Michelle E. Tarver

The Food and Drug Administration's Proactive toxic anterior segment syndrome Program.

Toxic anterior segment syndrome (TASS) is a rare inflammatory condition usually observed within the first 48 hours after uncomplicated anterior segment surgery. Over the decades since its initial description, a number of TASS outbreaks have been reported. For a few of these outbreaks, the inciting factors were identified, but for the majority, the precipitating factors were often postulated but not confirmed. In light of the limitations identified in these outbreak investigations, the Food and Drug Administrations (FDAs) Center for Devices and Radiological Health staff has embarked on a number of activities aimed at mitigating medical device-related TASS outbreaks. Under the FDA-designed Proactive TASS Program (PTP), FDA scientists have conducted animal studies to better explore the inflammatory potential of suspected ophthalmic device contaminants implicated in prior cases of TASS. For contaminants displaying a TASS-like reaction in these animal models, the FDA scientists have developed analytic test methods to measure the level of those contaminants in or on ophthalmic devices. Moreover, FDA researchers have developed methods to better capture the clinical information necessary to assist investigations of potential future outbreaks. Last, the FDA has partnered with the Centers for Disease Control and Prevention to facilitate a potential TASS investigation, including expediting the analysis of potentially contaminated medical devices. The PTP is an example of the FDA proactively developing test methods and disease surveillance methods geared toward protecting the publics health.

Evaluation of intraocular reactivity to metallic and ethylene oxide contaminants of medical devices in a rabbit model.

OBJECTIVE To evaluate the intraocular reactivity to metallic and ethylene oxide (EO) contaminants of ophthalmic devices in rabbits. DESIGN Two experimental animal studies. PARTICIPANTS Thirty-five New Zealand white rabbits. METHODS A metallic exposure study and an EO exposure study were performed. In the first study, both eyes of 25 rabbits were equally allocated to intracameral injections of alumina 0.2 μg, alumina 20 μg, copper sulfate 0.4 μg, copper sulfate 20 μg, or an aqueous control. In the second study, 10 rabbits were allocated (5 per group) to receive intracamerally an ophthalmic viscosurgical device (OVD) exposed to EO or not exposed to EO (control). All eyes were examined by slit lamp at baseline and 3, 6, 9, 24, 48, and 72 hours after exposure, with dilated indirect ophthalmoscopy being performed at 24 and 72 hours. Tonometry was performed only in the first study. MAIN OUTCOME MEASURES Grade of corneal clouding, anterior chamber (AC) flare, AC cells, AC fibrin, iridal hyperemia, cell and fibrin on the lens surface, vitreous haze and cells, lens opacities, intraocular pressure, and onset time. RESULTS For metallic compounds at the studys low doses, mean inflammatory grades were 0.2 or less above the control for all responses at all time points. For the high-dose alumina, mean inflammatory grades peaked at 6 to 9 hours at 0.5 to 0.7 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, and fibrin and declined over the remaining time points. For the high-dose copper sulfate, mean inflammatory grades peaked between 3 and 24 hours at 1.2 to 1.8 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, fibrin, and corneal clouding, then subsequently declined. The intraocular pressure changes appeared significant for only high-dose copper sulfate, with mean declines of 4.3 to 7.5 mmHg at 6 to 72 hours. No clinically meaningful differences in ocular inflammation were observed between the OVD exposed to EO and the OVD not exposed to EO. CONCLUSIONS Alumina and copper sulfate did not cause clinically meaningful ocular inflammation at the low study levels (levels expected with ophthalmic devices). Ethylene oxide exposure of an OVD was not associated with inflammation.

Symptoms and Satisfaction of Patients in the Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) Studies

Importance Patient-reported outcomes should be collected using validated questionnaires prior to and following laser in situ keratomileusis (LASIK) surgery. Objective To report the frequency of patient-reported visual symptoms, dry eye symptoms, satisfaction with vision, and satisfaction with LASIK surgery in the Patient-Reported Outcomes With LASIK (PROWL) studies. Design, Setting, and Participants The PROWL-1 and PROWL-2 studies were prospective, observational studies conducted from September 13, 2011, to June 27, 2014. The PROWL-1 study was a single–military center study of 262 active-duty Navy personnel 21 to 52 years of age. The PROWL-2 study was a study of 312 civilians 21 to 57 years of age conducted at 5 private practice and academic centers. The LASIK surgery and the postoperative care were performed based on the usual practice and clinical judgment at the site. Participants completed a self-administered, web-based questionnaire, preoperatively and postoperatively at 1 and 3 months (the PROWL-1 and -2 studies) and at 6 months (the PROWL-2 study). Exposures Participants underwent LASIK surgery for myopia, hyperopia, and/or astigmatism. Main Outcomes and Measures Visual symptoms (double images, glare, halos, and/or starbursts), dry eye symptoms, participant satisfaction (with vision and LASIK surgery), and clinical measures (visual acuity, refractive error, and slitlamp and posterior segment eye examination findings) were assessed preoperatively and at 1, 3, and 6 months postoperatively. Results A total of 262 participants were enrolled in the PROWL-1 study (mean [SD] age, 29.1 [6.1] years), and a total of 312 participants were enrolled in the PROWL-2 study (mean [SD] age, 31.5 [7.3] years). Visual symptoms and dissatisfaction with vision were common preoperatively. Overall, the prevalence of visual symptoms and dry eye symptoms decreased, although a substantial percentage of participants reported new visual symptoms after surgery (43% [95% CI, 31%-55%] from the PROWL-1 study and 46% [95% CI, 33%-58%] from the PROWL-2 study at 3 months). The percentages of participants in the PROWL-1 study with normal Ocular Surface Disease Index scores were 55% (95% CI, 48%-61%) at baseline, 66% (95% CI, 59%-72%) at 3 months, and 73% (95% CI, 67%-79%) at 6 months. The percentages of participants in the PROWL-2 study with normal Ocular Surface Disease Index scores were 44% (95% CI, 38%-50%) at baseline and 65% (95% CI, 59%-71%) at 3 months. Of those participants who had normal scores at baseline in both the PROWL-1 and -2 studies, about 28% (95% CI, 19%-37%) had mild, moderate, or severe dry eye symptoms at 3 months. While most participants were satisfied, the rates of dissatisfaction with vision ranged from 1% (95% CI, 0%-4%) to 4% (95% CI, 2%-7%), and the rates of dissatisfaction with surgery ranged from 1% (95% CI, 0%-4%) to 2% (95% CI, 1%-5%). Conclusions and Relevance The systematic administration of a questionnaire to patients who have undergone LASIK surgery is a new approach to assess symptoms and satisfaction. Our findings support the need for adequate counseling about the possibility of developing new symptoms after LASIK surgery.

Evaluation of Intraocular Reactivity to Organic Contaminants of Ophthalmic Devices in a Rabbit Model

OBJECTIVE To evaluate the intraocular reactivity to organic contaminants of ophthalmic devices in the rabbit. DESIGN Experimental animal study. PARTICIPANTS Fifty New Zealand white rabbits. METHODS The rabbits were allocated to 10 groups of 5 each to receive 2 different doses of human albumin and nonhuman nucleic acids and their respective vehicle controls, a denatured cohesive ophthalmic viscosurgical device (OVD) and a denatured dispersive OVD and their respective nondenatured controls. All 10 eyes in each treatment group received bilateral intracameral injection of the test materials. All the eyes in the study were examined by slit-lamp biomicroscopy at baseline and 6, 9, 24, 48, and 72 hours. Pachymetry was also performed on eyes exposed to albumin, protein vehicle control, and the OVDs at these time points. MAIN OUTCOME MEASURES Corneal thickness, grade of corneal clouding, anterior chamber (AC), cells, flare and fibrin, iridal hyperemia, cell and fibrin on lens surface, and onset time. RESULTS There were no inflammatory signs in any eyes exposed to human albumin. Anterior chamber cells (1+ to 3+) and flare and fibrin (1+ to 2+), along with cells and fibrin on the lens surface, were seen in the eyes exposed to the nucleic acid samples, and they resolved in 24 hours. Mild (mostly 1+) conjunctival congestion, cells, flare, and fibrin were seen in a few eyes exposed to the 2 denatured OVDs and their controls, with the response durations being shorter in the denatured OVD eyes (24 hours) than in the nondenatured OVD eyes (48 hours). Anterior chamber inflammation was generally observed in fewer denatured OVD eyes than in nondenatured OVD eyes, particularly the dispersive OVD eyes. CONCLUSIONS Intracameral injection of human albumin protein did not cause ocular inflammation. Nucleic acid intracamerally injected into rabbit eyes caused acute inflammation that quickly resolved. Cohesive and dispersive OVD denatured by drying and steam sterilization alone did not cause ocular inflammation.

Special Report: American Academy of Ophthalmology Task Force Consensus Statement for Extended Depth of Focus Intraocular Lenses.

With the advent of wavefront technology, our clinical understanding of human optics and visual performance allows intraocular lens (IOL) manufacturers to manipulate lens design to optimize our visual world. These specially designed extended depth of focus (EDF) lenses use optics that increase depth of focus, potentially allowing better intermediate vision while minimally affecting distance vision. The tradeoff with use of EDF lenses is a reduction in distance image quality if the aberration magnitude is too large. The American Academy of Ophthalmology Task Force Consensus Statement on EDF IOLs provides criteria to evaluate the implant performance under photopic, mesopic, and glare conditions. The criteria define minimum performance levels to categorize the device as an EDF IOL based on testing at distance, intermediate, and defocus curve testing. The consensus statement also provides recommendations on defocus curve testing methodology, lighting conditions, and the use of digitized charts with randomized presentation of test letters. Implementation of these recommendations will improve the sensitivity of testing and provide more objective data for the U.S. Food and Drug Administration and clinicians. Intermediate vision and varied lighting conditions have become more critical with the advent of smartphones, tablets, and desk computers. Concise objective testing of patients implanted with EDF IOLs using intermediate tasks will enable us to understand how these lenses perform under these circumstances. The human visual system is an elegant optical system that provides less-than-perfect images within our neural system. Our neural system then modifies and interprets the images based on past experiences to optimize our performance in daily activities. Understanding the relationship between optics and visual performance of EDF IOLs allows clinicians to guide our patients wisely on the advantages and limitations of such lenses. The information that follows will provide a consensus statement for EDF clinical studies to evaluate the clinical performance of patients receiving these IOLs.

Special Report: American Academy of Ophthalmology Task Force Recommendations for Specular Microscopy for Phakic Intraocular Lenses

The American Academy of Ophthalmology Task Force Consensus Statement on Specular Microscopy for investigational phakic intraocular lenses provides more detail than currently available guidelines on the management of specular microscopy evaluations to ensure subject safety during the clinical investigation of new phakic intraocular lenses (PIOLs). Although these recommendations were written for PIOLs, similar safety principles could be used for pseudophakic intraocular lenses in studies that require subject follow-up for similar or shorter durations. Specular microscopy is an important prognostic test that allows clinicians to identify unacceptable progressive corneal endothelial cell loss rates and potentially remove an offending implant before the damage causes irreversible corneal edema. These studies are critical not only to demonstrate the overall safety of the device being evaluated for the general population but also to protect participating study subjects. Although current American National Standards Institute (ANSI) guidelines exist for PIOL studies, these do not describe how the investigators should be notified and how they should follow subjects showing significant losses during the trial. Therefore, we have specified some recommendations concerning how information should pass between sponsors of such new PIOLs, reading centers, and the investigations, so that subject safety is adequately protected.

Special Report: American Academy of Ophthalmology Task Force Recommendations for Test Methods to Assess Accommodation Produced by Intraocular Lenses

FLORA LUM, MD JACK T. HOLLADAY, MD, MSEE ADRIAN GLASSER, PHD SCOTT MACRAE, MD SAMUEL MASKET, MD WALTER STARK, MD EVA RORER, MD MICHELLE E. TARVER, MD, PHD DON CALOGERO, MS GENE HILMANTEL, OD TIEUVI NGUYEN, PHD MALVINA EYDELMAN, MD The American Academy of Ophthalmology, San Francisco, California; Clinical Professor, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; Independent Consultant, Tampa, Florida; Flaum Eye Institute, University of Rochester, Rochester, New York; Advanced Vision Care, Clinical Professor, David Geffen School of Medicine, Jules Stein Eye Institute, UCLA, Los Angeles, California; Retired Distinguished Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland; Food and Drug Administration, Center for Devices and Radiological Health, Silver Spring, Maryland

Assessment of the Incorporation of Patient-Centric Outcomes in Studies of Minimally Invasive Glaucoma Surgical Devices

IMPORTANCE Minimally invasive glaucoma surgical (MIGS) devices are one option for lowering intraocular pressure in patients with glaucoma. OBJECTIVE To examine how often existing clinical studies of MIGS devices registered on ClinicalTrials.gov measure patient-centric outcomes that patients value directly. DESIGN, SETTING, AND PARTICIPANTS We searched ClinicalTrials.gov, a registry of publicly and privately supported clinical studies, on February 20, 2015, for records of MIGS device studies involving patients with glaucoma. Two investigators independently abstracted study design and outcome details from eligible records. We classified outcomes as patient-centric or not patient-centric using a prespecified definition. MAIN OUTCOMES AND MEASURES Proportion of patient-centric and nonpatient-centric outcomes registered on ClinicalTrials.gov. RESULTS We identified 51 eligible studies specifying 127 outcomes. Reduction in intraocular pressure was the most frequent outcome specified (78/127; 61%) and a primary outcome in 41 studies. Patient-centric outcomes-such as adverse events (n = 19; 15%), topical medication use (n = 16; 13%), visual acuity (n = 4; 3%), and health-related quality of life (n = 1; 1%)-were less frequently specified (n = 40; 32%) and a primary outcome in only 12 studies. CONCLUSION AND RELEVANCE Patient-centric outcomes that provide insight into the relative desirability and acceptability of the benefits and risks of MIGS devices are not well represented in current clinical studies.

Special Commentary: Food and Drug Administration and American Academy of Ophthalmology Sponsored: Developing Novel End Points for Premium Intraocular Lenses Workshop.

The pace of medical research and development, estimated at

Development of an 18-Item Measure of Symptom Burden in Patients With Glaucoma From the Collaborative Initial Glaucoma Treatment Study’s Symptom and Health Problem Checklist

85 billion in research and development by industry plus the National Institutes of Health in 2010 alone, has brought about significant breakthroughs in medical care in the United States. Yet, there has been widespread concern that this investment has not yielded novel product applications to the Food and Drug Administration (FDA) or the diffusion of innovative medical technologies into the marketplace. The factors slowing medical innovation and keeping devices from the hands of clinicians in this country are complex. The reasons range from the economic uncertainties and fluctuations in the past several years, the difficulties and complexities of the science governing product development, to the regulatory obligation to ensure the safety and efficacy of products reaching the marketplace. The environment for medical product development is complex, and multiple solutions and approaches are needed to improve the efficiency and throughput of the processes needed to bring products to fruition. The landscape of intraocular lens (IOL) product development is a prime example of this complex ecosystem. This is a burgeoning area of innovation, with many breakthrough designs to address the increasing need of patients with cataract to achieve clearer vision across a range of viewing distances without the aid of spectacles. These “premium” designs, which correct more than the spherical error at distance, include multifocal, accommodating, toric, and phakic IOLs. The first premium IOL was approved in 1997, and as of the March 28, 2014 workshop there were 3 multifocal, 1 accommodating, 4 toric, and 2 phakic IOLs approved in the United States. Approximately 14% of cataract patients receive premium IOL implants. Despite the recent increase in the number of premium IOL submissions to