ophthalmology introduction
TRANSCRIPT
Macugen (pegaptanib sodium injection)
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
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
• 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
4Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004
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
Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004
Clinical Trial Design IssuesClinical Trial Design Issues
Wiley A. Chambers, MDDeputy Division Director
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Study DesignStudy Design
• Parallel arms• Randomized by person• Double masked (investigator and patient)• Dose Ranging
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Inclusion 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
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Exclusion 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
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Number 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)
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Number 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
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DurationDuration
• Trials should be continued for at least 24 months
• Primary endpoint may be accepted at 12 months or more
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Multicenter TrialsMulticenter Trials
• At least 10 patients per arm per center
– Allow test of center/investigator interaction
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StratificationStratification
• Type of lesion (occult versus classic)
• Baseline visual acuity– (54-73 letters versus 34-53 letters)
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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
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Dose 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
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EfficacyEfficacy
• Statistical significance and clinical relevance in visual function at more than one time point
– Visual acuity– Visual field– Color vision
17Dermatology and Ophthalmology Advisory Committee Dermatology and Ophthalmology Advisory Committee August 27, 2004August 27, 2004
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
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Two 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
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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
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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
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Equivalence 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
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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
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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
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PediatricsPediatrics
• Choroidal neovascularization rarely occurs in pediatric populations
• Studies not required for New Drug Application