Document ID: EPA-HQ-ORD-2010-0617-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-09-13T04:00Z

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 additional information on two
informative 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 revising the Agency
repellent testing guidelines before release.

Assessment of Completed Carroll-Loye 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.

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.

Assessment of Completed Carroll-Loye Biological Research Study LNX-003:
Efficacy Test of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect
Repellents (20% Cream and 20% Spray) 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 Agency Guidelines for Performance Testing 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, including racial
and ethnic minorities; and

Encouraging the use of study designs that will enable investigators to
collect data that will allow quantitative measurement of the repellent
efficacy during the complete protection period.

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

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   HYPERLINK "http://www.epa.gov/osa/hsrb"
http://www.epa.gov/osa/hsrb .  You may also contact the HSRB Designated
Federal Officer, via e-mail at   HYPERLINK "mailto:phre@epa.gov"
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.

US ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD

Chair

Sean Philpott, PhD, MSBioethics, 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, 1664 N. Virginia Street, 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, 69
North Eagleville Road, Storrs, CT

Jerry A. Menikoff, MD, JD, Director, Office of Human Subjects Research,
Office of the Director, National Institutes of Health, Bethesda, 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

Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics
in Health Care, Veterans Health Administration 810 Vermont Ave., NW,
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

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 additional information on
two informative 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 picardin (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, Carroll-Loye Biological Research

Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research

Oral comments were provided by: 

Dr. Scott Carroll, Principal, Carroll-Loye Biological Research

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 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-Loye 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% picardin 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 Carroll-Loye 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 0.97μl/cm2 of product, equivalent to 0.9312 mg
product/μl. For the cream product, the volumetric dose rate was 1.94
μl/cm2, equivalent to 1.9012 mg product/μl. For the spray product the
mean picaridin dose was 98 mg per participant and 202 mg/participant for
the cream product. MOE calculations were based on an assumed 70 kg
participant and the acute dermal LD50 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 Complete Protection Time (CPT) for each subject. 

	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 Carroll-Loye Biological Research.

	The study was carefully conducted, with both sexes represented among
the participants and the endpoint being the first confirmed landing with
intent to bite (LIBe) for each participant. The margins of exposure
(MOE) 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?

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 Carroll-Loye (Carroll 2010a; Carroll 2010c)
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 1 of October 30, 2009
(Carley 2010a; 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 and Agency 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 and Agency 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 1 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
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.

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 on the integrity of the research or the
safety of participants. 

Assessment of Completed Carroll-Loye Biological Research Study LNX-003:
Efficacy 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% picardin 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 (Ixodes pacificus) 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 Carroll-Loye studies (LNX-001 and
LNX-002) were used for dose selection. For the spray product each
participant received 0.97μl/cm2 of product, equivalent to 0.9312 mg
product/μl. For the cream product, the volumetric dose rate was
1.94μl/cm2, equivalent to 1.9012 mg product/μl. 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 LD50 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 Complete Protection Time (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, there were enough data points to support calculation
of the Kaplan-Meier (K-M) median. The 20% cream had a mean CPT = 12.6 h
against Ix. scapularis and 15.3 h against D. variabilis. Most of these
data were right-censored and a median could not be calculated. For the
20% spray product, data collected with Ix. 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 2010b) 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 2010b) was conducted according to the protocol
previously approved by the HSRB (HSRB 2009b). The protocol fully
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
Carroll-Loye Biological (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 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 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 Carroll-Loye (Carroll 2010b) 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,
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 (c.f. Carley 2010b).

1.	The Board concurred with the conclusions and factual observations
relating to the study, as detailed in the EPA’s Ethics Review (Carley
2010b). 

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. 

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 Agency 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 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)(1)(i)), the preferred measure of repellent efficacy is the duration
of the Complete Protection Time (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 during the CPT
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
within the 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 (l)). 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 the DEET control without a clear scientific benefit would
raise ethical concerns. The Board thus recommended that the Agency
clarify how and when positive controls should be included in the study
design, either in the revised Guidelines or in the accompanying Standard
Evaluation Procedures (SEPs).

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 revised Guidelines, as currently written, intermingle scientific
and ethical considerations. The Board recommended that the Agency
reexamine the organization and wording of the document in order to
distinguish between the two.

5.	The Board also recommended that, with respect to discussions of
participant recruitment and vulnerability, the following changes be
made:

  The term “race/ethnicity” should be used instead of just
“race.”

b.	When considering issues of participant vulnerability, the primary
concern is not just arbitrary exclusion of potentially vulnerable
populations if provisions can be made to ensure the safety of the
participants. There is also the concern of potential benefits from
research participation for vulnerable groups. The Guidelines should be
revised to address this fact.

c.	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), which explicitly discusses such issues of language.
Investigators should also be urged to examine the recruitment population
in advance so that speakers of other languages are present as needed.

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. 2010b. 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; Icaridin)-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 21-22, 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.

W

X

ical Safety and Pollution Prevention, United States Environmental
Protection Agency.

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.

Final Draft Dated July 28, 2010

Final Draft Dated September 2, 2010

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