Regulatory Decision Summary for Iluvien

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal ingredient(s):

fluocinolone acetonide

Therapeutic area:


Type of submission:

New Drug Submission

Control number:

What was the purpose of this submission?


This New Drug Submission (NDS) was filed to obtain market authorization for Iluvien (Fluocinolone acetonide intravitreal implant, 0.19 mg) for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.


Why was the decision issued?


Overall, the risk-benefit profile of Iluvien 0.19 mg is considered favorable in the target population. The uncertainties and risks associated with Iluvien administration are considered to be addressed in the Product Monograph (PM).

The non-clinical data identified a risk of posterior/cortical cataract development associated with Iluvien administration in the 24-month study in rabbits, which is a known risk associated with intravitreal steroid administration.

No quantifiable concentrations of fluocinolone acetonide (FA) were detected in plasma samples at any time point during the 24-month period. Systemic absorption is negligible in rabbits following intravitreal injection with FA implants.

In a Phase 2b pharmacokinetic study in humans, no measurable systemic exposure to FA was demonstrated after intravitreal insertion of Iluvien, while FA concentration in the aqueous humor was observed after Iluvien implant insertion at the proposed dose for approximately 36 months.

Two virtually identical phase 3 (FAME) clinical trials were submitted in support of the proposed indication. In each FAME study, the primary efficacy variable was the proportion of responders (subjects with a ≥15-letter increase in the Best Corrected Visual Acuity (BCVA) test in the study eye from baseline to Month 24. Approximately 450 subjects were enrolled in each study and randomized in a 2:2:1 ratio to 1 out of 3 treatment groups: 0.2 mg FA intravitreal implant, 0.5 mg FA intravitreal implant, or sham injection. The study population is reflective of the target population (older subjects with type 2 diabetes who developed DME).

In the analysis of the pooled studies, the difference between the active treatment and the sham injection in terms of percent of responders at Month 24 was -12.5% for 0.2 µg/day FA (95% CI: ?19.5%, -5.5%; p = 0.002) and -12.4% for 0.5 µg/day FA (95% CI: -19.3%, -5.5%; p = 0.002). The onset of effect was relatively rapid, as the proportion of subjects with a ≥15-letter increase in BCVA from baseline was statistically significantly higher in each active treatment group, compared to the sham injection group, starting as early as Week 3. The treatment effect was maintained for the low dose group (p≤0.018) and the high dose group (p≤0.029) through Month 36. The duration of effect is also supported by pharmacokinetic data, since FA was measurable in the human aqueous humor through Month 36, for the 0.2 mg FA treatment group. The treatment effect was more pronounced in the 0.2 mg FA group in subjects with a worse vision at baseline (≤49 letters at baseline) and in subjects with a longer duration of DME, as compared to subjects with a shorter duration of DME. Secondary endpoints were generally more or less supportive of the primary efficacy results.

Cataract development is a known adverse event (AE) associated with intravitreal corticosteroid administration. A confounding effect of cataract development on visual acuity was observed in patients who were phakic at baseline and underwent cataract removal surgery during the study (thus becoming pseudophakic). The percentage of subjects with a ≥15-letter increase in BCVA score from baseline was similar between the treatment groups and the sham injection group. No statistically significant difference was observed; there was only a numerical trend towards a better response in the 0.2 mg FA treatment group. Since there are limited treatment options for DME, the benefit-risk ratio is considered favorable in phakic patients. However, phakic subjects should be informed of the almost unavoidable cataract formation while on treatment and be agreeable to undertaking and continuing the treatment. Overall, the primary efficacy endpoint was met in both pivotal studies, and the indication proposed by the sponsor is considered to be supported by the submitted data.

The overall safety of the inserter device and its utility was supported by the data provided.

The most common drug-related AEs in the study eye were cataract operations (40% of subjects), cataract development (37%), increased intraocular pressure (27%), and myodesopsia (8%). Nearly 80% of phakic subjects developed a cataract by the end of the study. The median time to cataract development was 14 months (between 9 and 18 months after implantation). The second serious ocular AEs associated with steroid administration was IOP elevation. The incidence of the IOP elevation was higher in study eyes (i.e., 4.3%, 26.9% and 36.6% in the sham injection group, 0.2 mg FA and 0.5 mg FA treatment groups, respectively) compared to 0%, 0.3% and 0% of non-study eyes; however, the IOP elevation was considered manageable with medication in most patients.


Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.