1. 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

2. Center for Drug Evaluation and Research August 2005 2 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.

3. Center for Drug Evaluation and Research August 2005 3 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

4. Center for Drug Evaluation and Research August 2005 4 Mission of the Center for Drug Evaluation and Research Assure that safe and effective drugs are available to the American people.

5. Center for Drug Evaluation and Research August 2005 5 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

6. Center for Drug Evaluation and Research August 2005 6 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

7. Center for Drug Evaluation and Research August 2005 7 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

8. Center for Drug Evaluation and Research August 2005 8 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

9. Center for Drug Evaluation and Research August 2005 9 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

10. Center for Drug Evaluation and Research August 2005 10 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

11. Center for Drug Evaluation and Research August 2005 11 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

12. Center for Drug Evaluation and Research August 2005 12 ERG Equivalent ERG equivalent to doubling of the visual angle –Not currently known ERG equivalent to doubling of the visual angle –Not currently known

13. Center for Drug Evaluation and Research August 2005 13 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

14. Center for Drug Evaluation and Research August 2005 14 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

15. Center for Drug Evaluation and Research August 2005 15 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

16. Center for Drug Evaluation and Research August 2005 16 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

17. Center for Drug Evaluation and Research August 2005 17 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

18. Center for Drug Evaluation and Research August 2005 18 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

19. Center for Drug Evaluation and Research August 2005 19 Drugs intended to affect electrophysiology Used as secondary endpoint to support primary endpoint in human clinical studies

20. Center for Drug Evaluation and Research August 2005 20 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?

21. Center for Drug Evaluation and Research August 2005 21 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

22. Center for Drug Evaluation and Research August 2005 22 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

23. Center for Drug Evaluation and Research August 2005 23 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

24. Center for Drug Evaluation and Research August 2005 24 Drugs which cause ERG changes in animals ERG studies conducted in humans unless a more sensitive screening test can be identified

25. Center for Drug Evaluation and Research August 2005 25 Fatal Paths ERG changes alone may require monitoring but do not usually stop drug development

26. Center for Drug Evaluation and Research August 2005 26 Histopathologic retinal changes Histopathologic retinal changes may requiring monitoring but may not stop drug development

27. Center for Drug Evaluation and Research August 2005 27 Retinal lesions and ERG changes Drugs which cause retinal lesions and ERG changes usually have their drug development terminated

28. Center for Drug Evaluation and Research August 2005 28 ERG Standards Testing expected to measure both rod and cone function in a variety of settings

29. Center for Drug Evaluation and Research August 2005 29 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

30. Center for Drug Evaluation and Research August 2005 30 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

31. Center for Drug Evaluation and Research August 2005 31 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

32. Center for Drug Evaluation and Research August 2005 32 QuestionsQuestions