Transcript FDA Update

Electroretinography: The
FDA’s Viewpoint
Wiley A. Chambers, MD
Deputy Director
Division of Anti-Infective and
Ophthalmology Products
Center for Drug Evaluation and Research
August 2005
Disclaimer
• The opinions and assertions expressed in this
presentation are the private views of the speaker. No
endorsement by the Food and Drug Administration is
intended or should be inferred.
• The speaker has no financial interest or other
relationship with the manufacturer of any commercial
product discussed or with the manufacturer of any
competing commercial product.
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Federal Food, Drug and
Cosmetic Act
• Regulation of Interstate Commerce
– Drugs –
pre market clearance
– Biologics – pre market clearance
– Devices – pre market clearance
– Foods
– Cosmetics
– NOT Procedures
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Mission of the Center for Drug
Evaluation and Research
• Assure that safe and effective
drugs are available to the
American people.
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Accomplished by
• Monitoring Drug Development Process during
Investigational Stages
– Most of this process is confidential
• Approving New Drug Products that are safe and
efficacious
– Confidential until approval and then designed
to be transparent
• Monitoring Adverse Events after Approval
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Food and Drugs Act
• 1906
– Prohibits interstate commerce of
misbranded and adulterated foods,
drinks and drugs
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Food Drug & Cosmetic Act
1938
• Response to Elixir Sulfanilamide
• Review of Drug Safety
• Pre-market Review of Drugs
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Benefit to Risk Ratio
• Influences design, size and monitoring of
clinical trials
• Influences decision to approve or not
approve a drug product
• Influences decision to withdraw a drug
product from the market
• Greater benefit justifies greater risk
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Benefit
• Determined by efficacy evaluations in
clinical trials
• Trials must be adequate and well
controlled
• Benefit of an approved drug product is
expected for the intended population if the
drug product is taken as labeled
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Efficacy Endpoints
• Clinically important changes
– Visual function
• Benefit
• Prevention of loss
– Anatomic Predictors of Clinical
Benefit
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Visual Function
• Visual Acuity
– Doubling of visual angle
– Mean 3 line change or percentage of
patients that change 3 lines
• Visual Field
– Prevention of meaningful loss
– Usually requires 5 replicated points at a
p<.05 level of significance
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ERG Equivalent
• ERG equivalent to doubling of the
visual angle
– Not currently known
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Anatomic Predictors of Efficacy
• Must predict a clinical benefit for
patient
– Prevention of retinal detachment
– Prevention of other anatomic
change which will lead to visual
loss
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Risk
• All drugs have some risk
• Risk assessed in adequate and well
controlled studies
• Risk assessed in other clinical studies
• Risk assessed in postmarketing settings
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Risk
• Assessment improves as more individuals
receive the drug product
• Usually not completely known until after
the drug product is marketed
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Utilization of ERG in Drug
Development
• Pre-clinical studies
– Drug intended to affect
electrophysiology
– Drugs which bind to melanin
– Drugs which cause retinal lesions
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Clinical studies
• Drugs intended to affect electrophysiology
• Drugs which have demonstrated ERG
abnormalities in animals
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Drugs intended to affect
electrophysiology
• Used as efficacy measure in animal
studies
– Assist in determining current dose
– Assist in determining duration of effect
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Drugs intended to affect
electrophysiology
•
Used as secondary endpoint to support
primary endpoint in human clinical
studies
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Need clinical significance to use
as a primary endpoint
• Is patient function affected?
• Is clinical management affected?
• Is it predictive of a future event?
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Drugs which bind to melanin
• If drug binds to melanin, drug
development may be stopped unless it is
shown that
– No histopathologic changes in areas of
binding or
– No ERG changes
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Drugs which cause retinal lesions
observed by funduscopy in
animals
• Drug development may be stopped unless
it is shown that
– No ERG changes
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Histopathologic Changes in
Animal Studies
• Drug development may be stopped unless
it is shown that
– No ERG changes
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Drugs which cause ERG changes
in animals
• ERG studies conducted in humans unless
a more sensitive screening test can be
identified
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Fatal Paths
• ERG changes alone may require
monitoring but do not usually stop drug
development
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Histopathologic retinal changes
• Histopathologic retinal changes may
requiring monitoring but may not stop
drug development
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Retinal lesions and ERG changes
• Drugs which cause retinal lesions and
ERG changes usually have their drug
development terminated
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ERG Standards
• Testing expected to measure both rod and
cone function in a variety of settings
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ERG Standards
• FDA does not usually set testing
standards
– Generally accepts ISCEV standards
– Requires explanation if ISCEV
standards are not followed
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Reporting ERG Results in Clinical
Trials
• Full numerical results are expected to be
reported (i.e., not pass/fail)
• Usually expect changes to be greater than
40% prior to considering abnormal
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Including ERG Results in Labeling
• Problematic
– Significance of animal findings are often
unknown
– Significance of human findings are
often not understood by most
physicians
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Questions
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