1 John M. Carley Kevin Sweeney Office of Pesticide Programs 

## EPA Review of Completed Carroll - Loye Study LNX

- 003 A laboratory test of the repellent efficacy 

### against 2 tick species of 2 conditionally registered formulations containing picaridin2 

## Organization of Presentation

 

## Background information  

## Science Assessment  

## Ethics Assessment3



## LNX - 003 Basics  Laboratory test of repellency of 2 picaridin repellents against laboratory- reared, pathogen - free ticks of 2 species  All subjects trained before study to handle ticks  20 subjects treated on one arm, 10 with each repellent, at standard dose rates established in earlier studies LNX- 001 and LNX- 002  Untreated arm of each subject used to confirm tick aggressiveness and subject attractiveness45



## LNX - 003 Design
 In each exposure cycle, repeated every 15 min until end of study: 

###  A tick of species A is tested for questing on untreated arm 

###  Qualified tick of species A is tested for repellency on treated arm 

###  A tick of species B is tested for questing on untreated arm 

###  Qualified tick of species B is tested for repellency on treated arm  Endpoint is first confirmed crossing for each tick species for each subject6



## LNX - 003 Protocol Review
 Protocol LNX- 003, 26 July 2009, was approved by IIRB, Inc. with a minor correction on 4 August 2009, and submitted to EPA on 6 August 2009  The protocol met the standard of completeness defined in 40 CFR 26.1125  EPA science and ethics review of 21 September 2009 was based on the initial protocol submission  The HSRB reviewed protocol LNX- 003 favorably at its meeting on 21 October 20097 

## Amendment 1, 30 October 2009  

### Responds to EPA and HSRB comments and to 

### initial California DPR review  

### Clarifies 

##  Procedures applying to one, both, or either tick species 

###  Subject screening for attractiveness to ticks 

###  Stopping rules  

### Corrects minor errors and confusing statements  

### Revises consent form and other documents8



## Review of Amendment 1  

### Submitted to IIRB, Inc. on 2 November 2009  

### Approved by IIRB, Inc. on 2 November 2009 after undocumented expedited review  

### Amended protocol approved by California DPR on 16 November 20099 

## LNX - 003 Execution & Reporting 7 January Training ticks received from CDC 15 - 23 January Subjects recruited and trained to

handle ticks 20 January Repellency ticks received from CDC 23 - 24 January Repellency testing 5 April Report completed 7 April Report submitted10 

## Science Assessment: LNX - 003 Kevin Sweeney Registration Division Office of Pesticide Programs11



## Objectives  To test the repellent efficacy of the test materials against nymphal ticks of 2 species  To satisfy a condition of registration



# Test Materials  EPA Reg. No. 39967 - 50 (cream)

39967 - 53 (pump spray)  Both contain 20% Picaridin12



## LNX - 003 Study Design
 20 subjects and 3 alternates were trained in the laboratory to handle lab - reared, pathogen - free ticks and to remove them before they could bury and bite  In efficacy trials 

###  10 subjects were treated with each test material 

###  10 subjects were tested on each of two successive days13



## LNX - 003 Study Design

— 2

 The untreated arm of each treated subject served to ensure that only actively questing ticks were used in efficacy testing  Each subject tested one nymphal tick of each species in each 15 - minute exposure period, until efficacy failure or approximately 15 hours post-treatment  Complete Protection Time (CPT) was calculated for each subject as the time from treatment to “First Confirmed Crossing” or “FCC”14



## Efficacy Doses and MOEs15 

## Data Analysis and Censorship  

### Spray product data provided enough information to calculate Kaplan - Meier median  

### Data for cream product were too heavily right 

### censored to support calculation of median  

### Mean CPT values and time to 25% failure reported for both products16 

## Efficacy Test Results: LNX - 00317



## Conclusions  The study design and conduct meet EPA Guideline and Good Laboratory Practices standards  The study results are sufficiently sound to support estimates of the duration of complete protection against Dermacentor and Ixodes ticks provided by 

###  EPA Reg. No. 39967 - 50 KBR 3023 All - Family Insect Repellent Cream (20% picaridin cream) 

##  EPA Reg. No. 39967 - 53 KBR 3023 All - Family Insect Repellent Spray (20% picaridin pump spray)18 

## Ethics Assessment: LNX - 003 John M. Carley Human Research Ethics Review Officer Office of Pesticide Programs19



## Documents Considered  Primary study report MRID 48053801  EPA Science & Ethics Review of Protocol LNX- 003  HSRB Report of October 2009 review of LNX- 003  IIRB, Inc. roster and procedures  EPA —IIRB, Inc. e - mail exchange of 20 Apr 2010 

## Completeness  The requirements of 40 CFR 26.1303 to document ethical conduct of the research are satisfied 1920 

## Response to Previous Ethics Reviews  In its 21 September 09 review of LNX- 003 EPA called for: 

###  Reclassification of two exclusion criteria as stopping rules • Satisfactorily addressed in Amendment 1 

###  Revision of statement in consent form concerning payment for uninsured medical expenses • Not addressed  In its 16 December 2009 final report of its October 2009 meeting the HSRB concurred with EPA’s review and recommended no additional refinements to this protocol 2021



## Applicable Standards  40 CFR § 26.1303, requiring documentation of the ethical conduct of the research  40 CFR § 26.1703, forbidding EPA to rely on data from research involving intentional exposure of pregnant or nursing women or of children  40 CFR § 26.1705, forbidding EPA to rely on data from research initiated after April 6, 2006 “unless EPA has adequate information to determine that the research was conducted in substantial compliance with subparts A through L of this part”  FIFRA § 12(a)(2)(P), which defines as unlawful “for any person . . . to use any pesticide in tests on human beings unless such human beings (i) are fully informed . . . and (ii) freely volunteer to participate in the test” 2122



## Findings  The requirements of 40 CFR § 26.1303 to document the ethical conduct of LNX- 003 have been satisfied  LNX- 003 did not involve intentional exposure of pregnant or nursing women or of children under 18  There were no protocol deviations, and notwithstanding the failure to revise consent form language as directed by EPA, the overall record shows that LNX - 003 was conducted in substantial compliance with all applicable requirements of 40 CFR part 26, subparts A- L  Subjects were fully informed and participated voluntarily 2223



## Conclusion

 Assuming LNX- 003 is determined to be scientifically acceptable, I find no barrier in law or regulation to EPA’s reliance on it in actions under FIFRA

2324 

## LNX - 003: Charge Questions 2(a) Is the CLBR study LNX- 003 sufficiently sound, from a scientific perspective, to be used to estimate the duration of complete protection against ticks provided by the tested repellents? 2(b) Does available information support a determination that study LNX- 003 was conducted in substantial compliance with subparts K and L 40 CFR Part 26?