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