Macugen (pegaptanib sodium injection)

1. Macugen (pegaptanib sodium injection) Dermatology and Ophthalmology Advisory Committee Meeting Rockville, Maryland August 27, 2004 Center for Drug Evaluation and Research

2. WelcomeDermatology and Ophthalmology Advisory Committee Meeting Wiley A. Chambers, MD Deputy Director Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products

3. Macugen (pegaptanib sodium injection)Advisory Committee MeetingAugust 27, 2004 • PDUFA 3 (Prescription Drug User Fee Act 2002) • Continuous Marketing Application Pilot 1 NDA Submission • Fast Track Products • Module Submissions • Action on the NDA will be taken after all modules are submitted and reviewed

4. Macugen (pegaptanib sodium injection)Advisory Committee MeetingAugust 27, 2004 • Today’s Discussion • Clinical Only • Comments on each Module are intended to be given within 6 months of Module submission • Action on NDA only given after review is completed on all modules • FDA’s Review is Ongoing

5. Clinical Trial Design Issues Wiley A. Chambers, MD Deputy Division Director

6. Study Design • Parallel arms • Randomized by person • Double masked (investigator and patient) • Dose Ranging

7. Inclusion Criteria • Choroidal neovascularization • Documented by fundus photography and angiography • Specific observable features • Membranes greater than a defined size with xx and yy features • Particular diagnostic test results • Leaking on fluorescein • Leaking on ICG

8. Exclusion Criteria • Patients with concurrent ocular disease that may also be associated with choroidal neovascularization should be excluded • Exclude Presumed Ocular Histoplasmosis • Exclude High myopia

9. Number of Studies • Safety and efficacy should be supported by at least two independent trials of at least two years duration • At least 2 trials for robustness of results • Independent trials (geographically separate)

10. Number of subjects • Clinical program should include enough patients to identify adverse events that occur at a rate of 1% or greater • Approximately 500 or more subjects • Concentration at least as high as proposed for market • Frequency at least as high as proposed for market

11. Duration • Trials should be continued for at least 24 months • Primary endpoint may be accepted at 12 months or more

12. Multicenter Trials • At least 10 patients per arm per center • Allow test of center/investigator interaction

13. Stratification • Type of lesion (occult versus classic) • Baseline visual acuity • (54-73 letters versus 34-53 letters)

14. Control • At least one study demonstrating superiority to control • Prefer Vehicle control • Minimize bias • Mechanical manipulation may initiate inflammatory mediators • Endophthalmitis never previously seen in vehicle group • Sham, reluctantly acceptable • Require multiple other doses in addition to sham • Increased chance of bias influencing results

15. Dose Ranging • Multiple Doses • Prefer to include a dose higher in concentration than the “best” dose • Prefer to include a dose lower in concentration than the “best” dose

16. Efficacy • Statistical significance and clinical relevance in visual function at more than one time point • Visual acuity • Visual field • Color vision

17. Evaluations • Best corrected distance visual acuity* • ETDRS equivalent at 4 meters • Dilated seven field fundus photographs • Fluorescein or indocyanine green angiography • Dilated ophthalmoscopy* • Dilated slit lamp exam * • Endothelial cell count** • Systemic clinical and laboratory evaluation** * Every visit ** Beginning and end of at least one study

18. Two versus Four Meters • Four meters is the standard • Ophthalmology 1996; 103:181-182 • At distances shorter than 4 meters: • Leaning can affect the number of line read • At 2 meters – ~17 inches equals 1 line of acuity • ETDRS showed poor reliability at 1 meter compared to 4 meters • More significant if a feature of treatment or an adverse event can lead to unmasking of treatment

19. Recommended EndpointsPercentage of Patients with • Doubling of the visual angle • 15 or more letters on ETDRS chart at 4 meters • Halving of the visual angle • 15 or more letters on ETDRS chart at 4 meters • Quadrupling of the visual angle • 30 or more letters on ETDRS chart at 4 meters

20. Recommended Endpoints (2)Difference in Group Mean • Statistically significant difference between groups in mean visual acuity of 15 or more letters

21. Equivalence Studies • Comparison to active agent which has demonstrated repeatedly consistent success • 95% confidence interval between the test product and control that preserves at least 50% of the established treatment effect

22. Analyses • Intent to Treat with last observation carried forward • Per-Protocol with observed values only • Worst case analysis • Dropouts for control counted as success • Dropout for test product counted as failure

23. Analysis (2) • Alpha recommended to be 0.05 or less • Two tailed • Power to detect a difference 0.8 or greater • Adjustment for any “look” at the data

24. Pediatrics • Choroidal neovascularization rarely occurs in pediatric populations • Studies not required for New Drug Application