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John M. CarleyJohn M. CarleyKevin SweeneyKevin Sweeney

Office of Pesticide ProgramsOffice of Pesticide Programs

EPA Review of Carroll-EPA Review of Carroll-Loye Protocol LNX-002Loye Protocol LNX-002

Proposal for a field test of biting fly repellency for two conditionally

registered formulationscontaining 20% picaridin

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Status SummaryStatus 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

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What’s Familiar about this Study?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

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What’s Different about this ProtocolWhat’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

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Science Assessment: LNX-002Science Assessment: LNX-002

Kevin Sweeney

Senior EntomologistRegistration Division

Office of Pesticide Programs

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LNX-002: ObjectivesLNX-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

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Test MaterialsTest 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

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Subject DosingSubject 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)

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Study DesignStudy 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

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Study Design—2Study 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

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Endpoints and Data AnalysisEndpoints 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

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Margins of ExposureMargins of Exposure

Arms Legs Arms Legs

Standard dose rate (μl/cm2) 2.51 2.36 0.97 0.83

Average skin area (cm2) 500 1142 500 1142

Average product dose (μl) 1255 2695 485 948

Average product dose (mg) 1281 2750 505 987

Average picaridin dose (mg) 256 550 101 197

Picaridin dose in mg/kg 3.66 7.86 1.44 2.82

Margin of Exposure (MOE) 547 255 1386 709

Spray 20%Lotion 20%

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Sample SizeSample 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

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Deficiencies Noted in EPA ReviewDeficiencies 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

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Compliance with Scientific Compliance with Scientific StandardsStandards

• 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

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Ethics Assessment: LNX-002Ethics Assessment: LNX-002

John M. Carley

Human Research Ethics Review OfficerOffice of Pesticide Programs

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Value to SocietyValue 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

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Subject SelectionSubject 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

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Risks to SubjectsRisks 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

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BenefitsBenefits

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

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Risk:Benefit Balance 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

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Independent Ethics ReviewIndependent 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

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Informed ConsentInformed 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

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Respect for SubjectsRespect 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

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Applicable Ethical StandardsApplicable 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

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Findings in EPA Ethics ReviewFindings 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

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Compliance with Ethical StandardsCompliance 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

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ConclusionConclusion

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

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LNX-002: Charge QuestionsLNX-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?