Intravitreal Corticosteroid Implants - CAM 90323HB

Description
An intravitreal implant is a drug delivery system, injected or surgically implanted in the vitreous of the eye, for sustained release of a pharmacologic agent to the posterior and intermediate segments of the eye. Three intravitreal corticosteroid implants, i.e., fluocinolone acetonide 0.59 mg (Retisert), fluocinolone acetonide 0.19 mg (Iluvien), and dexamethasone 0.7 mg (Ozurdex) are reviewed herein. Fluocinolone acetonide implants are nonerodible and deliver drug up to 30 to 36 months while dexamethasone implants are bioerodible and last up to 6 months.

A punctum implant is a drug delivery device that is inserted through the lower lacrimal punctum into the canaliculus, for sustained release of a pharmacologic agent to the ocular surface. Dexamethasone ophthalmic insert 0.4 mg (Dextenza) is the first corticosteroid intracanalicular insert and is reviewed herein.

Background
EYE CONDITIONS
Uveitis
Uveitis encompasses various conditions, of infectious and noninfectious etiologies, that are characterized by inflammation of any part of the uveal tract of the eye (iris, ciliary body, choroid). Infectious etiologies include syphilis, toxoplasmosis, cytomegalovirus retinitis, and candidiasis. Noninfectious etiologies include sarcoidosis, Behçet syndrome, and “white dot” syndromes such as multifocal choroiditis or “birdshot” chorioretinopathy. Uveitis may be idiopathic, have a sudden or insidious onset, a duration that is limited (< 3 months) or persistent, and a course that may be acute, recurrent, or chronic.

The classification scheme recommended by the Uveitis Study Group and the Standardization of Uveitis Nomenclature Working Group is based on anatomic location. Patients with anterior uveitis typically develop symptoms such as light sensitivity, pain, tearing, and redness of the sclera. In posterior uveitis, which comprises approximately 5% to 38% of all uveitis cases in the United States, the primary site of inflammation is the choroid or retina (or both). Patients with intermediate or posterior uveitis typically experience minimal pain, decreased visual acuity, and the presence of floaters (bits of vitreous debris or cells that cast shadows on the retina). Chronic inflammation associated with posterior segment uveitis can lead to cataracts, glaucoma, and structural damage to the eye, resulting in severe and permanent vision loss.

Treatment
The primary goal of therapy for uveitis is to preserve vision. Noninfectious uveitis typically responds well to corticosteroid treatment. Immunosuppressive therapy (e.g., antimetabolites, alkylating agents, T-cell inhibitors, tumor necrosis factor inhibitors) may also be used to control severe uveitis. Immunosuppressive therapy is typically reserved for patients who require chronic high-dose systemic steroids to control their disease. While effective, immunosuppressants may have serious and potentially life-threatening adverse effects, including renal and hepatic failure and bone marrow suppression.

Macular Edema After Retinal Vein Occlusion
Retinal vein occlusions are classified by whether the central retinal vein or one of its branches is obstructed. Central retinal vein occlusion and branch retinal vein occlusion differ in pathophysiology, clinical course, and therapy. Central retinal vein occlusions are categorized as ischemic or nonischemic. Ischemic central retinal vein occlusions are referred to as severe, complete, or total vein obstruction, and account for 20% to 25% of all central retinal vein occlusions. Macular edema and permanent macular dysfunction occur in virtually all patients with ischemic central retinal vein occlusion, and in many patients with nonischemic central retinal vein occlusion. Branch retinal vein occlusion is a common retinal vascular disorder in adults between 60 and 70 years of age and occurs approximately 3 times more often than central retinal vein occlusion.

Treatment
Intravitreal injections of triamcinolone are used to treat macular edema associated with central retinal vein occlusion, with a modest beneficial effect on visual acuity. The treatment effect lasts about 6 months, and repeat injections may be necessary. Cataracts are a common side effect, and steroid-related pressure elevation occurs in about one-third of patients, with 1% requiring filtration surgery.

Macular photocoagulation with grid laser improves vision in branch retinal vein occlusion but is not recommended for central retinal vein occlusion. Although intravitreal injections of triamcinolone have also been used for branch retinal vein occlusion, the serious adverse events have stimulated the evaluation of new treatments, including intravitreal steroid implants or the intravitreal injection of antivascular endothelial growth factor.

Diabetic Macular Edema
Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness in adults. The two most serious complications for vision are diabetic macular edema and proliferative diabetic retinopathy. At its earliest stage (nonproliferative retinopathy), microaneurysms occur. As the disease progresses, blood vessels that nourish the retina are blocked, triggering the growth of new and fragile blood vessels (proliferative retinopathy). Severe vision loss with proliferative retinopathy arises from leakage of blood into the vitreous. Diabetic macular edema is characterized by swelling of the macula due to gradual leakage of fluids from blood vessels and breakdown of the blood-retinal barrier. Moderate vision loss can arise from the fluid accumulating in the center of the macula (macular edema) during the proliferative or nonproliferative stages of the disease. Although proliferative disease is the main blinding complication of diabetic retinopathy, macular edema is more frequent and is the leading cause of moderate vision loss in people with diabetes.

Treatment
Tight glycemic and blood pressure control is the first line of treatment to control diabetic retinopathy, followed by laser photocoagulation for patients whose retinopathy is approaching the high-risk stage. Although laser photocoagulation is effective at slowing the progression of retinopathy and reducing visual loss, it does not restore lost vision. Alternatives to intravitreal implants include intravitreal injection of triamcinolone acetonide, which is used as off-label adjunctive therapy for diabetic macular edema. Angiostatic agents such as injectable vascular endothelial growth factor inhibitors, which block stages in the pathway leading to new blood vessel formation (angiogenesis), have demonstrated efficacy in diabetic macular edema.

Age-Related Macular Degeneration
Age-related macular degeneration is a degenerative disease of the retina that results in loss of central vision with increasing age. Two different forms of degeneration, known as dry and wet, may be observed. The dry form (also known atrophic or areolar) is more common and is often a precursor to the wet form (also known as exudative neovascular or disciform). The wet form is more devastating and characterized by serous or hemorrhagic detachment of the retinal pigment epithelium and development of choroidal neovascularization, which greatly increases the risk of developing severe irreversible loss of vision. Choroidal neovascularization is categorized as classic or occult.

Treatment
Effective specific therapies for exudative or wet age-related macular degeneration are an intravitreous injection of a vascular endothelial growth factor inhibitor, possibly thermal laser photocoagulation (in selected patients), and photodynamic therapy.

Intravitreal and Punctum Implants
Intravitreal and punctum implants deliver a continuous concentration of a pharmacologic agent to the eye over a prolonged period. The goal of therapy is to reduce inflammation in the eye while minimizing the adverse events of the therapeutic regimen.

Selection of the route of corticosteroid administration (topical, systemic, periocular, or intraocular injection) is based on the cause, location, and severity of the disease. Each therapeutic approach has drawbacks. For example, topical corticosteroids require frequent (e.g., hourly) administration and may not adequately penetrate the posterior segment of the eye due to their poor ability to penetrate ocular tissues. Systemically administered drugs penetrate poorly into the eye because of the blood-retinal barrier, and high-dose or long-term treatments may be necessary. Long-term systemic therapies can be associated with substantial adverse events such as hypertension and osteoporosis, while repeated (every 4 – 6 weeks) intraocular corticosteroid injections may result in pain, intraocular infection, globe perforation, fibrosis of the extraocular muscles, reactions to the delivery vehicle, increased intraocular pressure, and cataract development.

Corticosteroid implants are biodegradable or nonbiodegradable. Nonbiodegradable systems are thought to be preferable for treating chronic, long-term disease, while biodegradable products may be preferred for conditions that require short-term therapy. Although the continuous local release of steroid with an implant may reduce or eliminate the need for intravitreal injections and/or long-term systemic therapy, insertion or surgical implantation of the device carries risks, and the device could increase ocular toxicity due to increased corticosteroid concentrations in the eye over a longer duration. With any route of administration, cataracts are a frequent complication of long-term corticosteroid therapy.

Intraocular corticosteroid implants being evaluated include:

Retisert (nonbiodegradable fluocinolone acetonide intravitreal implant; Bausch & Lomb) is a sterile implant that consists of a tablet containing fluocinolone acetonide 0.59 mg, a synthetic corticosteroid that is less soluble in aqueous solution than dexamethasone. The tablet is encased in a silicone elastomer cup with a release orifice and membrane; the entire elastomer cup assembly is attached to a suture tab. Following implantation (via pars plana incision and suturing) in the vitreous, the implant releases the active drug at a rate of 0.3 to 0.4 μg/d over 2.5 years.
ILUVIEN (nonbiodegradable injectable intravitreal implant with fluocinolone acetonide; Alimera Sciences) is a rod-shaped device made of polyimide and polyvinyl alcohol. It is small enough to be placed using a 25-gauge applicator. It is expected to provide sustained delivery of fluocinolone acetonide for up to 3 years.
Ozurdex (previously known as Posurdex; biodegradable dexamethasone intravitreal implant; Allergan, Irvine, CA) is composed of a biodegradable copolymer of lactic acid and glycolic acid with micronized dexamethasone. This implant is placed into the vitreous cavity through the pars plana using a customized, single-use, 22-gauge applicator. The implant provides intravitreal dexamethasone for up to six months. The mean number of Ozurdex injections reported in the literature is 4.2 injections per year, and more than six consecutive injections have been reported.^1,2
Dextenza^® (biodegradable dexamethasone intracanalicular insert; Ocular Therapeutix™) is a rod-shaped hydrogel device that is designed to deliver a sustained and tapered release of 0.4 mg of dexamethasone over four weeks. Following ophthalmic surgery, it is inserted through the inferior punctum into the canaliculus of the operative eye. To allow for visualization and retention monitoring, the hydrogel device is conjugated with fluorescein. No removal is required as the device is designed to resorb and exit the nasolacrimal system independently.
Yutiq (non-biodegradable fluocinolone acetonide intravitreal implant; EyePoint Pharmaceuticals U.S. Inc.) is a sterile 3.3 mm-long implant consisting of fluocinolone acetonide 0.18 mg that is preloaded into a single-dose applicator and injected directly into the vitreous. It is designed to provide a sustained release of fluocinolone acetonide at an initial rate of 0.25 mcg/day within over a 36-month period.

Regulatory Status
In 2009, Ozurdex^® (dexamethasone 0.7 mg intravitreal implant; Allergan) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion. Subsequently, in September 2010, the indication was expanded to include treatment of noninfectious uveitis affecting the segment of the eye. In 2014, the indication was again expanded to include treatment of diabetic macular edema.

In September 2014, Iluvien^® (fluocinolone acetonide 0.19 mg intravitreal implant; Alimera Sciences) was approved by the FDA for the treatment of diabetic macular edema in patients previously treated with a course of corticosteroids and without a clinically significant rise in intraocular pressure.

In November 2004, Retisert™ (fluocinolone acetonide 0.59 mg intravitreal implant; Bausch & Lomb) was approved by the FDA for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye.

In October 2018, Yutiq^® (fluocinolone acetonide 0.18 mg intravitreal implant; EyePoint Pharmaceuticals Inc.) was approved by the FDA for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

In November 2018, Dextenza^® (dexamethasone 0.4 mg intracanalicular implant; Ocular Therapeutix) was approved by the FDA for the treatment of ocular inflammation and pain following ophthalmic surgery

Policy
Intravitreal corticosteroid implants (fluocinolone) are considered to be MEDICALLY NECESSARY for the treatment of:

Chronic, non-infectious intermediate, posterior, or pan uveitis, OR
Diabetic macular edema.

Intravitreal corticosteroid implants (dexamethasone) are considered to be MEDICALLY NECESSARY or the treatment of:

Chronic, non-infectious ocular inflammation or intermediate, posterior or pan uveitis, OR
Macular edema following branch or central retinal vein occlusion, OR
Diabetic macular edema.

Intravitreal corticosteroid implants are considered investigational and therefore NOT MEDICALLY NECESSARY for the treatment of:

Birdshot retinochoroidopathy, OR
Cystoid macular edema related to retinitis pigmentosa, OR
Idiopathic macular telangiectasia type 1, OR
Postoperative macular edema, OR
Circumscribed choroidal hemangiomas, OR
Proliferative vitreoretinopathy, OR
Radiation retinopathy, OR
Prophylaxis of cystoid macular edema in individuals with non-infectious intermediate or posterior uveitis and cataract undergoing cataract surgery.

Intracanicular Corticosteroid Implants

Intracanicular (punctum) corticosteroid implants (dexamethasone) are considered NOT MEDICALLY NECESSARY for the treatment of:

Ocular inflammation and pain following ophthalmic surgery, or
Ocular itching associated with allergic conjunctivitis.

Policy Guidelines
An intravitreal implant, used according to Food and Drug Administration-approved indications, may be an acceptable alternative in patients who are intolerant or refractory to other therapies or in patients who are judged likely to experience severe adverse events from systemic corticosteroids. Given the modest improvement in vision and potential adverse events, patients should be informed about the potential adverse events of a corticosteroid intravitreal implant (including cataracts), increased intraocular pressure, or hypotony, endophthalmitis, and risk for additional surgical procedures. Because of the differing benefits and risks of treatment with intravitreal implants compared with systemic corticosteroid therapy or intraocular injections, patients should make an informed choice among treatments.

Coding
Please see the Codes table for details.

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Noninfectious Uveitis
Intravitreal Fluocinolone Acetonide Implant (0.59 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal fluocinolone acetonide implant (0.59 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in patients with chronic noninfectious intermediate or posterior uveitis.

The question addressed in this evidence review is: Does intravitreal fluocinolone acetonide implant (0.59 mg) improve the net health outcome in patients with chronic noninfectious intermediate or posterior uveitis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with chronic noninfectious intermediate or posterior uveitis.

Interventions
The intervention of interest is the intravitreal fluocinolone acetonide implant (0.59 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Pivotal Trials
Two double-blind, randomized trials were conducted in patients with chronic (≥ 1-year history) noninfectious uveitis affecting the posterior segment of one or both eyes. The primary efficacy endpoint in both trials was the rate of recurrence of uveitis. These trials randomized patients to a fluocinolone acetonide 0.59-mg or 2.1-mg implant. In 2004, the U.S. Food and Drug Administration (FDA) approved only the 0.59-mg dose, and its approval was based on a comparison of rates of recurrence of uveitis affecting the posterior segment of the study eye in the 34-week period postimplantation compared with the rates of recurrence in the 34-week period preimplantation. Data from 224 patients were included.³ Subsequently, FDA reported recurrence rates one, two and three years postimplantation. Results are summarized in Table 1.

Table 1. Summary of Results From the FDA Pivotal Trial in Noninfectious Posterior Uveitis

Time Point	Uveitis Recurrence Rates, n (%)^a,b
	*Study 1 (N = 108)*	*Study 2 (N = 116)*
34 wk preimplant	58 (53.7)	46 (39.7)
34 wk postimplant	2 (1.8)	15 (12.9)
1 y postimplant	4 (3.7)	15 (12.9)
2 y postimplant	11 (10.2)	16 (13.8)
3 y postimplant	22 (20.4)	20 (17.2)
3 y postimplant^c	33 (30.6)	28 (24.1)

Adapted from Bausch & Lomb (2012).³
FDA: U.S. Food and Drug Administration.
^a Recurrence of uveitis for all postimplantation time points was compared with the 34-week preimplantation time point.
^bp < .01.
^cResults presented include imputed recurrences. Recurrences were imputed when a subject was not seen within 10 weeks of his or her final scheduled visit.

Jaffe et al. (2006) reported the results of one of the pivotal trials.⁴ These trials are not discussed in detail because the comparator was a nonapproved dose of fluocinolone acetonide. Briefly, the two trials randomized 278 patients and 239 patients to a fluocinolone acetonide 0.59-mg or 2.1-mg implant, respectively. Pooled data from both doses in the first trial showed a reduction in recurrence rates in implanted eyes compared with an increase in recurrence in nonimplanted eyes. An increase (> 6 mmHg) in intraocular pressure and cataracts were observed in implanted eyes compared with nonimplanted eyes. The second trial was reported only in FDA documents5, and results were similar to the first trial.

Additional Randomized Controlled Trials
Pavesio et al. (2010) reported on results of an industry-sponsored, open-label trial in which 140 patients with chronic noninfectious posterior uveitis were randomized to the fluocinolone acetonide 0.59-mg implant (n = 66) or systemic corticosteroid therapy (and immunosuppression when indicated; n = 74).⁶ To be included in the trial, subjects had to have at least a 1-year history of recurrent uveitis. The primary efficacy outcome was time to the first recurrence of uveitis. Patients in whom tapering of adjunctive anti-inflammatory therapy was insufficient despite receiving the implant were referred to as imputed or inferred failures. Results were therefore presented as both true recurrences and true plus inferred recurrences. When inferred recurrences were censored (11 subjects removed from the at-risk population), Kaplan-Meier analysis showed a significant decrease in the time to uveitis recurrence (6.3 months for 12 failures vs. 7.0 months for 44 failures). When all subjects were included in the analysis, time to uveitis recurrence did not differ statistically (p = .07). The relative risk (RR) of recurrence of uveitis was reduced by 71% with implants compared with standard therapy (RR = 0.29; 95% confidence interval [CI], 0.14 to 0.59; 132 eyes).⁷ Secondary efficacy outcomes included visual acuity improvement. Visual acuity in the implant group decreased after the surgery and again in the 15- to 18-month interval as a result of cataracts, then returned to baseline levels at 24 months, following extraction of cataracts. Visual acuity in the systemic corticosteroid group remained consistent over the 2-year study.

The Multicenter Uveitis Steroid Treatment Trial (2010), sponsored by the National Eye Institute, is a partially blind RCT (N = 255) designed to compare visual acuity at two years using fluocinolone acetonide implants with systemic corticosteroid therapy (and immunosuppression when indicated) in patients with intermediate, posterior, or panuveitis. Assessment of the primary outcome measure of best-corrected visual acuity using the Early Treatment Diabetic Retinopathy Study chart was blinded. After 24 months⁸ and 54 months⁹ of follow-up, the vision improvements from baseline in the implant groups compared with systematic therapy group were not statistically significant (+6.0 and +3.2 letters, p = .16; +2.4 and +3.1 letters; p = .073, respectively). Notably, approximately 21% of patients in the systemic group had received an implant by 54 months. At 24 and 54 months, the proportion of patients with a minimally important improvement did not differ significantly for any of the quality of life metrics (results not shown).^8,10 Patients receiving systemic therapy (in which corticosteroid-sparing immunosuppressive therapy was used to minimize ongoing use of prednisone to < 10 mg/d for the large majority of patients) was associated with relatively little additional systemic morbidity compared with implant therapy. Systemic adverse events were infrequent in both groups. At two years, the proportion of patients with systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg at any visit was lower in the implant group than in the systemic group (13% vs. 27%; hazard ratio = 0.44; p = .030), but the rate of antihypertensive treatment initiation did not differ substantially between the two groups (5% vs. 11%; hazard ratio = 0.40; p = .13), respectively. The incidences of other systemic adverse events, including hyperlipidemia, diabetes, osteoporosis, fractures, and blood count/chemistry abnormalities, were not statistically distinguishable between groups (data not shown). Weight was stable over time in both groups.

Systematic Reviews
Brady et al. (2016) reported on results of a Cochrane review of RCTs comparing fluocinolone acetonide or dexamethasone intravitreal implants with standard therapy in patients who had at least 6 months of follow-up posttreatment.⁷ The primary outcome was a recurrence of uveitis. Selected trials enrolled patients of all ages who had chronic noninfectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was “better than hand motion.” Two trials, Pavesio et al. (2010)6, and Kempen et al. (2011),⁸ were included and judged to be of moderate quality (both are discussed above). Because the two trials were designed to answer different questions (one measured recurrence, one visual acuity), reviewers did not combine efficacy data. However, they did perform a meta-analysis of common side effects, which showed increased risks of needing cataract surgery (RR = 2.98; 95% CI, 2.33 to 3.79; 371 eyes) and surgery to lower intraocular pressure (RR = 7.48; 95% CI, 3.94 to 14.19; 599 eyes) in the implant group compared with the standard therapy group through two years of follow-up. Reviewers were unable to conclude that the implants were superior to traditional systemic therapy for the treatment of noninfectious uveitis.

Adverse Events
As listed in the prescribing label, nearly all phakic patients who receive implants are expected to develop cataracts and require cataract surgery.³ Further, 75% of patients may experience elevated intraocular pressure and/or glaucoma severe enough to require intraocular pressure lowering medications and 35% filtering surgeries. Separation of implant components is another potential complication, and six-year cumulative risk of a spontaneous dissociation is 4.8% (95% CI, 2.4% to 9.1%).11,Late-onset endophthalmitis is also recognized as a surgical complication of intraocular implants.

Section Summary: Intravitreal Fluocinolone Acetonide Implant (0.59 mg) for Noninfectious Uveitis
Four RCTs have established the efficacy of fluocinolone acetonide implants (0.59 mg) for patients with noninfectious intermediate or posterior uveitis. Two of the 4 RCTs compared 2 doses of implants, and 2 trials compared implants with systemic steroids (and immunosuppression when indicated). All trials supported the efficacy of fluocinolone acetonide intravitreal implants in preventing recurrence and improving vision over a four-year follow-up. The head-to-head trial comparing implants with systemic corticosteroids did not show substantial superiority in the overall effectiveness of either approach. The major limitation of these implants is nearly all phakic patients will develop cataracts and will require cataract surgery. Further, most will also develop glaucoma, with 75% of patients requiring intraocular pressure lowering medications and 35% requiring filtering surgeries.

Intravitreal Dexamethasone Implant (0.7 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies or observation alone in patients with noninfectious intermediate or posterior uveitis.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in patients with noninfectious intermediate or posterior uveitis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with noninfectious intermediate or posterior uveitis.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
The comparators of interest are observation alone.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
The evidence for dexamethasone intravitreal implants consists of a pivotal, double-blind RCT, Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis (HURON — A Study of the Safety and Efficacy of a New Treatment for Non-Infectious Intermediate or Posterior Uveitis).¹² In this eight-week, manufacturer-sponsored, multicenter trial (46 study sites in 18 countries), 229 patients with noninfectious intermediate or posterior uveitis were randomized to 0.7-mg implants (n = 77), 0.35-mg implants (n = 76), or sham procedure (n = 76). The primary outcome measure was the proportion of eyes with a vitreous haze score of 0 (no inflammation) at week 8. At baseline, the mean vitreous haze score was approximately +2 (moderate blurring of the optic nerve head). At eight weeks posttreatment, the proportion of eyes with a vitreous haze score of 0 was 47% with the 0.7-mg implant and 12% with the sham procedure. At eight weeks, visual acuity, as assessed by a gain of 15 or more letters in best-corrected visual acuity from baseline, was achieved by 40% of patients who received implants compared with 10% who received sham control. The incidences of elevated intraocular pressure (≥ 25 mmHg) and cataracts in phakic eyes were higher in 0.7-mg implant-treated eyes versus sham control eyes (7.1% vs. 4.2% and 15% vs. 7%, respectively). Unlike the fluocinolone acetonide 0.59-mg implant, the long-term efficacy and safety data for the dexamethasone 0.7-mg implant are not available. Lightman et al. (2013) reported on 26-week data for vision-related functioning using National Eye Institute-Visual Function Questionnaire from HURON trial.¹³ Using the distribution- and anchor-based methods, the authors reported that a clinically meaningful change for the National Eye Institute-Visual Function Questionnaire-25 composite score was 3.86 and 10 points, respectively. Others have reported that range changes of 2.3 to 3.8 units in the composite score are meaningful.¹⁴ In the HURON trial, the proportion of patients with a 5 or more point improvement in the composite score at week 26 was 58% (42/73) in the 0.7-mg implant group and 32% (24/74) in the sham-controlled arm (p < .05).

Adverse Events
As listed in the prescribing label, in controlled studies, the most common adverse reactions reported by 20% to 70% of patients were cataracts, increased intraocular pressure, and conjunctival hemorrhage.¹⁵

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) for Noninfectious Uveitis
One RCT comparing two doses of implants with sham control has supported the efficacy of dexamethasone implants (0.7 mg) for patients with noninfectious intermediate or posterior uveitis. Results of this trial have demonstrated the efficacy of the dexamethasone 0.7-mg implant in reducing inflammation and resulted in clinically meaningful improvements in vision at week 8 compared with sham controls. Further, at week 26, patients treated with implants reported meaningful improvements in vision-related functioning. The major limitation of this trial was its lack of long-term follow-up. Further, as a class effect, use of dexamethasone implants resulted in higher incidences of cataracts and elevated intraocular pressure.

Intravitreal Fluocinolone Acetonide Implant (0.18 mg, Yutiq)
Clinical Context and Therapy Purpose
The purpose of intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq) is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in patients with chronic noninfectious posterior uveitis affecting the posterior segment of the eye.

The question addressed in this evidence review is: Does intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq) improve the net health outcome in patients with chronic noninfectious posterior uveitis affecting the posterior segment of the eye?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with chronic noninfectious posterior uveitis affecting the posterior segment of the eye.

Interventions
The intervention of interest is the intravitreal fluocinolone acetonide implant (0.18 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
For individuals with chronic (≥ 1-year history) noninfectious uveitis affecting the posterior segment of one or both eyes who receive fluocinolone acetonide (0.18 mg), the pivotal evidence includes two double-blind, randomized trials of 282 patients (range, 129 to 153 patients): A Phase III, Multi-National, Multi-Center, Randomized, Masked, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal Insert in Subjects With Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye (study #PSV-FAI-001) and A Multi-center, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects With Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye (study #PSV-FAI-005) (Table 2).^16,17 Results of one of the pivotal trials (study #PSV-FAI-001) were reported by Jaffe et al. (2019).¹⁷ The second trial was reported only in FDA documents.¹⁶ The primary efficacy endpoint in both trials was the proportion of recurrence of uveitis within six months. Secondary outcomes at 12 months have also been reported.

For the primary outcome of recurrence at six months, both trials consistently found significantly lower rates in the fluocinolone groups; but the effect size was much smaller in the unpublished trial (Table 3). Similarly, at 12 months, both trials found significantly lower recurrence rates in the fluocinolone groups, but the odds ratio had more than doubled in the published trial and decreased in the unpublished trial. Results were inconsistent between trials for the remainder of the key outcomes, appearing more favorable in the published trial. Most notable were the differences between trials in mean change in best-corrected visual acuity at 12 months (higher in the published trial, lower in the unpublished trials) and risk of increased intraocular pressure within 12 months (increased risk in the unpublished trial, but not in the published trial).

The most important limitation of these studies (Tables 4 and 5) is the higher rate of “imputed” recurrences in the sham groups compared to the fluocinolone group (16% vs. 57% at 6 months in study PSV-FAI-001 and 12% vs. 39% in study PSV-FAI-005). Overall, the majority of the recurrences were not directly observed, but were “imputed” based on either the study eye being treated with a prohibited local or systemic medication (oral, systemic, injectable, or topical corticosteroids or systemic immunosuppressants) or the participant had a missing ophthalmic assessment at the 6- or 12-month visit. This means that the between-groups difference in the recurrence rates was mostly driven by imputed outcomes. Although the use of prohibited medications may be a reasonable surrogate for the occurrence of uveitis-related symptoms, it is unclear whether such symptoms would meet the rigorous threshold for a clinical diagnosis of recurrence (e.g., a two-step or more increase in the number of cells in the anterior chamber per high-powered field [1.6 using a 1-mm]; a two-step or more increase in vitreous haze; or a deterioration in visual acuity of 15 letters or more of best-corrected visual acuity). Therefore, we can’t rule out that the imputation led to an overestimation of the number of recurrences. With more imputed recurrences in the sham group than the treatment group, then we also can’t rule out that this led to an overestimation of the treatment effect. For example, in the published RCT by Jaffe et al. (2019), when the results of observed recurrences were separately reported, the absolute between-group differences were numerically lower than in the imputed subgroups both at 6 months (sham rate – fluocinolone rate difference of 27.5% in observed group [n = 13] vs. 35.5% [n = 49]) and at 12 months (25.2% for observed group [n = 15] vs. 34.5% [n = 59]). In the unpublished trial PSV-FAI-005, the discrepancy was even larger. For example, at six months the absolute between-group difference in the observed recurrence subgroup was 5% (15% in sham and 10% in the fluocinolone group) versus 27% in the imputed group (39% in sham and 12 in the fluocinolone group). Further, we can’t rule out that visibility of the injected fluocinolone acetonide insert — or lack thereof — may have influenced the perceived need for use of prohibited medications. In the publication by Jaffe et al. (2019), they noted that “the injected insert typically remains in a peripheral location within the vitreous base and is not detected easily on routine ophthalmologic examination. Regardless, we cannot exclude the possibility that the insert could have been visible in some study participants.” Therefore, because of the inconsistency in key findings between the pivotal studies and the questions raised by the use of the imputed recurrence rates, the evidence is not sufficient to draw strong conclusions on the effect on health outcomes.

In 2020, the 3-year results from the pivotal study PSV-FAI-001 study were published (Table 3).¹⁸ Over 36 months of treatment, cumulative uveitis recurrences were significantly reduced with fluocinolone acetonide (0.18 mg) compared with sham (65.5% vs 97.6%, respectively). The time to the first recurrence in the fluocinolone acetonide (0.18 mg) group was significantly longer compared to sham-treatment (median 657 days; 95% CI, 395 to 105 vs median 70.5 days; 95% CI, 57 to 91). The number of recurrences per eye occurring over 36 months was significantly lower in the treatment group compared to sham and a higher proportion of eyes in the fluocinolone acetonide (0.18 mg) group had no uveitis recurrence compared to sham (34.5% vs 2.4%). Additionally, a greater proportion of eyes in the treatment group compared to sham had uveitis recur only once in three years (33.3% vs 11.9%, respectively). Of note, the 36-month results included imputed recurrences, as in the initial results. However, observed protocol-defined uveitis recurrences occurred in a greater percentage of the sham-treated eyes, whereas the percentage of eyes with an imputed recurrence was more similar in the two groups (59.8% and 69.0%, respectively). At 36 months, more eyes in the treatment group had a 15-letter or greater increase in best-corrected visual acuity from baseline compared to the sham-treated group (33.3% vs 14.7%). There was also a significantly greater mean change in best-corrected visual acuity over 36 months in the treatment group compared to sham. Intraocular pressure was well-controlled in both groups and similar for both groups at month 36. The proportion of eyes in the fluocinolone acetonide (0.18 mg) group that underwent intraocular pressure-lowering surgery was approximately half that in the sham-treated group. Cataract surgery was required more frequently over 36 months in the treatment group compared with the sham-treated group.

Table 2. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Jaffe et al. (2019); Study PSV-FAI-001; NCT01694186f¹⁷	U.S., Europe, Israel, and India	33	2013 – 2015	Diagnosis of noninfectious uveitis affecting the posterior segment of at least 1 eye (with or without anterior uveitis) for ≥ 1 y, with ≥ 2 recurrences requiring intervention	Fluocinolone acetonide (0.18 mg), n = 87	Sham, n = 42
PSV-FAI-005¹⁶	India	33	Unknown	Same as Jaffe et al. 2019	Fluocinolone acetonide (0.18 mg), n = 101	Sham, n = 52

NCT: National Clinical Trial; RCT: Randomized Controlled Trial; PSV-FAI-001: A Phase III, Multi-National, Multi-Center, Randomized, Masked, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal Insert in Subjects With Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye; PSV-FAI-005: A Multi-center, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects With Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye; RCT: randomized controlled trial.

Table 3. Summary of Key RCT Results

Study	6-mo Recurrence	12-mo Recurrence	Mean change in BCVA at 12 mo	Increased intraocular pressure within 12 mo²	Cataract within 12 mo
Jaffe et al. (2019)^17,¹⁶	129	129	124	129	129
Fluocinolone acetonide (0.18 mg)	24 (27.6%)¹	33 (37.9%)	+5.8	23 (26.4%)	24 (27.6%)
Sham	38 (90.5%)¹	41 (97.6%)	+3.3	11 (26.2%)	2 (4.8%)
OR (95% CI)	24.94 (8.04 to 77.39)	67.09 (8.81 to 511.06)	NR	NR	NR
PSV-FAI-005	153	153	142	153	153
Fluocinolone acetonide (0.18 mg)	22 (22%)¹	33 (33%)²	+3.0	29 (28.7%)	12 (11.9%)
Sham	28 (54%)¹	31 (60%)²	+7.4	1 (1.9%)	7 (13.5%)
OR (95% CI)	4.2 (2.0 to 8.6)	3.04 (1.52 to 6.08)	NR	NR	NR
	36-mo Recurrence	Mean number of recurrences per eye at 36-mo (SD)	Mean change in BCVA at 36 mo (SD)	Increased intraocular pressure within 36 mo	Cataract surgery over 36 mos
Jaffe et al. (2020) 3-year results¹⁸	129	129	129	129	129
Fluocinolone acetonide (0.18 mg)	57 (65.5%)¹	1.7 (2.4)	+9.1 (13)	14.5 (16.6%)	73.8%
Sham	41 (97.6%)¹	5.3 (3.8)	+2.5 (14.2)	14.8 (35.2%)	23.8%
OR (95% CI)	21.58 (2.83 to 164.7)	NR	NR	NR	NR
p-value	< .001	< .001	.020	NR	NR

BCVA: best-corrected visual acuity; CI: confidence interval; OR: odds ratio; NR: Not Reported; PSV-FAI-005: A Multi-center, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects With Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye; SD: standard deviation; RCT: randomized controlled trial.
¹ Primarily imputed, not observed recurrence.
² from FDA statistical review.

Table 4. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Jaffe et al. (2019); Study PSV-FAI-001; NCT01694186¹⁷				1. Imputed recurrence: 16% for active, 57% for sham
PSV-FAI-005¹⁶	5. Inadequately described in FDA review materials			1. Imputed recurrence: 12% for active, 39% for sham
Jaffe et al. (2020) 3-year results¹⁸				1. Imputed recurrence: 59.8% for active, 69% for sham

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

FDA: U.S. Food and Drug Administration; NCT: National Clinical Trial; PSV-FAI-001: A Phase III, Multi-National, Multi-Center, Randomized, Masked, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal Insert in Subjects With Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye; PSV-FAI-005: A Multi-center, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects With Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. 5. Inadequate description of methods
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Table 5. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Jaffe et al. (2019); Study PSV-FAI-001; NCT01694186¹⁷	4. Study participants did not have severe active inflammation at the time of the initial study treatment
PSV-FAI-005¹⁶	4. Study participants did not have severe active inflammation at the time of the initial study treatment
Jaffe et al. (2020) 3-year results¹⁸

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

NCT: National Clinical Trial; PSV-FAI-001: A Phase III, Multi-National, Multi-Center, Randomized, Masked, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal Insert in Subjects With Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye; PSV-FAI-005: A Multi-center, Controlled, Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects With Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Intravitreal Fluocinolone Acetonide Implant (0.18 mg, Yutiq) for Noninfectious Uveitis
For individuals with chronic noninfectious posterior uveitis affecting the posterior segment of the eye and who receive intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq), the evidence includes 2 pivotal RCTs. Relevant outcomes are symptom improvement, change in disease status, functional status, and quality of life. Harmful outcomes of interest are treatment-related morbidity. Both RCTs consistently found statistically significantly lower uveitis recurrence rates for intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq) at both 6 and 12 months. The 3-year follow-up for Jaffe et al. also found statistically significant lower uveitis recurrence rates at 36 months. However, serious limitations of these findings include inconsistency in the magnitude of the benefit at 12 months (odds ratio [OR] = 67.09; 95% CI, 8.81 to 511.06 in published RCT and OR 3.04; 95% CI, 1.52 to 6.08 in the unpublished RCT) and, with more imputed recurrences in the sham groups than the treatment groups, we also cannot rule out an overestimation of the treatment effect. For the remainder of key outcomes, results were inconsistent between RCTs, appearing more favorable in the published trial. Most notable were the differences between RCTs in mean change in best-corrected visual acuity at 12 months (higher for fluocinolone acetonide in the published trial, lower in the unpublished trials) and risk of increased intraocular pressure within 12 months (increased risk in the unpublished trial, but not in the published trial).

Macular Edema After Retinal Vein Occlusion
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) or intravitreal fluocinolone acetonide implant (0.59 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies or observation alone in patients with macular edema after retinal vein occlusion.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) or intravitreal fluocinolone acetonide implant (0.59 mg) improve the net health outcome in patients with macular edema after retinal vein occlusion?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with macular edema after retinal vein occlusion.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) or intravitreal fluocinolone acetonide implant (0.59 mg).

Comparators
The comparators of interest are observation alone.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Intravitreal Dexamethasone Implant (0.7 mg)
Systematic Reviews
In 2015, the American Academy of Ophthalmology published a technology assessment on therapies for macular edema associated with central retinal vein occlusion.¹⁹ The academy identified four clinical trials that provided level I evidence supporting the use of antivascular endothelial growth factor pharmacotherapies and two clinical trials providing level I evidence for intravitreal corticosteroid injection with the dexamethasone intravitreal implants or triamcinolone. Evidence on the safety and efficacy of other reported interventions was of lesser strength. The assessment noted that evidence on the long-term efficacy of corticosteroid treatments is limited and that intravitreal corticosteroids led to a higher frequency of adverse events, including cataracts and intraocular pressure elevation compared with antivascular endothelial growth factor treatments. There are limited data on combination therapy with antivascular endothelial growth factor and corticosteroid injections compared with monotherapy.

A Bayesian network meta-analysis of the efficacy and safety of treatments for macular edema secondary to branch retinal vein occlusion was published in 2015.²⁰ Eight RCTs (N = 1,743 patients) were included; patients were treated with ranibizumab as needed, aflibercept monthly, dexamethasone implant, laser photocoagulation, ranibizumab plus laser, or sham intervention. The probability of being the most efficacious treatment, based on letters gained, or for a gain of 15 letters or more, was highest for monotherapy of antivascular endothelial growth factor treatments (30% to 54% probability), followed by ranibizumab plus laser, and lowest (0% to 2% probability) for the dexamethasone implant, laser, or sham treatment. Treatment with ranibizumab resulted in an average increase of 8 letters compared with the dexamethasone implant. Patients treated with the dexamethasone implant had statistically significantly higher rates of ocular hypertension than patients given antivascular endothelial growth factor monotherapy (OR = 13.1).

Randomized Controlled Trials
Data presented to FDA for the dexamethasone intravitreal implant (Ozurdex) were from two six-month, double-masked RCTs called Global Evaluation of implantable dexamethasone in retinal Vein occlusion with macular edema (GENEVA) (167 clinical sites in 24 countries).^1,21 A six-month open-label extension of these two pivotal trials was reported in 2011.^1,2 A total of 1267 patients who had clinically detectable macular edema associated with either central retinal vein occlusion or branch retinal vein occlusion were randomized to a single treatment with a dexamethasone 0.7-mg implant (n = 427), dexamethasone 0.35-mg implant (n = 414), or sham control (n = 426). The primary outcome measure was time to achieve a 15-or-more letter improvement in best-corrected visual acuity. A secondary outcome was the proportion of eyes achieving a 15-or-more letter improvement from baseline at 180 days. In individual studies and pooled analysis, time to achieve a 15-or-more letter (3-line) improvement in best-corrected visual acuity was significantly faster with implants than with sham (p < .01) (data not shown). As evident from Table 6, the proportion of patients with a 15-or-more letter improvement from baseline in best-corrected visual acuity was higher in the implant with the FDA-approved dose (0.7 mg) than with sham for the first three months. There was no significant difference in the proportion of patients who improved by 15 letters or more at six-month follow-up. Note that the implant lasts for six months.

Table 6. Summary of Results From the FDA Pivotal Trial in Retinal Vein Occlusion

Time Point	Patients With ≥ 15 Letters Improvement From Baseline in BCVA, n (%)
	*Study 1*			*Study 2*
	*Implant (0.7 mg)*	*Sham*	p	*Implant (0.7 mg)*	*Sham*	p
Day 30	40 (20)	15 (7)	< .01	51 (23)	17 (8)	< .01
Day 60	58 (29)	21 (10)	< .01	67 (30)	27 (12)	< .01
Day 90	45 (22)	25 (12)	< .01	48 (21)	31 (14)	.039
Day 180	39 (19)	37 (18)	.780	53 (24)	38 (17)	.087

Adapted from Allergan (2014).¹⁵
BCVA: best-corrected visual acuity; FDA: U.S. Food and Drug Administration.

Additional Studies
Several additional RCTs have evaluated the comparative effects of dexamethasone intravitreal implants to other therapies and found mixed results.^{22,23,20,21,24,25,26} In the largest trial, Kupperman et al. (2007) reported on results for an RCT in which 315 patients with persistent macular edema of different etiology (diabetic retinopathy [n = 172], branch retinal vein occlusion [n = 60], central retinal vein occlusion [n = 42], uveitis [n = 14], or post-cataract surgery macular edema [n = 27]) were assigned to the dexamethasone 0.35-mg implant, the dexamethasone 0.7-mg implant, or observation.²³ At six months, the proportion of patients meeting the primary outcome of an improvement in visual acuity of 10 letters was 24%, 35%, and 13% in 0.35-mg implants, 0.7-mg implants, and observation-only groups, respectively. In a small trial in 50 patients, Pichi et al. (2014) found that the combination of dexamethasone 0.7-mg intravitreal implants plus macular grid laser increased both visual acuity and the interval between repeated implants.²⁰ Gado and Macky (2014; N = 60) reported no significant differences in visual acuity outcomes between dexamethasone implants and bevacizumab.²² Maturi et al. (2014) reported on results for 30 patients randomized to dexamethasone implants plus bevacizumab or bevacizumab monotherapy and found no additional benefit for visual acuity with the combination treatment at six months.²¹ Compared to antivascular endothelial growth factor for the treatment of macular edema after branch retinal vein occlusion, a meta-analysis by Ji et al. (2019) of six studies (one RCT, four retrospective studies, one prospective study; N = 452 eyes) found similar best-corrected visual acuity change at three or six months with dexamethasone intravitreal implants (0.7 mg), but a higher risk of intraocular pressure elevation for dexamethasone treatment.²⁵ In another 60 patients with macular edema following branch retinal vein occlusion from a single-center in New Delhi, a randomized, open-label trial by Kumar et al. (2019) found that best-corrected visual acuity gains at six months for 0.7 mg dexamethasone intravitreal implants, with or without laser photocoagulation (+9.50 and +10.50, respectively), were similar to intravitreal ranibizumab (1 injection of 0.5 mg) with laser photocoagulation (+10.00), but lower than for 3 injections of 0.5 mg ranibizumab without laser photocoagulation (+18.00)²⁴.

For the comparison to triamcinolone, the evidence includes the open-label multicenter PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT; NCT02374060) trial by Thorne et al. (2019), in which 192 patients with macular edema, defined as a central subfield thickness two standard deviations greater than the population normative mean, were randomized to receive periocular triamcinolone acetonide 40 mg, intravitreal triamcinolone acetonide 4 mg, or the 0.7 mg intravitreal dexamethasone implant.²⁶ Retreatment was permitted for the triamcinolone treatments at eight weeks and at 12 weeks for dexamethasone. The proportion of eyes with macular edema resolution varied between treatments at 8 weeks (61% for dexamethasone, 47% for intravitreal triamcinolone, 20% for periocular triamcinolone) but not at 24 weeks (41%, 36%, and 35%, respectively). Change in best-corrected visual acuity was similar for intravitreal dexamethasone, intravitreal triamcinolone, and periocular triamcinolone at 8 weeks (+9.53 vs. +9.70 vs. +4.37 letters) and 24 weeks (+9.21 vs. +9.60 vs. +4.07). The main limitation was that, at 24 weeks, follow-up was relatively short-term. Longer-term data will be needed to confirm these findings.

An open-label, prospective, real-world study evaluated the effectiveness of dexamethasone intravitreal implant (0.7 mg) in a subgroup of patients with treatment-naive diabetic macular edema (Fraser-Bell et al. 2021).²⁷ Of the 200 eyes enrolled in the original AUSSIEDEX study, 57 were treatment-naive. Changes in mean best-corrected visual acuity and central subfield retinal thickness from baseline to 52 weeks in this subgroup were +3.4 letters (p = .042) and -89.6 micrometers (p < .001), respectively, with a mean of 2.5 injections of dexamethasone intravitreal implant 0.7 mg. The most common adverse event was increased intraocular pressure, with 20% of eyes requiring intraocular-pressure lowering medications.

Intravitreal Fluocinolone Acetonide Implant (0.59 mg)
No RCTs were identified assessing the fluocinolone acetonide implants for the treatment of macular edema following retinal vein occlusion.

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) or Intravitreal Fluocinolone Acetonide Implant (0.59 mg) for Macular Edema After Retinal Vein Occlusion
Two identical RCTs have established the efficacy of dexamethasone intravitreal implants (0.7 mg) for patients with macular edema following retinal vein occlusion. The two RCTs compared two doses of implants with sham control. Compared with sham, both doses of the dexamethasone implant resulted in clinically meaningful improvements in visual acuity within 1 – 3 months postimplantation. Further, implant-treated patients achieved improvement in vision faster than the sham controls. However, the vision gain was similar at 6 months. Several additional RCTs and a meta-analysis have evaluated the comparative effects of dexamethasone intravitreal implants versus other therapies and found mixed results. A few notable findings include that the combination of implants with macular grid laser may increase the interval between repeated implants and dexamethasone intravitreal implants may have similar efficacy to other types of treatments. Further, as a class effect, the use of dexamethasone implants resulted in higher incidences of cataracts and elevated intraocular pressure.

No trials assessing the use of fluocinolone acetonide implants were identified.

Diabetic Macular Edema
Intravitreal Fluocinolone Acetonide Implant (0.59 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal fluocinolone acetonide implant (0.59 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with refractory diabetic macular edema.

The question addressed in this evidence review is: Does intravitreal fluocinolone acetonide implant (0.59 mg) improve the net health outcome in patients with refractory diabetic macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with refractory diabetic macular edema.

Interventions
The intervention of interest is the intravitreal fluocinolone acetonide implant (0.59 mg).

Comparators
The comparators of interest are standard of care (as needed laser or observation).

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Rittiphairoj et al. (2020) published a Cochrane review that evaluated the efficacy of intravitreal steroids for macular edema in diabetes.²⁸ It is an update of the previously published Cochrane review by Grover et al. (2008).²⁹ Ten trials were included, involving 4,505 eyes with diabetic macular edema. Among those, four trials examined the effectiveness of intravitreal steroid implantation with fluocinolone acetonide (Retisert) or the dexamethasone drug delivery system compared with sham or an anti-vascular endothelial growth factor agent (all discussed below) and six examined triamcinolone. Cochrane reviewers concluded that, compared to sham or control, intravitreal steroids may improve visual outcomes in people with diabetic macular edema, but that these benefits should be weighed against the risk of intraocular pressure elevation.

Randomized Controlled Trials
Pearson et al. (2011) reported on the three-year efficacy and safety results of an industry-sponsored, single-blind (evaluator) RCT in which 196 patients with persistent or recurrent unilateral or bilateral diabetic macular edema (referred to as refractory diabetic macular edema) were randomized to implants (n = 127) or standard of care, defined as additional laser as needed after six months or observation (n = 69).³⁰ All patients had received focal/grid laser photocoagulation before randomization. At six months, the proportions of patients who received laser retreatment in the implant and standard of care groups were 4% and 13%, respectively; the percentages after three years of follow-up were 15% and 41%, respectively. The primary efficacy outcome (≥ 15-letter improvement in best-corrected visual acuity at six months before any additional laser treatment) was achieved in 16.8% of implanted eyes versus 1.4% of the standard of care eyes (p < .05). Between six and 24 months, visual acuity was statistically significant in favor of the implant group but not beyond 30 months. At 3 years, there was no significant difference between the groups (e.g., 31.1% of implanted eyes vs. 20.0% of the standard of care eyes improved ≥ 15 letters). As expected, there were higher incidences of elevated intraocular pressure (≥ 30 mmHg; 61.4% vs. 5.8%), need for surgery to treat glaucoma (33.8% vs. 2.4%), and cataracts extraction in phakic eyes (91% vs. 20%), respectively, for eyes treated with implants compared with standard of care. The incidence of vitreous hemorrhage (40.2% vs. 18.8%), pruritus (38.6% vs. 21.7%), and abnormal sensation in the eye (37.0% vs. 11.6%), respectively, were also higher in the eyes treated with implants versus standard of care.

Section Summary: Intravitreal Fluocinolone Acetonide Implant (0.59 mg) for Diabetic Macular Edema
One RCT comparing fluocinolone acetonide implants (0.59 mg) with the standard of care (as needed laser or observation) has supported the efficacy of implants for patients with diabetic macular edema. The primary efficacy outcome, at least a 15-letter improvement in best-corrected visual acuity was significantly improved in a greater proportion of patients given implants versus laser at all time points assessed, except at or beyond 30 months. Note that this implant is active for 30 months. As a class effect, in patients with phakic eyes, the use of implants resulted in 90% requiring cataract surgery and 60% developing elevated intraocular pressure. Due to the substantial increase in adverse events and availability of agents with safer tolerability profiles (e.g., Vascular Endothelial Growth Factor inhibitors), this implant is not indicated for diabetic macular edema.

Intravitreal Fluocinolone Acetonide Implant (0.19 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal fluocinolone acetonide implant (0.19 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with diabetic macular edema.

The question addressed in this evidence review is: Does intravitreal fluocinolone acetonide implant (0.19 mg) improve the net health outcome in patients with diabetic macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with diabetic macular edema.

Interventions
The intervention of interest is the intravitreal fluocinolone acetonide implant (0.19 mg).

Comparators
The comparators of interest are standard of care (observation alone).

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Two double-blind, randomized trials, Fluocinolone Acetonide in Diabetic Macular Edema (FAME), have assessed patients with diabetic macular edema previously treated with laser photocoagulation. The primary efficacy endpoint of both trials was the proportion of subjects in whom vision had improved by 15 letters or more at two years from baseline. These trials randomized patients to fluocinolone acetonide 0.19-mg or 0.5-mg implants or to sham. Results of these trials were published by Campochiaro et al. (2011).³¹Of the patients included across the studies, 68.4% were white, 8.1% were Black or African American, 22.1% were Asian, and 12% were Hispanic or Latino. In 2014, the FDA approved the 0.19-mg dose based only on similar efficacy at two years between the low- and high-dose in improving vision by 15 letters or more from baseline (data not shown).³² Relevant results with FDA-approved dosing are summarized in Table 7. Campochiaro et al. (2012) subsequently reported on three-year results.³³ The percentage of patients who gained 15 letters or more using the last observation carried forward was 28.7% in the implant group and 18.9% in the sham group. Results of sensitivity analysis without imputation for missing data (≥ 70% follow-up) showed similar results; the percentages of patients who gained 15 letters or more in the two groups were 33.0% and 21.4%, respectively. Subgroup analysis showed greater improvement in visual acuity in patients who were pseudophakic compared with those who were phakic (difference in mean change in a number of letters at two years from baseline was 5.6 in pseudophakic patients vs. one letter in phakic patients).³² This was due to loss of vision from cataracts in phakic eyes that was observed more frequently in eyes with implants versus sham controls. Subgroup analysis also showed greater efficacy in patients with chronic (≥ 3 years) compared with nonchronic (< 3 years) diabetic macular edema.34, The difference in the proportion of patients who gained 15 or more letters in the implant group versus the sham control group with chronic diabetic macular edema patients was 21% and -5.5 % among nonchronic diabetic macular edema patients.

Table 7. Summary of Two-Year Results From the FDA Pivotal Trials in Diabetic Macular Edema

Outcome	Study 1 (N = 285)			Study 2 (N = 276)
	Implant (n = 190)	Sham (n = 95)	Difference (95% CI)	Implant (n = 186)	Sham (n = 90)	Difference (95% CI)
Gain of ≥ 15 letters, n (%)	51 (27)	14 (15)	12.1 (2.6 to 21.6)	57 (31)	16 (18)	13.0 (2.7 to 23.4)
Loss of ≥ 15 letters, n (%)	26 (14)	5 (5)	8.4 (1.8 to 15.1)	22 (12)	9 (10)	1.8 (-5.9 to 9.6)

Adapted from Alimera Sciences (2014)³²
Values are n (%) or as otherwise indicated.
CI: confidence interval; FDA: U.S. Food and Drug Administration.

Massin et al. (2016) reported on the results of a small prospective noncomparative study in 16 patients with diabetic macular edema insufficiently responsive to laser and antivascular endothelial growth factor who received fluocinolone acetonide 0.19-mg implants.³⁵ Two groups of patients were evaluated; group 1 (n = 6) included patients ineligible for antivascular endothelial growth factor therapy who received previous treatment with laser photocoagulation while group 2 (n = 10) included patients previously treated with laser photocoagulation and at least three monthly antivascular endothelial growth factor treatments. Central subfield thickness was reduced by -299 μm in group 1 and -251 μm in group 2 at 12 months. The mean change in area under the curve from baseline to last value for all eyes was +4.2 letters in group 1 and +3.9 letters in group 2. The benefit in best-corrected visual acuity letter score was more limited and heterogeneous (the effect was more pronounced in pseudophakic eyes) with some patients achieving high improvements of visual acuity, whereas others did not improve. A small number of patients and lack of a control arm limit the interpretation of these findings.

Adverse Events
As listed in the prescribing label, at the end of the 3-year follow-up, 82% (192/235) of phakic eyes with implants underwent cataract surgery compared with 50% (61/121) receiving the sham control.³² Among these patients, 80% of implant patients versus 27% of sham-controlled had cataract surgery, generally within the first 18 months of the trials. The proportion of patients with intraocular pressure elevation of 10 mmHg or more from baseline was three times higher in the implant group (34%) versus the sham group (10%). Respective proportions of patients with intraocular pressure of 30 mmHg or more were 20% and 4%, respectively. As a consequence, a higher proportion of patients in the implant group required surgery for glaucoma (5% vs. 1%).

Section Summary: Intravitreal Fluocinolone Acetonide Implant (0.19 mg) for Diabetic Macular Edema
Two RCTs have established the efficacy of fluocinolone acetonide implants (0.19 mg) for patients with diabetic macular edema. Both trials demonstrated the superiority of implants over sham controls. Implant-treated eyes showed clinically meaningful improvements in the vision at two and three years postimplant. Subgroup analysis showed greater improvements in visual acuity in patients who were pseudophakic than those who were phakic. The major limitation of these implants is that nearly 80% of all phakic patients will develop cataracts and will require cataract surgery. Further, intraocular pressure was elevated in 34% of patients who received this implant compared with 10% of controls, leading to the restricted indication for patients previously treated with corticosteroids who do not have a clinically significant rise in intraocular pressure.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in patients with diabetic macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with diabetic macular edema.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Two double-blind, randomized trials have assessed patients with diabetic macular edema. These trials randomized patients to a 0.7-mg or a 0.35-mg implant or a sham procedure. Retreatment was allowed if it was at least six months since the prior treatment and there was evidence of residual edema. The primary efficacy endpoint in both trials was the proportion of subjects in whom visual acuity had improved by 15 or more letters at 39 months from baseline or at the final visit for patients who exited the study at or prior to month 36. The month 39 extension was included to accommodate the evaluation of safety and efficacy outcomes for patients who received retreatment at month 36. Results of these trials were published by Boyer et al. (2014).³⁶ In 2014, the FDA approved the 0.7-mg dose.¹⁵ Relevant results with the FDA-approved dosing are summarized in Table 8. Only 14% of study patients completed the month 39 visit (16.8% from the implant, 12.2% from sham). The visual acuity improvements from baseline increased during a treatment cycle, peaked at 3 months posttreatment, and diminished after that (data not shown). This result was due to loss of vision related to the development of cataracts. Subgroup analysis showed greater improvements in visual acuity in patients who were pseudophakic than in those who were phakic (difference in mean change in the number of letters at 39 months from baseline was 4.2 letters in pseudophakic patients vs. 0.3 letters in phakic patients).³²

Table 8. Summary of 39-Month Results From the FDA Pivotal Trials in Diabetic Macular Edema

Outcome	Study 1 (N = 328)			Study 2 (N = 328)
	Implant (n = 163)	Sham (n = 165)	Difference (95% CI)	Implant (n = 165)	Sham (n = 163)	Difference (95% CI)
Gain of ≥ 15 letters, n (%)	34 (21)	19 (12)	9.3 (1.4 to 17.3)	30 (18)	16 (10)	13.0 (2.7 to 23.4)
Loss of ≥ 15 letters, n (%)	15 (9)	17 (10)	-1.1 (-7.5 to 5.3)	30 (18)	18 (11)	7.1 (-0.5 to 14.7)

Adapted from Allergan (2014).¹⁵
Values are n (%) or as otherwise indicated.
CI: confidence interval; FDA: U.S. Food and Drug Administration.

Subsequent to the 2014 pivotal trials and FDA approval, several small and/or short-term trials and retrospective studies have been published that evaluate the comparative effects of intravitreal dexamethasone implant (0.7 mg) versus other treatments — primarily antivascular endothelial growth factor in various subgroups of patients with diabetic macular edema (Table 9).^{36,37,38,39,40,41,42} In general, compared with primarily antivascular endothelial growth factor treatments, intravitreal dexamethasone implant (0.7 mg) was consistently associated with larger reductions in retinal thickness, but visual acuity changes were similar between treatment groups. While promising, as these findings are based on single small studies, several of which are nonrandomized, adequately powered and longer-term randomized trials are still needed to confirm these findings.

Table 9. Summary of Additional Studies of Intravitreal Dexamethasone Implant (0.7 mg) in Diabetic Macular Edema

Author, Year, study design, sample size	Population	Comparator	Summary of findings
Boyer et al. (2014), BEVORDEX RCT, N = 86	Patients with DME	Bevacizumab	Dexamethasone had greater reduction in 12-mo retinal thickness and similar for BCVA improvement of ≥ 10 letters. But, dexamethasone resulted in greater risk of vision loss > 10 letters and more adverse events.
Callanan et al. (2017), RCT, N = 363	Patients with DME	Ranibizumab 0.5 mg	Dexamethasone was noninferior to ranibizumab in mean average BCVA change based on the prespecified noninferiority margin of 5 letters, similar in retinal thickness reduction, but ocular adverse events were more frequent for dexamethasone.
Sharma et al. (2019), RCT, N = 40	Centre involved DME	Bevacizumab 1.25 mg or ranibizumab 0.5 mg	Dexamethasone had greater improvements in 3-mo retinal thickness, but similar visual acuity
Unpublished RCT, NCT02471651, N = 40	Persistent DME following anti-VEGF therapy	Continue on various anti-VEGF therapy	Treatments similar in 9-mo retinal thickness and visual acuity improvements
Bolukbasi et al. (2019), retrospective study; N = 57	Early treatment period of naive DME with serous retinal detachment	Intravitreal aflibercept 2 mg, 3 monthly injections	Dexamethasone had greater improvements in 3-mo retinal thickness, but similar visual acuity
Cakir et al. (2019); retrospective study, N = 39 eyes	Treatment-naïve DME with concurrent epiretinal membrane	Ranibizumab 0.5 mg	Dexamethasone had greater CMT reduction at 1 mo, but lower at 2-3 mos. Similar visual acuity.
Coelho et al. (2019), retrospective study; N = 46 eyes	Persistent or recurrent DME	Fluocinolone acetonide implant 0.19 mg	Similar in 24-mo retinal thickness and visual acuity improvements

BCVA: best-corrected visual acuity; BEVORDEX: Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema; CMT: central macular thickness; DME: Diabetic Macular Edema; NCT02471651: Dexamethasone Intravitreal Implant (0.7mg) for the Treatment of Persistent Diabetic Macular Edema Following Intravitreal Anti-Vascular Endothelial Growth Factor Therapy; RCT: randomized controlled trial; VEGF:vascular endothelial growth factor

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) for Diabetic Macular Edema
Two identical RCTs have established the efficacy of dexamethasone intravitreal implants (0.7 mg) for patients with diabetic macular edema. The two RCTs compared two doses of the implant with sham control. Compared with sham, both doses of the dexamethasone implant resulted in clinically meaningful improvements in visual acuity at 39 months postimplantation. The visual acuity improvement peaked at three months posttreatment but diminished after that, possibly due to the development of cataracts. Subgroup analysis showed greater improvements in visual acuity in patients who were pseudophakic than in those who were phakic. Evidence from various small and/or short-term trials and retrospective studies have found that, compared with primarily antivascular endothelial growth factor treatments, intravitreal dexamethasone implant (0.7 mg) was consistently associated with larger reductions in retinal thickness, but visual acuity changes were similar between treatment groups.

Intravitreal Dexamethasone Implant (0.7 mg) Plus Antivascular Endothelial Growth Factor Therapy
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in patients with diabetic macular edema.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy improve the net health outcome in patients with diabetic macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with diabetic macular edema.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy.

Comparators
The comparators of interest are standard of care.

Outcomes
The beneficial outcomes of interest are symptom improvement, change in disease status, functional status, and quality of life. Harmful outcomes of interest are treatment-related morbidity. Follow-up over the first few weeks following surgery is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
For individuals with diabetic macular edema who receive an intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy, the evidence includes two small randomized controlled trials of 169 patients (N range, 40 to 129) (Table 10).^37,43 The first RCT, published by Maturi et al. (2015), was single-blinded and used bevacizumab as the antivascular endothelial growth factor treatment.⁴³ The second RCT, published by Maturi et al. (2018) was double-blinded, used ranibizumab as the antivascular endothelial growth factor treatment, and focused on a ranibizumab-resistant population with persistent diabetic macular edema despite previous treatment.³⁷ Findings from both trials (Table 11) were consistent in demonstrating that although adding dexamethasone to an antivascular endothelial growth factor treatment can lead to a greater mean reduction in central subfield thickness, it does not improve visual acuity and can lead to a higher risk of intraocular pressure elevation. The main limitations of both RCTs (Tables 12 and 13) were their small sample size and the relatively short-term follow-up in the 2018 RCT. Based on the consistent lack of improvement in visual acuity, increased risk of intraocular pressure elevation, and imprecision, these RCTs provide insufficient evidence to determine that the technology results in a meaningful improvement in the net health outcome

Table 10. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					*Active*	*Comparator*
Maturi et al. (2018)³⁷	U.S.	40	2014 – 2016	Persistent DME, with visual acuity of 20/32 to 20/320 after at least 3 anti-VEGF injections; 57% White, 11.6% Black, 22.4% Hispanic/Latinx, 6.2% Asian, 0.8% Native Hawaiian/Pacific Islander	Dexamethasone 0.7 mg + continued 0.3-mg ranibizumab, n = 65 eyes	Sham + continued 0.3-mg ranibizumab, n = 64
Marturi et al. (2015)⁴³	U.S.	1	NR	DME with a CST of .250 mm measured by time-domain optical coherence tomography; 93% White, 7% Black	Bevacizumab 1.25 mg intravitreally at baseline + dexamethasone 0.7 mg implant at the 1-mo visit, n = 21	Bevacizumab 1.25 mg intravitreally at baseline and Mo 1, n = 19

CST: central subfield thickness; DME: Diabetic Macular Edema; NR: Not Reported; RCT: randomized controlled trial; VEGF: Vascular Endothelial Growth Factor.

Table 11. Summary of Key RCT Results

Study	Mean improvement in visual acuity (SD), letters	Mean change in central subfield thickness (SD), µm	Increased intraocular pressure
Maturi et al. (2018)^a,³⁷	127	127	127
Dexamethasone + continued ranibizumab	+2.7 (9.8)	-110 (86)	19 (29%)
Sham + continued ranibizumab	+3.0 (7.1)	-62 (97)	0
MD (95%CI)	-0.5 (-3.6 to 2.5)	-52 (-82 to -22)	p<.001
Maturi et al. (2015)^b,⁴³	35	35	35
Dexamethasone + bevacizumab	+5.4 (10.7)	-45 (107)	6 (33%)
Bevacizumab monotherapy	+4.9 (12.3)	-30 (100)	1 (5.9%)
P-value	.9	.03	NR

CI: confidence interval; MD: mean difference; NR: Not Reported; OR: odds ratio; RCT: randomized controlled trial; SD: Standard deviation.
^a 24-weeks.
^b 12 months.

Table 12. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Maturi et al. (2018)³⁷					4. Sample size lower than needed for 90% power
Maturi et al. (2015)⁴³	3. Unclear	1. Patients not blinded			1. Not reported

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. 5. Inadequate description of methods
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. 4. Insufficient power
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Table 13. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Maturi et al. (2018)³⁷	4. Enrolled populations do not reflect relevant diversity				1. 24 wks is a relatively short follow-up
Maturi et al. (2015)⁴³	4. Enrolled populations do not reflect relevant diversity

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4. Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) Plus Antivascular Endothelial Growth Factor Therapy for Diabetic Macular Edema
Two small RCTs have consistently demonstrated that although combined treatment with dexamethasone implants plus an antivascular endothelial growth factor treatment can lead to a greater mean reduction in central subfield thickness compared to the antivascular endothelial growth factor treatment alone, it does not improve visual acuity and can lead to a higher risk of intraocular pressure elevation. Therefore, these RCTs provide insufficient evidence to determine that the technology results in a meaningful improvement in the net health outcome.

Intravitreal Dexamethasone Implant (0.7 mg) Plus Laser Photocoagulation
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) plus laser photocoagulation is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with diabetic macular edema.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) plus laser photocoagulation improve the net health outcome in patients with diabetic macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with diabetic macular edema.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) plus laser photocoagulation.

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded

Review of Evidence
Randomized Controlled Trials
In 2013, Callanan et al. reported on a multicenter, double-masked, RCT (N = 253) that compared dexamethasone implant plus combination laser photocoagulation with sham treatment plus laser photocoagulation for the treatment of diabetic macular edema.⁴⁴Of the patients included in the study, 61.3% were white, 21% were Hispanic/Latino, 9.8% were Black, 2.7% were Asian, and 5.2% did not have their race or ethnicity reported. The percentage of patients in the combination group versus the sham group who gained 10 or more letters was greater at one month (31.7% vs. 11.0%, p < .001) and nine months (31.7% vs. 17.3%, p = .007) than at 12 months (27.8% vs. 23.6%), respectively. More patients in the sham group discontinued the study due to lack of efficacy (8.7% vs. 0.8%), which might have biased results. An increase in intraocular pressure of at least 10 mmHg was observed in 15.2% of eyes treated with dexamethasone implants. Also, cataracts-related adverse events were more common after treatment with dexamethasone implants (22.2% vs. 9.5%, p = .017).

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) Plus Laser Photocoagulation for Diabetic Macular Edema
One RCT with one-year follow-up comparing combination implants plus laser photocoagulation with laser photocoagulation alone found better visual acuity (as measured by a gain of ≥ 10 letters) at 9 months but not at 12 months. A differential lost to follow-up, lack of power calculations for sample size estimation, and lack of intention-to-treat analysis limit interpretation of results. Use of dexamethasone implants resulted in higher incidences of cataracts and elevated intraocular pressure.

Age-Related Macular Degeneration
Intravitreal Dexamethasone Implant (0.7 mg) Plus Antivascular Endothelial Growth Factor Therapy
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with age-related macular degeneration.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with age-related macular degeneration.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy.

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Kuppermann et al. (2015) reported on the results of industry-sponsored, single-masked, sham-controlled, randomized trial in which 243 patients with choroidal neovascularization secondary to age-related macular degeneration were allocated to dexamethasone implants (n = 123) or a sham procedure (n = 120).⁴⁵ All patients received two protocol-mandated intravitreal ranibizumab injections with the next injection given as needed based on established study criteria. The primary efficacy endpoint was the ranibizumab injection-free interval at six months. The median injection-free survival was 34 days in the implant group and 29 days in the sham control group. Though this difference was statistically significant (p = .016), the effect size was small and clinically insignificant. The proportions of patients who did not require rescue ranibizumab over the six-month study period were 8.3% in the implant group and 2.5% in the sham group (p = .048). There were no significant differences between groups in mean change from baseline best-corrected visual acuity. More patients in the dexamethasone implant group had increased intraocular pressure (13.2% vs. 4.2%; p = .014), but there were no differences between groups in cataract-related events. Notably, the trial had a short follow-up (six months).

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) Plus Antivascular Endothelial Growth Factor Therapy for Age-Related Macular Degeneration
One RCT has evaluated the impact of adding implants to a standard vascular endothelial growth factor inhibitor for patients with age-related macular degeneration. Results of this trial failed to demonstrate clinically meaningful reductions in the ranibizumab injection-free interval. Further, there was an intraocular pressure elevation in a greater proportion of patients receiving implants without any additional clinical benefit.

Other Conditions
Birdshot Retinochoroidopathy
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) or intravitreal fluocinolone acetonide implant (0.59 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with birdshot retinochoroidopathy refractory or intolerant to standard therapy.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with birdshot retinochoroidopathy refractory or intolerant to standard therapy.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) or intravitreal fluocinolone acetonide implant (0.59 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Cohort Studies
Birdshot retinochoroidopathy, also known as birdshot chorioretinopathy or vitiliginous chorioretinitis, is a chronic, bilateral rare form of posterior uveitis with characteristic hypopigmented lesions. No RCTs were identified for the treatment of this indication for any corticosteroid intravitreal implants. Bajwa et al. (2014) published a retrospective case series involving 11 patients (11 eyes) refractory or intolerant to conventional immunomodulatory therapy who received fluocinolone acetonide implants (0.59 mg).⁴⁶ Reported outcomes were disease activity markers. The proportion of patients with intraocular inflammation was 55% at baseline, which decreased to 10%, 11%, and 0% at year 1, 2, and 3, respectively. Active vasculitis was noted in 36.3% of patients at baseline and 0% at three-year follow-up. More than 20% reduction in central retinal thickness was noted in all patients with cystoid macular edema at six months, one year, two years, and three years postimplant. Another retrospective cohort study (2013), which included 11 eyes with birdshot chorioretinitis, reported improved control of inflammation and decreased reliance on adjunctive therapy with fluocinolone acetonide implants (0.59 mg).⁴⁷ Authors observed a more robust increase in intraocular pressure compared with the observed elevation in patients with other types of posterior uveitis and panuveitis. In another retrospective study, which included 32 eyes with birdshot chorioretinopathy who received fluocinolone acetonide implant (0.59 mg) with 12-month follow-up, Rush et al. (2011) also reported a decrease in vitreous haze from 26% at baseline to 100% at 12 months.48, In 2 small retrospective studies with 6 eyes in 3 patients⁴⁹ and six eyes in four patients,⁵⁰ respectively, reported the favorable effects of dexamethasone implants on ocular inflammation and macular edema during treatment. All eyes exhibited control of ocular inflammation and macular edema. In the first study, all three patients achieved best-corrected visual acuity of at least 20/25 during treatment. In the second, there was a mean improvement of 70 letters on best-corrected visual acuity using the Early Treatment Diabetic Retinopathy Study chart.

Section Summary: Birdshot Retinochoroidopathy
No RCTs were identified on the treatment of birdshot retinochoroidopathy with any corticosteroids intravitreal implants. Available evidence includes multiple observational studies that noted improvements in anatomic and visual acuity outcomes in patients refractory or intolerant to the current standard of treatment. Long-term follow-up for efficacy and safety is limited. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in refractory or intolerant patients with birdshot retinopathy.

Individuals With Cystoid Macular Edema Who Receive Intravitreal Dexamethasone Implant (0.7 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in individuals with cystoid macular edema.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in individuals with cystoid macular edema?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with cystoid macular edema. Cystoid macular edema results from cystic accumulation of fluid in multiple layers of the retina following the breakdown of the blood-retinal barriers. It is a sub-type of macular edema which can be caused by many underlying conditions, including uveitis, retinal vein occlusion, diabetic macular edema, retinitis pigmentosa, as well as following procedures such as cataract extraction.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
Various drugs and therapeutic strategies are used to treat cystoid macular edema, with no consensus on the optimal approach or combination of drugs.⁵¹ Intravitreally administered vascular endothelial growth factor antagonists (anti-VEGF) are an established treatment option.⁵² Other treatment options may include carbonic anhydrase inhibitors and/or nonsteroidal anti-inflammatory drugs.⁵³ In those that do not respond to anti-VEGF agents, intravitreal corticosteroids are typically used.⁵⁴

Outcomes
The beneficial outcomes of general interest are symptom improvement, change in disease status, functional status, and quality of life. Harmful outcomes of interest are treatment-related morbidity. Follow-up over the first few weeks following surgery is of interest for relevant outcomes. For visual acuity, the FDA considers a three-line or 15-or-more letter improvement from baseline in best-corrected visual acuity as a clinically significant change.⁵⁵

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
No large, multicenter, sham-controlled RCTs were identified on the treatment of this indication for any corticosteroids intravitreal implants.

The only RCT identified for this indication is for individuals who have cystoid macular edema related to retinitis pigmentosa. Park et al. (2019) published a small (N = 14), single-center, observation-controlled RCT from South Korea.⁵⁶ In this RCT,⁵⁶ 14 patients with bilateral cystoid macular edema related to retinitis pigmentosa with macular cystic changes as shown by spectral domain optical coherence tomography with central macular thickness of .250 mm in both eyes had one eye randomized to intravitreal dexamethasone implant 0.7 mg and the other eye was observed. At two months, compared to the control eyes, the intravitreal dexamethasone implant eyes resulted in improved central macular thickness (-147.5 µm vs. -14 µm, p < .001) and median change of best-corrected visual acuity (+6 vs. +1; p < .001). But, at month 6, the central macular thickness of the study eyes returned to baseline level and there were no longer any significant differences between the eyes. At month 12, 40% of study eyes and 12.5% control eyes experienced cataract formation or progression. But, none required cataract surgery.

Comparative Observational Studies
Three observational studies have compared intravitreal dexamethasone to other treatments in patients with cystoid macular edema.^54,52,57 Tables 14 and 15 summarize their key characteristics and results. These studies are heterogenous in the type of cystoid macular edema treated, the comparator treatment, and outcome assessment approaches. The strength and relevancy of their findings are limited as they have included only small numbers of patients and lack responder analysis of the proportion of patients with a 15-or-more letter improvement from baseline in best-corrected visual acuity.

Table 14. Summary of Key Comparative Observational Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment 1	Treatment 2	Follow-Up
Ozkok et al. (2016)⁵⁴	Prospective	U.S.	2009 – 2013	Refractory cystoid macular edema due to retinal vein occlusion, initially treated with bevacizumab	Intravitreal dexamethasone, n = 35	Intravitreal triamcinolone, n = 39	12 weeks
Laine et al. (2017)⁵²	Retrospective	Finland	2011 – 2015	Treatment-naive cystoid macular edema due to retinal vein occlusion	Intravitreal dexamethasone, n = 14	Intravitreal bevacizumab, n = 121	12 weeks
Veritti et al. (2019)⁵⁷	Prospective	Italy	2015 – 2016	Cystoid macular edema secondary to retinitis pigmentosa	Intravitreal dexamethasone, n = 30	Oral acetazolamide 500 mg/day, n = 30	12 months

Table 15. Summary of Key Comparative Observational Study Results: Dexamethasone versus Comparator

Study	BCVA	Central Retinal Thickness	Intraocular Pressure (mmHg)
Ozkok et al. (2016)⁵⁴	Final: 0.36 vs. 0.36; p = .920	Final: 310.3 vs. 311.6; p = .962	IOP increase > 6 mmHg or needed IOP decreasing drops: 20% vs. 25.6%; p = .462
Laine et al. (2017)⁵²	3-month mean gain estimated from graph: 0.33 vs. 0.37; p-value NR, but described as not significantly different	3-month reduction estimated from graph: -150 vs. -200; p-value NR, but described as not significantly different	IOP ≥ 25 mmHg and elevation ≥ 5 mmHg from baseline: 2 (14%) vs. 0; p = .010
Veritti et al. (2019)⁵⁷	+4.2 letters vs. +1.6 letters; p < .05	-327 µm vs. -180 µm; p < .001	Elevated IOP requiring topical treatment: 4 (13%) vs. 0; p = .11

BCVA: best-corrected visual acuity; IOP: intraocular pressure; NR: not reported

Noncomparative Observational Studies
Multiple case series have assessed improvements in visual acuity and anatomic changes following intravitreal dexamethasone implant (0.7 mg) in patients with cystoid macular edema of various etiologies.^{51,58,59,60,61} However, these studies have generally included only small numbers of patients (N range of 26 to 112) and lacked responder analysis of clinically meaningful changes in outcomes. One exception is the case series by Fortoul et al. (2015), which evaluated the efficacy of the first intravitreal injection of dexamethasone implant in 26 eyes with cystoid macular edema secondary to retinal vein occlusion over six months in a single center in France.⁶⁰ Fortoul et al. (2015) reported that although 88% of patients achieved at least a three-line improvement in best-corrected visual acuity at two months, this was not sustained and only 27.8% of eyes still achieved clinically significant response at six months.

Section Summary: Intravitreal Dexamethasone Implant (0.7 mg) for Cystoid Macular Edema
Evidence for this indication includes one observation-controlled RCT (N = 14), 3 comparative observational studies, and numerous case series. The RCT found improved mean visual acuity and eye anatomy outcomes with intravitreal dexamethasone compared to the control eyes, but these differences were not sustained at six months. The comparative observational studies included 269 patients (range, 60 to 135) and also lacked responder analysis of the proportion of patients with a 15-or-more letter improvement. One case series evaluated the proportion of patients with a 3-line improvement in best-corrected visual acuity. Although 88% of patients achieved this outcome at two months, the proportion with improvement was not sustained at six months (27.8%). Additional blinded, multicenter RCTs are needed that compare intravitreal dexamethasone to another established treatment. The trials should be adequately powered for measuring the proportion of patients in whom vision had improved by 15 letters or more.

Idiopathic Macular Telangiectasia Type 1
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with idiopathic macular telangiectasia type 1.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in individuals with idiopathic macular telangiectasia type 1?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with idiopathic macular telangiectasia type 1. Type 1 macular telangiectasia is a rare congenital and unilateral condition of the eye in which a focal expansion or outpouching and dilation of capillaries in the parafoveal region leads to vascular incompetence, atrophy, and central loss of vision. It is also considered a variant of Coats disease.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Reports
No RCTs were identified on the treatment of macular telangiectasia with any corticosteroids intravitreal implants. Three case reports with a total of nine patients with type 1 idiopathic macular telangiectasia treated with dexamethasone implants have described mixed results on improvements in visual acuity and reduction in inflammation.^50,62,63

Section Summary: Idiopathic Macular Telangiectasia Type 1
No RCTs were identified on the treatment of idiopathic macular telangiectasia type 1 with any corticosteroids intravitreal implants. Available evidence includes multiple case reports, which have noted mix results for visual acuity and inflammation-related outcomes. Long-term follow-up on efficacy and safety is limited. Better quality studies with long-term follow-up are needed to permit conclusions on the efficacy of corticosteroid implants in patients with this indication.

Individuals with Postoperative Chronic Macular Edema Who Receive Intravitreal Dexamethasone Implant (0.7 mg)
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in individuals with postoperative chronic macular edema.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in individuals with postoperative chronic macular edema.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with postoperative chronic macular edema. Postoperative chronic macular edema, also called pseudophakic cystoid macular edema or Irvine-Gass syndrome, is one of the most common causes of visual loss after cataract surgery. It is thought to occur as a consequence of inflammatory mediators that are upregulated in the aqueous and vitreous humors after surgical manipulation. It can lead to a permanent visual loss.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
There are no FDA approved treatments specifically for postoperative chronic macular edema. Also, there are no guidelines or position statements that provide definitive guidance on standard of care for postoperative chronic macular edema. However, first-line treatment typically involves topical corticosteroids and nonsteroidal anti-inflammatory drugs, either as monotherapy or combined therapy.^64,65 When postoperative chronic macular edema persists following topical treatments, then intravitreal corticosteroids and anti-vascular endothelial growth factor agents may be an option.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Mylonas et al. (2017) published an RCT that compared dexamethasone intravitreal implant to triamcinolone intravitreal injection in 29 patients with refractory postoperative cystoid macular edema.⁶⁶ Key characteristics and results of Mylonas et al. (2017) are reported in Tables 16 and 17 below. Participants were mostly female (72%) and the mean age was 73 years in the dexamethasone group and 71 years in the triamcinolone group. No primary outcome was specified. There were no significant differences between the groups in improvement in mean best corrected visual acuity, but central millimeter retinal thickness reduction was significantly greater for triamcinolone at 1 week and 6 months. Minimal information on adverse events was reported.

Table 16. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Mylonas et al. (2017)⁶⁶	Austria, Greece	2	Not reported	Refractory (minimum 3 months) macular edema, developing after cataract extraction or vitreoretinal surgery	Dexamethasone intravitreal implant, 0.7 mg	Triamcinolone intravitreal injection, 4 mg; retreatment after 3 months was dependent on functional and anatomic outcome

RCT: randomized controlled trial.

Table 17. Summary of Key RCT Results

Study	Best-Corrected Visual Acuity	Central Millimeter thickness	Intraocular pressure
Mylonas et al. (2017)⁶⁶	Mean (SD) at baseline, 1mo, 3mo, and 6 mo	Mean (SD) at baseline, 1w, 1m, 3mo, and 6mo	Data not provided; "All cases of IOP elevation were managed readily by observation or topical pressure lowering medications and no glaucoma surgery was necessary"
Dexamethasone	60 (10), 72 (10), 72 (11) and 66 (13)	548 (110), 406 (72), 357 (69), 391 (102), and 504 (159)
Triamcinolone	63 (13), 73 (11), 73 (11), and 71 (13)	516 (121), 350 (54) 355 (59), 389 (89), and 365 (74)
p-value	> .05	≤ .05 at 1w and 6m

IOP: intraocular pressure; RCT: randomized controlled trial; SD: standard deviation

Tables 18 and 19 summarize the relevance and design and conduct limitations of Mylonas et al. (2017).66,

Table 18. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Duration of Follow-up^e
Mylonas et al. (2017)⁶⁶	1. Refractory was undefined; thus, the adequacy of the intensity and duration of the first-line therapy regimen is unclear			6. The proportion of patients in whom vision had improved by 15 letters or more was not reported

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 19. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Mylonas et al. (2017)⁶⁶	3. Allocation concealment unclear	1. All the examiners were unmasked to the injected medication used			2. Power not calculated for primary outcome

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Comparative Observational Studies
Two observational studies have compared intravitreal dexamethasone to other treatments in patients with postoperative macular edema.^67,68 Tables 20 and 21 summarize their key characteristics and results. However, these studies have included only small numbers of patients and lack responder analysis of the proportion of patients with a 15-or-more letter improvement from baseline in best-corrected visual acuity.

Table 20. Summary of Key Comparative Observational Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment1	Treatment2	Follow-Up
Dang et al. (2014)⁶⁷	Prospective	China	2011 – 2013	Patients with diabetes and persistent PCME after 1-month of topical diclofenac and fixed-dose combination product of tobramycin/dexamethasone	Intravitreal dexamethasone, n = 18	Intravitreal triamcinolone, n = 25	6 months
Guclu et al. (2019)⁶⁸	Retrospective	Turkey	2013 – 2015	Previously untreated Irvine-Gass syndrome after phacoemulsification with posterior chamber intraocular lens implantation	Intravitreal dexamethasone, n = 32	Topical nepafenac, n = 30	6 months

PCME: pseudophakic cystoid macular edema.

Table 21. Summary of Key Observational Comparative Study Results

Study	Improvement in BCVA	Intraocular Pressure (mmHg)	Other adverse events
Dang et al. (2014)⁶⁷	Percentage of patients who gained improvements ≥ 10 letters; n = 43	Mean change, n = 43	% with conjunctival hemorrhage, n = 43
Intravitreal dexamethasone	33%	+1.6	4/18 (22.2%)
Intravitreal triamcinolone	36%	+3.4	2/25 (8%)
p-value	.856	.006	.184
Guclu et al. (2019)⁶⁸	Mean BCVA at baseline and 6 months (change), n = 62	Mean at baseline and 6 months (change), n = 62	Surgery-related complications (posterior capsule rupture, iridodialysis, vitreous incarceration, zonular dialysis)
Intravitreal dexamethasone	25 vs 49.3 (+24.3)	13.1 vs 14.9 (+1.8)	10/32 (31%)
Topical nepafenac	20.9 vs 32.9 (+12)	13.6 vs 13.6 (+0)	9/30 (30%)
p-value	.000	.184	NR

BCVA: best-corrected visual acuity; NR: not reported

Case Series
Multiple case series have assessed improvements in visual acuity and anatomic changes^{69,70,71,7.2,73,74,75,76} However, these studies have included only small numbers of patients and reported mean pre-post changes in visual acuity and eye anatomy that lack responder analysis using clinically meaningful changes in outcomes. Effectiveness and safety of dexamethasone implants for postsurgical macular edema including Irvine-Glass syndrome (EPISODIC), a 2017 observational retrospective study conducted in France, included 100 patients with postsurgical macular edema who received dexamethasone implants between 2011 and 2014 and who had a minimum of one-year follow-up.⁷⁷ Mean improvement in best-corrected visual acuity was 9.6 Early Treatment Diabetic Retinopathy Study letters at month 6 and 10.3 at month 12. The proportions of eyes with gains in best-corrected visual acuity of 15 or more letters were 32.5% and 37.5% at months 6 and 12, respectively. The average reduction in central subfield macular thickness was 135.2 and 160.9 μm at months 6 and 12.

Section Summary: Postoperative Chronic Macular Edema
Evidence for this indication includes 1 RCT (N = 29) that compared dexamethasone intravitreal implant, 0.7 mg to triamcinolone intravitreal injection 4 mg, two comparative observational studies, and numerous case series. The RCT found no statistically significant difference between treatments in mean visual acuity improvement at three or six months. The proportion of patients in whom vision had improved by 15 letters or more was not reported. The comparative observational studies included only small numbers of patients and also lack responder analysis of the proportion of patients with a 15-or-more letter improvement. In the largest case series (N = 100), 2 of every 5 patients experienced clinically meaningful improvements in visual acuity after one year of follow-up. Additional RCTs are needed that have clearly defined and representative populations (i.e., for chronic and refractory patients, documentation of intensity and duration of the first-line therapy regimens) and are adequately powered for measuring the proportion of patients in whom vision had improved by 15 letters or more.

Circumscribed Choroidal Hemangioma
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) plus photodynamic therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with circumscribed choroidal hemangioma.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) plus photodynamic therapy improve the net health outcome in individuals with circumscribed choroidal hemangioma?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with circumscribed choroidal hemangioma. Circumscribed choroidal hemangiomas are benign vascular hamartomas without systemic associations.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg) plus photodynamic therapy.

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded

Review of Evidence
Case Reports
No RCTs were identified on the treatment of circumscribed choroidal hemangiomas with any corticosteroid intravitreal implants. A single case report (2012) has described the use of photodynamic therapy combined with dexamethasone implants. Authors concluded that implants potentiated the effect of photodynamic therapy with less risk of local side effects than triamcinolone acetonide.⁷⁸

Section Summary: Circumscribed Choroidal Hemangiomas
No RCTs were identified on the treatment of circumscribed choroidal hemangiomas with any corticosteroid intravitreal implants. Available evidence includes a single case report that does not permit a conclusion on the efficacy and safety of adding dexamethasone implants to photodynamic therapy for the treatment of circumscribed choroidal hemangiomas. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with this indication.

Proliferative Vitreoretinopathy
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with proliferative vitreoretinopathy.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in individuals with proliferative vitreoretinopathy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with proliferative vitreoretinopathy. Proliferative vitreoretinopathy develops as a complication of rhegmatogenous retinal detachment. Proliferative vitreoretinopathy occurs in 8% to 10% of patients undergoing primary retinal detachment surgery and prevents the successful surgical repair of rhegmatogenous retinal detachment.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series/Reports
No RCTs were identified on the treatment of proliferative vitreoretinopathy with any corticosteroids intravitreal implants. A case series (2017) of five patients with proliferative vitreoretinopathy has described the combined use of surgery, endolaser, and dexamethasone implants.⁷⁹ A case report (2013) found a benefit of dexamethasone implants in preventing proliferative vitreoretinopathy in a patient with a rhegmatogenous retinal detachment, who experienced improvements in visual acuity and retinal attachment nine months postsurgery.⁸⁰

Section Summary: Proliferative Vitreoretinopathy
No RCTs were identified on the treatment of proliferative vitreoretinopathy with any corticosteroids intravitreal implants. Available evidence includes a case series and a case report. These studies reported multiple interventions, including dexamethasone implants in conjunction with surgery and laser, for preventing proliferative retinopathy after retinal detachment surgery. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with proliferative retinopathy.

Radiation Retinopathy
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone implant (0.7 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with radiation retinopathy.

The question addressed in this evidence review is: Does intravitreal dexamethasone implant (0.7 mg) improve the net health outcome in individuals with radiation retinopathy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with radiation retinopathy. Radiation retinopathy is delayed-onset damage to the retina due to exposure to ionizing radiation, typically after months and is slowly progressive.

Interventions
The intervention of interest is the intravitreal dexamethasone implant (0.7 mg).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Cohort Studies
No RCTs were identified on the treatment of radiation retinopathy with any corticosteroids intravitreal implants. In a retrospective study (2015), 12 eyes diagnosed with radiation maculopathy secondary to plaque brachytherapy were treated with dexamethasone implants.⁸¹ Anatomic improvements in foveal thickness were reported, with nonsignificant improvements in visual acuity. In a 2014 retrospective case series, two patients who developed radiation maculopathy after radiotherapy for uveal melanoma were treated with dexamethasone implants.⁸² They had limited responses to bevacizumab and intravitreal triamcinolone. Dexamethasone implants provided a prolonged period of anatomic stabilization. In a retrospective chart review of five patients with choroidal melanoma treated with dexamethasone implants for radiation macular edema, Baillif et al. (2013) reported mixed improvements in visual acuity.⁸³ The mean improvement in Early Treatment Diabetic Retinopathy Study letters was 5. Visual acuity improved for three patients (+4, +9, and +15 letters) and remained unchanged for two.

Section Summary: Radiation Retinopathy
No RCTs were identified on the treatment of radiation retinopathy with any corticosteroids intravitreal implants. Available evidence includes multiple observational studies that noted improvements in anatomic stability and visual acuity. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with radiation retinopathy.

Ocular Inflammation and Pain Following Ophthalmic Surgery
Clinical Context and Therapy Purpose
The purpose of punctum dexamethasone insert (0.4 mg) is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as standard therapy, in patients with ocular inflammation and pain following ophthalmic surgery.

The question addressed in this evidence review is: Does punctum dexamethasone insert (0.4 mg) improve the net health outcome in patients in patients with ocular inflammation and pain following ophthalmic surgery?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with ocular inflammation and pain following ophthalmic surgery.

Interventions
The intervention of interest is the corticosteroid intracanalicular insert, dexamethasone implant (0.4 mg), which is placed in the punctum by a physician during ophthalmic surgery.

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
For individuals scheduled to undergo clear corneal cataract surgery who receive punctum dexamethasone insert (0.4 mg), the best evidence includes three double-blind, sham-controlled trials of 926 patients (N range, 241 to 438) (Table 22).^84,85 The two initial phase 3 pivotal trials upon which the FDA approval was based were reported together in one publication by Walters et al. (2016).⁸⁵ The subsequent larger phase 3C trial was reported by Tyson et al. (2019).⁸⁴ Coprimary endpoints were identical across all 3 trials and included evaluating the absence of anterior chamber cells at day 14 and absence of pain at day 8.

Compared with the sham insert, all 3 trials generally consistently found significant improvements with the punctum dexamethasone insert (0.4 mg) across both coprimary efficacy endpoints, as well as for the absence of ocular pain at 14 days, with 2 exceptions (Table 23). In the second pivotal trial, the difference between the punctum dexamethasone insert (0.4 mg) and sham did not reach statistical significance for the proportion of patients with an absence of anterior chamber cells at day 14 (absolute difference was 8.1% compared with 18.5% to 21.5%). The other exception was that, absence of pain at day 14 was not reported as a secondary outcome in the large phase 3C trial by Tyson et al. (2019). Although that secondary outcome was not prespecified in the protocol, as anterior chamber cells were assessed at day 14, it seems reasonable that pain could have been assessed at that time as well. This raises a question about potential reporting bias. Adverse events were generally similar between punctum dexamethasone insert (0.4 mg) and sham. The most common types of adverse events were anterior chamber inflammation, iritis, and increased intraocular pressure. Although allocation concealment methods are unclear across the studies, they had no major methodological limitations (Tables 24 and 25).

Table 22. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Walters et al. (2016); Study 1 (OTX-13-002; NCT02034019)⁸⁵	U.S.	16	Not reported	≥ 18 yrs of age, with a visually significant cataract and scheduled to undergo clear corneal cataract surgery with phacoemulsification and implantation of a posterior chamber intraocular lens	Punctum dexamethasone insert (0.4 mg), n = 164	Sham, n = 83
Walters et al. (2016); Study 2 (OTX-13-003; NCT02089113)⁸⁵	U.S.	16	Not reported	Same as Walters et al. 2016 study 1	Punctum dexamethasone insert (0.4 mg), n = 161	Sham, n = 80
Tyson et al. (2019) (NCT02736175)⁸⁴	U.S.	21	Not reported	≥ 18 yrs of age, presence of a cataract and plans to undergo clear corneal cataract surgery with phacoemulsification and implantation of a posterior chambera posterior chamber intraocular lens	Punctum dexamethasone insert (0.4 mg, n = 216	Sham, n = 222

Study 1 (OTX-13-002): Phase 3 Study Evaluating Safety and Efficacy of OTX-DP for Treatment of Ocular Inflammation and Pain After Cataract Surgery; Study 2 (OTX-13-003): A Prospective, Multicenter, Randomized, Parallel-Arm, Double-Masked, Vehicle Controlled Phase 3B Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Ocular Inflammation and Pain After Cataract Surgery; NCT02736175: A Prospective, Multicenter, Randomized, Parallel-Arm, Double-Masked, Vehicle Controlled Phase 3C Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Ocular Inflammation and Pain After Cataract Surgery; RCT: randomized controlled trial.

Table 23. Summary of Key RCT Results

Study	Absence of Ocular Pain at Day 8, n (%)	Absence of Ocular Pain at Day 14, n (%)	Absence of Anterior Chamber Cells at Day 14, n (%)	Serious adverse events, n (%)	Increased intraocular pressure, n (%)
Walters et al. (2016) Study1⁸⁵	247	247	247	246	246
Punctum dexamethasone insert (0.4 mg)	NR (80.4%)	NR (79.6%)	54 (33.1%)	3 (1.9%)	11 (6.8%)
Sham	NR (43.4%)	NR (39.8%)	12 (14.5%)	5 (6.0)	3 (3.6%)
p-value	< .0001	< .0001	.0018		NR
Walters et al. (2016); Study 2⁸⁵	241	241	241	240	240
Punctum dexamethasone insert (0.4 mg)	NR (77.5%)	NR (76.9%)	63 (39.4%)	2 (1.2%)	7 (4.4%)
Sham	NR (58.8%)	NR (57.5%)	25 (31.3%)	3 (3.8%)	4 (5.0%)
p-value	.0025	.0019	.2182	NR	NR
Tyson et al. (2019)⁸⁴	438	NA	438	437	437
Punctum dexamethasone insert (0.4 mg)	NR (79.6%)	NR	NR (52.3%)	3 (1.4%)	16 (7.4%)
Sham	NR (61.3%)	NR	NR (31.1%)	2 (0.9%)	6 (2.7%)
p-value	< .0001	NR	< .0001	NR	NR

NA:not applicable; NR:not reported; Study 1 (OTX-13-002): Phase 3 Study Evaluating Safety and Efficacy of OTX-DP for Treatment of Ocular Inflammation and Pain After Cataract Surgery; Study 2 (OTX-13-003): A Prospective, Multicenter, Randomized, Parallel-Arm, Double-Masked, Vehicle Controlled Phase 3B Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Ocular Inflammation and Pain After Cataract Surgery; RCT: randomized controlled trial.

Table 24. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Walters et al. (2016) Study 1⁸⁵
Walters et al. (2016) Study 2⁸⁵
Tyson et al. (2019)⁸⁴	1. 14-day absence of pain not reported

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Study 1 (OTX-13-002): Phase 3 Study Evaluating Safety and Efficacy of OTX-DP for Treatment of Ocular Inflammation and Pain After Cataract Surgery; Study 2 (OTX-13-003): A Prospective, Multicenter, Randomized, Parallel-Arm, Double-Masked, Vehicle Controlled Phase 3B Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Ocular Inflammation and Pain After Cataract Surgery.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 25. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Walters et al. (2016) Study 1⁸⁵	3. Allocation concealment unclear
Walters et al. (2016) Study 2⁸⁵	3. Allocation concealment unclear
Tyson et al. (2019)⁸⁴	3. Allocation concealment unclear	4. Described as double-blind, but outcome assessor unspecified	2. Although 14-day pain was not listed as a planned outcome in the CT.gov protocol, it could have reasonably been assessed at day 14 along with chamber cells

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CT: clinical trials; Study 1 (OTX-13-002): Phase 3 Study Evaluating Safety and Efficacy of OTX-DP for Treatment of Ocular Inflammation and Pain After Cataract Surgery; Study 2 (OTX-13-003): A Prospective, Multicenter, Randomized, Parallel-Arm, Double-Masked, Vehicle Controlled Phase 3B Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Ocular Inflammation and Pain After Cataract Surgery.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician; 4. Unclear blinding of outcome assessment
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Ocular Inflammation and Pain Following Ophthalmic Surgery
For individuals scheduled to undergo clear corneal cataract surgery who receive punctum dexamethasone insert (0.4 mg), the evidence includes three RCTs. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Compared with the sham insert, all three trials generally consistently found significant improvements with the punctum dexamethasone insert (0.4 mg) across both coprimary efficacy endpoints of an absence of pain at eight days and absence of anterior chamber cells at day 14. Adverse events were generally similar between punctum dexamethasone insert (0.4 mg) and sham.

Intravitreal Dexamethasone 0.7 mg (Ozurdex) as Prophylaxis of Cystoid Macular Edema in Patients With Noninfectious Intermediate Uveitis or Posterior Uveitis and Cataract Undergoing Cataract Surgery
Clinical Context and Therapy Purpose
The purpose of intravitreal dexamethasone 0.7 mg (Ozurdex) as prophylaxis of cystoid macular edema in patients with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as systematic corticosteroids

The question addressed in this evidence review is: Does intravitreal dexamethasone 0.7 mg (Ozurdex) as prophylaxis of cystoid macular edema improve the net health outcome in patients with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery.

Interventions
The intervention of interest is intravitreal dexamethasone 0.7 mg (Ozurdex).

Comparators
The comparators of interest are standard of care.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
For individuals with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery who receive prophylactic intravitreal dexamethasone 0.7 mg (Ozurdex), the best evidence includes one single-center, open-label RCT of 43 patients in India (Table 26).⁸⁶ Compared with prophylaxis with systemic corticosteroids, intravitreal dexamethasone 0.7 mg led to similar rates of cystoid macular edema and change in best-corrected visual acuity and avoided the need for early steroid taper due to adverse effects on blood glucose, but potentially increased risk of developing intraocular pressure (Table 27). These findings should be interpreted with caution, however, to due important study limitations including its small sample size, unclear allocation concealment methods, and lack of blinding (Tables 28 and 29).

Table 26. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Sudhalkar et al. (2019)⁸⁶	India	1	2015 – 2016	≥ 18 yrs of age, previous unilateral recurrent noninfectious intermediate uveitis or posterior uveitis with CMO and cataract of sufficient degree to warrant surgery; well-controlled uveitis for at least 3 mo prior to scheduled date of cataract surgery	Intravitreal dexamethasone 0.7 mg, n = 20	Oral corticosteroids, n = 23

CMO: cystoid macular edema; RCT: randomized controlled trial.

Table 27. Summary of Key RCT Results

Study	Development of CMO at 6 mo, n (%)	BCVA at 6 mo	Developed ocular hypertension, n (%)	Required rapid taper of systemic steroids due to adverse blood glucose effects, n (%)
Sudhalkar et al. (2019)⁷⁰	43	43	43	43
Intravitreal dexamethasone 0.7 mg	1 (5%)	0.04 logMAR	4 (20%)	0
Oral corticosteroids	2 (8%)	0.06 logMAR	0	3 (13%)
p-value	NR, but described as NSD	.42	NR	NR

BCVA: best-corrected visual acuity; CMO: cystoid macular edema; NR :not reported; NSD: not significantly different; RCT: randomized controlled trial.

Table 28. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Sudhalkar et al. (2018)⁸⁶	4. Study population potentially had better prognosis than intended use

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 29. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Sudhalkar et al. (2018)⁸⁶	3. Allocation concealment unclear	1. Not blinded

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician; 4. Unclear blinding of outcome assessment
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Intravitreal Dexamethasone 0.7 mg (Ozurdex) as Prophylaxis of Cystoid Macular Edema in Patients With Noninfectious Intermediate Uveitis or Posterior Uveitis and Cataract Undergoing Cataract Surgery
For individuals with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery who receive intravitreal dexamethasone 0.7 mg (Ozurdex), the best evidence includes 1 single-center, open-label RCT of 43 patients in India. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Compared with oral corticosteroids, intravitreal dexamethasone 0.7 mg had similar benefits and avoided the need for early steroid taper due to adverse effects on blood glucose, but potentially increased risk of developing intraocular pressure. Due to important study limitations including its small sample size, unclear allocation concealment methods and lack of blinding, conclusions cannot be drawn based on these findings.

Summary of Evidence
Uveitis
For individuals with chronic noninfectious intermediate or posterior uveitis who receive an intravitreal fluocinolone acetonide implant (0.59 mg), the evidence includes 4 RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Two of the four RCTs compared two doses of implants, and two trials compared implants with systemic steroids (and immunosuppression when indicated). All trials supported the efficacy of intravitreal fluocinolone acetonide implants in preventing recurrence and improving visual acuity over a four-year follow-up. The head-to-head trial comparing implants with systemic corticosteroids did not show substantial superiority in the overall effectiveness of either approach. After 24 and 54 months of follow-up, visual acuity improved from baseline in the implant groups compared with the systematic therapy groups by +6.0 and +3.2 letters (p = .16) and +2.4 and 3.1 letters (p = .073), respectively. However, nearly all phakic patients receiving implants developed cataracts and required cataract surgery. Further, most also developed glaucoma, with 75% of patients requiring intraocular pressure lowering medications and 35% requiring filtering surgeries. Systemic adverse events such as hyperlipidemia, diabetes, osteoporosis, fractures, and blood count/chemistry abnormalities were infrequent and not statistically distinguishable between groups. The incidence of hypertension was greater in the systemic therapy group (27%) than in the implant group (13%), but rates of antihypertensive treatment initiation did not differ. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with noninfectious intermediate or posterior uveitis who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of this trial at eight weeks showed that the implant was effective in reducing inflammation (the proportion of eyes with no inflammation was 47% and 12% with implant and sham, respectively) and resulted in clinically meaningful improvement in vision at week 8 compared with sham controls (the proportion of patients with a gain of ≥ 15 letters in best-corrected visual acuity from baseline was > 40% with implants and 10% with sham). Further, at week 26, patients treated with implants reported meaningful increases in vision-related functioning. The major limitation of this trial was its lack of long-term follow-up. The use of implants resulted in higher incidences of cataracts and elevated intraocular pressure. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with chronic noninfectious posterior uveitis affecting the posterior segment of the eye and who receive intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq), the evidence includes two pivotal RCTs. Relevant outcomes are symptom improvement, change in disease status, functional status, and quality of life. Harmful outcomes of interest are treatment-related morbidity. Both RCTs consistently found statistically significantly lower uveitis recurrence rates for intravitreal fluocinolone acetonide implant (0.18 mg, Yutiq) at both six and 12 months. However, serious limitations of these findings include inconsistency in the magnitude of the benefit at 12 months (odds ratio 67.09; 95% confidence interval 8.81 to 511.06 in published RCT and odds ratio 3.04; 95% confidence interval 1.52 to 6.08 in the unpublished RCT) and, with more imputed recurrences in the sham groups than the treatment groups, we also can’t rule out an overestimation of the treatment effect. For the remainder of key outcomes, results were inconsistent between RCTs, appearing more favorable in the published trial. Most notable were the differences between RCTs in mean change in best-corrected visual acuity at 12 months (higher for fluocinolone acetonide in the published trial, lower in the unpublished trials) and risk of increased intraocular pressure within 12 months (increased risk in the unpublished trial, but not in the published trial). Due to these inconsistencies and serious methodological limitations, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Macular Edema
For individuals with macular edema after retinal vein occlusion who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes two RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with sham controls, implants resulted in clinically meaningful improvements in visual acuity within 1 to 3 months postimplant, and improvement in vision occurred faster. The difference in the proportion of patients with a gain of 15 or more letters in best-corrected visual acuity from baseline was more than 10% in favor of implants versus sham in both studies at 30, 60, and 90 days, but not at 180 days postimplant. The use of implants resulted in higher incidences of cataracts and elevated intraocular pressure. Several additional RCTs and a meta-analysis have evaluated the comparative effects of dexamethasone intravitreal implants versus other therapies and found mixed results. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with macular edema after retinal vein occlusion who receive an intravitreal fluocinolone acetonide implant (0.59 mg), no studies were identified. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Diabetic Macular Edema
For individuals with refractory (persistent or recurrent) diabetic macular edema who receive an intravitreal fluocinolone acetonide implant (0.59 mg), the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with the standard of care (as needed laser or observation), a greater proportion of patients with implants reported clinically significant improvement in vision at 6 months (1.4% vs. 16.8%, respectively) and subsequent time points assessed but not at or beyond 30 months of follow-up. Ninety percent of patients with phakic eyes who received implants required cataract surgery, and 60% developed elevated intraocular pressure. Due to the substantial increase in adverse events and availability of agents with better tolerability profiles (e.g., antivascular endothelial growth factor inhibitors), implant use in diabetic macular edema is questionable. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with diabetic macular edema who receive an intravitreal fluocinolone acetonide implant (0.19 mg), the evidence includes two RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Implant-treated eyes showed clinically meaningful improvements in the vision at two and three years postimplant. The percentage of patients who gained 15 letters or more was 28.7% in the implant group versus 18.9% in the sham group at three years. Subgroup analysis showed greater improvements in visual acuity in patients who were pseudophakic compared with those who were phakic (difference in mean change in the number of letters at 2 years from baseline was 5.6 letters in pseudophakic patients vs. one letter in phakic patients). A major limitation of these implants is that nearly 80% of all phakic patients will develop cataracts and will require cataract surgery. Further, intraocular pressure was elevated in 34% of patients who received this implant compared with 10% of controls. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with diabetic macular edema who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes three RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with sham control, two identically designed RCTs showed clinically meaningful improvements in vision with dexamethasone implants that peaked at three months and were maintained at 39 months (with retreatment). The difference in the proportion of patients with a gain of 15 or more letters in best-corrected visual acuity from baseline was 9.3% and 13.0% in the two trials, respectively, favoring implant versus sham at 39 months postimplant. Subgroup analysis of these trials showed greater improvements in visual acuity in patients who were pseudophakic compared with those who were phakic. Additionally, evidence from various small and/or short-term trials and retrospective studies have found that, compared with primarily antivascular endothelial growth factor treatments, intravitreal dexamethasone implant (0.7 mg) was consistently associated with larger reductions in retinal thickness, but visual acuity changes were similar between treatment groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with diabetic macular edema who receive an intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor therapy, the evidence includes two RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Findings from both RCTs were consistent in demonstrating that although adding dexamethasone to an antivascular endothelial growth factor treatment can lead to a greater mean reduction in central subfield thickness, it does not improve visual acuity and can lead to a higher risk of intraocular pressure elevation. Based on the consistent lack of improvement in visual acuity, increased risk of intraocular pressure elevation, and imprecision, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with diabetic macular edema who receive an intravitreal dexamethasone implant (0.7 mg) plus laser photocoagulation, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. One RCT with one-year follow-up demonstrated that combination implants plus laser photocoagulation compared with laser photocoagulation alone resulted in better visual acuity (as measured by a gain of ≥10 letters) at nine months but not at 12 months. However, the generally accepted standard outcome measure for change is 15 or more letters, and this standard was not used in this trial. The use of dexamethasone implants resulted in higher incidences of cataracts and elevated intraocular pressure. Further, a differential loss to follow-up, lack of power calculations for sample size estimation, and lack of intention-to-treat analysis preclude the interpretation of results. A larger RCT with adequate power is needed to confirm these findings. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Age-Related Macular Degeneration
For individuals with age-related macular degeneration who receive an intravitreal dexamethasone implant (0.7 mg) plus antivascular endothelial growth factor inhibitor, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of this trial did not demonstrate clinically meaningful reductions in the ranibizumab injection-free interval between combined treatments (34 days) and antivascular endothelial growth factor alone (29 days; p = .016). Further, intraocular pressure was elevated in a greater proportion of patients receiving implants without any additional clinical benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Other Conditions
For individuals with birdshot retinochoroidopathy refractory or intolerant to standard therapy who receive an intravitreal fluocinolone acetonide implant (0.59 mg) or intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Multiple observational studies have noted improvements in anatomic and visual acuity outcomes. Long-term follow-up for efficacy and safety is limited. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with refractory or intolerant birdshot retinopathy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with cystoid macular edema who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes one observation-controlled RCT (N = 14), three comparative observational studies, and numerous case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The RCT found improved mean visual acuity and eye anatomy outcomes with intravitreal dexamethasone compared to the control eyes, but these differences were not sustained at 6 months. The comparative observational studies included 269 patients (range, 60 to 135) and also lacked responder analysis of the proportion of patients with a 15-or-more letter improvement. One case series evaluated the proportion of patients with a three-line improvement in best-corrected visual acuity; although 88% of patients achieved this outcome at two months, the proportion with improvement was not sustained at 6 months (27.8%). Additional blinded, multicenter RCTs are needed that compare intravitreal dexamethasone to another established treatment. The trials should be adequately powered for measuring the proportion of patients in whom vision had improved by 15 letters or more. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with idiopathic macular telangiectasia type 1 who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple case reports. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Case reports have noted mixed results for visual acuity and inflammation-related outcomes. Long-term follow-up for efficacy and safety is limited. Better quality studies with long-term follow-up are needed to permit conclusions on the efficacy of corticosteroid implants in patients with idiopathic macular telangiectasia type 1. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with postoperative chronic macular edema (pseudophakic cystoid macular edema, Irvine-Gass syndrome) who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes one RCT (N = 29) that compared dexamethasone intravitreal implant, 0.7 mg to triamcinolone intravitreal injection 4 mg, two comparative observational studies and numerous case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The RCT found no statistically significant difference between treatments in mean visual acuity improvement at three or six months. The proportion of patients in whom vision had improved by 15 letters or more was not reported. The comparative observational studies included only small numbers of patients and also lack responder analysis of the proportion of patients with a 15-or-more letter improvement. In the largest case series (N = 100), 2 of every 5 patients experienced clinically meaningful improvements in visual acuity after one year of follow-up. Additional RCTs are needed that have clearly defined and representative populations (i.e., for chronic and refractory patients, documentation of intensity and duration of the first-line therapy regimens) and are adequately powered for measuring the proportion of patients in whom vision had improved by 15 letters or more. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with circumscribed choroidal hemangiomas who receive an intravitreal dexamethasone implant (0.7 mg) plus photodynamic therapy, the evidence includes a case report. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of the case report do not permit conclusions about the efficacy or safety of adding dexamethasone implants for circumscribed choroidal hemangiomas to photodynamic therapy. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with proliferative vitreoretinopathy who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes a case series and a case report. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. These studies have reported multiple interventions, including dexamethasone implants in conjunction with surgery and laser for preventing proliferative retinopathy after retinal detachment surgery. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with proliferative retinopathy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with radiation retinopathy who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Multiple observational studies have noted improvements in anatomic and visual acuity outcomes. Long-term follow-up for efficacy and safety is limited. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with radiation retinopathy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals scheduled to undergo clear corneal cataract surgery who receive punctum dexamethasone insert (0.4 mg), the evidence includes three RCTs. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. All three trials noted significant improvements with the punctum dexamethasone insert (0.4 mg) across both coprimary efficacy endpoints of an absence of pain at eight days and absence of anterior chamber cells at day 14. Adverse events were generally similar between punctum dexamethasone insert (0.4 mg) and sham. Based on the consistent benefits and lack of important increases in adverse event risk, evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with noninfectious intermediate uveitis or posterior uveitis and cataract undergoing cataract surgery who receive prophylaxis with intravitreal dexamethasone 0.7 mg (Ozurdex), the best evidence includes one single-center, open-label RCT of 43 patients in India. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Compared with oral corticosteroids, intravitreal dexamethasone 0.7 mg had similar benefits and avoided the need for early steroid taper due to adverse effects on blood glucose, but potentially increased risk of developing intraocular pressure. Due to important study limitations including its small sample size, unclear allocation concealment methods, and lack of blinding, evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2011 Input
The objective of this evidence review is to determine whether the use of intravitreal or punctum corticosteroid implants in patients with various ocular inflammatory conditions improves their net health outcomes.

Clinical input was sought to help determine whether the use of intravitreal or punctum corticosteroid implants for individuals with various ocular inflammatory conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from two respondents, including one specialty society-level response and one academic medical center-level response.

For individuals who have indications consistent with the U.S. Food and Drug Administration (FDA) labeling for intravitreal or punctum corticosteroid implants, clinical input supports this use provides a clinically meaningful improvement in net health outcome and indicates this use is consistent with generally accepted medical practice. It was noted that Ozurdex (intravitreal dexamethasone implant 0.7 mg) is used for short-term uveitis control while the Retisert (intravitreal fluocinolone acetonide implant 0.59 mg) implant is used for more long-term control of uveitis.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Ophthalmology
In 2019, the American Academy of Ophthalmology published its preferred Practice Pattern^® for retinal vein occlusions.⁸⁷ These stated: “Macular edema may complicate both central retinal vein occlusions and branch retinal vein occlusions. The first line of treatment for associated macular edema is anti-vascular endothelial growth factors. Intravitreal corticosteroids, with the associated risk of glaucoma and cataract formation, have demonstrated efficacy. Also, laser photocoagulation surgery in branch retinal vein occlusion has a potential role in treatment."

In 2019, the American Academy of Ophthalmology also published its preferred Practice Pattern^® for diabetic retinopathy.⁸⁸ Related to therapy with intravitreal corticosteroids, the academy stated: "Because of their side-effect profile, including cataract progression and elevated IOP [intraocular pressure], they [intravitreal corticosteroids] are generally used as second-line agents for DME [diabetic macular edema], especially for phakic patients."

National Institute for Health and Care Excellence
In 2019, the National Institute for Health and Care Excellence (NICE) released guidance on the use of fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien) for treating chronic diabetic macular edema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).⁸⁹ The NICE guidance states, “Fluocinolone acetonide intravitreal implant is not recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).” The NICE committee reached this conclusion based on their interpretation that “results from [Fluocinolone Acetonide in Diabetic Macular Edema] FAME may not be generalisable to people with chronic diabetic macular oedema in phakic eyes with symptomatic cataract seen in the NHS” because “in FAME, very few people had symptomatic cataract at baseline” and that the type of rescue therapy used in FAME is not used in NHS clinical practice.

In 2019, the NICE released guidance on the use of fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis.⁹⁰ NICE's guidance stated, "Fluocinolone acetonide intravitreal implant is recommended, within its marketing authorisation, as an option for preventing relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye."

In 2017, the NICE released guidance on the use of dexamethasone intravitreal implant (with adalimumab) for the treatment of noninfectious uveitis.⁹¹ NICE recommended the implant only in cases of “active disease” with “worsening vision” and the “risk of blindness.”

In 2011, the NICE provided guidance on the use of the dexamethasone intravitreal implant for macular edema secondary to retinal vein occlusion.⁹² The dexamethasone implant was recommended as an option for the treatment of macular edema following retinal vein occlusion. NICE also recommended it as an option for treating macular edema following branch retinal vein occlusion when treatment with laser photocoagulation has not been beneficial or suitable.

In 2015, the NICE provided guidance on the dexamethasone intravitreal implant (Ozurdex) for treating diabetic macular edema.⁹³ Ozurdex was recommended as a possible treatment for diabetic macular edema if there is “an artificial lens” and the edema either has “not improved with non-corticosteroid treatment, or such treatment is not suitable.”

In 2013, the NICE updated its guidance on the intravitreal fluocinolone acetonide implant (Iluvien), recommending Iluvien as an option for treating chronic diabetic macular edema that is insufficiently responsive to available therapies only if:

“The implant is to be used in an eye with an intraocular [pseudophakic] lens and
Their diabetic macular oedema has not got[ten] better with other treatments.”⁹⁴

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 30.

Table 30. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
*Ongoing*
NCT02556424^a	Efficacy and Tolerance Comparison Between Subconjunctival Injection of Triamcinolone and Intravitreal Implant of Dexamethasone for the Treatment of Inflammatory Macular Edema	142	Feb 2021
NCT02623426	Macular Edema Ranibizumab v. Intravitreal Anti-inflammatory Therapy Trial	240	Jul 2022
NCT01998412^a	Iluvien Registry Safety Study (IRISS)	559	Jan 2020 (active, not recruiting)
NCT05101928	Ozurdex as Monotherapy for Treatment of Non-infectious Intermediate, Posterior, or Panuveitis	84	Feb 2025
NCT05003258	Functional and Anatomical Outcomes of Dexamethasone Intra-vitreal Implant in Patients With Macular Edema Due to Retinal Vein Occlusion	25	Oct 2024
*Unpublished*
NCT01827722^a	Ozurdex^® Versus Ranibizumab Versus Combination for Central Retinal Vein Occlusion	45	Dec 2016 (unknown)
NCT02471651^a	Dexamethasone Intravitreal Implant for the Treatment of Persistent Diabetic Macular Edema	40	Oct 2018 (has results, but no peer-reviewed publication)
NCT03003416	Efficacy of Ozurdex^® in the Treatment of Diabetic Macular Edema	115	Dec 2018 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

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Bezatis A, Spital G, Hohn F, et al. Functional and anatomical results after a single intravitreal Ozurdex injection in retinal vein occlusion: a 6-month follow-up -- the SOLO study. Acta Ophthalmol. Aug 2013; 91(5): e340-7. PMID 23638803
Lei S, Lam WC. Efficacy and safety of dexamethasone intravitreal implant for refractory macular edema in children. Can J Ophthalmol. Jun 2015; 50(3): 236-41. PMID 26040225
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Klamann A, Bottcher K, Ackermann P, et al. Intravitreal Dexamethasone Implant for the Treatment of Postoperative Macular Edema. Ophthalmologica. 2016; 236(4): 181-185. PMID 27915343
Sudhalkar A, Chhablani J, Vasavada A, et al. Intravitreal dexamethasone implant for recurrent cystoid macular edema due to Irvine-Gass syndrome: a prospective case series. Eye (Lond). Dec 2016; 30(12): 1549-1557. PMID 27858937
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Dutra Medeiros M, Navarro R, Garcia-Arumi J, et al. Dexamethasone intravitreal implant for treatment of patients with recalcitrant macular edema resulting from Irvine-Gass syndrome. Invest Ophthalmol Vis Sci. May 07 2013; 54(5): 3320-4. PMID 23599334
Freissinger S, Vounotrypidis E, Wolf A, et al. Evaluation of Functional Outcomes and OCT-Biomarkers after Intravitreal Dexamethasone Implant for Postoperative Cystoid Macular Edema in Vitrectomized Eyes. J Ophthalmol. 2020; 2020: 3946531. PMID 32411428
Bellocq D, Pierre-Kahn V, Matonti F, et al. Effectiveness and safety of dexamethasone implants for postsurgical macular oedema including Irvine-Gass syndrome: the EPISODIC-2 study. Br J Ophthalmol. Mar 2017; 101(3): 333-341. PMID 27190126
Bazin L, Gambrelle J. [Combined treatment with photodynamic therapy and intravitreal dexamethasone implant (Ozurdex((R))) for circumscribed choroidal hemangioma]. J Fr Ophtalmol. Dec 2012; 35(10): 798-802. PMID 23040445
Sherif M, Wolfensberger TJ. Intraocular Dexamethasone Implant as Adjunct to Silicone Oil Tamponade for Proliferative Vitreoretinopathy. Klin Monbl Augenheilkd. Apr 2017; 234(4): 501-504. PMID 28147403
Reibaldi M, Russo A, Longo A, et al. Rhegmatogenous Retinal Detachment with a High Risk of Proliferative Vitreoretinopathy Treated with Episcleral Surgery and an Intravitreal Dexamethasone 0.7-mg Implant. Case Rep Ophthalmol. Jan 2013; 4(1): 79-83. PMID 23687501
Caminal JM, Flores-Moreno I, Arias L, et al. INTRAVITREAL DEXAMETHASONE IMPLANT FOR RADIATION MACULOPATHY SECONDARY TO PLAQUE BRACHYTHERAPY IN CHOROIDAL MELANOMA. Retina. Sep 2015; 35(9): 1890-7. PMID 26035401
Bui KM, Chow CC, Mieler WF. Treatment of recalcitrant radiation maculopathy using intravitreal dexamethasone (Ozurdex) implant. Retin Cases Brief Rep. 2014; 8(3): 167-70. PMID 25372430
Baillif S, Maschi C, Gastaud P, et al. Intravitreal dexamethasone 0.7-mg implant for radiation macular edema after proton beam therapy for choroidal melanoma. Retina. Oct 2013; 33(9): 1784-90. PMID 23652581
Tyson SL, Bafna S, Gira JP, et al. Multicenter randomized phase 3 study of a sustained-release intracanalicular dexamethasone insert for treatment of ocular inflammation and pain after cataract surgery. J Cataract Refract Surg. Feb 2019; 45(2): 204-212. PMID 30367938
Walters T, Bafna S, Vold S, Wortz G, Harton P, et al. (2016) Efficacy and Safety of Sustained Release Dexamethasone for the Treatment of Ocular Pain and Inflammation after Cataract Surgery: Results from Two Phase 3 Studies. J Clin Exp Ophthalmol 7:1000572. doi: 10.4172/2155-9570.1000572
Sudhalkar A, Vasavada A, Bhojwani D, et al. Intravitreal dexamethasone implant as an alternative to systemic steroids as prophylaxis for uveitic cataract surgery: a randomized trial. Eye (Lond). Mar 2020; 34(3): 491-498. PMID 31320735
Flaxel CJ, Adelman RA, Bailey ST, et al. Retinal Vein Occlusions Preferred Practice Pattern(R). Ophthalmology. Feb 2020; 127(2): P288-P320. PMID 31757503
Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic Retinopathy Preferred Practice Pattern(R). Ophthalmology. Jan 2020; 127(1): P66-P145. PMID 31757498
National Institute for Health and Care Excellence (NICE). Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema in phakic eyes after an inadequate response to previous therapy Technology appraisal guidance [TA613], 2019. https://www.nice.org.uk/guidance/ta613 Accessed February 5, 2022.
National Institute for Health and Care Excellence (NICE). Fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis Technology appraisal guidance [TA590] 2019; https://www.nice.org.uk/guidance/TA590/chapter/1-Recommendations Accessed February 6, 2022.
National Institute for Health and Care Excellence (NICE). Adalimumab and dexamethasone for treating non- infectious uveitis [TA460]. 2017; https://www.nice.org.uk/guidance/ta460. Accessed February 1, 2022.
National Institute for Health and Care Excellence (NICE). Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion [TA229]. 2011; https://www.nice.org.uk/guidance/ta229. Accessed February 2, 2022.
National Institute for Health and Care Excellence (NICE). Dexamethasone intravitreal implant for treating diabetic macular oedema [TA349]. 2015; https://www.nice.org.uk/guidance/ta349. Accessed February 3, 2022.
National Institute for Health and Care Excellence (NICE). Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy [TA301]. 2013; https://www.nice.org.uk/guidance/ta301.

Coding Section

Codes	Number	Description
CPT	67027	Implantation of intravitreal drug delivery system (e.g., ganciclovir implant), includes concomitant removal of vitreous
	67028	Intravitreal injection of a pharmacologic agent (separate procedure)
	68841 (effective 01/01/2022)	Drug-eluting implant insertion including punctal dilation when performed
	0660T (effective 07/01/2021)	Implantation of anterior segment intraocular nonbiodegradable drug-eluting system, internal approach
	0661T (effective 07/01/2021)	Removal and reimplantation of anterior segment intraocular nonbiodegradable drug-eluting implant
HCPCS	J7311	Fluocinolone acetonide, intravitreal implant
	J7312	Injection, dexamethasone, intravitreal implant, 0.1 mg
	J7313	Injection, fluocinolone acetonide, intravitreal implant (Iluvien), 0.1 mg
	J7314	Injection, fluocinolone acetonide, intravitreal implant (Yutiq), 0.1 mg
ICD-10-CM (effective 10/01/15)	J30.90-H30.93	Unspecified chorioretinal inflammation code range
	H34.811-H34.819	Central retinal vein occlusion
	H34.831-H34.839	Venous tributary (branch) occlusion
	H35.81	Retinal edema
ICD-10-PCS (effective 10/01/15)	08H033Z	Percutaneous insertion of infusion device, eye, right
	08H133Z	Percutaneous insertion of infusion device, eye, left
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2024 Forward

09/19/2024	Reformatting policy verbiage to be brand name neutral. No other changes to policy intent.
04/17/2024	Annual review, no change to policy intent.
01/01/2024	New Policy

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Intravitreal Corticosteroid Implants - CAM 90323HB