1 John M. Carley Kevin Sweeney Office of Pesticide Programs 

# EPA Review of Completed Carroll - Loye Study LNX

- 002 A field test of black fly repellency for two 

## conditionally registered formulations containing 20% picaridin2 

# Organization of Presentation

 

# Background information  

# Science Assessment  

# Ethics Assessment3



# LNX - 002: Basics  

## Field test in one habitat of repellency of 2 picaridin repellents against biting flies  

## 10 subjects treated with each repellent at 

## dose rates established in earlier LNX- 001  

## 2 untreated subjects to confirm pest pressure  

## Endpoint is first confirmed landing with intent to bite (Libe) for each subject4



# LNX - 002: Protocol Review
 Protocol of 23 March 2009, was approved by IIRB, Inc. on 24 March and submitted to EPA by Carroll - Loye Biological Research  EPA’s science and ethics review of 18 May 2009 found the protocol acceptable with minor changes  HSRB review on 25 June 2009 concurred with EPA but called for testing only with black flies or midges  Amendment 1, 13 August 2009, addressed EPA and HSRB comments and was approved by IIRB, Inc. on 18 August 2009  Amended protocol was approved by CDPR on 14 September 2009  HSRB leadership on 16 September 2009 decided scope of amendment did not necessitate re- review by HSRB5



# LNX - 002: Amendment 1  Provides for collection & analysis of new dosimetry data on the cream  As recommended by EPA 

###  Corrects drafting error for stopping rules 

###  Raises minimum landing pressure 

###  Changes exposure from 5 of every 30 min to 1 of every 15 min  As recommended by HSRB 

###  Focuses test on black flies 

###  Revises reference to 3rd - party insurance in consent form  Revises discussion of how data censorship will be minimized  Adds assay of subjects’ attractiveness to target insects  Revises protocol and consent form regarding number of subjects and details of subject participation6



# Study Execution 26 - 30 Sep 2009 Dose determination subjects recruited; dose

determination testing with cream conducted 2 Mar 2010 Progress report submitted to IIRB, Inc. 9 Mar 2010 IIRB, Inc. approves one-year extension 15 - 19 Mar 2010 Subjects recruited for field test 20 Mar 2010 Field test conducted 1 Apr 2010 Deviation report to IIRB Re: use of superseded

data collection form 5 Apr 2010 Study completion date 7 Apr 2010 Final report submitted to EPA 67



# Study Reporting & Review 7 Apr 2010 Primary report of LNX- 002 submitted to EPA 12 Apr 2010 EPA notified CLBR of missing record of IIRB, Inc.

approval of Amendment 1 19 Apr 2010 CLBR submitted supplement including IIRB, Inc.

approval of Amendment 1 7 Jun 10 CLBR submitted 2 nd supplement reporting discovery

that second black fly species not named in protocol had been present for field test

78 

# Documents Considered in EPA Reviews
 

### Primary Study Report MRID 48053802  

### Supplement 1 Re: IIRB approval MRID 48071301  

### Supplement 2 Re: Unnamed fly species MRID 48117601  

### EPA Science & Ethics Review of Protocol LNX- 002  

### HSRB Report of June 2009 review of LNX- 002  

### CLBR supplemental submission of IIRB, Inc. roster and procedures 89 

# Science Assessment: LNX - 002 Kevin Sweeney Registration Division Office of Pesticide Programs10



# Objectives  To test the black fly repellent efficacy of the test materials  To satisfy a condition of registration imposed by EPA 

# Test Materials  

## EPA Reg. No. 39967 - 50 (cream)

39967 - 53 (pump spray)  

## Both contain 20% Picaridin11 

# LNX - 002 Dose Determination  

### Amendment 1 added a dose-determination phase with 15 additional subjects using the cream, to supplement the dosing data collected in study LNX- 001  

### The new and old dosing data for the cream were 

### pooled to define the standard dose rate for the cream used in this study  

### The standard dose rate for the spray was based on the 

### data collected in LNX- 00112 

# LNX - 002 Field Study Design  

### 10 subjects treated with each formulation and 2 

### untreated control subjects participated in the one -day field trial in the Mojave desert  

### Untreated subjects monitored black fly pressure; each 

### attended by 2 technicians to aspirate landing insects  

### Treated and untreated subjects’ forearms were exposed to target insects for 1 minute at 15 - minute intervals  

### Duration of efficacy for each subject was measured as the time from treatment to “First Confirmed Landing with intent to bite” or “FCLibe”13



# Margins of Exposure  

### Based on the mean surface area of treated arms and an assumed mean bodyweight of 70 kg, the highest picaridin dose administered (cream on arms) delivered a mean dose per subject of 2.86 mg/kg  

### The limit dose for picaridin dermal toxicity in the rat is >2,000 mg/kg  

### The margin of exposure (MOE) for dermal toxicity of the 

### picaridin cream was at least 699  

### Mean dose for pump spray on arms was 1.43 mg/kg; MOE ≥ 139914



# Standard Doses and MOEs15



# Statistical Analysis  

## Data analyzed using Kaplan - Meier survival analysis  

## Median CPT times were calculable for both 

## product tests  

## Mean CPT and time to 25% failure were also reported16 

# Field Test Results: LNX - 00217



# Role of Data Censorship
 

### 5 of the 10 subjects treated with the cream experienced a FCLIBe  

### 6 of the 10 subjects treated with the spray experienced a FCLIBe  

### Censored datapoints led to underestimates of the mean and sd, but did not compromise K- M medians  

### Only three of the 9 subjects who did not experience failure received unconfirmed LIBes18 

# Significance of Protocol Deviations  

## Use of superseded data collection form  

## Presence of unnamed black fly species Simulium tescorum  

## 51⁄2 - month lapse between cream dose determination and field testing19



# 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 black flies 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 pump- spray)20 

# Ethics Assessment: LNX - 002 John M. Carley Human Research Ethics Review Officer Office of Pesticide Programs21 

# Completeness of Submission
 

### The primary study report, MRID 48053802, is generally complete  

### One deficiency noted: 

###  No record of IIRB, Inc. approval of Amendment 1 

###  Corrected by supplemental submission of MRID 48071301  

### All requirements of 40 CFR 26.1303 for 

### documentation of ethical conduct are satisfied by these two documents taken together 2122



# Protocol Deviations
 

### Three deviations: 

###  Primary study report documents use of superseded data collection form 

###  Supplemental report of 7 June 2010 documents presence of a second species of black fly at field test site 

###  More than 60 days elapsed between dose determination and field testing  

### None of these deviations affected the rights or safety of the subjects, or compromised informed consent 2223 

# Response to Previous Ethics Reviews  EPA’s single comment in its protocol review of 18 May 09 was satisfactorily addressed in Amendment 1  The HSRB’s request for clarification of “what 3 rd - party medical coverage means” was addressed in Amendment 1, but not ideally. CLBR added the words in red to clarify its promise to pay: “costs of such medical treatment that are not covered by your own insurance or by a third party that covers you ” EPA now recommends: “costs of such medical treatment that are not covered by your own insurance or by the insurance of a third party under which you are covered ” 2324



# 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” 2425



# Findings  

### The requirements of 40 CFR § 26.1303 to document the 

### ethical conduct of LNX- 002 are satisfied  

### LNX- 002 did not involve intentional exposure of pregnant or nursing women or of children under 18  

### Notwithstanding the minor deviations noted, LNX- 002 was conducted in substantial compliance with all applicable requirements of 40 CFR part 26, subparts K and L  

### Subjects were fully informed and participated voluntarily 2526



# Conclusion

 

### Assuming LNX- 002 is determined to be scientifically acceptable, I find no barrier in law or regulation to EPA’s reliance on it in actions under FIFRA

2627 

# LNX - 002: Charge Questions 1(a) Is the CLBR study LNX- 002 sufficiently sound, from a scientific perspective, to be used to estimate the duration of complete protection against black flies provided by the tested 

### repellents? 1(b) Does available information support a determination that study LNX- 002 was conducted in substantial compliance with subparts K and L of 40 CFR Part 26?