September 9, 2010


EPA-HSRB-10-01

Paul Anastas, PhD
EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460

Subject: June 23, 2010 EPA Human Studies Review Board Meeting Report

Dear Dr. Anastas,

       The United States Environmental Protection Agency (EPA or Agency) requested that the
Human Studies Review Board (HSRB) review two completed repellent efficacy studies
conducted by Carroll-Loye Biological Research, Inc. (CLBR) of Davis, California. These two
studies involved intentional exposure of human volunteers to picaridin-containing insect
repellents. The Agency proposes to rely on these two studies, conducted after publication of the
EPA's expanded final rule for protection of subjects in human research (40 CFR 26) on February
6, 2006 (71 Federal Register 24, 6137), for regulatory actions under the pesticide laws.

       The Agency also provided the HSRB with updates on two additional topics: revised
Agency guidelines for performance testing of topically applied repellent products, to be released
for use by investigators and sponsors of new studies; and the recent settlement agreement
reached between the Agency and six external parties to resolve litigation related to EPA's 2006
rule for the protection of human subjects of research.

       The enclosed report provides the Board's response to EPA charge questions presented at
the June 23,2010 meeting. In addition, the report includes some additional recommendations for
the Agency's repellent testing guidelines before release.

Assessment of Completed Carroll-Love Biological Research Study LNX-002; Efficacy Test
of KBR 3023 (Picaridin. Icaridin) - Based Personal Insect Repellents (20% Cream and
20% Sorav) with Black Flies Under Field Conditions.

Science

    •  The Board concurred with the Agency's assessment that this study provides scientifically
      valid results to assess the repellent efficacy against black flies for the formulations tested.
Ethics
     The Board concurred with the Agency's assessment that the study submitted for review
     was conducted in substantial compliance with subparts K and L of 40 CFR 26.
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September 9, 2010
Assessment of Completed Carroll-Love Biological Research Study LNX-003: Efficacy Test
of KBR 3023 (Picaridin; Lcaridin - Based Personal Insect Repellents (20% Cream and
20% S rav1 with Ticks Under Laboratory Conditions.
Science
The Board concurred with the Agency’s assessment that this study provides scientifically
valid results to assess the repellent efficacy against ticks for the formulations tested.
However, the high frequency of participants for whom the repellent’s protection time
exceeded the long duration of the study creates statistical challenges in evaluating a
specific protection time.
Ethics
The Board concurred with the Agency’s assessment that the study submitted for review
was conducted in substantial compliance with subparts K and L of 40 CFR 26.
Revised A2encv Guidelines for Performance Testin2 of Topically Applied Insect Repellents
The Board was not given a charge for consideration of the revised guidelines, but did
have several comments designed to enhance the utility of the document. The Board felt that the
revised Agency guidelines will provide sponsors and researchers with helpful guidance in the
design of future efficacy tests of topically applied insect repellents. Before releasing these
revised guidelines publicly, however, the Board recommended several changes or clarifications,
including:
• Removal of the maximum-likelihood method requirement in the data analysis section;
• Clarification of recommendations regarding the use of positive controls, particularly with
respect to the number of controls and the rationale for including them in the study;
• Careful consideration of recommendations regarding the recruitment and inclusion of so-
called ‘vulnerable’ populations; and
• Encouraging the use of study designs that will enable investigators to collect data that will
allow quantitative measurement of repellent efficacy in addition to determining the
complete protection time (CPT).
Finally, as at previous meetings, the Board underscored that it would continue to evaluate
protocols submitted for review to the HSRB based on appropriate statistical assumptions and
analytic plans and thus might recommend rejection of a protocol even if it followed the revised
Guidelines explicitly.
Sincerely,
Sean Philpott, PhD, MSBioethics
Chair
EPA Human Studies Review Board
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September 9, 2010
NOTICE
This report has been written as part of the activities of the EPA Human Studies Review
Board, a Federal advisory committee providing advice, information and recommendations on
issues related to scientific and ethical aspects of human subjects research. This report has not
been reviewed for approval by the Agency and, hence, the contents of this report do not
necessarily represent the view and policies of the Environmental Protection Agency, nor of other
agencies in the Executive Branch of the Federal government, nor does the mention of trade
names or commercial products constitute a recommendation for use. You may obtain further
information about the EPA Human Studies Review Board from its website at
http://www.epa.gov/osa/hsrb . You may also contact the HSRB Designated Federal Officer, via
e-mail at phre@epa.gov
In preparing this document, the Board carefully considered all information provided and
presented by the Agency presenters, as well as information presented by public commenters.
This document addresses the information provided and presented within the structure of the
charge by the Agency.
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September 9, 2010
US ENVIRONMENTAL PROTECTION AGENCY
HUMAN STUDIES REVIEW BOARD
Chair
Sean Philpott, PhD, MSB, Director for Research Ethics, The Bioethics Program of Union
Graduate College and the Mount Sinai School of Medicine, Schenectady, NY
Vice Chair
Janice Chambers, PhD, DABT, William L. Giles Distinguished Professor, Director, Center for
Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University,
Mississippi State, MS
Members
George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada-
Reno Center for Research Design and Analysis, University of Nevada-Reno, Reno, NV
Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor
of Health Policy and American Studies, The George Washington University, Washington, DC
Sidney Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology, Howard
University College of Medicine, Washington, DC
Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University,
Manhattan, KS
Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of
Arizona, Tucson, AZ
*Jose E. Manautou, PhD, Associate Professor of Toxicology, Department of Pharmaceutical
Science, University of Connecticut School of Pharmacy, Storrs, CT
Jerry A. Menikoff, MD, JD, Director, Office for Human Research Protections, Office of the
Secretary, Department of Health and Human Services, Rockville, MD
*Rebecca Parkin, PhD, MPH, Associate Dean for Research and Public Health Practice, School
of Public Health and Human Services, The George Washington University, Washington, DC
William Popendorf, PhD, MPH, Professor, Department of Biology, Utah State University,
Logan, UT
Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of
Nebraska Medical Center, Omaha, NE
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September 9, 2010
Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care,
Veterans Health Administration, Washington, DC
Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural
Sciences, University of Florida, Gainesville, FL
Human Studies Review Board Staff
Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science
Advisor, United States Environmental Protection Agency, Washington, DC
*Not in attendance at June 23, 2010 Public Meeting
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INTRODUCTION
On June 23, 2010, the United States Environmental Protection Agency’s (EPA or
Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues
concerning: two completed repellent efficacy studies involving two registered insect repellents
containing picaridin conducted subsequent to publication of the EPA’s expanded final rule for
protection of subjects in human research. In accordance with 40 CFR 26.1602, EPA sought
HSRB review of these completed studies. Each of these completed studies is discussed more
fully below.
In addition, the Agency provided the HSRB with updates on two additional topics: the
revised Agency guidelines for performance testing of topically applied repellent products, to be
released for use by investigators and sponsors of new studies; and a recent settlement agreement
reached between the Agency and six external parties to resolve litigation related to EPA’s 2006
rule for the protection of human subjects of research. A summary of the Board’s conclusions
concerning the Agency’s revised guidelines for performance testing of topically applied repellent
products is also provided below.
REVIEW PROCESS
On June 23, 2010, the Board conducted a public face-to-face meeting in Arlington,
Virginia. Advance notice of the meeting was published in the Federal Register as “Human
Studies Review Board; Notice of Public Meeting” (75 Federal Register 109, 32461).
Following welcoming remarks from Agency officials, the Board heard presentations from
EPA on the following topics: two completed insect repellent efficacy studies involving
intentional human exposure to two registered insect repellents containing picaridin (LNX-002
and LNX-003) conducted by Carroll-Loye Biological Research, Inc. (CLBR) of Davis, CA.
The Board also asked clarifying questions of several study sponsors and/or research
investigators, including:
Dr. Scott Carroll, Principal, CLBR
Mr. Shawn King, Director of Operations, CLBR
Oral comments were provided by:
Dr. Scott Carroll, Principal, CLBR
No written public comments were provided.
For their deliberations, the Board considered the materials presented at the meeting, oral
comments, and Agency background documents (e.g., published literature, sponsor and
investigator research reports, study protocols, data evaluation records, and Agency science and
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September 9, 2010
ethics reviews of proposed protocols and completed studies). A comprehensive list of
background documents is available online at http://www.regulations.gov.
CHARGE TO THE BOARD AND BOARD RESPONSE
Assessment of Completed Carroll-Love Biological Research Study LNX-002: Efficacy Test
of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and
20% Spray) with Black Flies Under Field Conditions .
Overview of the Study
LNX-002 was a field-based study to measure the effectiveness of picaridin as a black fly
repellent when used in one of two compound formulations (20% picaridin KBR 3032 All-Family
Insect Repellent Cream and 20% picaridin KBR 3023 All-Family Insect Repellent Spray).
A total of 25 participants (selected from a pool of 119 volunteers diverse in age and
ethnicity) participated in this study. There were 15 participants (8 female and 7 male) in the
dosimetry phase. Twenty treated and two untreated volunteers participated in the efficacy test,
with three more subjects serving as alternates. Ten participants tested each product formulation.
Dosimetry data accumulated in a previous CLBR study (LNX-001), along with additional
dosimetry data collected from 15 volunteers in LNX-002, were used for dose selection. For the
spray product each participant received 0.97p.l/cm 2 of product, equivalent to 0.9312 mg
product4tl. For the cream product, the volumetric dose rate was 1.94 j .l/cm 2 , equivalent to
1.9012 mg product4tl. For the spray product the mean picaridin dose was 98 mg per participant
and 202 mg/participant for the cream product. The Margin of Exposure (MOE; how many fold
lower the average human exposure is than the dose known to cause toxicity in animal models)
calculations were based on an assumed 70 kg participant and the acute dermal LD5O value for
picaridin at the limit dose of greater than 2,000 mg/kg. For the cream product the MOE = 690
and for the spray product the MOE = 1429, both values exceed the target MOE = 100.
The efficacy of picaridin as a black fly repellent was determined in a study conducted at a
field site in the Mojave Desert of Southeastern California. Ten participants each were randomly
assigned to one of two repellent treatments at the site for a total of ten volunteers per treatment.
Each treatment was applied to an equal number of males and females. Participants were treated
approximately 2.5 hours before field exposure. Untreated controls and participants treated with
repellent were exposed to black flies for one minute every 15 minutes until the repellent failed.
Treated participants were partnered in groups of two and each partner monitored the front of
their own exposed forearm and the back of their partner’s forearm. Black flies landing with
intent to bite (LIBe) were recorded, aspirated into containers, and identified in the laboratory.
Participants remained in the test until the repellent failed as determined by the first confirmed
LIBe, or until the end of the test period, whichever came first. The time at which the repellent
failed equaled the CPT for each subject.
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September 9, 2010
Eleven of the 20 volunteers experienced a confirmed LIBe. Mean CPT values were not
significantly different for the two formulations, with mean CPT calculated at 9.9 h for both
products. Median CPT values also were calculable for both products and were nearly the same,
10.1 h for the cream product and 9.8 h for the spray product.
Science
Charge to the Board
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 test repellents?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Sweeney 2010a) that this study
provides scientifically valid results to assess the repellent efficacy against black flies for the
formulations tested.
HSRB Detailed Recommendations and Rationale
This study (Carroll 2010a; Carroll 2010c) was conducted according to a protocol that had
been amended to take into account recommendations of the EPA and the HSRB (EPA HSRB
2009a).
The conduct of the dosimetry study and the field study were very similar to the conduct
of previous field repellent efficacy studies conducted by CLBR.
The study was careflully conducted, with both sexes represented among the participants
and the endpoint being the first LIBE) for each participant. The MOEs were high enough to not
be a significant factor in the use of either formulation.
The protocol had one scientific deviation that was considered minor. Namely, a black fly
species not named in the protocol was present during field testing. Board members felt that this
deviation did not materially affect the scientific integrity and validity of the study.
Ethics
Charge to the Board
Does available information support a determination that study LNX-002 was conducted
in substantial compliance with subparts K and L 40 CFR Part 26?
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Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley 2010a) that the study
submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR
26.
HSRB Detailed Recommendation and Rationale
The documents provided by CLBR (Carroll 201 Oa; Carroll 201 Oc) state that the study
was conducted in compliance with the requirements of the US EPA Good Laboratory Practice
Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; FIFRA §
12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study was
reviewed and approved by a commercial human subjects review committee, Independent
Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL. Documentation provided to the
EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule
(45 CFR Part 46, Subpart A) and found it in compliance. IIRB, Inc. also reviewed and approved
Amendment I of October 30, 2009 (Carley 201 Oa; IIRB, Inc. 2010).
1. The Board concurred with the conclusions and factual observations relating to the study, as
detailed in the EPA’s Ethics Review (Carley 2010a). Specifically:
a. Prior HSRB andAgency Review. The requirements of 40 CFR §26.1125 for prior
submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol
were satisfied. The study (Carroll 2010a; Carroll 2010c) was conducted in accordance
with the protocol previously approved by the HSRB (EPA HSRB 2009a). The Agency’s
ethics review of May 18, 2009 identified no deficiencies requiring correction relative to
40 CFR 26, subparts K and L, or to FIFRA § 12(a)(2)(P) (Carley 2010a). Because the
study was conducted in California, the approval of CDPR was also required before the
study could be initiated. CDPR granted final approval of the amended protocol and
supporting documents on September 14, 2009.
b. Responsiveness to HSRB andAgency Reviews. Following the HSRB review, the protocol
and consent form were modified through Amendment 1 of August 13, 2009 (Carley
2010a; Carroll 2010c). This amendment incorporated changes responsive to the
comments of EPA, the HSRB, and California Department of Pesticide Regulation
(CDPR), as well as additional corrections initiated by the investigators and, at the request
of the sponsor, provision for collecting additional dose-determination data for the cream
formulation, to be pooled with that originally collected in study LNX-001. Agency
suggestions were also addressed satisfactorily in Amendment 1. The reference to third
party coverage of costs of medical treatment noted by the HSRB was revised in
Amendment 1. IIRB, Inc. granted approval to Amendment I and supporting documents
on August 18, 2009 (Carley 2010a; Carroll 2010c).
c. Substantial Compliance with Reporting Requirements (40 CFR §26 subpart M). The
primary study report initially failed to address the requirement of 40 CFR §26 subpart M,
§26.1303(b) to submit copies of “official notification to the sponsor or investigator ... that
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research involving human subjects has been reviewed and approved by an IRB.” This
omission was corrected by the submission of a supplemental document catalogued as
MRID 48071301 (Carroll 2010c). Taking the two submissions together, along with the
separately submitted documents reporting the roster and procedures of the IIRB, Inc.,
(2010), the requirements of 40 CFR §26.1303 to document the ethical conduct of the
research were fully satisfied. Several Board members also remarked that, while current
regulations only require “substantial” compliance with these reporting requirements, the
submitted documents and supplementary materials from IIRB, Inc. met fully the
regulatory reporting requirements. However, some Board members raised concerns about
the regulatory meaning of the term “substantial” in the absence of clear parameters or
guidance.
2. The Board concluded that this study met all applicable ethical requirements for research
involving human participants, in accordance with the following criteria that had been stated
in the Board’s prior review of this study protocol:
a. Acceptable risk-benefit ratio. The risks to study participants were minimized
appropriately and were justified by the potential societal benefits, particularly data on the
efficacy of these new formulations as personal insect repellents.
• Minors and pregnant or lactating women were excluded from participation, with
pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by
opt-out. The potential of stigma resulting from study exclusion was also appropriately
minimized.
• Based on toxicological data currently available for picaridin, coupled with appropriate
exclusion criteria, study participants were unlikely to be at risk of adverse side effects
with exposure.
• Clear stopping rules and medical management procedures were in place, and no adverse
events related to product exposure were reported.
• The study was designed to minimize the likelihood of black fly bites.
b. Voluntary and informed consent of all participants
• The study protocol included several mechanisms designed to minimize coercive
recruitment and enrollment. Monetary compensation was not so high as to unduly
influence participation.
3. There were three minor protocol deviations reported, including: 1) use of a superseded data
collection form; 2) The presence of a second species of biting black fly at the field test site;
and 3) a gap of greater than 60 days between dose determination and field testing. The Board
concluded, however, that these three deviations from the protocol were minor and did not
affect the integrity of the research or the safety of participants.
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Assessment of Completed Carroll-Love Bioloaical Research Study LNX-003: EtTicacv Test
of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and
20% Spray) with Ticks Under Laboratory Conditions .
Overview of the Study
LNX-003 was a laboratory-based study to measure the effectiveness of picaridin as a tick
repellent when used in one of two compound formulations (20% picaridin KBR 3032 All-Family
Insect Repellent Cream and 20% picaridin KBR 3023 All-Family Insect Repellent Spray). The
efficacy of picaridin as a tick repellent was determined in a controlled laboratory setting by
placing laboratory-raised, pathogen-free Western black-legged ticks (Ixodespac fIcus) and
American dog ticks (Dermacentor variabilis) on picaridin-treated and untreated forearms of
study volunteers, and then measuring the speed and distance that moving ticks would penetrate
into the treated area at 15-minute intervals. Each treated participant served as their own untreated
control. Tick questing behavior was confirmed on the untreated arm of each subject before the
tick was used for repellency testing.
Dosimetry data accumulated in previous CLBR studies (LNX-001 and LNX-002) were
used for dose selection. For the spray product each participant received 0.97 tl/cm 2 of product,
equivalent to 0.9312 mg productlp.l. For the cream product, the volumetric dose rate was
1 .94p.I/cm 2 , equivalent to 1.9012 mg product/pi. For the spray product the mean picaridin dose
was 100 mg per participant and 192 mg/participant for the cream product. MOE calculations
were based on an assumed 70 kg subject and the acute dermal LD5O value for picaridin at the
limit dose of greater than 2,000 mg/kg. For the spray product the mean picaridin dose was 100 mg
per subject and 192 mg/subject for the cream product. For the cream product the MOE = 741 and
for the spray product the MOE = 1429, both values exceed the target MOE = 100.
A total of 23 participants (selected from a pool of 119 volunteers diverse in age and
ethnicity) participated in this study. Three were alternate participants; twenty were treated. In the
test phase, ten subjects participated in each product treatment test on each day. Treatments were
randomized within each gender. There were an equal number of male and female test subjects.
Each volunteer participated on only one day of the test, but testing included both tick species. All
ticks, repelled or not, were removed from the arm of the participant before they had time to bite.
Exposure to each tick was for a period of 3 minutes on each arm. Further exposures to each
species were stopped for any subject who experienced a “crossing” by that species into the
treated area of the forearm confirmed by another crossing in either of the subsequent two
exposure periods. This endpoint was used to calculate the CPT for each subject.
Despite an extremely long duration of testing (15.25 h), more than half the study
participants did not experience a confirmed crossing. Thus, it was not possible to calculate a
median time to failure for the 20% cream. Although there was also significant right-censorship
of the data for the 20% spray (i.e. the actual duration of protection for participants who did not
experience a confirmed crossing was not known, but was assumed to be greater than I 5.25h),
there were enough data points to support calculation of the Kaplan-Meier median. The 20%
cream had a mean CPT = 12.6 h against Ix. scapularis and 15.3 h against D. variabilis. Most of
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these data were right-censored and a median could not be calculated. For the 20% spray product,
data collected with lx. scapularis resulted in a median CPT of 15 h while the mean CPT equaled
14.1 h. The mean CPT against D. variabilis was 14 h and the median CPT was 14.1 h.
Science
Charge to the Board
Is the CLBR study LNX-003 sufficiently sound, from a scientific perspective, to be used
to estimate the duration of complete protection against ticks provided by the tested repellents?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Sweeney 20 lOb) that this study was
conducted in accordance with Good Laboratory Practices as described in 40 CFR § 160, the draft
EPA Guidelines §810.3700, and its own previously approved protocols and that its results
provide scientifically sound data that can be used to estimate the duration of complete protection
against ticks. However, the high frequency of participants for whom the repellent’s protection
time exceeded the long duration (15.25 hours) of the study creates statistical challenges in
evaluating a specific protection time.
HSRB Detailed Recommendations and Rationale
This study (Carroll 20 lOb) was conducted according to the protocol previously approved
by the HSRB (HSRB 2009b). The protocol fuiiy addressed the EPA’s comments in its review of
the protocol and responded to HSRB comments at the meeting in October 2009. The study
incorporated the results of prior dosimetry studies and lessons learned from previous laboratory
tick repellent efficacy studies conducted by CLBR (Carroll 2010b). The study seems to have
been carefully conducted with twenty participants (10 male and 10 female), two formulations of
one repellent at the same concentration (a cream and spray, tested on separate days), and
exposures to two genera of ticks (nymphal deer ticks (Ixodes scapularis) and nymphal American
dog ticks (Dermacentor variabilis)) during each 15-minute interval for as long as 15.25 hours.
The MOE’s were very high (741 and 1429 for the cream and spray, respectively) and therefore
protective of the participating volunteers. The report was clearly written and detailed.
There was interest expressed by some Board members regarding the possible influence of
subjective differences in the manipulations (the “guiding” of the ticks shortly after they were
placed on each participant) upon the results; however, discussion revealed that the time scale of
these manipulations was sufficiently short in relation to the three minutes they were allowed to
remain on the arm to not be of concern.
There was concern expressed by some Board members regarding the high rates of right
censorship (especially the 60% and 80% rate in the cream formulation) caused by the lack of
confirmed crossings by either tick species within the study duration (despite it lasting just over
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15 hours). It was not possible to calculate a median CPT for the cream formulation using
Kaplan-Meier survival analysis. The Agency may wish to consider the importance of these
computations and the use of Kaplan-Meier median complete protection time and its 95% lower
confidence interval when making decision regarding the efficacy of insect repellents in future
studies.
Ethics
Charge to the Board
Does available information support a determination that study LNX-003 was conducted
in substantial compliance with subparts K and L 40 CFR Part 26?
Board Response to the Charge
HSRB Recommendation
The Board concurred with the Agency’s assessment (Carley 20 lOb) that the study
submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR
26.
HSRB Detailed Recommendations and Rationale
The document provided by CLBR (Carroll 201 Ob) states that the study was conducted in
compliance with the requirements of the US EPA Good Laboratory Practice Regulations for
Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; FIFRA § 12(a)(2)(P); and
the California Code of Regulations Title 3, Section 6710. The study was reviewed and approved
by a commercial human subjects review committee, IIRB, Inc. Documentation provided to the
EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule
(45 CFR Part 46, Subpart A) and found it in compliance (Carley 201 Ob).
1. The Board concurred with the conclusions and factual observations relating to the study, as
detailed in the EPA’s Ethics Review (Carley 20 lOb).
2. The Board concluded that this study met all applicable ethical requirements for research
involving human participants, in accordance with the following criteria that had been stated
in the Board’s prior review of this study:
a. Acceptable risk-benefit ratio. The risks to study participants were minimized
appropriately and were justified by the potential societal benefits, particularly data on the
efficacy of these new formulations as personal insect repellents.
• Minors and pregnant or lactating women were excluded from participation, with
pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by
opt-out. The potential of stigma resulting from study exclusion was also appropriately
minimized.
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• Based on toxicological data currently available for picaridin, coupled with appropriate
exclusion criteria, study participants were unlikely to be at risk of adverse side effects
with exposure.
• Clear stopping rules and medical management procedures were in place, and no adverse
events related to product exposure were reported.
• The study was designed to minimize the likelihood of tick bites.
• Finally, the efficacy trial was conducted with laboratory-raised ticks free of known
pathogens.
b. Voluntary and informed consent of all participants
• The study protocol included several mechanisms designed to minimize coercive
recruitment and enrollment. Monetary compensation was not so high as to unduly
influence participation.
Revised A2ency Guidelines for Performance Testing of Topically Applied Insect Repellents
( Product Performance Test Guidelines. OPPTS 810.3700: Insect Repellents to be Applied
to Human Skin .
In order to improve the quality and reliability of repellent data submitted to the Agency,
the EPA has developed a non-binding guidance document (Product Performance Test
Guidelines. OPPTS 810.3700: Insect Repellents to be Applied to Human Skin) describing the
methodology recommended by the Agency for collection of the necessary data to support
registration and labeling of topically applied products (Office of Chemical Safety and Pollution
Prevention 2010). These revised guidelines will replace the current ‘Product Performance Test
Guidelines. OPPTS 810.3700: Insect Repellents for Human Skin and Outdoor Premises”
released by the Agency in December 1999.
A draft version of these guidelines was first reviewed by the Board at its June 2006
meeting, and again at its October 2008 meeting (EPA HSRB 2006; EPA HSRB 2008). In these
reviews the Board made many suggestions for strengthening the scientific and ethical conduct of
this kind of research, and has encouraged EPA to further revise and publish its guidelines for
researchers considering this type of study.
The EPA is expected to announce in the Federal Register the availability of these new
draft guidelines, for immediate use for sponsors and investigators.
HSRB Evaluation
While the Board was not given a charge for consideration of the guidelines, it did have
several comments to enhance the utility of the document. Specifically, the Board felt that the
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document was well written and will provide sponsors and researchers with helpful guidance in
the design of future efficacy tests of topically applied insect repellents. Before releasing these
revised guidelines publicly, however, the Board recommended the following changes or
clarifications:
1. Currently (as described in the revised Guidelines’ Objectives (c)(l)(i)), the preferred measure
of repellent efficacy is the duration of the CPT. CPT is important, but it is not the only (and
perhaps not always the best) measure of effectiveness. A quantitative measure of the
repellent’s effectiveness might also be useful. For example, if opportunities to make re-
applications are limited but less protection is acceptable, then consumers may wish to use a
repellant with a long CPT. If the repellant can easily be re-applied however, consumers may
want to choose a product with higher effectiveness. The Agency thus may want to encourage
the use of study designs that yield a valid measure of repellent effectiveness and CPT.
Further discussion is also needed as to the set of endpoints to present and the types of
statistical analyses to be done to accurately determine repellent effectiveness and CPT.
2. The revised Guidelines strongly encourage the use of “positive [ repellent] controls” (such as
DEET) in the design of repellent studies (c.f. Sec. (c)(viii) in the context of scientific study
design and in each of the specific guidance sections (j), (k), and (1)). The Board felt that the
justification for the use of positive controls seemed weak. It was not clear from a scientific
perspective just how such data would be used to interpret a given study or what value it
would add, while increasing the number of additional human participants exposed to pests
and the DEET control without a clear scientific benefit would raise ethical concerns. The
Board thus recommended that the Agency clarif ’ why, how and when positive controls
should be included in the study design.
3. Maximum likelihood methods, as described in the Guidelines’ statistical analysis section,
require that the distribution of data be known. The Agency thus should remove from this
section the recommendation that maximum likelihood estimates be used if this distribution is
not known and the data cannot be transformed to fit an underlying distribution. Use of
maximum likelihood methods would, in this case, be inappropriate.
4. The Board also recommended that, with respect to discussions of participant recruitment and
vulnerability, the following changes be made:
a. The term “race/ethnicity” should be used instead ofjust “race” in order to be consistent with
Office of Management and Budget (0MB) categories on race and ethnicity.
b. The Board also suggested that the EPA reexamine issues of language in recruitment and
consent materials in the Guidelines, referring the Agency specifically to the Board’s
October 2009 report (EPA HSRB 2009b, 24), which explicitly discusses such issues of
language and recommends that the Agency and study sponsors adapt the practices described
in the Office of Minority Health’s National Standards for Culturally and Linguistically
Appropriate Services in Health (Office of Minority Health 2001). Investigators should also
be urged to examine the recruitment population in advance so that speakers of other
languages are present as needed.
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September 9, 2010
REFERENCES
Carley, J.M. 2010a. Ethics Review of Completed Carroll-Loye Black Fly Repellent Field
Efficacy Study LNX-002. Dated May 20, 2010. Unpublished document prepared by the Office of
Chemical Safety and Pollution Prevention, United States Environmental Protection Agency.
Carley, J.M. 20 lOb. Request for Additional Documentation. Email Exchange between United
States Environmental Protection Agency and Independent Institutional Review Board, Inc. Dated
April 20, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution
Prevention, United States Environmental Protection Agency.
Carley, J.M. 2010c. Ethics Review of Completed Carroll-Loye Tick Repellent Laboratory
Efficacy Study LNX-003. Dated May 20, 2010. Unpublished document prepared by the Office of
Chemical Safety and Pollution Prevention, United States Environmental Protection Agency.
Carroll, S. 2010a. Efficacy Test of KBR3023 (Picaridin; Lcaridin)-Based Personal
Insect Repellents (20% Cream and 20% Spray) with Black Flies under Field Conditions. Dated
April 5, 2010. Unpublished document prepared by Carroll-Loye Biological Research. MRID
48053802.
Carroll, S. 2010b. Efficacy Test of KBR3023 (Picaridin; Icaridin)-Based Personal
Insect Repellents (20% Cream and 20% Spray) with Ticks Under Laboratory Conditions. Dated
April 5, 2010. Unpublished document prepared by Carroll-Loye Biological Research. MRID
48053801.
Carroll, S. 2010c. Supplemental Submission to EPA MRID 40853802. Dated April 19, 2009.
Unpublished document amendment prepared by Carroll-Loye Biological Research. MRID
48071301.
EPA Human Studies Review Board. 2006. June 27-30, 2006 Human Studies Review Board
Meeting Report.
EPA Human Studies Review Board. 2008. October 2 1-22, 2008 Human Studies Review Board
Meeting Report.
EPA Human Studies Review Board. 2009a. June 24-25, 2009 Human Studies Review Board
Meeting Report.
EPA Human Studies Review Board. 2009b. October 20-21, 2009 Human Studies Review Board
Meeting Report.
Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster and Procedures.
Unpublished materials prepared by IIRB.
Office of Chemical Safety and Pollution Prevention. 2010. Product Performance Test Guidelines.
OPPTS 810.3700: Insect Repellents to be Applied to Human Skin. Draft document prepared by
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September 9, 2010
the Office of Chemical Safety and Pollution Prevention, United States Environmental Protection
Agency.
Office of Minority Health, Department of Health and Human Services. 2001. National Standards
for Culturally and Linguistically Appropriate Services in Health Care: Final Report. Washington,
DC: U.S. Department of Health and Human Services.
Sweeney, K.J. 2010a. Science Review of Human Study of Black Fly Repellent Performance.
Dated May 24, 2010. Unpublished document prepared by the Office of Chemical Safety and
Pollution Prevention, United States Environmental Protection Agency.
Sweeney, K.J. 2010b. Science Review of Human Study of Tick Repellent Performance. Dated
May 24, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution
Prevention, United States Environmental Protection Agency.
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