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

2. Dermatology and Ophthalmology Advisory Committee August 27, 2004 Welcome Dermatology and Ophthalmology Advisory Committee Meeting Wiley A. Chambers, MD Deputy Director Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products Wiley A. Chambers, MD Deputy Director Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products

3. Dermatology and Ophthalmology Advisory Committee August 27, 2004 3 Macugen (pegaptanib sodium injection) Advisory Committee Meeting August 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 4 Macugen (pegaptanib sodium injection) Advisory Committee Meeting August 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 Clinical Trial Design Issues Wiley A. Chambers, MD Deputy Division Director Wiley A. Chambers, MD Deputy Division Director

6. Dermatology and Ophthalmology Advisory Committee August 27, 2004 6 Study Design Parallel arms Randomized by person Double masked (investigator and patient) Dose Ranging Parallel arms Randomized by person Double masked (investigator and patient) Dose Ranging

7. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 Patients with concurrent ocular disease that may also be associated with choroidal neovascularization should be excluded –Exclude Presumed Ocular Histoplasmosis –Exclude High myopia

9. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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) 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 11 DurationDuration Trials should be continued for at least 24 months Primary endpoint may be accepted at 12 months or more Trials should be continued for at least 24 months Primary endpoint may be accepted at 12 months or more

12. Dermatology and Ophthalmology Advisory Committee August 27, 2004 12 Multicenter Trials At least 10 patients per arm per center –Allow test of center/investigator interaction At least 10 patients per arm per center –Allow test of center/investigator interaction

13. Dermatology and Ophthalmology Advisory Committee August 27, 2004 13 StratificationStratification Type of lesion (occult versus classic) Baseline visual acuity – (54-73 letters versus 34-53 letters) Type of lesion (occult versus classic) Baseline visual acuity – (54-73 letters versus 34-53 letters)

14. Dermatology and Ophthalmology Advisory Committee August 27, 2004 14 ControlControl 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 16 EfficacyEfficacy Statistical significance and clinical relevance in visual function at more than one time point –Visual acuity –Visual field –Color vision Statistical significance and clinical relevance in visual function at more than one time point –Visual acuity –Visual field –Color vision

17. Dermatology and Ophthalmology Advisory Committee August 27, 2004 17 EvaluationsEvaluations 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 19 Recommended Endpoints Percentage 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 20 Recommended Endpoints (2) Difference in Group Mean Statistically significant difference between groups in mean visual acuity of 15 or more letters

21. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 22 AnalysesAnalyses 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 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 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. Dermatology and Ophthalmology Advisory Committee August 27, 2004 24 PediatricsPediatrics Choroidal neovascularization rarely occurs in pediatric populations Studies not required for New Drug Application Choroidal neovascularization rarely occurs in pediatric populations Studies not required for New Drug Application