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In our University journal club we discussed a large, retrospective study of cataract surgery endophthalmitis rates before and after instituting the use of an intracameral fluoroquinolone antibiotic. We identified several factors involved in the use of off-label, compounded moxifloxacin in intraocular surgery. The introduction of phacoemulsification for cataract surgery led to the potential for smaller incisions. Intraocular lens technology improved to allow for foldable lenses, obviating the requirement to enlarge the incision. This allowed for clear corneal incisions, which unfortunately allow bidirectional passage of liquid. Preservatives were introduced into multi-dose ophthalmic products in the mid 20th century to retard microbial growth. However, more recently, chronic use of benzalkonium chloride has led to concerns about concerns about conjunctival toxicity, especially in patients with ocular surface disease. In the formulation of ocular moxifloxacin, developers were able to develop a "self-preserved", multi-dose product. Other concerns with eyedrops include varying levels of adherence and performance, and the expansion of compounding pharmacies from a named-patient basis to widespread national delivery, with concerns for lower quality. Integrating these factors, use of intracameral moxifloxacin as a prophylactic during cataract and other anterior segment surgery has become a standard of care in much of the U.S. We are concerned that the current position is on a narrow ledge-the standard of care for millions of surgeries each year based upon off-label, compounting use of a single product. We discuss possible ramifications and solutions to this public health issue.

Introduction: Currently, the only modifiable risk factor to slow or halt the progression of glaucoma is the lowering of intraocular pressure (IOP). Netarsudil 0.02% is a new medication that was app...

Purpose To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Design Double-masked, randomized, multicenter, parallel-group, noninferiority clinical study. Methods After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata. Results On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients. Conclusions In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients.

The use of contact lenses as ocular drug delivery systems has been considered intuitive for decades. However, at this time, there are no approved products using such systems. In this article, we review the challenges with current therapies, pharmacokinetics, and pharmacodynamics of different drug classes and the patient population. In addition, we note the relative lack of clinical studies, and list potential products in active development at this time. In particular, we address the alignment of time course of the therapeutic need, the pharmacokinetics of the molecule, and the delivery characteristics of the systems (e.g., pulsatile vs. zero-order). We also discuss the needs of various populations including the elderly (who may have motor and cognitive issues as well as presbyopia) and the young. While a contact lens delivery system may also provide refractive correction, to date, most of the studies have used noncorrective (plano) lenses. We also considered nanotechnology-based carrier systems. We generalize the development of contact lens delivery systems to all ocular delivery systems in which there are relatively few product approvals and long development times.

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown. Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P

To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension.Double-masked, randomized noninferiority clinical trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2).After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 months from both studies are provided in this report.Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clinically and statistically significant reductions from baseline intraocular pressure (P.001), and was noninferior to timolol in the per-protocol population with maximum baseline IOP25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P.0001 for netarsudil vs timolol).In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications.

To discuss recent advances in the medical management of glaucoma and to highlight future medical therapies currently in development.In 1996, latanoprost (Xalatan) was approved in the United States as a new chemical entity and new class (prostaglandin analogs) for the topical treatment of ocular hypertension and glaucoma. In the period from the late 1990s-2010s, while there were additional new chemical entities, fixed dose combinations, and formulation improvements, there were no new classes of ocular hypotensive medications approved worldwide. We summarize new pharmacological treatments that are currently in clinical trials - new classes, new molecules and new delivery systems.Although challenges in medical treatment of glaucoma exist, particularly in patient adherence, medical therapy remains the first line treatment for almost all glaucoma patients. Few new medications for glaucoma therapy are currently available for our patients, but multiple drugs with novel mechanisms of action, new formulations, and new delivery mechanisms are currently in development.

The ideal biomarker would be a simple laboratory or clinical evaluation before treatment, which would predict subsequent therapeutic response. This might include selection of which patients might respond to that treatment. While other disciplines such as neurology and oncology have biomarkers, ophthalmology is limited to one-elevated intraocular pressure as a surrogate for progressive glaucomatous field loss. US law in 2016 required the Food and Drug Administration (FDA) to set up a system to qualify biomarkers. The system now exists-with most validated or pending biomarkers limited to safety and infection. The American Academy of Ophthalmology selected dry eye disease as one of three diseases in which to standardize outcomes in ophthalmology research. There have been a number of biomarkers proposed for evaluating ocular surface disease and its treatment. None currently meets the scientific or regulatory basis for being a valid biomarker-however, additional research may result in validity. Given the FDA's scientific basis, it is unlikely that an unproven biomarker could be used for regulatory approval, even for a "SubPart H" conditional new drug application. Elsewhere in ophthalmology, we know that even patients who share the same disease gene or mutation may differ substantially in penetrance and clinical expression. Thus, it is not unexpected that ocular surface disease, a heterogeneous disease with a variable presentation of signs and symptoms, has yet to have validated biomarkers that reach the level of evidence that allows their use for diagnosis, prognosis, therapy, and for making decisions in drug development.

To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night.This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29.We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively.In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity.NCT02057575.

Glaucoma is the second leading cause of blindness in the world and current pharmacotherapies for glaucoma have remained relatively unchanged (with the exception of fixed combinations of previously available medications) since the mid-1990s with the development of prostaglandin analogues. Now, with both new formulations and new classes of medications with novel mechanisms of action, the medical therapy of glaucoma may be heralding a new dawn in medical management. Areas covered: This review outlines new topical therapies for intraocular pressure (IOP) lowering treatment, in addition to new formulations, preservative-free options, and advances in glaucoma medical therapy delivery. We performed a comprehensive search for published studies for glaucoma medical therapy using the electronic database PubMed. A manual search for each therapy or delivery system was also performed. Expert commentary: These advances in glaucoma therapy have the potential to overcome many barriers to glaucoma's medical care, particularly in terms of adherence. However, both time and research are needed to prove the relative efficacy and safety of these new pharmacotherapies and products, helping us decide their role in the treatment of elevated intraocular pressure. We are hopeful that these new developments in therapy may bring more options for glaucoma medical therapy.

This study assessed the effect of mirabegron on ocular safety in healthy volunteers.This was an 8-week, randomized, double-masked, placebo-controlled study.Consenting adults aged ≥18 years with a normal intraocular pressure (IOP, ≥10 to ≤21 mmHg) were eligible to enter the study. Of the 321 randomized subjects, 305 completed the study. Subjects were randomized 1:1 to a supratherapeutic dose of oral mirabegron 100 mg or placebo once daily for 56 days. The IOP was measured at screening, baseline, day 10, and day 56/end of treatment using Goldmann applanation tonometry. Visual acuity and biomicroscopy were also evaluated. The primary endpoint was the mean change from baseline in the IOP at 56 days or end of treatment with mirabegron versus placebo. Secondary outcome variables included change from baseline to day 10 in the IOP, and increases in the IOP of ≥6 mmHg and ≥10 mmHg in either eye from baseline to day 10 and day 56.The mean (standard error, SE) IOP at baseline was 15.3 (0.16) mmHg for mirabegron and 15.4 (0.16) mmHg for placebo; values at day 56 were 15.0 (0.16) mmHg and 15.2 (0.17) mmHg, respectively. The adjusted mean IOP change from baseline to day 56 was -0.3 mmHg for mirabegron and -0.2 mmHg for placebo (-0.1 mmHg difference [95% confidence interval, CI, -0.4 to 0.3]). For the primary endpoint, mirabegron was noninferior to placebo, based on the prespecified limit of 1.5 mmHg. No statistically significant treatment effects on the IOP were seen at day 10. No subject discontinued due to increased IOP. Clinically significant increases from baseline in the IOP occurred rarely and only with placebo treatment. Changes in the visual acuity and biomicroscopy were not suggestive of a mirabegron effect. No treatment-emergent adverse event (AE) of glaucoma was reported.Mirabegron 100 mg orally once daily for 8 weeks of treatment does not increase the IOP, and was generally safe and well tolerated.

Background and Objective: To evaluate the relationship between preoperative visual field severity and postoperative intraocular pressure as risk factors for visual field progression. Patients and Methods: Patients undergoing trabeculectomy (TRAB, n = 92 eyes of 73 patients) or combined trabeculectomy and cataract extraction by phacoemulsification (COMBO, n = 49 eyes of 41 patients) by one surgeon with at least 6 months of follow-up were reviewed. Results: Both the COMBO and TRAB treatment groups experienced a substantial decrease in mean intraocular pressure (4.7 ± 6.0 and 10.1 ± 6.5 mm Hg) and mean number of ocular hypotensive medications (1.8 ± 1.2 and 2.2 ± 1.5), respectively. In the subset of 47 eyes with reliable visual fields, the COMBO group experienced a mean improvement in mean deviation of 2.75 dB, and the TRAB group experienced only minimal changes in visual fields. Conclusion: In general, visual fields did not worsen following trabeculectomy or combined surgery.

©2010 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack G. Treatment adherence in ophthalmology and astrophysics. 2010;8(2):91-95. hrough my work with the University of California, Santa Cruz Foundation, I recently visited the W. M. Keck Observatory. Situated on the summit of 13,796 foot Mauna Kea on the island of Hawaii are the world’s largest optical and infrared telescopes. The twin telescopes’ primary mirrors are 10 meters in diameter and are each composed of 36 hexagonal segments that work in concert as a single piece of reflective glass (http://www.keckobservatory. org/, Figures 1A and 1B). My visit to this amazing research facility put me in a mindset of astrophysics. One key concept in astrophysics is “dark matter.” The concept was conceived to deal with the difference between the matter that can be observed through its electromagnetic radiation (eg, light and other emissions) and the matter whose presence can be inferred from its gravitation effects. Dark matter may make up a predominant proportion of the matter in the universe. Another astrophysical concept is that in star formation, as the proto-planetary system accretes material from the accretion disk, there are outgoing jets of material.1 Each of these concepts, in turn, got me thinking about the inefficiency of pharmacotherapy in ophthalmology. There are major gaps between the doctor’s prescription and the patient’s compliance and performance. Doctors prescribe medications, and patients are expected to get the prescriptions filled and to take the medications as prescribed. The issue of treatment adherence in ophthalmology has been studied for several decades and was the topic of a recent editorial.2 In the 1970s, Glover, Urquhart, and colleagues developed electronic devices that recorded the opening and inversion of a bottle cap.3 Kass and colleagues used these devices to track how patients with glaucoma used q.i.d. pilocarpine and b.i.d. timolol.4-6 They found that patients used 76% and 83% of prescribed doses, respectively. Norell developed a plastic box with a holder for a 25-mL medicine bottle, with an elastic flap that recorded when the bottle was removed. Approximately 78% of patients met the criterion for adequate use of t.i.d. pilocarpine (dosing at an interval of 8 hours or less).7 Another study by the same group found that only 59% of patients met the compliance criterion (missing 5 doses or less over 20 days).8 Using a more advanced, commercial version of a monitor that records bottle openings (MEMS, AARDEX, Union City, CA), researchers found ~79%-90% of doses taken for b.i.d. pirenzepine in myopic children,9,10 and 97% for q.d. prostaglandins in patients with glaucoma.11 Also developed was a product-specific device that records an event when the patient pushes a lever (Travalert® Dosing Aid for q.d. travoprost, Alcon, Fort Worth, TX). Reports are that approximately 70%-80% of prescribed doses were used,12,13 although this device has some technological problems.14 For chronic therapy, review of pharmacy records provides a measure of treatment adherence. One assumes that, on average, a patient should use a one-month supply of medication per month and renew the prescription on that basis. Any decrease from this theoretical rate would reflect underdosing and, thus, inadequate treatment compliance. These studies are analogous to “pill counts” (counting how many T

5601. 2008 17. Bhavsar AR, Ip MS, Glassman AR. The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007;144:454-6 18. Parrish R, Sternberg P, Jr. Does “offlabel” mean off limits for patient care? Am J Ophthalmol 2007;143:853-5 19. Novack GD. Pipeline: Risks and benefits. Ocul Surf 2006;4:58-60 NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES Ophthalmic Products Related to the

Age-related macular degeneration (AMD) is a progressive, degenerative disease of the macula that threatens central vision. It initially occurs in a “dry” form, and can progress to choroidal neovascularization (CNV) or geographic atrophy. It is the leading cause of blindness among European-descended people older than 65 years, with a prevalence of 1.5%. The treatment of CNV in developed nations in 2007 is substantially different than it was in 1997. Focal, photocoagulating, laser therapy was replaced by intravenous verteporfin and then by intravitreal pegaptanib, which is now being replaced by intravitreal ranibizumab and off-label use of bevacizumab. Other than a ranibizumab versus verteporfin trial, there are no published comparative studies of the three approved pharmacological treatments for CNV. Although frequent intravitreal injections are accepted as a current standard of care, their use is still far from ideal. Thus, there is an opportunity for improving therapy of CNV with respect to mechanism-targeted treatments, efficacy, and route of administration.

©2007 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack G. Notification vs approval. 2007;5(3):255-258. hen a pharmaceutical firm wants to begin evaluating their compound in humans in the US, they are required to file an Investigational New Drug (IND) Application (21 CFR 312.1) with the US Food and Drug Administration (FDA). The IND is technically a request for an exemption from US law prohibiting interstate shipment of investigational drugs and assurance that the FDA will not stop (does not reject as unsafe) the initial clinical trial described in the IND. The sponsoring firm provides information on the preclinical biology of the compound (pharmacodynamics, pharmacokinetics, and toxicology), pharmaceutics and manufacturing, and the planned clinical study. Also included is the name and qualifications of the proposed clinical investigator(s). The application must have sufficient safety information at exaggerated doses to allow estimation of the potential benefit-risk ratio. The application is submitted using FDA Form 1571 (http://www.fda.gov/opacom/morechoices/fdaforms). The content of an IND is detailed in 21 CFR 312.23. An interesting, and I believe unique, aspect of the US IND process is that this is a notification (ie, unless we hear from you in 30 days, we will start our clinical study) rather than an approval (ie, we will start the studies after you authorize it; 21 CFR 312.40). This is the difference between the teenager saying “I’m taking the car, bye” and “May I take the car?” With respect to medical devices, the situation has some parallels and some differences from pharmaceuticals. Sponsoring firms wishing to evaluate an investigational medical device in humans in the U.S. must submit an investigational device exemption (IDE), which includes manufacturing and preclinical information on the device. There is also a 30-day review period from the FDA. However, in this case, the sponsor must wait for written approval from the FDA (21 CFR 812.42). Thus, the device review system is an approval, not a notification. There are other categories where only a notification, rather than a prior approval, is required by the FDA. These apply to changes to the formulation or manufacturing process for an approved drug. For some “moderate changes,” the manufacturer may identify these issues as either “Changes Being Effected in 30 Days” (21 CFR 314.70(c)(3)) or “Changes Being Effected” (21 CFR 314.70(c)(7)). In the first case, the FDA has 30 days to contact the sponsor to disallow the change. In the second case, if the FDA disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug product made with the manufacturing change. For some “minor changes,” the manufacturer may make the change and notify the FDA in its next annual report (21 CRF 314.70). Going back to the IND process, as a resident of California, a geographically large state with pharmaceutical manufacturing facilities and experienced clinical investigators, what if I don’t want to technically ship the investigational drug across state lines? Do I still have to file an IND with the FDA? The answer is yes — the California equivalent of the FDA, the Food and Drug Branch (www.dhs.ca.gov/fdb/) will defer an applicant to the federal process. Also of note is that the firm does not have to show that the compound is effective in animal models (eg, this compound cures keratoconjunctivitis in animals), but rather to provide a rationale for the planned human investigation (eg, this compound releases mucin from the conjunctiva, and release of mucin may improve keratoconjunctivitis sicca). Thus, at least for the US, the FDA does not “approve” INDs — they just don’t reject them. In general, the situation is similar in developed nations around the world with respect to the need for application to the regulatory authorities in order to conduct human studies of investigational pharmaceuticals.

Ophthalmic diseases include both those analogous to systemic diseases (eg, inflammation, infection, neuronal degeneration) and not analogous (eg, cataract, myopia). Many anterior segment diseases are treated pharmacologically through eye drops, which have an implied therapeutic index of local therapy. Unlike oral dosage forms administered for systemic diseases, eyedrops require patients not only to adhere to treatment, but to be able to accurately perform-ie, instill drops correctly. Anatomical and physiological barriers make topical delivery to the anterior chamber challenging-in some cases more challenging than absorption through the skin, nasal passages, or gut. Treatment of the posterior segment (eg, vitreous, retina, choroid, and optic nerve) is more challenging due to additional barriers. Recently, intravitreal injections have become a standard of care with biologics for the treatment of macular degeneration and other diseases. Although the eye has esterases, hydroxylases, and transporters, it has relatively little CYP450 enzymes. Because it is challenging to obtain drug concentrations at the target site, ocular clinical pharmacokinetics, and thus pharmacokinetic-pharmacodynamic interactions, are rarely available. Ophthalmic pharmaceuticals require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Although applied locally, ocular medications may be absorbed systemically, which results in morbidity and mortality (eg, systemic hypotension, bronchospasm, and bradycardia).

Glaucoma is a chronic progressive optic neuropathy that is characterized by optic nerve changes and visual field loss. Elevated intraocular pressure (IOP) is the main modifiable risk factor. Chronic instillation of daily eyedrops to lower IOP is the primary treatment of choice, although it requires patient adherence and correct performance. We have developed a nanoliposome drug delivery system for the longer term delivery of latanoprost. In the present open-label, pilot study, the safety and efficacy of a single subconjunctival injection of liposomal latanoprost was evaluated in six subjects with a diagnosis of either ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Subconjunctival injection of liposomal latanoprost was well tolerated by all six subjects. From a baseline IOP of 27.55 ± 3.25 mmHg, the mean IOP decreased within 1 h to 14.52 ± 3.31 mmHg (range 10-18 mmHg). This represented a mean decrease of 13.03 ± 2.88 mmHg (range 9-17 mmHg), or 47.43 ± 10.05 % (range 37-63 %). A clinically and statistically significant IOP reduction (≥20 % IOP reduction, P = 0.001 to 0.049) was observed through 3 months after injection. The nanomedicine reported here is the first nanocarrier formulation that has an extended duration of action in humans, beyond a couple of weeks. The findings in this study open up a new treatment modality, which will greatly enhance patient compliance and improve treatment outcomes. The current study provides the evidence and support for further clinical studies of liposomal latanoprost in the treatment of glaucoma.

A new formulation of timolol with sorbic acid, timolol-LA (TLA) (Istaloldagger), has been developed which increases its ocular bioavailability. In the present study, we desired to evaluate the ocular comfort and systemic bioavailability of TLA in healthy volunteers in comparison to standard timolol maleate ophthalmic solution (TIM).This study was a randomized, double-masked, active-controlled, crossover evaluation of 0.5% TLA and 0.5% TIM, bid, in 12 normal healthy volunteers. Visits were at Days 0, 1, 2, 4 and 8 in each period, and there was a minimum 7 day interperiod washout.At all three post-dosing evaluation times (Day 1: Peak, Day 8: Trough, and Day 8: Peak), the 95% confidence interval for the difference between TLA and TIM was not more than 0.37 ng/mL. After administration of TLA, there was a greater incidence of burning/stinging and tearing, but not foreign body sensation, relative to TIM. In general, most symptoms were mild in intensity, and no subject discontinued treatment due to ocular discomfort. Both treatments decreased IOP to a similar level.TLA was relatively comfortable, with a safety profile consistent with further clinical development, and, with bid dosing (exaggerated [2X] that anticipated for clinical use), had a systemic bioavailability similar to that of TIM 0.5%, bid. The incidence of burning and stinging was higher with TLA than with TIM, although reports were mild in severity and did not result in any patient discontin uations. Although the results are of interest, further evaluation in a larger trial may be warranted.

Background: Timolol maleate, a nonselective β-adrenoceptor antagonist applied topically to the eye as a solution, is well known for its ocular hypotensive efficacy. A gellan formulation of timolol maleate is given once daily and has been shown to be as effective as timolol maleate solution, but is associated with ocular symptoms that may limit its utility. A new timolol maleate solution has been formulated that contains potassium sorbate (timolol-LA [TLA; Istalol®]) to enhance the ocular bioavailability of timolol instilled into the eye, as well as half the benzalkonium chloride preservative found in timolol maleate. Objective: The objective of this trial was to assess the ocular hypotensive efficacy and safety profile of TLA 0.5% solution once daily with those of timolol maleate ophthalmic solution (TIM) 0.5% twice daily in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: This multicenter, prospective, randomized, double-masked, parallel-group clinical trial was conducted at 21 participating private practices across the United States. Patients aged ≥18 years with OAG or OHT in 1 or both eyes and an unmedicated intraocular pressure (IOP) of ≥22 mm Hg were randomized to receive either TLA once daily or TIM twice daily bilaterally for 12 months. The primary outcome measure was IOP (95% CIs) on treatment difference at each visit (ie, equivalence analysis). The safety profile was assessed based on biomicroscopic and ophthalmoscopic examination and patient symptoms. Results: A total of 332 patients (203 women, 129 men; mean [SEM] age, 64.6 [11.8] years [range, 29–92 years]) entered the study. Of these, 290 patients (87.3%) completed it. At none of the visits did the 95% CIs for between-treatment comparisons exceed 1.5 mm Hg and, at most of the visits, these intervals did not exceed 1.0 mm Hg. Mean baseline IOP was ∼25 mm Hg in both groups. IOP was reduced at all posttreatment visits to 18 to 19 mm Hg at peak and to ∼19 to 20 mm Hg at trough drug level in both treatment groups. Mean reductions from baseline were 6 to 7 mm Hg at peak and 5 to 6 mm Hg at trough (25.5%–28.7% and 20.8%–24.7%, respectively). Seventeen patients (5.1%) withdrew due to adverse events (AEs) (10 patients [6.0%] and 7 patients [4.2%] in the TLA and TIM groups, respectively). Based on biomicroscopic and ophthalmoscopic examination and volunteered symptoms, the safety profile was similar between the 2 treatments, except for burning and stinging on instillation, with an incidence of 41.6% in the TLA group and 22.9% in the TIM group ( P = 0.001). Nearly all cases of burning and stinging were mild (94.2% [65 events] with TLA and 90.0% [36 events] with TIM), and none of the patients discontinued treatment due to this AE. Conclusions: TLA solution, a nonselective β-adrenoceptor antagonist, given once daily in the morning, was found to be statistically equivalent in ocular hypotensive efficacy (as defined a priori) compared with TIM, given twice daily, and with an acceptable safety profile in this study population of adult patients.

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.

Purpose To determine the long-term efficacy and safety of noncontact transscleral neodymium:yttrium–aluminum–garnet (Nd:YAG) cyclophotocoagulation (CP) for the treatment of neovascular glaucoma (NVG). Design Retrospective, noncomparative, interventional case series. Participants One hundred fifteen eyes of 111 subjects treated from December 1987 to January 2001. Methods Eyes with uncontrolled NVG underwent noncontact Nd:YAG CP. Treatment parameters and pretreatment and posttreatment intraocular pressures (IOP) were reviewed. Preoperative and postoperative IOP were compared using a paired Student's t test. Success was defined as an IOP ≤22 mmHg, with or without medications, in the absence of phthisis bulbi, and without having undergone further surgical procedures. Results were subjected to a Kaplan–Meier life-table analysis. Results Mean follow-up was 27.0 ± 34.3 months (range, 1–148 months). Mean preoperative IOP was 47.4 ± 11.1 mmHg (range, 26–70 mmHg). Mean postoperative IOP was 18.3 ± 12.2 mmHg (range, 0–44 mmHg). The mean number of treatment sessions was 1.4 ± 0.7 (range, 1–6), with 82 eyes (71.3%) having only one treatment. Kaplan–Meier survival analysis showed a probability of continued success at 1 year of 65.0%, at 3 years of 49.8%, and at 6 years of 34.8%. Phthisis developed in 8.6% of the eyes. Conclusions Noncontact Nd:YAG CP provides long-term IOP reduction in eyes with medically uncontrolled NVG. This can be associated with complications that include inflammation, visual loss, and hypotony. Repeat treatment may be necessary.

Purpose To report the efficacy and safety of transconjunctival mitomycin-C as an adjunct to needle revision of failing filtering blebs. Design Retrospective, consecutive, noncomparative interventional case series. Participants Forty-one patients (42 eyes) undergoing bleb revisions by a single surgeon at a single institution from May 1997 to January 2001. Methods The authors retrospectively reviewed charts of 42 eyes that underwent needle revision of the failing filtering bleb using transconjunctival application of mitomycin-C. Needling of the bleb was performed with a 25-gauge needle. The site of the needle puncture was sutured and followed by application of transconjunctival mitomycin-C (0.5 mg/ml) by means of a sponge left in contact with the conjunctival epithelium for 6 minutes. A group of patients received additional subconjunctival injections of 5-fluorouracil in the postoperative period. Success was defined as a reduction in intraocular pressure of 30% without the use of antiglaucoma medications and no further surgical procedures to control intraocular pressure. Main outcome measures Intraocular pressure, visual acuity, complications, number of glaucoma medications used at the final visit. Results Mean preoperative intraocular pressure was 22.1 ± 8.0 mmHg, which was reduced by 9.6 ± 7.9 mmHg to a mean postoperative intraocular pressure of 12.5 ± 6.1 mmHg. Mean follow-up was 17.6 ± 13.5 months. Kaplan-Meier survival analysis showed a probability of continued success at 12 months of 76.1%, and at 24 months of 71.6%. The most common complication was hyphema in 7.1% of patients. Twenty-six eyes also received postoperative injections of 5-fluorouracil. Conclusions Transconjunctival mitomycin-C may enhance success of the needling procedure in failing filtering blebs.

Glaucoma can be considered a disease of the aging eye. Most medications used to treat glaucoma are in topical eyedrop form and may cause numerous untoward systemic effects in older persons. In recent years, several new ocular hypotensive medications have become available. These medications are being used more commonly because there is a growing trend by ophthalmologists to aggressively lower intraocular pressure. Therefore, geriatricians require a comprehensive knowledge of medications used to treat glaucoma, in addition to an understanding of their mechanism of action profiles of untoward effects and possible interactions with other diseases or medications. Therefore, we performed a review of the medications recently introduced into clinical practice. We selected drugs approved by the U.S. Food and Drug Administration between 1996 and September 2001. The safety profiles of these agents and their untoward side effects were reviewed by class: topical carbonic anhydrase inhibitors (brinzolamide: ocular tolerance, taste perversion), β-adrenoceptor antagonists (timolol: bradycardia and bronchospasm), α-adrenergic agonists (brimonidine: oral dryness, headache, and fatigue), and prostaglandin analogs (latanoprost, bimatoprost, travoprost, and unoprostone isopropyl: ocular hyperemia, iris color changes). The function of this review is to make geriatricians more aware of the efficacy and untoward effects of medications recently introduced into clinical practice. We recommend that geriatricians perform a medication review on all medications their patients use, including eye drops.

f you ask people familiar with I clinical research or drug development about the phases of clinical research, they will readily recite the following: Phase 1 studies are safety and pharmacokinetic studies in normal volunteers; Phase 2 are pilot safety and efficacy studies in patients; Phase 3 are pivotal safety and efficacy studies in patients; and Phase 4 are post-approval studies. This simple categorical system is evidenced in the U.S. Food & Drug Administration (FDA) Form 1571 for an Investigational New Drug (IND) application and amendments. Section 8 asks to list “Phase(s) of clinical investigation to be conducted.” There are boxes for Phase 1, 2, 3, or “other.” However, in 1997, the International Conference on Harmonisation, a consortium of drug developers and regulatory scientists from Japan, Europe, and North America, took the following position in the E8 “General Considerations for Clinical Trials” guidance: “It is important to recognize that the phase of development provides an inadequate basis for classification of clinical trials because one type of trial may occur in several phases (Figure 1). It is important to appreciate that the phase concept is a description, not a set of requirements. It is also important to realize that the temporal phases do not imply a fixed order of

AR-13324 is a small-molecule inhibitor of Rho kinase and a norepinephrine transporter. The objective of this 28-day study was to evaluate the ocular hypotensive efficacy and safety of AR-13324 ophthalmic solution compared with a positive control, latanoprost ophthalmic solution, in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).Double-masked, randomized study in 22 private practice ophthalmology clinics.Participants were required to be adults with a diagnosis of OAG or OHT with unmedicated intraocular pressure (IOP) in the range of 22 to 36 mmHg.Patients were randomized to receive AR-13324 ophthalmic solution 0.01%, daily (pm), AR-13324 ophthalmic solution 0.02% daily (pm), or latanoprost 0.005% daily (pm) for 28 days.The primary efficacy endpoint was the mean diurnal IOP across subjects within the treatment group at day 28.Randomized and treated were 224 patients, 213 (95.1%) of whom completed the study. On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mmHg in the AR-13324 0.01%, 0.02%, and latanoprost groups, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mmHg (P0.001). The 5.7-mmHg reduction in IOP by AR-13324 0.02% did not meet the criterion for noninferiority to latanoprost. The most frequently reported adverse event was conjunctival/ocular hyperemia, with a combined incidence of 52%, 57%, and 16%, respectively. On day 28 at 08:00 hours, the incidence of mild to moderate hyperemia by biomicroscopy was 18%, 24%, and 11%, respectively.AR-13324 0.02% was less effective than latanoprost by approximately 1 mmHg in patients with unmedicated IOPs of 22 to 35 mmHg. The major safety finding was ocular hyperemia, which was more common for both concentrations of AR-13324 than for latanoprost.

The purpose of this study was to evaluate the ocular safety and tolerability of the P2Y(2) receptor agonist, INS365, when applied as eye drops in normal human subjects. This study was a double-masked, placebo-controlled, randomized, within subject paired-comparison, dose-escalation study in five cohorts of ten healthy subjects. The concentrations of INS365 ophthalmic solution were 0.5, 1.0, 2.0, and 5.0% given three times over six hours. Safety was assessed by general and ophthalmic examination and symptomatology. Unanesthetized Schirmer tests were performed in the last cohort of 10 subjects to evaluate the acute effects of INS365 on tear secretion. There were no significant differences in the number of subjects with ocular events reported in placebo-treated eyes compared to INS365-treated eyes. Two adverse events were possibly related to INS365: painless blepharospasm and an increase in lacrimation after 5.0% INS365 instillation. Unanesthetized Schirmer testing showed no acute effects of INS365 on tear secretion, compared to its vehicle, in healthy subjects, in which reflex tearing often produced maximal Schirmer values. INS365 ophthalmic solution was well-tolerated when administered by ocular instillation. Stimulation of ocular surface P2Y(2) receptors was not associated with ocular tolerability issues in healthy subjects.

©2009 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack GD, Crockett RS. Regression to the mean. 2009;7(3):163-165. W e are frequently involved in evaluating studies of new ophthalmology agents. The efficacy of some treatments can be measured in mm Hg with a tonometer or by letters on an eye chart. In ocular surface disease, it can be demonstrated by mm of wetting of a Schirmer strip. However, frequently, efficacy is measured with use of categorical scales for signs or symptoms rated by clinical investigators or patients. The variability of the disease and the variability of these categorical scales can produce variability in results.1 In vehicle-controlled studies, where one seeks to find a difference in favor of the new agent, variability is the enemy. However, another frequently heard enemy is “regression to the mean.” In group meetings when this term is used, heads nod in apparent agreement — but what does this really mean, and how do you minimize such a confounding effect? Regression toward the mean, in statistics, is the phenomenon whereby members of a population with extreme values on a given measure for one observation will, for purely statistical reasons, probably give less extreme measurements on other occasions when they are observed. To illustrate this point, we provide data gathered from a nonophthalmic source. One of the authors (GDN) is a bicycle rider, and among his routes is a 22.5-mile road ride with approximately 1100 feet of climbing. It is a circle course, so the net effect of wind is assumed to be zero. Shown in Figure 1 is the distribution of elapsed time for 78 rides in 2007 and 2008. The mean time was 86 minutes, with a standard deviation of 3 minutes. You can see there were some really fast rides (80 minutes is the best [Figure 2]) and some slow ones (95 minutes is the worst). At 84 minutes, the mode, the most frequent time, was slightly faster than the mean, with the median 86 minutes. In statistical terms, this distribution is relatively “normal” — ie, a bell-shaped curve. Now imagine you are designing a study of the impact of new bicycle wheels on cyclists’ performance. You would want to have a rider who was slow enough that there was a potential for improvement. So, assume you select a ride time of 90 minutes or slower for entry. Assuming that the experience of one rider is descriptive of the “patient” population, that would be met 9% of the time. You could give the riders the new wheels and then observe their ride times. If the ride time decreased, you could conclude that the wheels resulted in improved performance. However, another interpretation is that the rider just “regressed to the mean” — ie, irrespective of the new wheels, the rider just performed closer to the average time of 86 minutes. What other tools are available to the trial designer to minimize confounding interpretations of this experiment? You could select a ride time of 87 minutes or less. This would be met 40% of the time, and since it is near the mean, “regression to the mean” is less likely. However, it challenges an initial assumption — a fast rider may not have as much potential for improvement (ie, a floor effect). You could require that riders qualify not on 20

To evaluate the ocular hypotensive efficacy, ocular and systemic safety, and systemic exposure of two formulations of 0.5% AR-12286 Ophthalmic Solution.This was a double-masked, single-centre, crossover study in 18 normal adult volunteers. Volunteers were randomised to one of two dosing sequences: Formulation A once daily, both eyes (OU) for 8 days, a 7-day minimum washout, and then Formulation B, or the reverse. The main outcome measures were ocular tolerability, intraocular pressure (IOP) and blood levels of AR-12286 and its metabolites.Systemic absorption was low, with a majority of subjects showing no measurable drug concentration in plasma (1 ng/ml) at any time point with either formulation. The most frequent ocular adverse events were conjunctival hyperaemia, eye irritation, instillation site reaction, increased lacrimation, and blurred vision which were relatively short-lived and judged as not clinically significant. Both formulations of AR-12286 produced substantial reductions from baseline IOP ranging from 3 to 7 mm Hg (p0.0001).No differences were noted in ocular safety between formulations of AR-12286 0.5%, dosed once daily in the morning for 8 days. AR-12286 produced little systemic exposure to the parent compound or two known metabolites. Clinically and statistically significant reductions in IOP were seen in these normotensive subjects.

56 s physicians and surgeons, ophthalmologists use both drugs and medical devices to treat their patients. While the ophthalmologist and the patient integrate these two approaches, the invention, development, and regulatory approval of drugs and devices are very different. As a scientist working with both drugs and medical devices, I am reminded of the comedy routine of the late George Carlin, in which he compares baseball and football. For example, “Baseball is played on a diamond, in a park, while football is played on a gridiron, in a stadium” and “Baseball begins in the spring, the season of new life. Football begins in the fall, when everything’s dying.” 1 As previously described in this column, the major U.S. regulatory laws governing pharmaceuticals are the Pure Food and Drug Act (1903 and 1906, addressing the purity of vaccines and drugs); Federal Food, Drug and Cosmetic Act (1938, addressing safety); Kefauver-Harris amendment (1962, addressing safety and effectiveness); Drug Price Competition and Patent Term Restoration Act (1984, Hatch-Waxman Act, which provides patent extension for innovators, but made it easier for generic drugs to gain approval after patent expiry); and the Prescription Drug User Fee Act (PDUFA, 1992, which requires pharmaceutical firms to pay a fee to the The Development of Drugs vs Devices

Background: To surgically treat patients with macular holes, the authors previously reported both anatomic (re-attachment) and visual success (2 lines of improvement) in a series of 52 eyes. They now have operated on an additional 118 eyes using similar techniques, for a total of 170 eyes. Methods: After ophthalmologic examination and history, the authors operated on suitable patients. The surgical objectives included relief of all tangential traction and retinal tamponade with intraocular gas. All eyes were followed for at least 6 months postoperatively. Results: In the total population of 170 eyes, anatomic success was achieved in 73% and vision improved at least two lines in 55%. Twenty-nine percent (49/170) of patients had a visual acuity of 20/40 or better at last examination. Patients with symptoms of less than 6 months' duration managed better than those with symptoms of longer duration ( P = 0.3001). In the former group of 66 eyes, anatomic success was achieved in 80% (n = 53), whereas visual acuity improved at least two lines in 68% (n = 45) and at least four lines in 55% (n = 36). Conclusions: The authors suggest that macular hole surgery may provide meaningful improvement in visual acuity in most patients, especially in those whose symptoms are of less than 6 months' duration.

Objectives: To evaluate the performance of patients with ocular hypertension and glaucoma who are experienced in the instillation of topical ocular hypotensive medications. Methods: We conducted a prospective, open-label study at a single private practice site. We enrolled 139 patients with a diagnosis of glaucoma or ocular hypertension who used 1 or more topical ocular hypotensive medications for at least 6 months and who instilled their own medications. Patients were questioned regarding their use of topical ocular hypotensive medications, and we used a video recording to evaluate patient performance of eyedrop instillation with 2 bottle designs. Results: Patients reported relatively good performance on eyedrop instillation. One hundred twenty-nine of 139 patients (92.8%) reported no problem putting in their eyedrops, and 86 of 139 (61.9%) believed that they never missed their eye when administering the drops. The proportions of patients who were able to instill a single drop into the eye without touching the bottle to the eye were 14 of 64 (21.9%) with a 15-mL bottle and 36 of 117 (30.8%) with a 2.5-mL bottle. Conclusions: Under a single direct observation, patients experienced in the use of topical ocular hypotensive agents performed relatively poorly when instilling a single eyedrop into the eye without touching the bottle tip to the eye or the ocular adnexae. Trial Registration: clinicaltrials.gov Identifier: NCT00522600