Electroretinography: The FDA’s Viewpoint

1. Electroretinography: The FDA’s Viewpoint Wiley A. Chambers, MD Deputy Director Division of Anti-Infective and Ophthalmology Products

2. Disclaimer • 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. 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

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

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

6. Food and Drugs Act • 1906 • Prohibits interstate commerce of misbranded and adulterated foods, drinks and drugs

7. Food Drug & Cosmetic Act1938 • Response to Elixir Sulfanilamide • Review of Drug Safety • Pre-market Review of Drugs

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

9. Benefit • 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. Efficacy Endpoints • Clinically important changes • Visual function • Benefit • Prevention of loss • Anatomic Predictors of Clinical Benefit

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

12. ERG Equivalent • ERG equivalent to doubling of the visual angle • Not currently known

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

14. Risk • 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. Risk • Assessment improves as more individuals receive the drug product • Usually not completely known until after the drug product is marketed

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

17. Clinical studies • Drugs intended to affect electrophysiology • Drugs which have demonstrated ERG abnormalities in animals

18. Drugs intended to affect electrophysiology • Used as efficacy measure in animal studies • Assist in determining current dose • Assist in determining duration of effect

19. Drugs intended to affect electrophysiology • Used as secondary endpoint to support primary endpoint in human clinical studies

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?

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

22. Drugs which cause retinal lesions observed by funduscopy in animals • Drug development may be stopped unless it is shown that • No ERG changes

23. Histopathologic Changes in Animal Studies • Drug development may be stopped unless it is shown that • No ERG changes

24. Drugs which cause ERG changes in animals • ERG studies conducted in humans unless a more sensitive screening test can be identified

25. Fatal Paths • ERG changes alone may require monitoring but do not usually stop drug development

26. Histopathologic retinal changes • Histopathologic retinal changes may requiring monitoring but may not stop drug development

27. Retinal lesions and ERG changes • Drugs which cause retinal lesions and ERG changes usually have their drug development terminated

28. ERG Standards • Testing expected to measure both rod and cone function in a variety of settings

29. ERG Standards • FDA does not usually set testing standards • Generally accepts ISCEV standards • Requires explanation if ISCEV standards are not followed

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

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

32. Questions