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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 picaridin
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Organization of Presentation

 Background information

 Science Assessment

 Ethics Assessment
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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 attractiveness
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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 subject
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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 2009 
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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 documents
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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 2009
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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 submitted
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Science Assessment: LNX-003

Kevin Sweeney

Registration Division

Office of Pesticide Programs
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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% Picaridin
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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 days
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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”
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Efficacy Doses and MOEs

Mean 

Repellent 

Applied

Mean Picaridin 

Applied

Mean 

Dose in 

70-kg adult

MOE

Spray 0.52 g 104 mg 1.49 mg/kg 1342

Cream 0.96 g 192 mg 2.74 mg/kg 730
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Data Analysis and Censorship

 Spray product data provided enough 

information to calculate Kaplan-Meier median

 Data for cream product were too heavily rightcensored to support calculation of median

 Mean CPT values and time to 25% failure 

reported for both products
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Efficacy Test Results: LNX-003

Cream Spray

Mean CPT ± sd 

(95% CI)

12.6 ± 4.3 h 

(9.5 - 15.7 h)

14.1 ± 1.8 h 

(12.7 - 15.4 h)

Kaplan-Meier 

Median CPT * 15.0 h

Time to 25% 

failure >15.4 h 13.1 h

Mean CPT ± sd 

(95% CI)

15.3 ± 0.3 h 

(9.5 - 15.7 h) 

14.0 ± 1.6 h 

(12.8 - 15.2 h)

Kaplan-Meier 

Median CPT * 14.1 h

Time to 25% 

failure 9.7 h 12.0 h

Ix. scapularis D. variabilis

* Insufficient data to calculate Kaplan-Meier Median CPT for Cream
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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 pumpspray)
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Ethics Assessment: LNX-003

John M. Carley

Human Research Ethics Review Officer

Office of Pesticide Programs
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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

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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

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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” 

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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

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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

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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?