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Electroretinography: The Electroretinography: The FDA’s ViewpointFDA’s ViewpointWiley A. Chambers, MD

Deputy DirectorDivision of Anti-Infective and

Ophthalmology Products

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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.

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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

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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

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Food Drug & Cosmetic ActFood Drug & Cosmetic Act19381938

• Response to Elixir Sulfanilamide

• Review of Drug Safety

• Pre-market Review of Drugs

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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

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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

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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

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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?

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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

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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

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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

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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

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QuestionsQuestions