electroretinography: the fda’s viewpoint
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Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Electroretinography: The Electroretinography: The FDA’s ViewpointFDA’s ViewpointWiley A. Chambers, MD
Deputy DirectorDivision of Anti-Infective and
Ophthalmology Products
2Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
DisclaimerDisclaimer• 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.
3Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Federal Food, Drug and Federal Food, Drug and Cosmetic ActCosmetic Act
• Regulation of Interstate Commerce– Drugs – pre market clearance– Biologics – pre market clearance– Devices – pre market clearance– Foods– Cosmetics– NOT Procedures
4Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Mission of the Center for Drug Mission of the Center for Drug Evaluation and ResearchEvaluation and Research
• Assure that safe and effective drugs are available to the American people.
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Accomplished byAccomplished 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 ActFood and Drugs Act
• 1906
– Prohibits interstate commerce of misbranded and adulterated foods, drinks and drugs
7Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Food Drug & Cosmetic ActFood Drug & Cosmetic Act19381938
• Response to Elixir Sulfanilamide
• Review of Drug Safety
• Pre-market Review of Drugs
8Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Benefit to Risk RatioBenefit 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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BenefitBenefit
• 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 EndpointsEfficacy Endpoints
• Clinically important changes
– Visual function• Benefit• Prevention of loss
– Anatomic Predictors of Clinical Benefit
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Visual FunctionVisual 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 EquivalentERG Equivalent
• ERG equivalent to doubling of the visual angle
– Not currently known
13Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Anatomic Predictors of EfficacyAnatomic 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
14Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
RiskRisk
• 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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RiskRisk• 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 Utilization of ERG in Drug DevelopmentDevelopment
• Pre-clinical studies
– Drug intended to affect electrophysiology
– Drugs which bind to melanin
– Drugs which cause retinal lesions
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Clinical studiesClinical studies
• Drugs intended to affect electrophysiology
• Drugs which have demonstrated ERG abnormalities in animals
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Drugs intended to affect Drugs intended to affect electrophysiologyelectrophysiology
• Used as efficacy measure in animal studies
– Assist in determining current dose
– Assist in determining duration of effect
19Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Drugs intended to affect Drugs intended to affect electrophysiologyelectrophysiology
• Used as secondary endpoint to support primary endpoint in human clinical studies
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Need clinical significance to use Need clinical significance to use as a primary endpointas a primary endpoint
• Is patient function affected?
• Is clinical management affected?
• Is it predictive of a future event?
21Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Drugs which bind to melaninDrugs 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
22Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Drugs which cause retinal lesions Drugs which cause retinal lesions observed by funduscopy in observed by funduscopy in
animalsanimals
• Drug development may be stopped unless it is shown that
– No ERG changes
23Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Histopathologic Changes in Histopathologic Changes in Animal StudiesAnimal Studies
• Drug development may be stopped unless it is shown that
– No ERG changes
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Drugs which cause ERG changes Drugs which cause ERG changes in animalsin animals
• ERG studies conducted in humans unless a more sensitive screening test can be identified
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Fatal PathsFatal Paths
• ERG changes alone may require monitoring but do not usually stop drug development
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Histopathologic retinal changesHistopathologic retinal changes
• Histopathologic retinal changes may requiring monitoring but may not stop drug development
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Retinal lesions and ERG changesRetinal lesions and ERG changes
• Drugs which cause retinal lesions and ERG changes usually have their drug development terminated
28Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
ERG StandardsERG Standards
• Testing expected to measure both rod and cone function in a variety of settings
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ERG StandardsERG 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 Reporting ERG Results in Clinical TrialsTrials
• 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 LabelingIncluding ERG Results in Labeling
• Problematic
– Significance of animal findings are often unknown
– Significance of human findings are often not understood by most physicians
32Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
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