Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema.

BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

VITRECTOMY FOR DIABETIC COMPLICATIONS: A Pooled Analysis of Randomized Controlled Trials Using Modern Techniques and Equipment.

PURPOSE: To report updated clinical outcomes in subjects undergoing pars plana vitrectomy (PPV) using modern techniques and equipment for the treatment of proliferative diabetic retinopathy-related complications. Pooled analysis of five randomized clinical trials conducted at the same institution and included both study and control subjects from the trials. METHODS: There were 943 subjects who prospectively underwent small-gauge PPV with antivascular endothelial growth factor pretreatment for proliferative diabetic retinopathy-related complications and completed 6-month follow-up. RESULTS: The visual acuity of the study population improved from median 2.00 (interquartile range 1.3, 2.3) at baseline to median 1.00 (interquartile range 0.5, 1.3) at 6 months. One hundred and eighty-four patients (19.5%) achieved 20/50 or better acuity, and 652 patients (69.1%) achieved 20/200 or better acuity at 6 months. The vision improved or remained stable in 901 patients (95.5%), and 11 patients (1.2%) developed no light perception at 6 months. Intraoperative complications occurred in 343 cases (36.4%), and 199 cases (21.1%) experienced a postoperative complication. The most common postoperative complication was vitreous hemorrhage in 124 cases (62.3% of all complications). Unplanned secondary PPV was necessary in 86 cases (9.1%). CONCLUSION: This study reports updated clinical outcomes in patients undergoing PPV for proliferative diabetic retinopathy-related complications which compares favorably with the age before small-gauge PPV and antivascular endothelial growth factor pretreatment.

Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial.

Importance: Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown. Objective: To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation. Design, Setting, and Participants: Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018. Interventions: Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits. Main Outcomes and Measures: The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported. Results: Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups. Conclusions and Relevance: Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT01909791.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.

PURPOSE: AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). DESIGN: Open-label, dose-escalation clinical trial. PARTICIPANTS: Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks. METHODS: Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. MAIN OUTCOME MEASURES: Safety assessments, change from baseline BCVA, and change from baseline CST. RESULTS: All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 µm in 5 patients and by 50 to 100 µm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA. CONCLUSIONS: No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator.

Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.

OBJECTIVE: To report 5-year results from a previously reported trial evaluating intravitreal 0.5 mg ranibizumab with prompt versus deferred (for ≥24 weeks) focal/grid laser treatment for diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit in the prompt and deferred groups, respectively. METHODS: Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and prompt or deferred (≥24 weeks) focal/grid laser treatment. MAIN OUTCOME MEASURES: Best-corrected visual acuity at the 5-year visit. RESULTS: The mean change in visual acuity letter score from baseline to the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference, -2.6 letters; 95% confidence interval, -5.5 to +0.4 letters; P = 0.09). At the 5-year visit in the prompt versus deferred laser groups, there was vision loss of ≥10 letters in 9% versus 8%, an improvement of ≥10 letters in 46% versus 58%, and an improvement of ≥15 letters in 27% versus 38% of participants, respectively. From baseline to 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 versus 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively. CONCLUSIONS: Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment. Although more than half of eyes in which laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years.

Practicing End-of-Life Conversations: Physician Communication Training Program in Palliative Care.

A Physician Communication Training Program (PCTP) utilizing scripts based on actual family conferences with patients, families, and the health care team was developed at one medical center in the Northeast. The program was designed, adapted, and directed by a palliative care social worker. The primary goal of the program is to help residents and attending physicians build better communication skills in establishing goals of care and in end-of-life planning. The scripts focus on improving physicians' basic skills in conducting family meetings, discussing advance directives, prognosis, brain death, and withdrawal of life support. Excerpts from the scripts utilized in the program are included. Feedback from participants has been positive, with all respondents indicating improvement in their capacity to take part in these challenging conversations.

Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01489189.

Ethical Gaps in Ophthalmology in the United States.

Purpose: To highlight gaps in the professional ethics of ophthalmology. Design: Perspective. Methods: Presentation of problematic cases in ophthalmologic ethics with juxtaposition of ethical, legal, and conscientious viewpoints informed by relevant literature. Results: What is legal, ethical, and conscientious overlap but are not identical. Professional ethical guidelines, when they exist, are stricter than what the law requires, but are silent on several contemporary controversies. Conscientious guidelines can vary from loosest to strictest as they apply to individuals with wide variability. The relationship of ophthalmology to society changes, and ethical guidelines lag for some of the interactions. Conclusion: The rules of ethics for ophthalmology need to be updated and evidence of activity and oversight made public. Failure to do so invites greater external regulation.

Assessing Private Equity Involvement in Ophthalmology: Parallels with the Past, Concerns for the Future.

PURPOSE: To discuss the history and current state of private equity in ophthalmology and explore potential implications for ophthalmology practices, physicians, and patients. DESIGN: Perspective. METHODS: Review of selected articles in ophthalmology and non-ophthalmology medical literature and commentary based on the authors' experiences. RESULTS: Investment in ophthalmology appeals to private equity firms because of high procedural volumes, fragmented private practices, opportunities for real estate ownership, and an aging population in need of eye care. As a result, acquisition of private practices by large private equity companies has swelled since 2015. Metropolitan areas and practices that possess ambulatory surgical centers or a high proportion of retina surgeons receive the greatest investment. However, little objective data exists regarding the benefits of this trend. Initial research suggests that private equity ownership may negatively impact patient care through greater costs, shorter appointments, and fewer Medicare/Medicaid patients seen. Skeptics of private equity also highlight concerns that include financial risk falling primarily on the acquired practice itself, a short-term business approach that rewards profit maximization, and the erosion of physician autonomy. Furthermore, young ophthalmologists express reservations about working for private equity firms. 78% of trainees indicated they would not consider employment by a private equity owned practice and 81.4% of vitreoretinal fellows voiced concerns about autonomy and job security. Proposed legislation aimed at limiting private equity acquisitions is currently under review at the statewide level, adding additional uncertainty to the future of private equity involvement in ophthalmology. CONCLUSION: Although investment by private equity offers potential financial rewards and operational improvements for practices, it also raises significant concerns reminiscent of those experienced by physician practice management companies in the 1990s. Nonanecdotal data is needed to assess the benefits and future of private equity involvement in ophthalmology.

Charity Care in Ophthalmology, 2024.

PURPOSE: To review changes in the provision of charity eye care in the past 50 years with hypothesized resulting effects on surgical training and patient outcomes. DESIGN: Perspective. METHODS: Case report, comparison of experience in community and training program settings, and selected literature review. RESULTS: The population to which charity care applies has shrunk as broader insurance coverage has been legislated, but in 2023 remains at approximately 7.3% of the US population. In areas with ophthalmology training programs, house staff supervised by faculty provide most of the charity care. In areas without training programs, a shrinking pool of willing private practitioners provides charity care. Because there is no organized financial support behind provision of charity, nonanecdotal data needed to assess the problem and guide decision making are lacking. CONCLUSIONS: Charity eye care in ophthalmology in 2024 is a patchwork of transient, local efforts that have a few common themes: absent material basis for sustainability, a narrowing base of support by clinicians, transfer of care to training programs, and financial vetting of applicants by nonclinicians. Unless universal health care legislation passes, which would eliminate the issue, suggestions for improvement include broader voluntary participation by private practice ophthalmologists in charity eye care, allocation of charity care spending by nonprofit hospitals to support this effort, and clinician-determined criteria for provision of charitable surgery supported by involved hospital systems.

Characteristics, Management, and Outcomes of Acute Life-Threatening Asthma in Adult Intensive Care.

BACKGROUND: There is limited evidence regarding the management of acute life-threatening asthma in intensive care units (ICUs), and few guidelines have details on this. We aimed to describe the characteristics, management, and outcomes of adults with life-threatening asthma requiring ICU admission. METHODS: In this single-centre retrospective observational study, we included consecutive adults with acute asthma requiring ICU admission between 1 January 2016 and 31 December 2023. Our primary outcome was requirement for invasive mechanical ventilation (IMV). RESULTS: We included 100 patients (median age 42.5 years, 67% female). The median pH, PaCO2, and white cell count (WCC) on ICU admission were 7.37, 39 mmHg, and 13.6 × 109/L. There were 30 patients (30%) who required IMV, and the best predictors of IMV requirement were pH (AUC 0.772) and PaCO2 (AUC 0.809). In univariate analysis, IMV requirement was associated with both increasing WCC (OR 1.14) and proven bacterial infection (OR 8.50). A variety of respiratory support strategies were utilised, with 38 patients (38%) receiving only non-invasive respiratory support. CONCLUSIONS: Our data highlight key characteristics which may be risk factors for acute asthma requiring ICU admission and suggest that pH, PaCO2, and WCC are prognostic markers for disease severity. Our overall outcomes were good, with an IMV requirement of 30% and a 28-day mortality of 1%.

Sturdy for common things: cultivating moral sensemaking on the front lines of practice.

This essay argues that the field of bioethics should concern itself especially with the process of making moral sense that unfolds among clinicians, patients and family members during common but high-stakes conversations occurring on the front lines of practice. The essay outlines the parameters of a bioethics grounded in the moral experience of patients, families and practitioners. It challenges ethicists, educators, and clinician leaders to commit themselves to advocating and developing creative approaches to learning that will cultivate the moral sensibilities of frontline clinicians in this critically important domain of practice.

A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. DESIGN: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. METHODS: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. MAIN OUTCOME MEASURE: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. RESULTS: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. CONCLUSION: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema.

OBJECTIVE: To describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial. DESIGN: Discussion of treatment protocol for DME. PARTICIPANTS: Subjects with vision loss resulting from DME involving the center of the macula. METHODS: The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser treatment in eyes with vision loss resulting from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. To share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. MAIN OUTCOME MEASURES: Clinical guidelines based on a DRCR.net protocol. RESULTS: The treatment protocol required real-time feedback from a web-based data entry system for intravitreal injections, focal/grid laser treatment, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. CONCLUSIONS: Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effort tracking metrics provide data for optimal budgeting and workload management in therapeutic cancer clinical trials.

Clinical trials operations struggle to achieve optimal distribution of workload in a dynamic data management and regulatory environment, and to achieve adequate cost recovery for personnel costs. The University of Michigan Comprehensive Cancer Center developed and implemented an effort tracking application to quantify data management and regulatory workload to more effectively assess and allocate work while improving charge capture. Staff recorded how much time they spend each day performing specific study-related and general office tasks. Aggregated data on staff use of the application from 2006 through 2009 were analyzed to gain a better understanding of what trial characteristics require the most data management and regulatory effort. Analysis revealed 4 major determinants of staff effort: 1) study volume (actual accrual), 2) study accrual rate, 3) study enrollment status, and 4) study sponsor type. Effort tracking also confirms that trials that accrued at a faster rate used fewer resources on a per-patient basis than slow-accruing trials. In general, industry-sponsored trials required the most data management and regulatory support, outweighing other sponsor types. Although it is widely assumed that most data management efforts are expended while a trial is actively accruing, the authors learned that 25% to 30% of a data manager's effort is expended while the study is either not yet open or closed to enrollment. Through the use of a data-driven effort tracking tool, clinical research operations can more efficiently allocate workload and ensure that study budgets are negotiated to adequately cover study-related expenses.

Creating an effort tracking tool to improve therapeutic cancer clinical trials workload management and budgeting.

Quantifying data management and regulatory workload for clinical research is a difficult task that would benefit from a robust tool to assess and allocate effort. As in most clinical research environments, The University of Michigan Comprehensive Cancer Center (UMCCC) Clinical Trials Office (CTO) struggled to effectively allocate data management and regulatory time with frequently inaccurate estimates of how much time was required to complete the specific tasks performed by each role. In a dynamic clinical research environment in which volume and intensity of work ebbs and flows, determining requisite effort to meet study objectives was challenging. In addition, a data-driven understanding of how much staff time was required to complete a clinical trial was desired to ensure accurate trial budget development and effective cost recovery. Accordingly, the UMCCC CTO developed and implemented a Web-based effort-tracking application with the goal of determining the true costs of data management and regulatory staff effort in clinical trials. This tool was developed, implemented, and refined over a 3-year period. This article describes the process improvement and subsequent leveling of workload within data management and regulatory that enhanced the efficiency of UMCCC's clinical trials operation.

Cross-cultural adaptation of an innovative approach to learning about difficult conversations in healthcare.

BACKGROUND: The Program to Enhance Relational and Communication Skills (PERCS) was developed at a large hospital in the United States to enhance clinicians' preparedness to engage in difficult conversations. AIM: To describe the implementation of PERCS in an Italian hospital and assess the program's efficacy. METHODS: The Italian PERCS program featured 4-h experiential workshops enrolling 10-15 interdisciplinary participants. The workshops were organized around the enactment and debriefing of realistic case scenarios portrayed by actors and volunteer clinicians. Before and after the workshop, participants rated their perceived preparation, communication and relational skills, confidence, and anxiety on 5-point Likert scales. Open-ended questions explored their reflections on the learning. T-tests and content analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: 146 clinicians attended 13 workshops. Participants reported better preparation, confidence, and communication skills (p < 0.001) after the workshops. The program had a different impact depending on the discipline. Participants valued the emphasis on group feedback, experiential and interdisciplinary learning, and the patient's perspective, and acquired: new communication skills, self-reflective attitude, reframed perspective, and interdisciplinary teamwork. CONCLUSION: PERCS proved culturally adaptable to the Italian context and effective in improving participants' sense of preparation, communication skills, and confidence.

Quantifying Conflict of Interest in the Choice of Anti-VEGF Agents.

PURPOSE: To quantify the economic incentives associated with the choice of anti-VEGF drugs for retinal diseases. METHODS: An economic model was created based on the distribution of use and number of injections of bevacizumab (B), versus aflibercept or ranibizumab (AR); published Medicare reimbursement rates; published rebates; estimated unreimbursed drug use; estimated use of drug company samples; and published costs-of-drugs. Differential economic incentives associated with the choice of drugs were calculated over a range of distributions of drug use. RESULTS: The splits in drug choice ranged from 92% AR/8% B to 31% AR/69% B, and in annual injection numbers from 2000 to 6000 with a median of 4000 in one 5-person retina service. Assumed values for rebates were 1% for drug company rebate, 1% for group purchasing organization rebate, and 5 for number of unreimbursed injections per year. The differential economic incentive of a 92% AR/8% B split compared to a 31% AR/69% B split for the median annual number of injections was $266, 893. CONCLUSION: Using real-world data, the economic incentive associated with a choice of more expensive anti-VEGF drugs is large. Accounting for unreimbursed drug use and the cost of additional staff required to manage expensive drug inventory does not nullify the incentive. To what degree this financial incentive influences ophthalmologists' choice of drugs is unknown, but not trivial. Financial disclosure of the conflicts of interest in the drugs recommended for treatment should be discussed with patients.