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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 Viewpoint
Electroretinography: The Electroretinography: The FDA’s ViewpointFDA’s Viewpoint
Wiley A. Chambers, MDDeputy Director
Division of Anti-Infective and Ophthalmology Products
Wiley A. Chambers, MDDeputy Director
Division of Anti-Infective and Ophthalmology Products
2Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
DisclaimerDisclaimerDisclaimerDisclaimer
• 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.
• 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
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
• 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
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.
• Assure that safe and effective drugs are available to the American people.
5Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Accomplished byAccomplished byAccomplished 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
• 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
6Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Food and Drugs ActFood and Drugs ActFood and Drugs ActFood and Drugs Act
• 1906
– Prohibits interstate commerce of misbranded and adulterated foods, drinks and drugs
• 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
Food Drug & Cosmetic ActFood Drug & Cosmetic Act19381938
• Response to Elixir Sulfanilamide
• Review of Drug Safety
• Pre-market Review of Drugs
• 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 RatioBenefit 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
• 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
9Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
BenefitBenefitBenefitBenefit
• 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
• 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
10Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Efficacy EndpointsEfficacy EndpointsEfficacy EndpointsEfficacy Endpoints
• Clinically important changes
– Visual function• Benefit• Prevention of loss
– Anatomic Predictors of Clinical Benefit
• Clinically important changes
– Visual function• Benefit• Prevention of loss
– Anatomic Predictors of Clinical Benefit
11Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Visual FunctionVisual FunctionVisual 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
• 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
12Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
ERG EquivalentERG EquivalentERG EquivalentERG Equivalent
• ERG equivalent to doubling of the visual angle
– Not currently known
• 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 EfficacyAnatomic 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
• 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
RiskRiskRiskRisk
• All drugs have some risk
• Risk assessed in adequate and well controlled studies
• Risk assessed in other clinical studies
• Risk assessed in postmarketing settings
• All drugs have some risk
• Risk assessed in adequate and well controlled studies
• Risk assessed in other clinical studies
• Risk assessed in postmarketing settings
15Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
RiskRiskRiskRisk
• Assessment improves as more individuals receive the drug product
• Usually not completely known until after the drug product is marketed
• Assessment improves as more individuals receive the drug product
• Usually not completely known until after the drug product is marketed
16Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Utilization of ERG in Drug Utilization of ERG in Drug DevelopmentDevelopment
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
• Pre-clinical studies
– Drug intended to affect electrophysiology
– Drugs which bind to melanin
– Drugs which cause retinal lesions
17Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Clinical studiesClinical studiesClinical studiesClinical studies
• Drugs intended to affect electrophysiology
• Drugs which have demonstrated ERG abnormalities in animals
• Drugs intended to affect electrophysiology
• Drugs which have demonstrated ERG abnormalities in animals
18Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Drugs intended to affect Drugs intended to affect electrophysiologyelectrophysiology
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
• 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
Drugs intended to affect Drugs intended to affect electrophysiologyelectrophysiology
• Used as secondary endpoint to support primary endpoint in human clinical studies
• Used as secondary endpoint to support primary endpoint in human clinical studies
20Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Need clinical significance to use Need clinical significance to use as a primary endpointas a primary endpoint
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?
• 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 melaninDrugs 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
• 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
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
• 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
Histopathologic Changes in Histopathologic Changes in Animal StudiesAnimal Studies
• Drug development may be stopped unless it is shown that
– No ERG changes
• Drug development may be stopped unless it is shown that
– No ERG changes
24Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Drugs which cause ERG changes Drugs which cause ERG changes in animalsin animals
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
• ERG studies conducted in humans unless a more sensitive screening test can be identified
25Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Fatal PathsFatal PathsFatal PathsFatal Paths
• ERG changes alone may require monitoring but do not usually stop drug development
• ERG changes alone may require monitoring but do not usually stop drug development
26Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Histopathologic retinal changesHistopathologic retinal changesHistopathologic retinal changesHistopathologic retinal changes
• Histopathologic retinal changes may requiring monitoring but may not stop drug development
• Histopathologic retinal changes may requiring monitoring but may not stop drug development
27Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Retinal lesions and ERG changesRetinal lesions and ERG changesRetinal lesions and ERG changesRetinal lesions and ERG changes
• Drugs which cause retinal lesions and ERG changes usually have their drug development terminated
• 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 StandardsERG StandardsERG Standards
• Testing expected to measure both rod and cone function in a variety of settings
• Testing expected to measure both rod and cone function in a variety of settings
29Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
ERG StandardsERG StandardsERG StandardsERG Standards
• FDA does not usually set testing standards
– Generally accepts ISCEV standards
– Requires explanation if ISCEV standards are not followed
• FDA does not usually set testing standards
– Generally accepts ISCEV standards
– Requires explanation if ISCEV standards are not followed
30Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Reporting ERG Results in Clinical Reporting ERG Results in Clinical TrialsTrials
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
• 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
31Center for Drug Evaluation and Research Center for Drug Evaluation and Research August 2005August 2005
Including ERG Results in LabelingIncluding ERG Results in LabelingIncluding 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
• 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
QuestionsQuestionsQuestionsQuestions