EPA Review of Carroll-Loye Protocol LNX-002

1. EPA Review of Carroll-Loye Protocol LNX-002 Proposal for a field test of biting fly repellency for two conditionally registered formulations containing 20% picaridin John M. Carley Kevin Sweeney Office of Pesticide Programs

2. Status Summary • Protocol LNX-002, submitted by Carroll-Loye Biological Research, proposes a field study of the repellent efficacy of two conditionally registered formulations containing 20% picaridin against biting flies • The initial submission, as supplemented with additional information from the IRB, meets the standard of completeness defined in 40 CFR §26.1125, and is ripe for HSRB review

3. What’s Familiar about this Study? • The protocol is similar to mosquito repellent field studies from CLBR previously reviewed by the HSRB • The test materials are the same as those tested by CLBR against mosquitoes in LNX-001 • The protocol proposes to use the “typical consumer dose” established in LNX-001 • The test materials are the same as those tested by ICR against stable flies in the laboratory in the completed study A-382

4. What’s Different about this Protocol • It is the first protocol to be reviewed by the HSRB for a field trial of repellent efficacy against biting flies • Only one field trial, in a single habitat • Intermittent exposures for 5-minute periods every 30 minutes • New format for a CLBR protocol • Fully incorporates previous EPA and HSRB comments • Streamlines the organization of the protocol to improve clarity and reduce redundancy

5. Science Assessment: LNX-002 Kevin Sweeney Senior Entomologist Registration Division Office of Pesticide Programs

6. LNX-002: Objectives The objectives of this study are: • To test the repellent efficacy characteristics of the test material against biting flies in the field • To satisfy a condition of registration

7. Test Materials • EPA Reg. No. 39967-50 (lotion) 39967-53 (pump spray) • Both contain 20% Picaridin • Oral LD-50 > 5,000 mg/kg • Dermal LD-50 > 2,000 mg/kg

8. Subject Dosing • Dose rates are those established for the same test materials in study LNX-001 • Because lotion and spray treatments are easily distinguishable, the study will be only partially blinded • Technicians recording results will not know which treatment was applied to which subject(s)

9. Study Design • 10 subjects treated with each formulation and 2 untreated control subjects will participate in a single field trial • Untreated subjects will monitor biting fly pressure • Both treated and untreated subjects will be exposed to biting flies for 5 minutes of every 30 minutes • No positive or vehicle controls are proposed

10. Study Design—2 • Field site: California Central Valley • Expected biting fly populations: • Biting midges (Leptoconops carteri), or • Black flies (Simulium cf. vittatum) • Measured variables: • Subject limb area • Biting pressure (must be ≥ 1 LIBe/5 minutes) • First Confirmed LIBe (FCLIBe) • Time to FCLIBe

11. Endpoints and Data Analysis • Duration of “complete protection time” (CPT) will be calculated as the mean time across all treated subjects from treatment to “first confirmed landing with intent to bite” or “FCLIBe” • CPT will be presented with standard deviation and 95% confidence interval • Untreated controls will not be used for comparison of treatment means • Other analyses—including Kaplan-Meier survivor analysis—will be conducted if appropriate

12. Margins of Exposure

13. Sample Size • Sample size of 10 with 2 controls is justified as a compromise between financial and scientific concerns, adequate to achieve statistically meaningful results • EPA guideline recommends 6 replicates • EPA believes a sample size of 10 treated subjects is acceptable for a study of this type

14. Deficiencies Noted in EPA Review • Standard of Biting Pressure is not well-justified • A standard of 1 LIBe in 5 minutes may not be high enough to ensure a valid test • Low standard may lead to few failures and right-censored data • Shift from sampling for 1 minute in 15 to 5 minutes in 30 is not explained

15. Compliance with Scientific Standards • If amended to address the concerns raised in the EPA review, CLBR protocol LNX-002 is likely to yield scientifically reliable information, satisfying the following scientific criteria from the framework recommended by the HSRB: • It would produce important information that cannot be obtained except from research with human subjects • It has clear scientific objectives • The study design should produce adequate data to achieve those objectives

16. Ethics Assessment: LNX-002 John M. Carley Human Research Ethics Review Officer Office of Pesticide Programs

17. Value to Society • Proposed study would test the repellent efficacy of two test formulations against biting flies in the field • Both test formulations are conditionally registered; product-specific field efficacy testing is required to support label claims of repellency against biting flies • Biting flies can be serious nuisance pests; a potentially attractive alternative to other available repellents would be of benefit to many users

18. Subject Selection • Subjects will be recruited among people who have expressed interest in participating in future repellency tests, supplemented by word-of-mouth referrals • Inclusion and Exclusion factors are well defined and appropriate • Two experienced subjects meeting special inclusion criteria will serve as untreated controls • No eligible subjects come from populations who would be especially vulnerable

19. Risks to Subjects • Test repellents will irritate the eyes on contact, and are harmful if swallowed • Possible exposure to biting arthropods • Possible exposure to arthropod-borne disease • Physical stress of participation • Breach of privacy

20. Benefits • No direct benefit to subjects • Primary direct beneficiary is sponsor • If materials are proven effective and remain on the market, indirect beneficiaries will include repellent users who prefer one of these products to other repellents

21. Risk:Benefit Balance • No reasonable opportunities have been overlooked to further reduce risk while maintaining scientific robustness • Probability of residual risks to subjects is accurately characterized as “extremely small” • Risks to subjects are reasonable in light of the expected societal benefits of the knowledge likely to be gained

22. Independent Ethics Review • The Independent Investigational Review Board (IIRB) of Plantation FL: • Reviewed and approved the protocol and informed consent materials • Is independent of the sponsors and investigators • Is registered with OHRP • Is seeking accreditation from AAHRPP • IIRB “Human Research Protection Program Plan” included in supplemental submission of IRB materials

23. Informed Consent • Description of subject recruiting and consent processes is complete and satisfactory • Separate IRB-approved Consent Forms are provided for treated subjects and for untreated controls • Consent Forms include all elements required by regulations • Language and reading level of Consent Forms is appropriate

24. Respect for Subjects • Methods proposed for managing information about prospective and enrolled subjects will effectively protect their privacy • Subjects will be free to withdraw at any time, and will be reminded of this often • Compensation: • Proposed level of compensation is appropriate • Subjects who withdraw will be compensated for time spent up to the point of withdrawal • Alternate subjects who are not needed for the field trial will be compensated for their inconvenience • Medical care for research-related injuries will be provided at no cost to subjects

25. Applicable Ethical Standards • This is a proposal for third-party research involving intentional exposure of human subjects to a pesticide, with the intention of submitting the resulting data to EPA under the pesticide laws • The primary ethical standards applicable to the conduct of this research are 40 CFR 26, Subparts K and L • Attachment 1 to the EPA Review contains a point-by-point evaluation of how this protocol addresses the requirements of 40 CFR 26 Subparts K and L and additional criteria recommended by the HSRB

26. Findings in EPA Ethics Review • No deficiencies relative to 40 CFR 26, subparts K and L, or to FIFRA §12(a)(2)(P) were identified in this review • We defer to reviewers in the California Department of Pesticide Regulation to assess compliance with applicable California state requirements • One minor drafting error noted in the protocol discussion of stopping rules should be corrected

27. Compliance with Ethical Standards • All requirements of §26.1111, §26.1116, and §26.1117 are met • All requirements of §26.1125 are met • All requirements of §26.1203 are met • All elements of NAS recommendation 5-1 are satisfied • All elements of NAS recommendation 5-2 are satisfied

28. Conclusion • If further revised to correct the identi-fied drafting error, CLBR protocol LNX-002 will meet the applicable requirements of 40 CFR part 26, subparts K and L

29. LNX-002: Charge Questions • If the proposed field repellency study protocol LNX-002 is revised as suggested in EPA’s review and if the research is performed as described: Is the research likely to generate scientifically reliable data, useful for assessing the efficacy of the tested materials in repelling biting flies in the field? Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L?