1 john m. carley kevin sweeney office of pesticide programs epa review of carroll-loye protocol...
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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?