EPA Review of CarrollLoye Protocol LNX002

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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

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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

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Whats 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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Whats 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-002

• Kevin Sweeney
• Senior Entomologist
• Registration Division
• Office of Pesticide Programs

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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

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Test Materials

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

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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)

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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

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Study Design2

• 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 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 analysesincluding Kaplan-Meier survivor
  analysiswill be conducted if appropriate

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Margins of Exposure
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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

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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

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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

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Ethics Assessment LNX-002

• John M. Carley
• Human Research Ethics Review Officer
• Office of Pesticide Programs

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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

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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

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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

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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

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RiskBenefit 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 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 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 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 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 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 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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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

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LNX-002 Charge Questions

• If the proposed field repellency study protocol
  LNX-002 is revised as suggested in EPAs 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?