOC (n=69) n(%) Elevated intraocular pressure 88 (69.3) 8 (11.6) Cataract (aggravated) 71 (55.9) 15 (21.7) Vitreous haemorrhage 51 (40.2) 13 (18.8) Pruritus 49 (38.6) 15 (21.7) Abnormal sensation in the eye 47 (37.0) 8 (11.6) Macular oedema 44 (34.6) 25 (36.2) Eye pain 34 (26.8) 11 (15.9) Diabetic retinopathy 29 (22.8) 19 (27.5) Reduced visual acuity 29 (22.8) 16 (23.2) Eye irritation 28 (22.0) 7 (10.1) Increased lacrimation 28 (22.0) 6 (8.7) Photophobia 27 (21.3) 15 (21.7) Blurred vision 27 (21.3) 11 (15.9) Vitreous floaters 27 (21.3) 6 (8.7) FA: fluocinolone acetonide; SOC: standard of care A total of 78 out of 127 (61%) implant patients and 4 of 69 (6%) standard of care patients experienced elevated IOP (≥30 mmHg) at some stage over the 4-year postimplantation period. Also during this period, a significantly lower IOP (≤7 mmHg) was observed in 28 out of 127 (22%) implant patients and 6 of 69 (9%) standard of care Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 26 patients. Cataracts were extracted in 91 per cent of implanted phakic eyes compared to 20 per cent of standard of care phakic eyes. Effectiveness Scant effectiveness data were presented. The majority of outcomes were presented as p values involving treatment group comparisons (Table 4). Every statistically significant value presented within Table 4 represents an improvement of the intravitreal implant over standard of care. Table 4 Comparison of effectiveness outcomes between implant and standard of care groups15 Time VA (≥3 line improvement) Macular oedema Diabetic retinopathy severity Fluorescein angiography leakage Cystoid grade 12 weeks NR NR NR p=0.001 p<0.0001 6 months p<0.0012 p<0.0001 p=0.0006 p<0.0001 p=0.001 9 months p<0.002 NR NR NR NR 1 year p=NS p<0.0001 p=0.0016 p=0.006 p=NS 2 years p=0.0016 p=0.016 p=0.012 p=NS p=NS 3 years p=NS p=NS p<0.02 p=NS p=NS 4 years p=NS NR NR NR NR NR: not reported; NS: not significant; SOC: standard of care; VA: visual acuity This study compared the fluocinolone acetonide implant to standard of care, which in the treatment protocol is defined as either focal/grid laser photocoagulation (intervention) or observation (no intervention) at the investigator’s discretion. No specific numbers outlining the number of standard of care patients who received photocoagulation or observation were provided; and this poses a significant problem when determining the relative effectiveness of fluocinolone acetonide implants to these two comparators. As a result, the effectiveness of laser photocoagulation may appear lower as the outcomes of these patients have been pooled with patients who received no treatment (observation). In addition, this may bias in favour of the comparative effectiveness of the fluocinolone acetonide implant and so the results of this study should be approached with caution. Campochiaro et al (2010)2 Study description This industry-funded, 3-year phase II RCT was conducted at seven sites in the United States between August 2007 and August 2011. The objective was to compare the pharmacokinetics, safety and effectiveness of intravitreal fluocinolone acetonide inserts in patients who received a 0.2 Pg dose (n=20) to patients who received a Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 27 0.5 Pg dose (n=17). As a result, this study has been treated as case series (level IV evidence) for the purpose of this assessment. The current report presents one-year interim results. Selected baseline characteristics are presented in Table 5; there were reportedly no significant differences between study groups. Table 5 Important baseline characteristics2 Characteristic 0.2 μg/d (n=20) 0.5 μg/d (n=17) Mean BCVA, ETDRS score (letters ± SEM) 61.6 ± 3.38 54.9 ± 4.84 Mean age 66.6 ± 2.10 67.4 ± 2.50 Gender (% female) 50% 35.3% Mean foveal thickness, centrepoint (μm ± SEM) 425.7 ± 25.62 514.4 ± 40.53 Phakic 14 (70%) 7 (41.4%) Aphakic 0 (0%) 1 (6%) Pseudophakic 6 (30%) 9 (53%) Lens status BCVA: best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; SEM: Standard error of the mean Safety There were a total of four deaths, none of which were drug-related. The two most common adverse events were vitreous floaters and sub-conjunctival haemorrhage, which occurred in 30 and 35 per cent, and 25 and 35 per cent of 0.2 and 0.5 μg/day groups, respectively. These tended to be transient and were attributed to the insertion procedure. No other specific adverse events were reported, nor was the number of total adverse events. Effectiveness Visual acuity was significantly improved in both groups at three months (Table 6), and at six months for the 0.5 μg/day group; however, by 12 months postimplantation, visual acuity was not significantly improved compared to baseline. There was a significant reduction in centrepoint foveal thickness at three, six and 12 months post-implantation (Table 7). A moderate, sustained reduction in foveal thickness was observed in the 0.2 μg/day treatment group at all time points. In the 0.5 μg/day group, there was a significant reduction in thickness at three months; however, this value was reduced by almost half at 12 months. Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 28 Table 6 Improvements in visual acuity at three, six and 12 months post-implantation2 Change in BCVA Follow-up period 0.2 μg/day (baseline = 61.6 ± 3.38) 0.5 μg/day (baseline = 54.9 ± 4.84) Mean ± SEM p value Mean ± SEM p value 3 months 5.1 ± 2.2 0.032 7.5 ± 2.2 0.004 6 months 2.7 ± 2.5 NS 6.9 ± 3.1 0.040 12 months (main efficacy outcome) 1.3 ± 2.6 NS 5.7 ± 3.2 NS BCVA: best corrected visual acuity; SEM: standard error of the mean Table 7 Decrease in foveal thickness at three, six and 12 months post-implantation 2 Change in excess centrepoint foveal thickness Follow-up period 0.2 μg/day (baseline = 425.7 ± 25.62) 0.5 μg/day (baseline = 514.4 ± 40.53) Mean ± SEM p value Mean ± SEM p value 3 months -76.8 ± 18.2 0.000 -213.4 ± 51.5 0.001 6 months -87.0 ± 98.9 0.001 -175.7 ± 49.1 0.002 12 months -77.3 ± 28.7 0.014 -136.4 ± 53.8 0.022 SEM: standard error of the mean There was no increase in IOP in the 0.2 μg/day group at three, six or 12 months postimplantation, and no patients required any IOP-lowering interventions. There was a mild increase in the 0.5 μg/day group, which peaked at three months and declined thereafter. Five subjects in this treatment arm (29%) required IOP-lowering drops, and one subject (6%) required an Ahmed valve to reduce IOP. Finally, within the 12 month post-implantation observation period, five patients in each group (35% and 71% of phakic patients in 0.2 and 0.5 μg/day groups, respectively) were judged to have significant progression of cataract. Two patients in each group (14% and 29% of phakic patients in 0.2 and 0.5 μg/day groups, respectively) required cataract surgery. Campochiaro et al (2011)16 Study description The FAME study (NCT00344968) consisted of two industry-funded, randomised, double-blinded, sham injection-controlled multi-centre studies (FAME A and FAME B). These studies adhered to the same protocol, all results were pooled, and no distinction was made between the two on either clinicaltrials.gov or in the published literature. A total of 900 patients from the US, Canada, Europe and India were enrolled between September 2007 and December 2010 and were randomised into one of Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 29 three treatment groups on a 2:2:1 basis: 0.2 μg/day of fluocinolone acetonide (n=375), 0.5 μg/day of fluocinolone acetonide (n=393), and ‘sham comparator’, which consisted of pressing the hub of a syringe against the conjunctiva to simulate administration of the insert (n=185). Treatment groups were matched with respect to age, gender, lens status, IOP, best corrected visual acuity (BCVA; measured in ETDRS letters) and centrepoint thickness. Safety and effectiveness were assessed at one week, six weeks and three months post-treatment, and every three months thereafter to 36 months. In all groups, the use of laser treatment was permitted to treat persistent oedema at any stage following the six-week follow-up. The primary outcome was an improvement from baseline BCVA of 15 letters or more at 24 months. Loss to follow-up by 24 months was high: 75 out of 375 (20%) patients in the 0.2 μg/day group, 75 out of 393 (19%) patients in the 0.5 μg/day group, and 42 of 185 (23%) patients in the sham group. Safety The primary drug-related adverse event observed in patients treated with fluocinolone acetonide was the requirement for cataract surgery in phakic patients (Table 8). Other adverse events observed at higher rates in fluocinolone acetonide groups were glaucoma and increased IOP, with an associated increase in the need for trabeculectomy and trabeculoplasty. Table 8 Adverse events in the FAME study16 Adverse event Sham injection, n (%) 0.2 μg/day FA, n (%) 0.5 μg/day FA, n (%) Glaucoma 1 (0.5) 6 (1.6) 9 (2.3) Increased IOP 0 12 (3.2) 13 (3.3) Cataract surgery 13 (23.1)* 154 (74.9)* 200 (84.5)* Trabeculectomy 0 8 (2.1) 19 (4.8) Other glaucoma surgery 1 (0.5) 5 (1.3) 5 (1.3) Trabeculoplasty 0 3 (0.8) 9 (2.3) FA: fluocinolone acetonide; IOP: intraocular pressure.* the percentage of patients who were phakic at baseline who underwent cataract surgery Effectiveness In general, greater improvements in BCVA were seen in the fluocinolone acetonidetreated groups compared to the sham group (Table 9); however, a higher percentage of patients treated with fluocinolone acetonide had a BCVA of 20/200 or worse at 24 months post-treatment (no p values provided). Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 30 Table 9 Improvements in visual acuity between sham and FA groups 16 Outcome Sham control 0.2 μg/day FA 0.5 μg/day FA BCVA of ≥15 letters (%) 16% 28% (p=0.002)* 28% (p=0.002)* Mean increase in BCVA (letters, from baseline) 1.7 4.4 (p=0.02)* 5.4 (p=0.017)* Final BCVA of 20/40 (%) 22% 31% (p=0.0185)* 33% (p=0.0064)* Final BCVA of ≥20/200 (%) 12% 14% 14% BCVA: best corrected visual acuity; FA: fluocinolone acetonide * all p values represent comparisons between FA and sham treatments A rapid reduction in centrepoint thickness was experienced in both treatment groups; however, this was not sustained in the long-term when compared to patients in the sham-treated group who underwent a reduced but sustained reduction over the 24-month post-treatment period. At this time point, retinal thickness was a mean of 340 Pm in the sham group, compared to 293 Pm (p=0.005) and 308 Pm (p<0.001) in the 0.2 and 0.5 μg/day fluocinolone acetonide groups, respectively. A total of 51, 47 and 40 per cent of 0.2 μg/day fluocinolone acetonide, 0.5 μg/day fluocinolone acetonide and sham patients had a foveal thickness of >250 Pm at the 24-month follow-up period. In those instances where additional treatments were necessary, the authors classified such occurrences as protocol deviations; and occurred in 28.6, 12.5 and 13.9 per cent of sham, 0.2 μg/day fluocinolone acetonide and 0.5 μg/day fluocinolone acetonide groups, respectively. Grover et al (2009)17 A recent Cochrane review has been published assessing the use of intravitreal steroids for patients with DMO.17 The review included two unpublished studies reporting the outcomes of two patient cohorts assessed by the same author and both studies administered fluocinolone acetonide implants for the treatment of DMO. The first study18 investigated the resolution of macular oedema as well as the change in retinal thickness and visual acuity at 6, 12 and 24-month follow up. A total of 80 patients were randomised into three groups, of which 41 eyes received 0.5mg of fluocinolone acetonide implants, 11 eyes received 2 mg of fluocinolone acetonide implants and 28 eyes received standard care. At 12-month follow-up authors did not find any evidence of effect on three or more lines of visual acuity in patients receiving fluocinolone acetonide implants compared to standard care. The second study19 randomised a total of 197 patients to receive either a fluocinolone acetonide implant (n=127) or standard care (n=70) using a 2:1 ratio. The primary outcome was Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 31 improvements in visual acuity, retinal thickness and Diabetic Retinopathy Severity Score, as well as resolution of retinal thickening at 12, 24 and 36 months. At 36month follow up the authors reported a marginal statistically significant effect in three or more lines of visual acuity in the fluocinolone acetonide implant group compared to standard care or observation. Cost impact No cost data were available; however, information found in the 2011 Alimera Sciences Inc.™ Annual Report indicated that whilst the Iluvien® product has not been priced in any jurisdiction, Alimera Sciences Inc.™ has developed estimates of anticipated pricing in countries in which Iluvien® has been recommended for marketing authorisation (the UK, Austria, France, Germany, Italy, Portugal and Spain). The estimated pricing is based on the burden of DMO, the lack of any approved therapies for chronic DMO, perception of the overall cost-to-benefit ratio of Iluvien®, and the current pricing in the European Union of therapies to treat DMO and other retinal diseases.20 Costing data were requested from Alimera Sciences Inc.™; however, a response was not received. Four products are direct competitors to Iluvien®: Genentech’s Lucentis (ranibizumab injection), Allergan Inc.’s Ozurdex (dexamethasone intravitreal implant), Regeneron/Bayer’s Eyelea (aflibercept), and Alcon Inc.’s TRIESENCE (triamcinolone acetonide injectable suspension). A report from the National Institute for Health & Clinical Excellence (NICE) in the UK states that the price of Ozurdex is £870 (AUD $1,400) for one 6-month insert ($2,800 per year)21. The PBS-listed price per injection of ranibizumab (Lucentis) is $1,967, while off-label use of bevacizumab (Avastin) is approximately one 40th of the cost, at $50 per dose.13 Ethical, cultural or religious considerations No ethical, cultural or religious considerations were identified in the literature. Other issues Whilst Iluvien® has not received FDA approval for the treatment of DMO in the US, the 2011 Annual Report released by Alimera Sciences Inc.™ indicated that the company is expected to meet with the FDA in the second half of 2012 to discuss the CRL received in November 2011.20 In addition, the pursuit of FDA approval was reported as a key component of the company’s business strategy. Summary of findings Implantation of the fluocinolone acetonide implant appears to provide an immediate advantage over standard of care, indicating improvement in visual acuity and Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 32 reduced foveal thickness; however, this advantage is reduced significantly over time. A high incidence of ocular complications, in particular increased IOP and an accelerated requirement for cataract extraction were reported in the included studies. Differences in effectiveness between fluocinolone acetonide and standard of care ceased to be significant at between one and three years post-treatment.15 Whilst there were significant improvements in visual acuity and foveal thickness for both fluocinolone acetonide concentrations when compared to the sham intervention at 24 month follow-up, no measurements were reported at 36 month follow-up in the FAME study.16 As a result, no direct clinical evidence is able to substantiate the clinical claim that fluocinolone implants provide clinically superior results due to the novel three-year sustained release formulation. No data compares fluocinolone implants with other forms of treatment aside from standard of care15 where the study combined data of those who did not receive treatment (observation) and those who received laser photocoagulation. The FAME study16 simply compared fluocinolone acetonide implants with a sham injection group, demonstrating that fluocinolone acetonide is more effective than no treatment; however, with several effective techniques available with which to treat DMO (laser photocoagulation, VEFG inhibitors, other corticosteroids), comparative data are essential in ascertaining whether fluocinolone implants are a comparatively safe and effective treatment for DMO. HealthPACT assessment: A further review of the product may be required when Alimera Sciences Inc. ™ conducts additional clinical studies as requested by the FDA. As a result, HealthPACT recommended that this product be monitored for 36 months. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies: 4 Total number of level I studies: 1 Total number of level II studies: 2 Total number of level IV studies: 1 References 1. Mitchell, P.&Foran, S. (2008). Guidelines for the Management of Diabetic Retinopathy. [Internet]. NHMRC. Available from: Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 33 http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di15.pdf? q=publications/synopses/_files/di15.pdf [Accessed 27 April 2012]. 2. Campochiaro, P. A., Hafiz, G.et al (2010). 'Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert'. Ophthalmology, 117 (7), 1393-9 e3. 3. Antonetti, D. A., Lieth, E.et al (1999). 'Molecular mechanisms of vascular permeability in diabetic retinopathy'. Semin Ophthalmol, 14 (4), 240-8. 4. Bandello, F., Battaglia Parodi, M.et al (2010). 'Diabetic macular edema'. Dev Ophthalmol, 47, 73-110. 5. pSivida (2012). Products / Iluvien. Available from: http://www.psivida.com/products-iluvien.html [Accessed 27 April 2012]. 6. AIHW (2011). Diabetes prevalence in Australia: detailed estimates for 200708. Diabetes series no. 17. Cat. no. CVD 56. Available from: http://www.aihw.gov.au/publication-detail/?id=10737419311 [Accessed 30 April 2012]. 7. AIHW (2012). Incidence of insulin-treated diabetes in Australia 2000-2009. Available from: http://www.aihw.gov.au/diabetes/incidence/ [Accessed 30 April 2012]. 8. Yau, J. W., Rogers, S. L.et al (2012). 'Global prevalence and major risk factors of diabetic retinopathy'. Diabetes Care, 35 (3), 556-64. 9. Eyewiretoday (2011). Iluvien Receives Marketing Authorization in Austria for the Treatment of Chronic Diabetic Macular Edema. Available from: http://eyewiretoday.com/view.asp?20120424iluvien_receives_marketing_authorization_in_austria_for_the_treatment_of _chronic_diabetic_macular_edema [Accessed 04 May 2012]. 10. Reuters (2012). Alimera Sciences Inc (ALIM.O). Available from: http://www.reuters.com/finance/stocks/ALIM.O/key-developments [Accessed 27 April 2012]. 11. Browning, D. Diabetic Macular Edema. In: DJ B, editor. Diabetic Retinopathy Evidence Based Management. New York: Springer; 2010. p. 141-202. 12. Mayer, C. (2007). 'Current Treatment Approaches in Diabetic Macular Edema'. Ophthalmologica, 221 (2), 118-31. 13. Harvey, K. J., Day, R. O.et al (2011). 'Saving money on the PBS: ranibizumab or bevacizumab for neovascular macular degeneration?'. Med J Aust, 194 (11), 567-8. 14. Lang, G. E. (2012). 'Diabetic macular edema'. Ophthalmologica, 227 Suppl 1, 21-9. 15. Pearson, P. A., Comstock, T. L.et al (2011). 'Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial'. Ophthalmology, 118 (8), 1580-7. Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 34 16. Campochiaro, P. A., Brown, D. M.et al (2011). 'Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema'. Ophthalmology, 118 (4), 626-35 e2. 17. Grover, D., Li, T.&Chong, C. (2009). 'Intravitreal steroids for macular edema in diabetes (Review)'. Cochrane Database of Systematic Reviews, (1). 18. Groves N Reviewed by Pearson P A (2002). 'Steroid implants reduces retinal thickness, improves vision.'. Opthalmology Times, November 15, 2004, 24-6. 19. Groves N Reviewed by Pearson P A (2005). 'Patients with DME have response to fluocinolone acetonide intravitreal implant in study outcomes'. Opthalmology Times, August 1, 2006, 38. 20. Alimera Sciences (2012). Annual review for 2011. Available from: http://apps.shareholder.com/sec/viewerContent.aspx?companyid=ABEA4IAIIR&docid=8518223 [Accessed 04 May 2012]. 21. NICE (2011). NICE STA of OZURDEX(R) (dexamethasone intravitreal implant) Additional Analyses requested following Appraisal Consultation, NICE http://www.nice.org.uk/nicemedia/live/13037/54697/54697.pdf. Search criteria to be used (MeSH terms) Iluvien, fluocinolone acetonide, diabetic macular edema, corticosteroid implant, diabetic retinopathy Appendix A Expert clinical opinion Clinical review 1 The clinical review of two expert ophthalmologists in the sub-specialties of refractive, cornea, cataract and vitreoretinal surgery was received. The technique used to administer the flucinolone acetonide implant was highlighted as an area of clinical importance, as it can be either injected (solution formulation) or surgically implanted (implant). The three studies by Pearson et al14, 20, 21 all surgically implanted the flucinolone acetonide, whilst both studies by Campochiaro et al2, 15 delivered the flucinolone acetonide insert via injection using a 25-gauge needle. Overall, investigators in earlier trials more commonly performed surgical implantation of the steroid implant. This resulted in a higher incidence of glaucoma and cataracts following surgery; an issue reported by Dr Andrew Pearson, the author of the two unpublished trials included in The Cochrane Review by Gover et al 16, as well as the RCT14 included in this Technology Brief. As reported by Dr Andrew Pearson20, patients in the first RCT in which patients received either fluocinolone acetonide implants which were surgically implanted compared to standard care (either focal/grid laser photocoagulation or observation) patients receiving Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 35 fluocinolone acetonide implants experienced delayed improvement in visual acuity due to the development of cataracts following surgery. The expert clinicians also observed a higher incidence of glaucoma requiring surgery. Expert clinical opinion indicated that the decreased incidence of glaucoma, observed when the newer sustained release formulation fluocinolone acetonide implants were used, may be due to a lower dose release rate; however indicated that the use of steroids for DMO may be waning. This is a result of initial short-term improvement in visual acuity and central macular thickness which is not maintained at one to two years; while the visual results appear to be no better than standard laser therapy. Whilst no comparative studies are available that compare fluocinolone acetonide (and other steroid implants) to anti-VEGF agents, the expert clinicians indicated that some clinicians prefer to use anti-VEGF agents with or without adjuvant laser therapy as their experiences with this treatment regimen has been superior compared to steroid implants. Clinical review 2 The clinical review of two ophthalmologists was received. Due to the unacceptably high rate of adverse events, clinicians would be unlikely to use corticosteroid implants, such as Illuvien, to manage DMO, and will continue to be managed with laser and increasingly with anti-VEGF agents. Corticosteroids would occasionally be used for pseudophakic eyes. The implants used in the included studies have an unacceptably high rate of ocular side effects, in the form of glaucoma and cataract. As several studies have indicated patients with diabetic retinopathy, and in particular DMO, appear worse after cataract surgery, as they tend to lose vision due to an acceleration of retinopathy and macular oedema post-operatively. In addition, expert clinical advice indicates that these implants may also play a role in severe uveitis cases. The included studies are additionally limited by study design, in that only laser treatment was used as a comparator, whereas standard of care has shifted towards the use of anti-VEGF agents. As a consequence, it is unclear what benefit use of the implants would confer over current standard of care, particularly as use of anti-VEGF agents are not associated with high rates of glaucoma or cataract. Consequently, the evidence base is insufficient and randomised controlled trials are required that compare the implant to appropriate comparators that represent standard of care, and would include both laser treatment and anti-VEGF agents. Intravitreal corticosteroid implant for the treatment of diabetic macular oedema: August 2012 36