# Presentation: 336901

##  Macugen (pegaptanib sodium injection) 

**Dermatology and Ophthalmology Advisory Committee Meeting**
**Rockville, Maryland**
**August 27, 2004**

**Center for Drug Evaluation and Research**** **

## WelcomeDermatology and Ophthalmology Advisory Committee Meeting

**Wiley A. Chambers, MD**
**Deputy Director**
**Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products**

## 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**

## 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**

## Clinical Trial Design Issues

**Wiley A. Chambers, MD**
**Deputy Division Director**

## Study Design

**Parallel arms**
**Randomized by person**
**Double masked (investigator and patient)**
**Dose Ranging**

## 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**

## 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**

## 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)**

## 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**

## Duration

**Trials should be continued for at least 24 months**
**Primary endpoint may be accepted at 12 months or more**

## Multicenter Trials

**At least 10 patients per arm per center**
**Allow test of center/investigator interaction**

## Stratification

**Type of lesion (occult versus classic)**
**Baseline visual acuity**
** ****(54-73 letters versus 34-53 letters)**

## 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**

## 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**

## Efficacy

**Statistical significance and clinical relevance in ****visual function**** at more than one time point**
**Visual acuity**
**Visual field**
**Color vision**

## 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**

## 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**

## 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**

## Recommended Endpoints (2)Difference in Group Mean

**Statistically significant difference between groups in mean visual acuity of 15 or more letters**

## 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**

## 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**

## 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**

## Pediatrics

**Choroidal neovascularization rarely occurs in pediatric populations**
**Studies not required for New Drug Application**