Abstract
Purpose:
Commercially available chlorhexidine gluconate (CHG) has a beyond-use date of 24 h. This study evaluated the stability and sterility of 0.05% CHG for 30 days after opening and compared its cost to povidone iodine (PI) for intravitreal injection antisepsis.
Methods:
0.05% CHG was aliquoted into 1-mL syringes and stored at room temperature or refrigerated. Turbidity, pH, high-performance liquid chromatography (HPLC), and sterility testing were performed. A cost analysis was conducted.
Results:
0.05% CHG remained stable for at least 30 days. All samples had measured turbidity <0.5 nephelometric turbidity units. The pH of all samples remained between 5.0 and 7.0. HPLC demonstrated CHG concentration at day 30 relative to day 0 of 98.52% ± 4.16% at room temperature and 99.99% ± 3.38% at 2°C –6°C. The cost per week to perform 150 injections using 0.05% CHG was $463.25 when opening a new bottle daily compared with $16.73 for 5% PI. This cost decreased to $23.16 when utilizing a bottle of CHG for 30 days.
Conclusion:
0.05% CHG remains stable and sterile for at least 30 days after opening. The ability to use CHG for at least 30 days after its opening significantly decreases its utilization expense.
Keywords: chlorhexidine gluconate, endophthalmitis, intravitreal injection, povidone iodine
Introduction
Intravitreal injection (IVI) is the most frequently performed procedure in ophthalmology offering benefits, including maintenance and recovery of vision. However, the IVI procedure is not without risk. Procedure-related endophthalmitis is the most concerning with an incidence between 0.028% and 0.056%. 1,2 Topical ophthalmical povidone iodine (PI) is the current gold standard for antisepsis prior to IVI. 3 –5 A survey of retina specialists in the United States found that >99% reported using PI before IVI for antisepsis. 6
While PI is generally well tolerated for IVI antisepsis, a significant number of patients experience discomfort and even pain that can last for hours to days postinjection leading to dissatisfaction with the treatment. These symptoms can be difficult to differentiate from infectious endophthalmitis, resulting in increased phone calls from patients, as well as unscheduled office visits. In select instances, it can lead to a lack of treatment adherence.
Topical chlorhexidine gluconate (CHG) is an alternative antiseptic agent with broad-spectrum antibacterial coverage that has been effective in preventing infections in other areas of medicine. 7,8 CHG has been shown to result in low rates of endophthalmitis when used for prophylaxis before IVIs. 9 –11 A randomized controlled trial comparing alcohol-free CHG and PI that studied patient pain scores, ocular surface characteristics, and antimicrobial efficacy found that eyes treated with CHG had lower pain scores, less corneal epitheliopathy, and no difference in positive microbial cultures or adverse events. 12
Given these results, CHG may be a useful option for IVI antisepsis, particularly for patients with a PI sensitivity, but possibly for all patients. The widespread adoption of CHG for IVI antisepsis has been slowed by practical and financial concerns. A bottle of PI (Betadine 5%, Alcon, Fort Worth, Texas) has a volume of 30 mL and costs ∼$16.73. A bottle of commercially available, alcohol-free, 0.05% aqueous CHG (Irrisept, Irrimax Corporation, Lawrenceville, Georgia) costs between $92.65 (150 mL) and $125.97 (450 mL) and is limited by a beyond-use date (BUD) of 24 h after opening. Given the small volume of antiseptic solution required to sterilize the ocular service per injection, typically <1 mL, a commercially available bottle of alcohol-free aqueous CHG that is thrown away after 24 h results in significantly greater expense to a retina practice compared with a bottle of PI that is also labeled as single use, but most practitioners aliquot the bottle and use the PI for multiple days outside of its label. An alternative option for patients is to obtain their own CHG from a compounding pharmacy; however, this can cost between $111.00 and $175.00 for a single bottle that can only be used for a single office visit, which is inconvenient and expensive. Moreover, a BUD of 28 days is common for compounded CHG, essentially requiring a new bottle for each injection if the IVI frequency is 4 weeks or greater.
The purpose of this study was to determine if commercially available alcohol-free 0.05% CHG remains stable and sterile up to 30 days after opening when stored in 1-mL syringes both at room temperature and refrigerated between 2°C and 6°C. In addition, we report a cost analysis comparing the use of commercially available PI to commercially available 0.05% CHG and to patient-obtained compounded 0.1% CHG.
Methods
Materials
All chemicals were of analytical grade. A measure of 0.05% alcohol-free CHG (Irrisept) was purchased from Irrimax Corporation (Lawrenceville, Georgia). High-performance liquid chromatography (HPLC)-grade water, HPLC-grade acetonitrile, potassium phosphate dibasic anhydrous, and HPLC-grade O-phosphoric acid were purchased from Fisher Chemicals (Fair Lawn, New Jersey).
Preparation of 0.05% chlorhexidine gluconate syringes
All compounding was performed in a certified, Class II, Type B2 biological safety cabinet. A stock bottle of Irrisept (0.05% CHG, Lot number 2H017) was opened in an ISO 5 environment. The dispensing attachment was connected to this stock bottle, and the solution was transferred to a sterile Petri dish. One milliliter of sterile syringes were filled from the solution in the dish. After all syringes were filled, they were capped tightly with sterile Luer-Lok caps from Becton Dickinson (Franklin Lakes, New Jersey). The syringes were refrigerated (between 2°C and 6°C) or stored at room temperature (25°C with 60% relative humidity). Three syringes at each storage condition were assessed for physical and chemical stability over a period of 30 days. Stability was assessed on days 0, 3, 7, 15, 22, and 30. The syringes were capped and protected from light exposure throughout the study period. The storage conditions were closely monitored throughout the study.
Physical stability testing
Turbidity
The physical stability of the admixtures was assessed by visual examination and turbidity measurements as per the US Pharmacopeia Chapter 788 guidelines. 13 All preparations were evaluated against black and white backgrounds for the visible particulate matter, cloudiness, and any color changes. The turbidity of each sample was also measured using AQ3010 Turbidimeter, and triplicate determinations were done for each of the samples. Physical instability was defined as visible particulate matter, haze, color change, or a change in measured turbidity of 0.5 nephelometric turbidity units (NTU) or more, as per the stability and compatibility study guidelines for the American Journal of Health-System Pharmacy. 14
pH
pH is an important parameter that governs the stability of a product as a change in pH can cause the precipitation of the product. The pH was measured at each sampling point with a pH meter using three-point standardization with standard buffer solutions (pH of 4.0, 7.0, and 10.0) as per the US Pharmacopeia Chapter 791 guidelines. 15 A pH between 5.0 and 7.0 was deemed acceptable as this is the provided pH range according to the manufacturer. 16
Chemical evaluation
All chromatographic studies were performed on a Dionex UltiMate 3000 HPLC system connected with a variable wavelength detector. The separations were performed on a Symmetry C18 column (75-mm length and 4.6-mm internal diameter, Waters Associates, Milford, Massachusetts) with a 3.5-μm particle diameter. The mobile phase was 80% solvent A (phosphate buffer, pH 3.0) and 20% solvent B (acetonitrile). Each CHG syringe was transferred to an HPLC vial, and the assay of CHG was performed using a calibrated HPLC. Calibration of the HPLC method was performed by constructing a standard curve using known concentrations (50, 100, 250, 400, and 500 μg/mL) of CHG. The HPLC method parameters can be found in Table 1 and the standard curve in Figure 1. The current HPLC method was established as a stability-indicating method by studying the accelerated degradation of CHG. The stability-indicating ability of the method was explored by accelerating the degradation of standard 500 µg/mL of CHG in 1 M HCl, 1 M NaOH, and 30% H2O2 solutions. These solutions were heated at 70°C for 30 min, 1 h, and 2 h, and the samples were withdrawn before and after heating each of the solutions. All samples from each time point were analyzed thrice (intraday variation) on three different days (interday variation). The accuracy was calculated at each concentration as the ratio of the measured concentration to the nominal concentration multiplied by 100%.
Table 1.
HPLC Method Parameters
| Parameter | Condition |
|---|---|
| Flow rate | 0.25 mL/min |
| Run time | 3 min |
| Sample temperature | Ambient |
| Column temperature | 30°C |
| Injection volume | 2 µL |
| Detection | UV 239 nm |
FIG. 1.
Standard curve of chlorhexidine gluconate assay. Standard curve of chlorhexidine gluconate at varying concentrations exhibits good linearity for the high-performance liquid chromatography method utilized in this study, which is necessary in order to detect degradation. The average coefficient of determination was 0.99.
The stability of CHG was determined by calculating the percentage of the initial amount at each sampling point. The drug was considered stable only if the concentration exceeded 90% of the initial concentration. This chemical evaluation met the standards outlined in the US Pharmacopeia chapter on CHG Topical Solution. 17
Sterility testing
Sterility testing was performed on days 0, 15, and 30 as per the US Pharmacopeia Chapter 71 guidelines. 18 Soybean-casein digest medium was prepared as per the manufacturer’s guidelines. The sterility of 0.05% CHG stored in syringes was confirmed by incubating 1 mL of CHG from a syringe with 10 mL of the media. The vials were stored at 37°C and observed for growth on days 0, 15, and 30.
Cost analysis
The cost of various formulations of commercially available PI and CHG was obtained by contacting several medical supply companies. Compounding pharmacies were also surveyed to determine the cost of patient-obtained CHG. The volume of PI used by four vitreoretinal surgeons during antisepsis for 10 IVIs was recorded in order to determine the range of volumes utilized per injection by different providers with varying injection techniques and preferences for antisepsis. The maximum amount of PI used was 0.2 mL per injection. Based on this volume, the cost of different antisepsis per 150 injections was calculated to determine what it would cost a retina practice each week to use CHG compared with PI for antisepsis.
Results
Stability and sterility testing
Stability testing was performed by withdrawing three syringes each at room temperature and refrigerated conditions on days 0, 3, 7, 15, 22, and 30 (Tables 2 and 3). All syringes at both temperature conditions remained clear throughout the study without any particulate matter observed by visual inspection. A measured turbidity value of <0.5 NTU was observed for all samples at all time points at both conditions. There was no significant change in pH during the study period, and all samples were within the manufacturer’s acceptable pH range of 5.0–7.0 under both conditions.
Table 2.
Turbidity, pH, and Chemical Stability Data of Chlorhexidine at Room Temperature
| Time point | Sample 1 | Sample 2 | Sample 3 | Mean ± standard deviation |
|---|---|---|---|---|
| Nephelometric turbidity unit values | ||||
| Day 0 | 0.11 | 0.11 | 0.12 | 0.11 ± 0.01 |
| Day 3 | 0.08 | 0.11 | 0.06 | 0.08 ± 0.03 |
| Day 7 | 0.17 | 0.21 | 0.13 | 0.17 ± 0.04 |
| Day 15 | 0.12 | 0.14 | 0.22 | 0.16 ± 0.05 |
| Day 30 | 0.21 | 0.2 | 0.18 | 0.20 ± 0.02 |
| pH | ||||
| Day 0 | 5.96 | 5.96 | 5.97 | 5.96 ± 0.01 |
| Day 3 | 6.38 | 6.39 | 6.38 | 6.38 ± 0.01 |
| Day 7 | 6.56 | 6.69 | 6.58 | 6.61 ± 0.07 |
| Day 15 | 6.51 | 6.49 | 6.52 | 6.51 ± 0.02 |
| Day 30 | 6.86 | 6.88 | 6.83 | 6.86 ± 0.03 |
| High-performance liquid chromatography chemical evaluation (percent relative to day 0) | ||||
| Day 0 | 100 | 100 | 100 | 100 ± 0 |
| Day 3 | 100.07 | 103.42 | 105.56 | 103.02 ± 2.77 |
| Day 7 | 101.27 | 100.01 | 103.04 | 101.44 ± 1.52 |
| Day 15 | 101.86 | 102.02 | 95.58 | 99.82 ± 3.67 |
| Day 30 | 97.21 | 95.18 | 103.18 | 98.52 ± 4.16 |
Table 3.
Turbidity, pH, and Chemical Stability Data of Refrigerated Chlorhexidine
| Time point | Sample 1 | Sample 2 | Sample 3 | Mean ± standard deviation |
|---|---|---|---|---|
| Nephelometric turbidity unit values | ||||
| Day 0 | 0.01 | 0 | 0 | 0.00 ± 0.01 |
| Day 3 | 0.06 | 0.06 | 0.06 | 0.06 ± 0.00 |
| Day 7 | 0.05 | 0.012 | 0.11 | 0.06 ± 0.05 |
| Day 15 | 0.15 | 0.11 | 0.2 | 0.15 ± 0.05 |
| Day 30 | 0.01 | 0 | 0.02 | 0.01 ± 0.01 |
| pH | ||||
| Day 0 | 5.96 | 5.96 | 5.97 | 5.96 ± 0.01 |
| Day 3 | 6.28 | 6.32 | 6.31 | 6.30 ± 0.02 |
| Day 7 | 6.68 | 6.62 | 6.61 | 6.64 ± 0.04 |
| Day 15 | 6.55 | 6.55 | 6.70 | 6.60 ± 0.09 |
| Day 30 | 6.74 | 6.72 | 6.67 | 6.71 ± 0.04 |
| High-performance liquid chromatography chemical evaluation (percent relative to day 0) | ||||
| Day 0 | 100 | 100 | 100 | 100 ± 0 |
| Day 3 | 102.68 | 95.88 | 100.02 | 99.53 ± 3.43 |
| Day 7 | 97.42 | 95.49 | 97.62 | 96.84 ± 1.17 |
| Day 15 | 95.52 | 101.25 | 102.82 | 99.86 ± 3.84 |
| Day 30 | 103.77 | 98.99 | 97.23 | 99.99 ± 3.38 |
The HPLC method developed for this study was reproducible and consistent with accepted criteria described within the literature. 19,20 The failure of an assay to detect the degradation peaks of a compound is the most common source of error in stability studies. The degradation profiles of CHG in acid, base, and peroxide are shown in Figure 2. Under acidic and basic conditions, there was a gradual decline in the peak area of CHG, whereas in peroxide there was an instantaneous decrease in the peak area of CHG. Under all three conditions, the peaks of the blank acid, base, and peroxide did not overlap with the peak of nondegraded CHG at its retention time of 1.95 min. Therefore, this HPLC stability-indicating method was able to accurately detect CHG and definitively separate it from any degradants that could potentially form due to chemical instability during the study period of 30 days.
FIG. 2.
Stability plot and degradation peaks of chlorhexidine gluconate in the presence of acid, base, and peroxide. The ability to detect degradation with peaks that do not overlap with standard chlorhexidine is necessary in order to test for stability.
HPLC was performed on all samples at both conditions (Tables 2 and 3). Standard concentrations of 0.05% CHG (50, 100, 250, 400, and 500 μg/mL) were analyzed using the standardized HPLC conditions outlined in the Methods section (Table 1). A good linearity was exhibited in this concentration range with this HPLC method; the average coefficient of determination (r 2) was 0.99. The slope of the curve illustrated an excellent agreement with the coefficient of variability (Fig. 1). The stability of 0.05% CHG was determined by calculating the percentage of the initial amount at each time point. All samples at all time points at both temperature conditions were well above the 90% threshold (range 95.18%–105.56% for room temperature samples and range 95.49%–103.77% for the refrigerated samples). The average concentration relative to the initial concentration was 98.52% ± 4.16% at day 30 for room temperature samples and 99.99% ± 3.38% for refrigerated samples. Representative chromatograms from a room temperature sample at days 0, 7, 15, and 30 are shown in Figure 3.
FIG. 3.
Representative chromatograms from a room temperature sample at days 0, 7, 15, and 30 demonstrate stability at all time points.
Sterility testing was performed on all samples at days 0, 15, and 30 on soybean-casein digest medium. The contents of each 1-mL syringe were incubated at 37°C with 10 mL of media. No growth was observed at any time point.
Cost analysis
The volume of PI used by four vitreoretinal surgeons to perform a total of 40 IVIs ranged from 0.1 to 0.2 mL per injection. For simplicity, we utilized the maximum volume, 0.2 mL, as the volume of antisepsis for all calculations to make these calculations more generalizable, as a range of volumes could be used by retina specialists to provide antisepsis before IVI. Assuming that 0.2 mL of PI is needed for each injection, a 30-mL bottle of PI can be used to provide 150 injections per week, or ∼30 injections per day, assuming minimal waste. Calculations were performed for each available formulation of CHG (commercially available or patient-obtained) to determine the cost of CHG use compared with PI for antisepsis.
Table 4 contains the available antisepsis options for endophthalmitis prophylaxis before IVIs and the cost per mL for each option. Notably commercially available 0.05% CHG (150 mL) is slightly more expensive per mL ($0.62/mL) than the PI ($0.56/mL) often used by retina practices, and 0.05% CHG (450 mL) is significantly less expensive per mL ($0.28/mL) than either PI or CHG 150 mL. Table 5 contains the cost, including shipping, of using commercially available PI, commercially available 0.05% CHG, and patient-obtained compounded 0.1% CHG. Utilizing a new bottle of 0.05% CHG (150 mL) each day in accordance with its BUD of 24 h is significantly more expensive than utilizing a 30-mL bottle of PI for 5 days to provide 150 injections, $463.25 versus $16.73, a 2,769.0% increase in cost per week. Patient-obtained CHG, while not directly increasing costs to the retina practice, is inconvenient and can be a financial hardship to patients as the available options cost a total of $111 to $175 per bottle (inclusive of shipping). The weekly cost for IVI-related antisepsis using patient-obtained CHG, assuming 150 injections in 150 unique patients, would be between $16,650 and $26,250 compared with $16.73 when using commercially available PI, an increase in cost between 99,521.8% and 156,903.8%. The on-label use of commercially available PI calls for single use of each 30-mL bottle. The weekly cost in this scenario, assuming 150 injections in 150 unique patients, is $2,509.50, a 15,000% increase in cost compared with off-label multiuse of the same bottle of PI.
Table 4.
Types of Antisepsis and Associated Costs
| Antisepsis name and volume | Cost, including shipping (USD) | Cost per milliliter (USD/mL) |
|---|---|---|
| Betadine (30 mL) | $16.73 | $0.56 |
| Irrisept (150 mL) | $92.65 | $0.62 |
| Irrisept (450 mL) | $125.97 | $0.28 |
| Chlorhexidine 0.1% (15 mL) from compounding pharmacy A | $111.00 | $7.40 |
| Chlorhexidine 0.1% (5 mL) from compounding pharmacy B | $175.00 | $35.00 |
Table 5.
Cost Analysis of Different Types of Antisepsis for 150 Injections per Week
| Antisepsis | Bottles needed | Total volume (mL) | Waste (mL) | Cost per week | Cost relative to betadine |
|---|---|---|---|---|---|
| Betadine (30 mL) | 1 | 30 | 0 | $16.73 | Not applicable (%) |
| Betadine (30 mL) on label single use | 150 | 4,500 | 4,470 | $2,509.50 | 15,000 |
| Chlorhexidine 0.1% (each patient brings from compounding pharmacy A 15 mL) | 150 (150 eyes of 150 unique patients) | 2,250 | 2,200 | $16,650 | 99,521.8 |
| Chlorhexidine 0.1% (each patient purchases from compounding pharmacy B 5 mL) | 150 (150 eyes of 150 unique patients) | 750 | 720 | $26,250 | 156,903.8 |
| Irrisept 150 mL (new bottle each day due to beyond-use date of 24 h) | 5 | 750 | 720 | $463.25 | 2,769.0 |
| Irrisept 150 mL (new bottle every 30 days given stability findings) | 1/4th of a bottle | 37.5 | 7.5 | $23.16 | 138.4 |
After analyzing the injection technique of four different vitreoretinal surgeons, it was determined that the amount of commercially available povidone iodine, 5% betadine (Alcon, Fort Worth, Texas) ranged from 0.1 to 0.20 mL. For simplicity we utilized the volume of the provider that used the most betadine per injection and that there was no waste. Therefore, a 30-mL bottle of betadine could be used to perform 150 injections (30/0.2 = 150 injections).
Given the findings of this study that commercially available 0.05% CHG remains stable in 1-mL syringes for at least 30 days, a cost analysis was performed using 0.05% CHG (Table 5). Assuming that 1 bottle of PI (30 mL) can treat 150 patients a week for $16.73, one-fourth of a 150-mL bottle of commercially available CHG should be able to treat the same number of patients for $23.16, a slightly higher cost per week.
Discussion
This study demonstrates that commercially available 0.05% CHG remains stable when assessing turbidity, pH, and chemical stability by HPLC analysis for at least 30 days past its BUD of 24 h when stored in prefilled syringes at temperatures between 2°C and 6°C, as well as at room temperature. The CHG solution remained sterile within the 1-mL syringes as no microbiological growth was observed at 30 days when plated on soybean-casein digest medium. These stability and sterility results suggest that retina practices could utilize commercially available alcohol-free aqueous 0.05% CHG for at least 30 days after opening a single bottle if the CHG is aliquoted into 1-mL syringes for storage. This method of CHG preparation and storage would significantly decrease the cost associated with using CHG for IVI antisepsis and allow practices to offer this option for patients with PI sensitivity.
Our cost analysis highlights the difficulty of utilizing commercially available CHG that must be thrown away each day as this represents a nearly 28-fold increase in the cost of antisepsis each week compared with PI, assuming 150 injections per week. Patient-obtained compounded CHG is another option; however, the associated cost is often prohibitively high for patients. The stability and sterility results of our study suggest that one bottle of 0.05% CHG (150 mL) can be used to provide antisepsis for 600 injections a month for $92.65 compared with four bottles of PI for $66.92, a slight increase in cost for the potential benefit of reduced patient discomfort. Interestingly, a common, commercially available form of PI 5% is labeled as single-use only. If used on-label for 150 injections, the cost of PI without a similar study demonstrating its stability beyond single use is $2,509.50 compared with $23.16 for one-fourth of a bottle of commercially available CHG that remains stable for at least 30 days. For providers that perform more injections per month, using the 450 mL bottle of commercially available CHG could be associated with an even lower cost.
There are a few studies that have reported using CHG for antisepsis for IVI. One report of 40,535 IVIs using CHG found an endophthalmitis rate of 0.0074%, which compares favorably to previous studies using PI. 1,9,21,22 A recent retrospective trial comparing 31,135 IVIs using alcohol-based CHG prophylaxis with 139,817 IVIs using PI prophylaxis found a higher rate of endophthalmitis with CHG, 0.064% compared with 0.021% (P < 0.001). 10 However, the authors in this study painted the conjunctiva and deliberately minimized contact with the cornea to reduce the likelihood of alcohol-associated corneal epitheliopathy. In contrast, the CHG used in our study was alcohol-free and could be more freely administered to the entire ocular surface. While rates of endophthalmitis are extremely low with CHG prophylaxis, these recent results may lead retina specialists to reserve CHG prophylaxis only for those patients who have demonstrated a sensitivity to PI. As suggested in a previous study, over a third of patients receiving PI for IVI antisepsis reported discomfort. 12
There are limitations to this study. The cost estimates may vary depending on the number of injections performed, market pricing, and individual preferences on how the antisepsis is administered before injection. In addition, some practices may choose to use both agents for antisepsis, which could impact cost. Only one brand of 1-mL syringe capped with a Luer-Lok cap was studied in an in vitro model, which may not reflect the real effect of this antiseptic agent in vivo. Finally, the current study did not investigate the role of chlorhexidine for routine patient care; additional work would help better compare these two agents.
Our study demonstrates that commercially available 0.05% CHG remains stable in 1-mL syringes for at least 30 days under two different temperature conditions. This is considerably longer than the current BUD of 24 h recommended by the manufacturer. Using these results, retina practices could consider using CHG for antisepsis before IVI given that the cost of CHG is comparable to PI when using a single 150-mL bottle every four weeks.
Financial Disclosures
A.F.D.: No financial disclosures. B.M.: No financial disclosures. V.S.: No financial disclosures. M.T.: No financial disclosures. JH: Consulting fees from IvericBio, Gyroscope Therapeutics, Baush and Lomb, and OccuRx. J.V.: No financial disclosures. M.S.: No financial disclosures. E.Y.K.: No financial disclosures. Y.H.: No financial disclosures. G.K.: No financial disclosures. S.J.G.: Consulting fees from Allergan, Apellis, Bausch and Lomb, Boehringer Ingelheim, Coherus, Eyepoint, Hoffmann-LaRoche, Johnson and Johnson, Merck Manuals, and New Work Medical Inc. Payments or honoraria lectures, presentations, speakers bureaus, article writing, or educational events from Allergan, Apellis, Bausch and Lomb, Boehringer Ingelheim, EyePoint, Genentech, Hoffman-LaRoche, New World Medical Inc., and Regeneron. Support for attending meetings and/or travel from Apellis and Regeneron. Participation on a Data Safety Monitoring Board or Advisory Board with Bausch and Lomb. Leadership or fiduciary role in other board, society, committee, or advocacy group with American Academy of Ophthalmology and the American Society of Retina Specialists. Receipt of Equipment, materials, drugs, medical writing, gifts, or other services from Carl Zeiss Meditec AG.
Authors’ Contributions
A.F.D.: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, validation, visualization, writing—original draft, and writing—review and editing. B.M.: Conceptualization, funding acquisition, visualization, and writing—editing and review. V.S.: Data curation, formal analysis, investigation, methodology, resources, validation, visualization, writing—original draft, and writing—review and editing. M.T.: Conceptualization, formal analysis, and writing—review and editing. JH: Conceptualization, formal analysis, and writing—review and editing. J.V.: Conceptualization, formal analysis, and writing—review and editing. M.S.: Conceptualization, formal analysis, and writing—review and editing. E.Y.K.: Conceptualization, formal analysis, and writing—review and editing. Y.H.: Conceptualization, formal analysis, and writing—review and editing. G.K.: Conceptualization, data curation, formal analysis, investigation, methodology, resources, supervision, validation, visualization, writing—original draft, and writing—review and editing. S.J.G.: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, supervision, writing—original draft, and writing—review and editing.
Author Disclosure Statement
Each author warrants that he has no commercial associations that might pose a conflict of interest in connection with the submitted article. All financial disclosures are included following the references.
Funding Information
A.F.D.: Funding from the J. Arch McNamara Research Fund of Wills Eye Hospital. V.S.: Funding from the National Institutes of Health Institutional Training Grant (T32GM008562). J.H.: Funding from the J. Arch McNamara Research Fund of Wills Eye Hospital. Grants or contracts from IvericBio, Genentech/Roche, and Aldeyre Therapeutics. S.J.G.: Grants or contracts from the American Academy of Ophthalmology, Apellis, Bayer Healthcare, Boehringer Ingelheim, Genentech, Kodiak Biosciences, NGM Bio, and Regeneron.
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