Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles.

PURPOSE: To identify current challenges facing ophthalmic pharmaceutical start-ups in developing new products. METHODS: Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. RESULTS: The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. CONCLUSION: The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs.

What data sources do ophthalmologists trust?

To survey ophthalmologists regarding sources they trust when incorporating new medical knowledge into their practice. The survey was distributed primarily to US-based ophthalmologists. Questions were derived based on the lead author's research experience from congresses and discussions and from mentions in the medical literature. In total, 77 physicians completed the survey of 1886 sent (4% response rate). Regarding study design, physicians preferred a well-controlled, randomised, double-masked trial (99%) with multicentred investigational site across a wide geographical area (80%). Authorship of a research article was most desired from a well-known key opinion leader (KOL) (75%) or any KOL leader at a university (75%). The most selected journal type was a subspecialty publication (86%) and second a multispecialty high impact journal (77%). Study sponsorship was most desired from the NIH or other government agencies (71%) or a university (71%). Doctors preferred clinical opinions from an ophthalmic medical society (75%). For the source of new clinical data, physicians indicated an unsponsored peer-reviewed journal article (77%) or a lecture at a large ophthalmic congress (74%) as the preferred source. Ophthalmologists generally desire sponsors, study designs and opinions that appear free of bias on which to base their clinical practice decisions.

The Source and Impact of Specific Parameters that Enhance Well-Being in Daily Life.

The purpose of this study was to review four parameters (forgiveness, gratitude, hope and empathy) frequently noted when evaluating well-being. We reviewed clinical studies from 1966 to present. We included 63 articles. All four of the parameters were shown to generally improve an individual's well-being. These parameters demonstrated a positive influence within more specific societal issues including improvement in social relationships, delinquent behavior and physical health. These parameters were generally derived from training and religion. This study suggests that these parameters may improve either one of general well-being, pro-social and positive relational behavior and demonstrate positive health effects.

A neuropsychological comparison of siblings with neurological versus hepatic symptoms of Wilson's Disease.

Wilson's Disease (WD) (also known as hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of abnormal copper metabolism, with an estimated prevalence of approximately 1 in 30,000. The clinical features associated with WD are highly varied. However, subtypes generally reflect neurological, hepatic, and psychiatric symptoms. The present case study reports two brothers with a recent diagnosis of WD. Neurological symptoms and cognitive deficits were exhibited in one brother (BL) in the form of extrapyramidal features, while the other brother (AL) only exhibited hepatic symptoms. Extensive neuropsychological testing was conducted on both siblings to compare cognitive profiles. Results for BL indicated significantly impaired motor functioning and information processing speed, which impacted him significantly at school. Aspects of executive dysfunction were also apparent in addition to reduced visual and verbal memory, working memory, and attention. Results for AL revealed evidence of verbal memory difficulties and aspects of executive dysfunction. Comparison is made of the distinct and common cognitive characteristics of the cases presented in terms of implications for early intervention and management of cognitive difficulties.

Description of Ophthalmic Pharmaceutical and Device Start-Up Companies.

AIMS: To describe the number, type and location of ophthalmic companies and their associated product areas and indications. METHODS: A retrospective, non-patient-based, observational review of ophthalmic pharmaceutical and device companies with a new product in development. Data was compiled by Internet searches. RESULTS: We identified 190 companies currently developing ophthalmic products: 134 (71%) were privately held and 56 (29%) publicly held, while 136 (72%) were in the United States and 53 (28%) were outside the United States. There were 436 total products of which 338 (78%) were pharmaceuticals and 98 (22%) devices. With pharmaceuticals we identified 46 separate indications with age-related macular degeneration (n = 75), glaucoma (n = 52) and dry eye (n = 46) as most common; anti-vascular endothelial growth factor, hormone therapy and anti-inflammatory products were also common classes. With devices there were 30 indications with glaucoma (n = 26), age-related macular degeneration (n = 19) and dry eye (n = 6) as most common; drug delivery, ocular implants and prostheses were less common classes. CONCLUSIONS: Ophthalmology as a specialty is benefited by a wide effort in new medicine and device development. However, a concentration of effort into relatively few indications suggests a potential lack of market analysis and possible difficulty for many companies in commercializing their product.

Techniques to Reduce the Placebo Effect in Glaucoma Clinical Trials.

AIM: To evaluate techniques used to reduce the placebo effect in prior well-controlled, single or double-masked placebo-controlled glaucoma trials. METHODS: This study was a retrospective, non-patient-based, observational review of phase I-III trials with a placebo arm for glaucoma medicines available after 1977. RESULTS: This study included 20 articles with 20 placebo control arms consisting of 458 patients evaluating 10 different glaucoma medications with 58 treatment arms. There was no statistical difference across the evaluated types of study designs to limit the placebo effect either for the morning trough or diurnal curve. The average reduction of the intraocular pressure in the placebo groups was 1.6 ± 1.5 mm Hg for the morning trough and 1.3 ± 1.3 mm Hg for the diurnal curve across all studies. CONCLUSION: The results of this study suggest that current design techniques described in the literature to limit the placebo effect appear ineffective compared to no additional techniques.

Fitness to stand trial, human rights and possibilities from England and Wales.

The capacity of individuals with disability, including cognitive or mental health impairments, to access justice on an equal basis has been considered recently in several Australian jurisdictions. Impairments can render individuals vulnerable in the legal system, affecting their reliability as a witness or their fitness to be tried, especially when limited support is available to help these individuals meet the test and criteria for fitness to stand trial. This article considers the situation in Australia in light of human rights perspectives and compares it with the England and Wales approach where special support measures have been introduced to help individuals access justice. The article recommends that better support measures be introduced in Australia that would be consistent with a human rights framework calling for support to enable individuals with disability to access justice. In particular, the introduction of intermediaries, as used in England and Wales, would go some way towards helping vulnerable individuals to access justice.

Association of strength of community service to personal wellbeing.

To assess the impact of community service on personal wellbeing in a mid-west church-based population. A prospective survey evaluating: self-reported community service, the perceived benefit of the service and its association to personal wellbeing. 309 participants were included of whom 92 % were employed full or part time, homemakers or students. Those who served in some capacity had better scores on five Wellbeing questions including: contentment, peace, joy, purpose and community acceptance (P < 0.02), but not better self-perceived mental or physical health (P > 0.05). People who served had a better combined Wellbeing score than those who could not serve (P = 0.03). A higher number of hours served/week was associated with better Global Wellbeing (P = 0.02). The greatest perceived benefit of service was related to enhancing wellbeing of others and the service organization itself (P < 0.0001). Church going adults, who are serving in some capacity in their church or community, may demonstrate heightened personal wellbeing compared to those who are not assisting others.

Average versus highest intraocular pressure analyses in glaucoma clinical trials.

PURPOSE: To evaluate methods which account for both eyes as a single, independent variable in glaucoma clinical trials. METHODS: A review of clinical trial articles published between January 1995 and April 2011 evaluating currently used topical glaucoma medications. RESULTS: This analysis included 17 articles with 36 treatment arms of which 14 were prostaglandins, 13 ß-blockers, 6 topical carbonic anhydrase inhibitors and 3 α-agonists. Twenty-four articles used average intraocular pressure (IOP) analysis, 12 used the highest IOP analysis and none utilized the randomized eye method. At untreated baseline, there was a difference in the IOP between average IOP and highest baseline IOP analyses at 8 a.m. (p = 0.001) and for the diurnal curve (p = 0.02) as well as specifically for ß-blockers (p = 0.002) at 8 a.m. and ß-blockers for the diurnal curve (p = 0.01). CONCLUSIONS: This study suggests that the highest IOP analysis method generally provides slightly higher IOPs at baseline than the average IOP analysis method.

Review of clinical medicine and religious practice.

The purpose was to evaluate faith-based studies within the medical literature to determine whether there are ways to help physicians understand how religion affects patients' lives and diseases. We reviewed articles that assessed the influence of religious practices on medicine as a primary or secondary variable in clinical practice. This review evaluated 49 articles and found that religious faith is important to many patients, particularly those with serious disease, and patients depend on it as a positive coping mechanism. The findings of this review can suggest that patients frequently practice religion and interact with God about their disease state. This spiritual interaction may benefit the patient by providing comfort, increasing knowledge about their disease, greater treatment adherence, and quality of life. The results of prayer on specific disease states appear inconsistent with cardiovascular disease but stronger in other disease states.

Phase â /â ¡, Double-Masked, Randomized, Vehicle-Controlled Study of H-1337 Ophthalmic Solution for Glaucoma and Ocular Hypertension.

PURPOSE: To perform a phase Ⅰ/Ⅱ evaluation of an H-1337 ophthalmic solution in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). DESIGN: This was a phase I/II, randomized, double-masked, vehicle-controlled, dose-response study conducted at 6 private practice sites in the United States. The study was registered with clinicaltrials.gov as NCT03452033. PARTICIPANTS: Eighty-seven subjects with bilateral POAG or OHT were enrolled. METHODS: After washout of ocular hypotensive medications as required, the subjects were randomized to receive either the H-1337 ophthalmic solution at 0.06%, 0.2%, and 0.6% or its vehicle twice daily unilaterally in the study eye for the first 3 days and then twice daily in both eyes from day 4 to 28. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change in intraocular pressure from baseline (day 0) for each group on day 28 at hour 4 compared with the vehicle. RESULTS: In the primary efficacy end point, i.e., mean change from the baseline on day 28 at hour 4, the mean change from the baseline was - 4.45 ± 3.801, - 5.16 ± 3.114, - 4.93 ± 3.110, and - 0.39 ± 2.355 in the 0.06%, 0.2%, and 0.6% H-1337 and vehicle groups, respectively. The difference between each active group and the vehicle group was statistically significant (P < 0.0001). Treatment-emergent adverse events (TEAEs) occurred in 49% of subjects who received H-1337 (range, 41% [0.2% arm]-64% [0.6% arm] across the H-1337 arms) and 18% of subjects who received the vehicle. The majority of TEAEs were mild in severity; 3 subjects who received H-1337 had a TEAE of moderate intensity (instillation site erythema, blurred vision, and muscle strain). CONCLUSIONS: The H-1337 ophthalmic solution showed clinically and statistically significant ocular hypotensive activity and was well tolerated, with a relatively low incidence of hyperemia. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Risk factors associated with progression in exfoliative glaucoma patients.

PURPOSE: To evaluate exfoliative glaucoma (XFG) patients over 5 years, determining risk factors associated with progression or non-progression of glaucoma. METHODS: A retrospective, observational study. Patients were chosen from consecutive charts and data collected from each available visit included in the follow-up period. Data were abstracted for non-progressed XFG patients for 5 years and for progressed patients until glaucoma worsened. Progression was determined from patient records and by disc photographs. RESULTS: There were 71 (53%) progressed and 63 (47%) non-progressed XFG patients.Baseline parameters demonstrated worse visual field damage (p=0.014) and more prescribed medicines (p=0.03) in progressed patients. The mean intraocular pressure (IOP) for progressed patients was 18.7±4.3 and 17.3±3.4 mm Hg for non-progressed patients (p=0.047). The mean IOP that best separated the groups was 17 mm Hg with 60% staying non-progressed at or below this level and 30% above this level. At the last visit, progressed patients had more medicines prescribed (1.7) than non-progressed patients (1.3, p=0.005). A multivariate regression analysis showed higher mean, peak and variance of IOP, number of glaucoma medications at the final visit and presence of a disc hemorrhage (n=5) as independent risk factors for progression (p≤0.05). CONCLUSION: IOP reduction in XFG may be essential in reducing disease progression. The presence of disc hemorrhage in XFG may suggest an increased probability of progression despite treatment to within the normal IOP range.

Association of strength of religious adherence with attitudes regarding glaucoma or ocular hypertension.

BACKGROUND: To evaluate the impact of religious adherence on a patient's outlook on disease in a glaucoma population. METHODS: A prospective survey analysis of patients with open-angle glaucoma or ocular hypertension evaluating self-reported global religious adherence, adherence to specific basic activities and knowledge of faith ('maturity') and 'comfort' (ability to cope, attitude toward glaucoma, motivation to take medication and God's concern). This specific analysis was limited to self-professed Christians. RESULTS: 248 patients were included and religious adherence was correlated to religious activity and knowledge (p < 0.0001). Patients who scored as adherent on at least 1 of 4 maturity questions had greater benefit than less adherent patients from each of the 5 comfort questions (p < 0.0001). We found an increased statistical separation on each of the 5 comfort questions between religiously adherent and less adherent individuals for patients who scored as adherent on any 2 (n = 40), 3 (n = 50) or all 4 (n = 57) of the maturity questions (p < 0.001). CONCLUSIONS: This study suggests, at least for the Christian faith, that religious patients are subjectively more prone to cope with treatment and that religiosity increases the self-confidence, and possibly the quality of life, of patients with glaucoma or ocular hypertension. Whether this necessarily translates into better glaucoma practices remains to be demonstrated by further studies.

Intraocular pressure reduction in normal-tension glaucoma patients in South Korea.

To evaluate the potential benefit of intraocular pressure (IOP) reduction in normal-tension glaucoma (NTG) patients in South Korea. A retrospective, multi-center analysis of Korean NTG patients with 5-years follow-up, typical glaucomatous optic disc and/or visual field changes and no recorded IOP >21 mmHg. Progression was identified by Advanced Glaucoma Intervention Study visual field scoring. There were 90 (42%) progressed patients and 127 (58%) stable patients included in the study. Mean IOP measured higher in the progressed (14.3 ± 2.2 mmHg) than stable patients (14.0 ± 1.9 mmHg), but was not statistically different between the groups (P = 0.29). The mean IOP that best discriminated stable patients was ≤15 mmHg, but no statistical difference existed in the numbers of progressed versus stable patients at ≤15 mmHg compared to >15 mmHg (P = 0.07). Multivariate regression analysis showed that the baseline number of glaucoma medicines and visual field as well as mean, peak and fluctuation of IOP were significant risk factors for glaucomatous progression (P < 0.01). This study suggests that in Korean NTG patients, despite relatively similar IOPs between progressed and stable patients, and based on multivariate regression analysis, IOP may be a risk factor for glaucomatous progression.

Risk factors for subject withdrawals in clinical trials evaluating glaucoma medications.

BACKGROUND: To evaluate risk factors for subject withdrawals from multicenter clinical trials evaluating glaucoma medications. METHODS: An analysis of prospective, randomized, multicenter, parallel, active-controlled clinical trials with 70 subjects/treatment arm published from 1996-2008. RESULTS: We analyzed 36 glaucoma studies including 17,511 subjects at 1,294 clinical sites. There were 2,060 (12%) subject withdrawals with 669 (32%) for administrative errors, 945 (46%) for adverse events (AEs), 197 (10%) for inadequate intraocular pressure (IOP) control and 249 (12%) for unknown reasons. By multilinear regression analysis, no positive risk factors for early subject withdrawals were observed following a Bonferroni correction (p > or = 0.01). A positive correlation was observed for medication errors and protocol violations to withdrawals due to ocular AEs and total administrative errors (p < 0.0001). Protocol violations alone were correlated to subject withdrawals for any AE (total/month) and systemic AEs (p < 0.0001). Females and Caucasians were correlated to medication errors (p < 0 .0001). Among medical therapies, alpha-agonists, beta-blockers, the carbonic anhydrase inhibitor/beta-blocker fixed combination and prostaglandins were correlated with systemic AEs (p < or = 0.005) while the alpha-agonists were correlated with withdrawals for poor IOP control (p = 0.00056). CONCLUSIONS: Subject withdrawals from clinical trials for total administrative errors or AEs potentially might be reduced by choosing sites with lower historical rates of protocol violations or medication dispensing errors. Drug class choice also may influence subject withdrawals for AEs and poor IOP control.

Long-term benefit of reduced intraocular pressure in primary open-angle glaucoma patients in Ethiopia.

PURPOSE: To determine the incidence of progression of primary open-angle glaucoma at individual levels of mean intraocular pressure (IOP) in patients in Ethiopia. METHODS: A retrospective, multicenter, cohort analysis of patient records with at least 5 years of potential follow-up were evaluated for risk factors associated with progressive optic disc and visual field loss. RESULTS: There were 300 patients with the potential of 5 years of follow-up. In total, 166 patients progressed before 5 years and 134 remained stable for the full 5-year follow-up period. Of the total sample, 84% of patients with IOPs < or =19 (n=117/139), 53% of patients with IOPs of 20 (n=9/17), 14% of patients with IOPs of 21-24 (n=9/63), and 0% of the patients with IOPs of > or =25 mmHg (n=0/79) remained stable over at least 5 years. The mean IOP was 17.4+/-2.1 in the stable group and 25.0+/-5.9 mmHg in the progressed group (p<0.0001). The highest average peak IOP was 24.5+/-4.5 in the stable group and 29.0+/-6.1 mmHg in the progressed group (p<0.0001). A multivariant regression analysis to determine risk factors for progression was positive for mean IOP (p=0.0097). CONCLUSIONS: This study suggests that IOP reduction in a developing country, despite potential limitations in diagnostic techniques, follow-up, and compliance, can be effective in reducing the risk of glaucomatous progression over long-term follow-up.

Incidence of conjunctival exposure following drainage device implantation in patients with glaucoma.

PURPOSE: To evaluate prior studies including a glaucoma drainage device and to describe the timing and incidence of conjunctival exposure. A meta-analysis of previously published articles. METHODS: Articles included were prospective, single cohort, or comparative parallel design, with a mean treatment period of at least 3 months and at least 30 patients per treatment arm. We limited our analysis to studies that evaluated the most common devices, including Ahmed, Baerveldt, and Molteno. RESULTS: We included 38 studies containing 45 treatment arms (16 Ahmed, 12 Baerveldt, and 17 Molteno). These studies included 3,105 patients and 3,255 eyes with an average follow-up of 26.1+/-3.3 months. The overall incidence of exposure was 2.0+/-2.6% (n=64) of eyes with an average exposure/month of 0.09+/-0.14%. There was no significant correlation between study length and incidence of exposure (p=0.11), although multivariate regression analysis identified length of follow-up as a risk factor for exposure (p=0.001). Among individual drainage devices, there was no significant difference in the incidence of exposure (p=0.22) or percent exposure per month (p=0.18). In addition, no difference existed in the incidence of exposure between sizes for the Baerveldt 250, 350 or 500 mm (p=0.7), number of plates for the Molteno Single or Double (p=0.3), nor between the composition of the Ahmed Silicone or Polypropylene (p=0.7). CONCLUSIONS: This study suggests that tube exposure of glaucoma implants is unusual and the incidence does not differ between the Ahmed, Baerveldt, and Molteno implants. However, exposure appears to occur at any time within the first 5 years following implantation.

Ophthalmologist attitudes regarding fixed combination treatment for glaucoma in the European Union.

PURPOSE: To survey ophthalmologists in the European Union to determine their fixed combination (FC) preferences. METHODS: A multiple-choice survey was sent to randomly chosen ophthalmologists throughout the European Union and bordering countries by electronic mail delivery. Ophthalmologists were resent the survey on two more occasions if no response was obtained. RESULTS: In total, 50 surveys were received from 530 distributed (9.4% response) from 16 countries. More ophthalmologists prescribed an FC as second (80%) or third choice (64%) therapy than first choice (30%, p=0.0036). As first (p<0.0001) and third choice (p=0.011), the dorzolamide/timolol FC was most commonly prescribed, while as second choice the latanoprost/timolol FC (p<0.0001) was most popular. Overall, 98% (49/50) of doctors believed FC therapy improved patient care most often by better compliance (n=49) and quality of life(n=48, p<0.0001). Most ophthalmologists believed that there was a difference in efficacy between the FC products (32/50, 64%) with the most effective being the bimatoprost/timolol FC (n=12, 24%, p=0.029). However, fewer ophthalmologists perceived safety differences between the products (34/50, 68%). For prostaglandins, dosing time was suggested in the morning by 18 (36%) ophthalmologists and in the evening by 24 (48%) (p=0.35). CONCLUSIONS: FCs in the European Union are a potentially popular method to reduce intraocular pressure, being prescribed most commonly as second or third choice therapy. The perceived advantages to FC therapy are greater adherence to the medicine and improved patient quality of life.

Cost-effectiveness of treating ocular hypertension.

PURPOSE: To assess the cost-effectiveness of treating ocular hypertension (OHT) in the United States. DESIGN: A Markov model was constructed to perform a cost-effectiveness analysis. PARTICIPANTS: Patients with OHT. METHODS: The health states considered were stable OHT and glaucoma. Practice patterns for the model were derived from the Ocular Hypertension Treatment Study (OHTS), and transition probabilities were derived from previous literature. Specific unit costs used for medications, patient visits, and diagnostic and therapeutic procedures were obtained from Blue Cross/Blue Shield. The time horizon was 5 years. Costs were discounted at 3% per annum. MAIN OUTCOME MEASURE: Long-term cost effectiveness of treating OHT to prevent the development of glaucoma. RESULTS: The incremental cost-effectiveness ratio (ICER) for all OHT patients to prevent 1 case from progressing to primary open-angle glaucoma was $89,072. However, the minimally cost-effective ICER level after adjustment for risk factors identified by multivariate analysis in the OHTS were: 20 years above the average of 56 years, ICER of $45,155; 4 mmHg above the average pressure of 25 mmHg, ICER of $46,748; 40 microm less than the average central corneal thickness of 573 mum, ICER of $36,683; and a vertical cup-to-disc ratio of 0.2 wider than the average of 0.4, ICER of $35,633. CONCLUSIONS: Based on the results and practice patterns of the OHTS, treating all OHT patients seems not to be cost-effective. However, treating selective OHT patients with risk factors identified in the OHTS, for example, advancing age, higher pressures, thinner central corneal thickness, and wider vertical cup-to-disc ratios, does seem to be cost-effective for preventing the onset of glaucomatous damage.

Dorzolamide/timolol fixed combination versus latanoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension.

PURPOSE: The efficacy of dorzolamide/timolol fixed combination (DTFC) versus latanoprost/timolol fixed combination (LTFC) in open-angle glaucoma or ocular hypertensive patients. METHODS: Patients were randomized to DTFC or LTFC for 6 weeks and switched to opposite treatment for Period 2. RESULTS: Thirty-two completed patients had a mean diurnal IOP of 19.5+/-3.2 mmHg for DTFC and 18.9+/-3.4 mmHg for LTFC (p=0.12), with no significant difference found between DTFC and LTFC at any timepoint following a Bonferroni correction (p>or=0.01). CONCLUSIONS: Patients treated with DTFC and LTFC have a statistically similar ocular hypotensive effect.