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Retina drug trials dominated discussion at FDA-NEI conference
Clinically meaningful endpoints, the role of OCT and the impact of Lucentis were among the topics debated by experts at the meeting.
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WASHINGTON – A recent 2-day conference, sponsored by the National Eye Institute and the U.S. Food and Drug Administration, sought to open a dialogue between federal agencies and ophthalmic researchers regarding clinical trial design and study endpoints.
The meeting set out specifically to examine clinical endpoints used to measure the safety and efficacy in pre-approval trials of new treatments for retinal disease, namely diabetic retinopathy and age-related macular degeneration.
A representative from the Coverage Analysis Group of the Centers for Medicare and Medicaid Services participated in the exchange.
Karl G. Csaky, MD, PhD, the head of the NEI’s Laboratory of Retinal Diseases and Therapeutics, served as the moderator of the forum. More than 20 other physicians and scientists presented scientific information and/or participated in round table deliberations that followed each of the five panel presentations.
The five panel topics were “visual acuity parameters as outcome measures,” “Endpoints for diabetic retinopathy,” “Design and endpoints for neovascular AMD,” “Design and endpoints for geographic atrophy,” and “Post-marketing drug surveillance.”
At least 100 observers, mainly from the ophthalmic pharmaceutical and medical device industries, listened intently while the discussants exchanged ideas on questions posed to the panel.
Clinically meaningful endpoints
The discussants agreed that all endpoints should be clinically meaningful in terms of representing functional improvement in vision.
 Alan E. Reider |  Allison Weber-Shuren |
The first panel, focusing on the role of visual acuity, aimed to answer whether other visual acuity measures, besides the proportion of patients with either a three-line gain or three-line loss, can be used as a primary outcome.
The panel also debated how the NEI and FDA would be assured that statistically significant differences in visual function outcomes are clinically important.
After presentations from Rick Ferris, MD, of the NEI, Rhea Lloyd, MD, of the FDA and Maureen McGuire, PhD, of the University of Pennsylvania, the round table exchange centered on the reliability of visual acuity and what alternative diagnostic tools, if any, offer more reliable and meaningful endpoints.
There was considerable dialogue regarding ocular coherence tomography (OCT). Participants acknowledged the clinically important role of OCT in current treatment protocols but repeatedly noted that existing data on current OCT technology are not sufficient to conclude that OCT can be considered a surrogate endpoint for AMD trials.
Panelists enthusiastically noted that recently introduced OCT technologies might permit specific anatomic localization of retinal edema and be more predictive of treatment success.
Diabetic retinopathy, AMD
The second and third panels focused on the endpoint expectations for treatments for diabetic retinopathy and wet AMD, respectively. Panel two tackled questions on whether trials testing treatments for diabetic retinopathy must include a 3-year follow-up period (the standard follow-up required today by the FDA) and what role, if any, anatomic endpoints such as development of macular edema or changes in OCT should play in diabetes trials.
One presenter suggested that perhaps 2-year trials in diabetic retinopathy might be sufficient to judge drug efficacy in cases in which a patient’s condition improves in year 1 (year 2 would include additional follow-up).
Other discussants raised concerns about whether studies over such a short time frame can offer credible results and instill confidence that the study agent is altering the natural course of the disease, given the slow and unpredictable nature of macular edema associated with diabetic retinopathy. They argued that the condition’s slow progression and regression make it difficult to know whether any clinical changes are related to the treatment.
This variability and the lack of more sensitive endpoints, a speaker from the FDA noted, hinder determinations regarding efficacy within a shorter time frame and also may make it more difficult to tease out risks.
Nevertheless, the speaker from the FDA suggested the agency might consider a 2-year trial design for phase 3 trials of diabetic retinopathy treatment in certain circumstances. In such cases, sponsors would need to show statistically significant efficacy at month 24 as compared to baseline and show no decrease in efficacy for a 6-month period prior to month 24.
Lucentis
The main topic discussed by the third panel was Lucentis (ranibizumab, Genentech/Novartis), and how the availability of this drug has, for the first time, provided physicians and patients a real option for treating AMD because it gives patients a chance to regain vision, rather then just hope for arresting vision loss.
Panelists felt that Lucentis treatment could likely serve as the control arm for clinical trials of new treatments for AMD and that this would increase the cost of conducting these trials in the future. Panelists also agreed that in order for future AMD treatments to be considered clinically similar to Lucentis they would have to show an improvement in visual acuity within three letters of the effect of Lucentis.
Also of important note, the CMS representative announced that the agency may issue within 1 to 2 years a national coverage decision on therapies for AMD.
Other issues
The fourth panel explored whether the rate and the extent of anatomic progression of atrophy represent clinically important study outcomes.
This panel started with presentations from, among others, Michael Klein, MD, of the University of Oregon, Martin Nevitte, MD, a medical officer in the Division of Anti-Infective and Ophthalmology Products at the FDA, and Janet Sunness, MD, the medical director of Hoover Services for Low Vision and Blindness, Greater Baltimore Medical Center.
The fifth panel discussed an issue with implications beyond ophthalmic therapies: post-marketing drug surveillance. This panel, opened by Scott Cousins, MD, and Jonathan C. Javitt, MD, MPH, discussed mechanisms for obtaining and substantiating data on drug-induced complications in patients receiving treatment for retinal disease.
There was general sentiment that the current system lacks cost-effective methods to capture data in a timely and user-friendly manner. Dr. Javitt suggested that a sentinel database system offers one possible solution, provided it is deployed and maintained appropriately.
For more information:
- Allison Weber Shuren, MSN, JD, can be reached at Arent Fox PLLC, 1050 Connecticut Ave. NW, Washington, DC 20036; 202-857-6462; fax: 202-857-6395; e-mail: shuren.allison@arentfox.com.