1. No category

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
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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
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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
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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
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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
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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
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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
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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
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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.
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