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The Value of Area Under the Curve Analysis
as an Outcome Measure in the Assessment
of a Continuous Microdosing Fluocinolone
Acetonide Implant (ILUVIEN ® )
Sepehr Bahadorani 1 and Michael A Singer 2
1. University of Texas Health Science Center at San Antonio, San Antonio, Texas, US; 2. Medical Center Ophthalmology Associates, San Antonio, Texas, US
T he treatment of diabetic macular edema (DME) has become one of the most challenging management issues faced by ophthalmologists in
daily practice. This is partly due to the multifactorial nature of DME, progression of the disease and the clinical capacity needed to administer
intravitreal injections. In recent years, the treatment options for DME have expanded to include intravitreal injections of anti-vascular
endothelial growth factor (VEGF) agents and steroids, and most recently, the use of intravitreal implants. In determining clinically relevant endpoints
for clinical studies of these treatments, it is important to consider the patient’s journey and experience with a treatment over a specific time-period
rather than isolated outcomes at a pre-specified time-point. Area under the curve (AUC) is an ideal tool for data analysis particularly when it comes
to sustained release therapies such as dexamethasone (Ozurdex ® , Allergan Inc., California, US) and intravitreal fluocinolone acetonide implant
(0.2µg/day FAc implant; Iluvien ® , Alimera Sciences Inc., Georgia, US). Unlike single time-point outcomes, AUC analysis provides the average letters
gained per day over the entire treatment period, providing a better measure of long-term effectiveness. A recent analysis using the AUC approach
highlights the significant visual acuity benefit resulting from the 0.2µg/day fluocinolone acetonide (FAc) implant during the FAME (Fluocinolone
Acetonide for Macular Edema) trials. A step-by-step instruction is included in this article that allows statistical analysis of the AUC data from both
functional and anatomical outcomes, using a free software tool to further facilitate the use of this technique for future investigators.
Keywords Diabetic macular edema, intravitreal implants, ILUVIEN
Disclosure: Sepehr Bahadorani has nothing to declare in relation to this article.
Michael Singer would like to disclose consultant speaker research for Allergan,
consultant speaker research for Genentech, speaker research for Regeneron and
consultant research for Alimera Sciences.
Acknowledgements: The authors would like to acknowledge the help from Aron
Trevino, who confirmed the accuracy of the AUC R code. Medical writing support was
provided by Katrina Mountfort and James Gilbart at Touch Medical Media, supported
by Alimera Sciences.
Authorship: All named authors meet the International Committee of Medical
Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility
for the integrity of the work as a whole, and have given final approval to the version
to be published.
Open Access: This article is published under the Creative Commons Attribution
Noncommercial License, which permits any noncommercial use, distribution,
adaptation, and reproduction provided the original author(s) and source are given
Received: March 7, 2017
Accepted: March 22, 2017
Citation: US Ophthalmic Review, 2017;10(1):46–51
Corresponding Author: Michael A Singer, 9157 Huebner Road, San Antonio,
TX 78240, US. E: email@example.com
Support: The publication of this article was supported by Alimera Sciences, who was
given the opportunity to review the article for scientific accuracy before submission.
Any resulting changes were made at the authors’ discretion.
Supplementary information to this article is available online at
Vascular exposure to hyperglycemia over extended periods, destroys
the retinal endothelial cell tight junctions and leads to the development
of macular edema with consequent visual loss. 1 Indeed, diabetic macular
edema (DME) is the most common cause of visual impairment in diabetic
patients. 2 At the same time, considering that the incidence of diabetes is on
the rise, it becomes prudent to effectively address DME. According to the
World Health Organization (WHO) study, the global incidence of diabetes
has risen from 108 million in 1980 to 422 million in 2014 and attributes to
2.6% of global blindness. 3 These estimates are expected to rise further due
to the increasing prevalence of diabetes, ageing of the population and the
increasing life expectancy of those with diabetes.
Until recently, the standard of care for DME was laser photocoagulation,
which slows progression of vision loss but rarely results in improvement of
vision, even after 3 years of treatment. According to the Early Treatment of
Diabetic Retinopathy Study (ETDRS), laser treatment of clinically significant
macular edema (CSME) decreases the risk of moderate vision impairment
(15 letters) by half over 3 years. 4 Nonetheless, the introduction of intravitreal
pharmacologic agents, namely the anti-vascular endothelial growth factor
(VEGF) agents and corticosteroids, has changed the prognosis of DME from
stabilization of vision to improvement.
Pathogenesis and treatment
The pathogenesis of DME is attributed to the destruction of endothelial cell
tight junctions but more specifically, it is thought that, as a consequence of
non-perfusion and hypoxia in diabetic retinopathy, production of VEGF and
other inflammatory cytokines attributes to the distortion of vascular barriers.
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