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NEI and FDA Collaborate to Address Clinical Trial Issues for Glaucoma Drug and Device Diagnostics and Therapies

Program Co-Chairs Robert N. Weinreb, M.D. (left) and Paul Kaufman, M.D. (right) with NEI Director Paul Sieving, M.D., Ph.D.
Program Co-Chairs Robert N. Weinreb, M.D. (left) and Paul Kaufman, M.D. (right) with NEI Director Paul Sieving, M.D., Ph.D.
On March 13-14, 2008, the National Eye Institute (NEI) within the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) held a Glaucoma Clinical Drug Trial Design and Endpoints Symposium. This collaborative meeting, which involved both the drug and device approval divisions within the FDA—specifically the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH)—engaged glaucoma investigators and clinicians in a discussion of how results from research studies can apply to clinical trials used to support the approval of new drug and device diagnostics and therapies for glaucoma.

Anne Coleman, M.D. (University of California-Los Angeles), who addressed quality of life indicators, with NEI co-sponsor Rick Ferris, M.D.
Anne Coleman, M.D. (University of California-Los Angeles), who addressed quality of life indicators, with NEI co-sponsor Rick Ferris, M.D.
"This was a landmark meeting, and the glaucoma community made considerable progress. We learned from NEI how to improve clinical trial design, and heard a great deal of flexibility from the FDAs drug and device staff regarding new outcomes endpoints that may be used to support approvals of the next generation of diagnostic and therapeutic products," said Robert N. Weinreb, M.D. (Hamilton Glaucoma Center/University of California-San Diego), who served as Program Co-Chair with Paul Kaufman, M.D. (University of Wisconsin at Madison). Dr. Kaufman added that, "This was an excellent opportunity for investigators to understand from FDA what is involved in the testing of new drugs on new sites within the eye and in ways we have never treated before. We now know the approval process can be faster than was thought possible due to FDAs receptivity to new endpoints for clinical trials. This will enable researchers to 'telescope' clinical trials based on these new guidelines and potentially reduce the cost and time of getting new therapies to patients."

FDA co-sponsors Malvina Eydelman, M.D. (Center for Devices and Radiological Health) and Wiley Chambers, M.D. (Center for Drug Evaluation and Research)
FDA co-sponsors Malvina Eydelman, M.D. (Center for Devices and Radiological Health) and Wiley Chambers, M.D. (Center for Drug Evaluation and Research)
Glaucoma, the second leading cause of preventable vision loss in the United States, is a complex set of neurodegenerative diseases that damages the optic nerve and leads to loss of visual function. If untreated, it can lead to blindness. An estimated
2.2 million Americans have the disease, and an additional two million do not know they have it, as it often has no symptoms until substantial vision loss occurs. Every American over the age of 60 is at risk, and certain minority populations are at especially high risk, with African Americans having a three times greater risk of developing the disease than white Americans. Glaucoma is the leading cause of irreversible vision loss in African Americans and Hispanics.

 

 

 

 

 

Murray Fingeret, O.D. (VA NY Health System), a panel discussant, Scott Christensen (The Glaucoma Foundation) and speaker Christopher Girkin, M.D. (University of Alabama at Birmingham). Dr. Girkin  serves as a lead investigator in the NEI-funded African Americans With Glaucoma Study.
Murray Fingeret, O.D. (VA NY Health System), a panel discussant, Scott Christensen (The Glaucoma Foundation) and speaker Christopher Girkin, M.D. (University of Alabama at Birmingham). Dr. Girkin serves as a lead investigator in the NEI-funded African Americans With Glaucoma Study.
Even though elevated intra-ocular pressure (IOP) does not necessarily mean that a person has glaucoma, the current FDA-approved drug and device therapies have focused on reducing IOP since there is consensus in the medical community that lowering pressure inside the eye can, in many cases, slow glaucoma damage or vision loss. This was demonstrated in several NEI-funded studies, including the Early Manifest Glaucoma Trial (EGMT), which demonstrated that IOP reducing drugs slowed progression of the disease, and the Ocular Hypertension Treatment Study (OHTS), which demonstrated that IOP reducing drugs delayed the onset of glaucoma in people at high risk. The OHTS study also identified anatomical risk factors, including changes in the optic nerve and thinness of the cornea, which may be predictive of the disease.

Advances in visual imaging technologies have enabled researchers to better detect structural changes in the nerve fiber layer of the retina and the contours of the optic nerve head. To be used as outcomes variables in clinical trials submitted to the FDA, these structural changes must be demonstrated to have a high correlation with functional changes in vision to assure the clinical significance of a new therapy.

Rohit Varma, M.D. (Doheny Eye Institute/University of Southern California) presented  findings from  NEI's Los Angeles Latino Eye Study (LALES), in which glaucoma was undetected and untreated in 75 percent of those diagnosed with the disease
Rohit Varma, M.D. (Doheny Eye Institute/University of Southern California) presented findings from NEI's Los Angeles Latino Eye Study (LALES), in which glaucoma was undetected and untreated in 75 percent of those diagnosed with the disease
As researchers noted, glaucoma is a complex disease in which detectable structural and functional changes may not progress linearly or in concert, that is, early disease may be detected and characterized primarily by observable structural change, middle stage by both, and end stage primarily by measurable functional change. As a result, the regulatory process should be flexible to reflect this disparity between detectable structural and functional changes especially when considering, for example, a new class of neuro-protective drugs that could mitigate damage to the optic nerve before it is manifested in visual function change. Much of the meetings discussion focused on how these new structural endpoints—which would be a direct endpoint, rather than a surrogate endpoint such as IOP—are incorporated into clinical trials and, as appropriate, correlated to visual function and concomitant quality of life indicators to ensure clinical significance and ultimate benefit to patients.

Left to right: David Greenfield, M.D. (Bascom Palmer Eye Institute/University of Miami), Jack Cioffi, M.D. (Devers Eye Institute) and Jeffrey Liebmann, M.D. (Manhattan Eye, Ear, and Throat Hospital) addressed aspects of  structural and functional changes in glaucoma
Left to right: David Greenfield, M.D. (Bascom Palmer Eye Institute/University of Miami), Jack Cioffi, M.D. (Devers Eye Institute) and Jeffrey Liebmann, M.D. (Manhattan Eye, Ear, and Throat Hospital) addressed aspects of structural and functional changes in glaucoma
"The development of an exciting new generation of treatments for glaucoma will require close collaboration between researchers and the FDA if we are to be able to demonstrate that the treatments are safe and effective in the shortest time possible," said NEI Clinical Director Rick Ferris, M.D. He was joined by symposium co-sponsors Wiley Chambers, M.D. (CDER/Acting Director, Division of Anti-Infective and Ophthalmic Products) and Malvina Eydelman, M.D. (CDRH/Director, Division of Ophthalmic and ENT Devices) in predicting a new generation of glaucoma drugs and devices, including combinations of those products that deliver drug therapies directly into the eye.

 

 

 

 

 

 

 

Dr. Ferris, Mildred Olivier, M.D. (Midwest Glaucoma Center) and ARVO Executive Director Joanne Angle
Dr. Ferris, Mildred Olivier, M.D. (Midwest Glaucoma Center) and ARVO Executive Director Joanne Angle
The Glaucoma Endpoints meeting, which was managed by the Association for Research in Vision and Ophthalmology (ARVO), is the second collaborative meeting between the NEI and FDA, following up on the November 2006 Ophthalmic Clinical Trial Design and Endpoints Symposium, which focused on new treatments for age-related macular degeneration (AMD, the leading cause of blindness in older Americans), and diabetic retinopathy (the leading cause of vision loss in working-age Americans). That meeting, also managed by ARVO, grew out of NAEVR-initiated meetings between the NEI and FDA to discuss the potential impact of research on the product approval process.

NAEVR Executive Director James Jorkasky and William Boyd, M.D. (FDA/CDER)
NAEVR Executive Director James Jorkasky and William Boyd, M.D. (FDA/CDER)
"The dialogue at the Glaucoma Endpoints meeting was timely, as it occurred one week after the first-ever World Glaucoma Day (March 6, 2008), which was held to expand awareness of glaucoma incidence and research into the disease," said NAEVR Executive Director James Jorkasky, who added that the American Glaucoma Society conducted a March 6 Advocacy Day on Capitol Hill that included 100 Congressional office visits in which its members urged an increase in Fiscal Year 2009 NIH/NEI funding using NAEVR-generated materials.