Functional Vision Endpoints: OCTGT Perspective Samuel B. Barone, M.D. Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research NEI/FDA Endpoints Symposium May 6, 2011

2 Disclosure No financial conflicts with any FDA regulated product

3 FDA Organization Office of the Commissioner –Office of Combination Products CDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnostic devices CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cell therapy, gene therapy, donor screening tests for blood and tissue safety, devices CDER (Center for Drug Evaluation and Research): drugs, monoclonal antibodies, therapeutic proteins) CVM CFSAN NCTR

4 CBER Organization Immediate Office of Director Office of Blood Research and Review Office of Cellular, Tissue and Gene Therapies Office of Vaccines Research and Review Office of Compliance and Biological Quality Office of Biostatistics and Epidemiology Office of Communication, Training and Manufacturers Assistance Office of Management

5 OCTGT Products Cellular therapies Gene therapies Tumor vaccines and immunotherapy Devices used for cells and tissues Human cells and tissues for transplant Combination products

6 OCTGT Ophtho Product Submissions 5 7 5

7 5 4

8 Clinical Development Considerations Novel products/routes of administration Size of patient population Age of disease onset Disease progression Efficacy endpoints

9 Safety Concerns Product –Immune response ? Need for immunosuppressive regimen –Tumor formation Procedure –Route of administration Johnson et al., Molecular Vision, 2008; 14: 2211–2226.

10 Patient Population Size –Age-related macular degeneration 1.75 million Friedman, Arch Ophthalmol, 2004; 122(4):564. –Stargardt disease 30,000 Riveiro-Alvarez et al., BJO, 2009; 93(10):1359. –Leber congenital amaurosis 4,000 Stone, AJO, 2007; 144(6):791. Age –Pediatric population

11 Natural History Time Course –Onset –Progression Variability –Individuals –Eyes Lack of Predictability SR Dubovy, AFIP Ophthalmic Pathology for the Ophthalmologist, Stargardt Disease

12 Efficacy Endpoints

13 Assessing Vision (Best Corrected) Visual Acuity Visual Field Pupillary Response Color Vision Contrast Sensitivity Photostress Recovery Electrophysiologic Testing Imaging

14 Vision Endpoints Visual acuity: a 3-line (15-letter) change –clinically meaningful benefit in comparison between treatment arms or before and after treatment Visual Field Surrogate Endpoints Secondary Endpoints

15 Maguire, High, et al. Measured improvement in retinal function: –Dark adaptometry –Pupillometry –Electroretinography –Nystagmus/eye movement measurements –Ambulatory behavior Ability to navigate a standardized obstacle course Lancet, 2009; 374(9701):

16 Effectiveness? Endpoint not obtainable? –Low vision –No well established surrogate endpoint –Objective anatomic measurements with unknown meaning to patient Subjective improvement

17 Summary OCTGT Perspective OCTGT is currently evaluating ophtho products Potential challenges: –Small and younger disease populations –Natural history variable –New therapies/treatment modalities where safety is not as well established Functional Vision Endpoints: –Capture meaningful subjective patient experience as an objective measurable data point –May be susceptible to bias; masking is essential

18 Cellular, Tissue, and Gene Therapies Advisory Committee Meeting to discuss cellular and gene therapy products for the treatment of retinal disorders –Efficacy endpoints in peds/adult populations –Repeat/second eye admin safety issues –Eval of product delivery into target site June 29, 2011 Crowne Plaza Hotel, Silver Spring, MD

19 OCTGT Regulatory Resources OCTGT Learn Webinar Series: sEvents/ucm htm sEvents/ucm htm Regulatory Questions: Contact the Regulatory Management Staff in OCTGT at or or by calling (301)

20 More Information: CBER Homepage Search –“advisory committees” for CTGAC June 29, 2011 –“OCTGT learn” for biologicals regulatory process Search go