Center for Drug Evaluation and Research August 2005 Electroretinography: The FDA’s Viewpoint Wiley A. Chambers, MD Deputy Director Division of Anti-Infective and Ophthalmology Products Wiley A. Chambers, MD Deputy Director Division of Anti-Infective and Ophthalmology Products

Center for Drug Evaluation and Research August 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. 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.

Center for Drug Evaluation and Research August 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 Regulation of Interstate Commerce –Drugs – pre market clearance –Biologics – pre market clearance –Devices – pre market clearance –Foods –Cosmetics –NOT Procedures

Center for Drug Evaluation and Research August Mission of the Center for Drug Evaluation and Research Assure that safe and effective drugs are available to the American people.

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August Food 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

Center for Drug Evaluation and Research August Food Drug & Cosmetic Act 1938 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

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August Efficacy 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

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August ERG Equivalent ERG equivalent to doubling of the visual angle –Not currently known ERG equivalent to doubling of the visual angle –Not currently known

Center for Drug Evaluation and Research August 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 Must predict a clinical benefit for patient –Prevention of retinal detachment –Prevention of other anatomic change which will lead to visual loss

Center for Drug Evaluation and Research August 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 All drugs have some risk Risk assessed in adequate and well controlled studies Risk assessed in other clinical studies Risk assessed in postmarketing settings

Center for Drug Evaluation and Research August RiskRisk 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

Center for Drug Evaluation and Research August Utilization of ERG in Drug Development 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

Center for Drug Evaluation and Research August Clinical 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

Center for Drug Evaluation and Research August Drugs intended to affect electrophysiology 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

Center for Drug Evaluation and Research August Drugs intended to affect electrophysiology Used as secondary endpoint to support primary endpoint in human clinical studies

Center for Drug Evaluation and Research August Need clinical significance to use as 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?

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August Drugs which cause retinal lesions observed by funduscopy in animals 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

Center for Drug Evaluation and Research August Histopathologic Changes in Animal 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

Center for Drug Evaluation and Research August Drugs which cause ERG changes in animals ERG studies conducted in humans unless a more sensitive screening test can be identified

Center for Drug Evaluation and Research August Fatal Paths ERG changes alone may require monitoring but do not usually stop drug development

Center for Drug Evaluation and Research August Histopathologic retinal changes Histopathologic retinal changes may requiring monitoring but may not stop drug development

Center for Drug Evaluation and Research August Retinal lesions and ERG changes Drugs which cause retinal lesions and ERG changes usually have their drug development terminated

Center for Drug Evaluation and Research August ERG Standards Testing expected to measure both rod and cone function in a variety of settings

Center for Drug Evaluation and Research August ERG 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

Center for Drug Evaluation and Research August 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 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

Center for Drug Evaluation and Research August Including 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

Center for Drug Evaluation and Research August QuestionsQuestions