Electroretinography: The FDA

1
Electroretinography The FDAs 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 plt.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