macugen (pegaptanib sodium injection) dermatology and ophthalmology advisory committee meeting...

Macugen (pegaptanib sodium injection) Macugen (pegaptanib sodium injection)

Dermatology and Ophthalmology Advisory Dermatology and Ophthalmology Advisory Committee MeetingCommittee MeetingRockville, MarylandRockville, MarylandAugust 27, 2004August 27, 2004

Dermatology and Ophthalmology Advisory Dermatology and Ophthalmology Advisory Committee MeetingCommittee MeetingRockville, MarylandRockville, MarylandAugust 27, 2004August 27, 2004

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004

WelcomeWelcomeDermatology and Ophthalmology Advisory Committee MeetingDermatology and Ophthalmology Advisory Committee Meeting

WelcomeWelcomeDermatology and Ophthalmology Advisory Committee MeetingDermatology and Ophthalmology Advisory Committee Meeting

Wiley A. Chambers, MDDeputy Director

Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products

Wiley A. Chambers, MDDeputy Director

Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products

3Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004

Macugen (pegaptanib sodium injection)Advisory Committee Meeting

August 27, 2004


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



August 27, 2004


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

Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004

Clinical Trial Design IssuesClinical Trial Design IssuesClinical Trial Design IssuesClinical Trial Design Issues

Wiley A. Chambers, MDDeputy Division DirectorWiley A. Chambers, MDDeputy Division Director


Study DesignStudy DesignStudy DesignStudy 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


Inclusion CriteriaInclusion CriteriaInclusion CriteriaInclusion 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


Exclusion CriteriaExclusion CriteriaExclusion CriteriaExclusion 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


Number of StudiesNumber of StudiesNumber of StudiesNumber 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)


Number of subjectsNumber of subjectsNumber of subjectsNumber 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


DurationDurationDurationDuration

• 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


Multicenter TrialsMulticenter TrialsMulticenter TrialsMulticenter 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


StratificationStratificationStratificationStratification

• 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)


ControlControlControlControl

• 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


Dose RangingDose RangingDose RangingDose 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


EfficacyEfficacyEfficacyEfficacy

• 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


EvaluationsEvaluationsEvaluationsEvaluations

• 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


Two versus Four MetersTwo versus Four MetersTwo versus Four MetersTwo 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


Recommended EndpointsRecommended EndpointsPercentage of Patients withPercentage of Patients with

Recommended EndpointsRecommended EndpointsPercentage of Patients withPercentage 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


Recommended Endpoints (2)Recommended Endpoints (2)Difference in Group MeanDifference in Group Mean

Recommended Endpoints (2)Recommended Endpoints (2)Difference in Group MeanDifference in Group Mean

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

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


Equivalence StudiesEquivalence StudiesEquivalence StudiesEquivalence 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


AnalysesAnalysesAnalysesAnalyses

• 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


Analysis (2)Analysis (2)Analysis (2)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


PediatricsPediatricsPediatricsPediatrics

• 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

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