Ophthalmology Introduction

Document Sample
Ophthalmology Introduction Powered By Docstoc
					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




  Dermatology and Ophthalmology Advisory Committee
  August 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

    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                    3
        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
   August 27, 2004                                    4
Clinical Trial Design Issues

         Wiley A. Chambers, MD
         Deputy Division Director


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




     Dermatology and Ophthalmology Advisory Committee
     August 27, 2004                                    6
               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
   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    7
              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



   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    8
             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)



   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    9
            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

   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    10
                            Duration
• Trials should be continued for at
  least 24 months

• Primary endpoint may be accepted at
  12 months or more




   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    11
               Multicenter Trials
• At least 10 patients per arm per
  center

  – Allow test of center/investigator
    interaction




   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    12
                      Stratification
• Type of lesion (occult versus classic)

• Baseline visual acuity
  – (54-73 letters versus 34-53 letters)




   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    13
                                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



     Dermatology and Ophthalmology Advisory Committee
     August 27, 2004                                        14
                    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



   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    15
                             Efficacy
• Statistical significance and clinical
  relevance in visual function at more
  than one time point

  – Visual acuity
  – Visual field
  – Color vision

   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    16
                          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

      Dermatology and Ophthalmology Advisory Committee
      August 27, 2004                                    17
      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
    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                     18
       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




    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                    19
    Recommended Endpoints (2)
               Difference in Group Mean


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




    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                    20
              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
   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    21
                            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
    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                    22
                        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




    Dermatology and Ophthalmology Advisory Committee
    August 27, 2004                                    23
                          Pediatrics
• Choroidal neovascularization rarely
  occurs in pediatric populations

• Studies not required for New Drug
  Application




   Dermatology and Ophthalmology Advisory Committee
   August 27, 2004                                    24

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:7
posted:7/22/2012
language:
pages:24