Dear editor
I read “Efficacy and safety of different doses of a slow release corticosteroid implant for macular edema: meta-analysis of randomized controlled trials” published in May 2015 by Liu et al.1 The purpose of this article was to report the meta-analysis for the efficacy and safety of intravitreal corticosteroid implants for macular edema. However, there are some factual errors which mean the current article is misleading and these errors need to be pointed out to the readers of Drug Design, Development and Therapy.
First point – from the title of the article, the reader is expecting to read about corticosteroids that are licensed for use for macular edema. At this point the author should have specified that the therapy area being reviewed is diabetic macular edema (DME) and that Retisert (fluocinolone acetonide) is not licensed for this indication.2 ILUVIEN® (190 micrograms fluocinolone acetonide intravitreal implant in applicator) and Ozurdex (dexamethasone),3 however, are indicated for the treatment of DME.
Second point – ILUVIEN now has marketing authorizations in Austria, Belgium, the Czech Republic, Denmark, Finland, France, Germany, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the United Kingdom for the treatment of vision impairment associated with chronic DME, considered insufficiently responsive to available therapies.4 Contrary to the statement in the “Discussion”, in November 2014 ILUVIEN was approved by the US Food and Drug Administration for the treatment of DME in patients who have previously been treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.5 Hence there are slight differences between the European and USA licenses (these are summarized in Table 1).
Table 1.
Summary of the pivotal trial data for ILUVIEN and Ozurdex
| Heading | Ozurdex | ILUVIEN | |
|---|---|---|---|
| Disease area | DME | Chronic DME (European license) | DME (US FDA label) |
| Active | Dexamethasone (DEX) | Fluocinolone acetonide (FAc) | |
| Formulation | Biodegradable | Non-bioerodible (polyimide tube) | |
| Dose | 700 µg | 190 µg | |
| Release rate | 6 µg DEX per day | 0.2 µg FAc per day | |
| Phase III clinical trial in DME | 206207-010 and 011 | FAME trials (FAME A and B) | |
| a. Description of studies. b. The primary endpoint. c. The number of patients studied in the studies. |
a. Two identically designed Phase III trials (206207-010 and 011) that were randomized, masked and sham-controlled. b. The primary endpoint for these studies at the end of 36 months was the average change in BCVA from baseline with one of the trials failing to reach its primary endpoint. c. A total of 1,048 subjects were randomized. |
a. The FAME trials were performed under a single protocol as randomized, double-masked, sham injection-controlled, parallel-group, multicenter studies conducted over a 36-month period and included a pre-planned subgroup analysis to assess efficacy in chronic DME patients. b. The primary endpoint in the FAME trials was 24 months. The secondary endpoint was at 36 months (and the basis for the license and indication approved in Europe). Both FAME trials independently met their primary efficacy endpoints of ≥15 letter improvement in BCVA over baseline. c. A total of 956 subjects were randomized |
|
| Efficacy | |||
| Percentage of patients gaining ≥15 letters at 24 and 36 months | 36 months: 22.2% vs 12.0% (6 µg DEX vs sham control) [difference vs sham control =10.2%] | 24 months: 34.4% vs 13.4% (0.2 µg FAc vs sham control) [difference vs sham control =21.0%] 36 months: 34.0% vs 13.4% (0.2 µg FAc vs sham control) [difference vs sham control =20.6%] |
24 months: 28.7% vs 16.2% (0.2 µg FAc vs sham control) [difference vs sham control =12.5%] 36 months: 28.7% vs 18.9% (0.2 µg FAc vs sham control) [difference vs sham control =9.8%] |
| Mean BCVA | #36 months: 3.5 vs 2.0 letters (6 µg DEX vs sham control) [difference vs sham control =1.5 letters] | 24 months: +6.0 vs 2.2 letters (0.2 µg FAc vs sham control) [difference vs sham control =3.8 letters] 36 months: +7.6 vs 1.8 letters (0.2 µg FAc vs sham control) [difference vs sham control =5.8 letters] |
24 months: +4.4 vs 1.7 letters (0.2 µg FAc vs sham control) [difference vs sham control =2.7 letters] 36 months: +5.3 vs 2.0 letters (0.2 µg FAc vs sham control) [difference vs sham control =2.3 letters] |
| Duration of action of one injection | Up to 6 months | Up to 36 months | |
| Safety | |||
| a. Cataract-related adverse events | 67.9% vs 20.4% (6 µg DEX vs sham control) [difference vs sham control =47.5%] | 86.0% vs 51.5% (0.2 µg FAc vs sham control) where cataract was considered an adverse event [difference vs sham control =34.5%] | 81.7% vs 50.4% (0.2 µg FAc vs sham control) where cataract was considered an adverse event [difference vs sham control =31.3%] |
| b. Cataract-related extraction | 59.2% vs 7.2% (6 µg DEX vs sham control) [difference vs sham control =52.0%] | 85.1% vs 36.4% (0.2 µg FAc vs sham control) where cataract was considered an adverse event [difference vs sham control =48.7%] | 80.0% vs 27.3% (0.2 µg FAc vs sham control) where cataract was considered an adverse event [difference vs sham control =52.7%] |
| c. Elevated IOP | 41.5% vs 9.1% (6 µg DEX vs sham control) required IOP-lowering drops [difference vs sham control =36.0%] | 35.9% vs 15.2% (0.2 µg FAc vs sham control) required IOP-lowering drops [difference vs sham control =20.7%] | 38.4% vs 14.1% (0.2 µg FAc vs sham control) required IOP-lowering drops [difference vs sham control =24.3%] |
| d. Underwent IOP-lowering surgery | 0.6% vs 0.0% (6 µg DEX vs sham control) [difference vs sham control =0.6%] | *5.3% vs 0.0% (0.2 µg FAc vs sham control) underwent IOP-lowering surgery [difference vs sham control =5.3%] | *4.8% vs 0.5% (0.2 µg FAc vs sham control) underwent IOP-lowering surgery [difference vs sham control =4.3%] |
Notes:
Average change from baseline and calculated using area under curve approach.
In patients previously treated with an ocular steroid injection, none underwent IOP-lowering surgery and all IOP-lowering surgeries in subjects treated with ILUVIEN® occurred in patients having no history of ocular steroid injection.6,7
Abbreviations: BCVA, best-corrected visual acuity; IOP, intraocular pressure; DME, diabetic macular edema; US FDA, US Food and Drug Administration.
Third point – in Europe the license for ILUVIEN is based on efficacy data reported at 36 months in the FAME trials.6 In Table 1 the authors cite Retisert, which is not the name of the licensed medicine, and support this with data from Campochiaro et al published in 2011. However, this is misleading as the study cited was performed with ILUVIEN and has now been superseded by Campochiaro et al in 2012 which reports the 3-year results.6
Fourth point – the authors refer to the efficacy and safety data for ILUVIEN and Ozurdex but have not accurately presented the current data and corrected the data to reflect USA and European licensed data. Table 1 has been generated to help the reader understand the differences between pivotal trial data for ILUVIEN and Ozurdex6,7 and the licensed indications for ILUVIEN in the USA and Europe.6,7
In conclusion, it is hoped that the inaccuracies that have been identified will help clarify that ILUVIEN® is an approved therapy for the treatment of DME and available in 17 European countries and also the USA. Moreover, there are differences between the use of ILUVIEN in Europe and the USA as well as between ILUVIEN and Ozurdex, both corticosteroids licensed for DME, and these differences are detailed in Table 1 to help avoid any unnecessary confusion.
Footnotes
Disclosure
The author is a consultant in medical affairs to Alimera Sciences in Europe.
References
- 1.Lui Q, He M, Shi H, et al. Efficacy and safety of different doses of a slow-release corticosteroid implant for macular edema: meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2015;9:2527–2535. doi: 10.2147/DDDT.S82929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hall J. Comment on: “Use of the Fluocinolone Acetonide Intravitreal Implant for the Treatment of Noninfectious Posterior Uveitis: 3-Year Results of a Randomized Clinical Trial in a Predominantly Asian Population”. Ophthalmol Ther. 2015;4(1):65–66. doi: 10.1007/s40123-015-0029-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hall J. Letter to the editor: dexamethasone intravitreal implant in the treatment of diabetic macular edema. Clin Ophthalmol. 2015;9:2119–2121. doi: 10.2147/OPTH.S93836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. medicinces.org.uk [homepage on the Internet] Summary of Product Characteristics for ILUVIEN 190 μg intravitreal implant in applicator. EMC; 2015. [Accessed: March 19, 2016]. [updated November 9, 2015]. Available from: https://www.medicines.org.uk/emc/medicine/27636. [Google Scholar]
- 5.Alimera Sciences. [press release] [Accessed 26 February 2016]. Available from: http://investor.alimerasciences.com/releasedetail.cfm?ReleaseID=873291.
- 6.Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125–2132. doi: 10.1016/j.ophtha.2012.04.030. [DOI] [PubMed] [Google Scholar]
- 7.Boyer DS, Yoon YH, Belfort R, Jr, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904–1914. doi: 10.1016/j.ophtha.2014.04.024. [DOI] [PubMed] [Google Scholar]