1 William Jordan Senior Policy Advisor Office of Pesticide Programs 

## OPP Policy Decisions Regarding 

## Insect Repellent Efficacy Testing2



## Policy Issues  

### Objective of repellent efficacy testing  

### Choice of endpoint for repellent efficacy studies  

### Statistics & handling of censored data 

# General Considerations  

### Consistency of approach  

### History of testing methods/implementation3 

## Issue 1: Objective of Repellent Testing  

## Preferred objective is to measure duration of complete protection  

## Consistent with market research by both EPA and registrants: Repellent users expect and demand complete protection4 

## Issue 2: Choice of Endpoint  

### Preferred study endpoint is first confirmed failure event  

### Failure events vary depending on species: 

###  Landing (or bite) for mosquitoes and flies 

###  Crossing for ticks and chiggers  

### Choice of confirmed events as endpoints reduces variability5 

## Issue #3: Statistics & Data Censoring  

### Preferred summary statistic is Kaplan - Meier median Complete Protection Time with 95% c.i.  

### If K- M median is not calculable, mean CPT with 

### 95% c.i. is acceptable  

### Underestimates of mean and variance resulting from treating censored data points as confirmed 

### failure events are acceptable for regulatory purposes6 John M. Carley Office of Pesticide Programs 

## Product Performance TestGuidelines OPPTS 810.3700: Insect Repellents to be Applied to Human Skin7



## Role of Guidelines  Data requirements 

###  Defined by regulation 

###  Interpreted and applied case- by-case  Test guidelines 

###  Advisory, not mandatory 

###  If a particular data requirement is imposed, here’s how we recommend you address it  Standard Evaluation Procedures (SEPs)  Labeling standards8 

## Assumptions Underlying Guideline  

### OPP will continue to require laboratory and field tests of topical repellent efficacy  

### Guideline should include standard methods 

### for commonly required types of repellent efficacy testing  

### Guideline should serve as a single source 

### for all guidance directly relevant to sponsors and investigators conducting repellent efficacy tests9 

## Events Since October 2008  

### HSRB Comments 

###  On guideline draft of September 2008 

###  On subsequently reviewed protocols and completed studies  

### Other Comments  

### WHO Repellent Testing Guidelines  

### Consumer Research10



## EPA Response  

### Compile all HSRB and other comments  

### Use multidisciplinary internal workgroup to analyze comments by topic and issue  

### Consult with repellent scientists from USDA  

### Identify and resolve policy questions  

### Revise guideline within policy framework in response to comments11



## Scope of This Guideline  Guideline includes 

###  Technical guidance for commonly required standard performance tests for skin -applied repellents 

###  What investigators need to know about the Human Studies Rule to prepare protocols and conduct studies likely to be reviewed favorably by EPA and the HSRB  Guideline does not include technical guidance for 

###  Non -standard or rarely performed tests 

###  Tests of repellency of impregnated fabrics or clothing 

###  Tests of products intended to repel insects from indoor or outdoor spaces12 

## Overall Structure of Guideline  

### Introduction and Definitions  

### General guidance applying to all repellent studies 

###  Developing a protocol 

###  Review of protocols 

###  Changes to approved protocols 

###  Execution 

###  Reporting 

##  Records retention  

### Guidance applying to commonly required tests  

### References and Appendices13 

## Commonly Required Standard Tests  

### Lab tests to determine typical consumer dose  

### Lab tests with mosquitoes  

### Lab tests with biting flies  

### Field tests with mosquitoes  

### Field tests with biting flies  

### Lab tests with ticks or chiggers14



## Changes in this Revision  

### Reflection of policy decisions  

### Streamlined organization  

### Changes in general guidance 

###  Study design 

###  Statistics 

###  Ethics  

### Changes in specific guidance15 

## General Guidance: Study Design  Clarify limited appropriateness of multiple treatments per subject  Recommend treated subjects not also serve as untreated controls  Recommend positive controls in all studies (20% deet in ethanol at standard 1 g/600 cm 2 rate)  Emphasize importance of representative samples  Recommend testing attractiveness to target pests to qualify subjects16 

## General Guidance: Statistics  

## Recommend longer test duration and earliest practical treatment to reduce potential for data censorship  

## Revise discussion of sample size  

## Revise discussion of analysis plan17



## General Guidance: Ethics  Clarify—  Prerequisite research  Risks of concern are only those associated with participation in research (vice background risks)  Regulations require benefits discussion and assessment of relation of benefits to risks  Subjects from potentially vulnerable populations should not be arbitrarily excluded if special care would provide adequate protection of their safety and welfare  Rationale for discouraging distant travel  Cite Flesch - Kincaid Grade Level as measure of readability  Call for specifying how investigators will confirm candidate understanding18 

## Specific Guidance: Dose Determination  

## Clarify methods— 

##  For measuring subject skin area 

##  For calculating standard dose  

## Identify additional reporting elements19 

## Specific Guidance: Mosquitoes & Flies  Lab tests: Clarify rearing techniques, cage size, insect density  Field tests: Clarify subject placement and behavior; revise site-selection criterion for pre-test absence of WNV  Recommend standard positive control  Discourage use of treated subjects as untreated controls  Identify additional reporting elements  Merge and harmonize M & F guidance20 

## Specific Guidance: Ticks & Chiggers  

### Clarify description of recommended method  

### Recommend refining definition of “crossing” to suit species and life stage used in testing  

### Accept concurrent testing with 2 species  

### Clarify rearing techniques, number of ticks, test conditions, subject preparation  

### Recommend standard positive controls21



## Next Steps  

### Publish this guideline for immediate use  

### Further refine this guideline in response to comments and new developments  

### Continue development of additional guidelines: 

##  Impregnated materials and space repellents 

###  Exposure studies