Document ID: EPA-HQ-ORD-2009-0030-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-11T04:00Z

March 3, 2009

Minutes of the

United States Environmental Protection Agency (EPA) 

Human Studies Review Board (HSRB) 

February 17, 2009 Public Teleconference Meeting

Docket Number:  EPA-HQ-ORD-2009-0030

Committee Members:	(See EPA HSRB Members list – Attachment A) 

Date and Time:  	Tuesday, February 17, 2009, 12:30 PM – 4:50 PM
(Eastern Time)

(See Federal Register Notice – Attachment B) 

Location: 		via teleconference 

Purpose: 	The EPA HSRB provides advice, information, and recommendations
on issues related to the scientific and ethical aspects of human
subjects research. 

Attendees: 	Chair: 			Celia B. Fisher, Ph.D.

Vice Chair:		William S. Brimijoin, Ph.D.

Board Members: 	Alicia Carriquiry, Ph.D.

			Gary L. Chadwick, PharmD, MPH, CIP 

Janice Chambers, Ph.D., D.A.B.T. 

Richard Fenske, Ph.D., MPH

Susan S. Fish, PharmD, MPH

Dallas E. Johnson, Ph.D.

Michael D. Lebowitz, Ph.D., FCCP

Lois D. Lehman-Mckeeman, Ph.D.

Rebecca Parkin, Ph.D., MPH

Sean Philpott, Ph.D., M.Bioethics

Ernest D. Prentice, Ph.D.

Linda J. Young, Ph.D.

Meeting Summary:	Meeting discussions generally followed the issues and
general timing as presented in the meeting Agenda (Attachment C), unless
noted otherwise in these minutes. 

Introduction and Identification of Board Members

	Dr. Celia Fisher (Chair, HSRB) opened the teleconference meeting with
an introduction and identification of the HSRB, or Board, members
participating in the call.  Dr. Fisher welcomed Board members,
U.S. Environmental Protection Agency (EPA or Agency) staff, and members
of the public to the February 17, 2009 HSRB teleconference meeting. 
She acknowledged the efforts of Dr. Paul Lewis (Designated Federal
Officer [DFO], HSRB, Office of the Science Advisor [OSA], EPA) and
members of EPA’s Office of Pesticide Programs (OPP) in planning and
preparing for this meeting.  

Meeting Administrative Procedures

	Dr. Lewis welcomed Board members and thanked them and his EPA
colleagues for their efforts in preparing for this meeting and also
welcomed members of the public.  He noted that this meeting represented
the first teleconference at which the Board would review a completed
study.  Dr. Lewis acknowledged the efforts of Mr. Hamaad Syed (OPP, EPA)
for providing technical support for the teleconference and providing
access to meeting documents.  He introduced Dr. Daniel Strickman (USDA
Agricultural Research Service), who served as a consultant on
spatial/area repellents for this meeting.  

	As DFO, Dr. Lewis serves as liaison between the HSRB and EPA and
ensures that Federal Advisory Committee Act (FACA) requirements—open
meetings, timely announcements of meetings in the Federal Register, and
meeting materials made available at a public docket—are met.  As DFO,
he also works with the appropriate officials to ensure that all
applicable ethics regulations are satisfied.  Each Board member has
filed a standard government financial disclosure form that has been
reviewed by Dr. Lewis and the OSA Deputy Ethics Officer in consultation
with EPA’s Office of General Counsel to ensure that all ethics
disclosure requirements have been met.  Consultants [Dr. Dan Strickman]
also were briefed on conflict of interest issues.  Dr. Lewis reminded
participants that meeting times would be approximate and that public
comments would be limited to 5 minutes.  

As per FACA requirements, the meeting minutes will include descriptions
of matters discussed and the conclusions reached by the Board.  As the
DFO, Dr. Lewis will prepare the minutes and have them certified by the
HSRB Chair within 90 calendar days of the meeting.  In addition, the
minutes will be available at the public docket and posted on the HSRB
Web site.  

Welcoming Remarks

	Dr. Pai-Yei Whung (Chief Scientist, OSA, EPA) welcomed Board members
and thanked them for their work in preparing for the meeting.  She
acknowledged the efforts of the Board in contributing to the success of
EPA’s human subjects protection program.  Dr. Whung welcomed members
of the public and thanked her EPA colleagues for their efforts in
preparing for the meeting.

	Dr. Whung noted that during this teleconference meeting, Board members
would review and offer advice on two completed studies by Carroll-Loye
Biological Research.  Study SPC-001 was a field study to evaluate three
formulations of mosquito repellent containing picaridin.  Study SPC-002
was a laboratory study that evaluated the ability of these products to
repel ticks.  These protocols were reviewed favorably by the Board at
the October 2007 HSRB meeting.  To assist the Board in its future
reviews of spatial and area insect repellents, which are devices (such
as citronella candles) that emit a repellent and prevent insects from
entering the space, the Agency, at the request of Dr. Fisher, invited
Dr. Strickman to help familiarize the Board with technical aspects of
spatial/area repellent testing.  The Board will discuss various aspects
of spatial/area repellent testing in part to identify necessary
information to support adequate reviews of such protocols.

EPA Follow-up on Pesticide Specific HSRB Recommendations

	Mr. William Jordan (OPP, EPA) noted that the protocols for the studies
to be reviewed during this teleconference meeting had been favorably
reviewed by the Board, the studies themselves are straightforward and
well executed, and thus review of the completed studies should be
uncomplicated.

	Mr. Jordan offered thanks on behalf of EPA for the efforts of the Board
in providing the Board report for the October 2008 HSRB meeting in a
timely manner.  The completed report aided decision-making by the
Agricultural Handlers Exposure Task Force (AHETF).  The Task Force used
the report to improve the protocols it plans to submit for review at the
March-April 2009 HSRB meeting.  If reviewed favorably, the protocols
could be executed in 2009.  EPA also has made registration decisions
based on Board recommendations pertaining to its review of completed
repellent studies at the October 2008 meeting.  In response to a
question from Dr. Fisher, Mr. Jordan explained that because EPA has
not yet finished certain sections of the Insect Repellent Guidelines
(particularly those pertaining to statistics), the Board will not review
these guidelines at the March-April 2009 meeting.

Carroll-Loye Biological Research Tick Repellent Efficacy Study (SPC-002)

	Dr. Fisher reminded EPA and Board members about the statement in the
October 2008 meeting that the recommendations of the HSRB are not
finalized until formal Board approval of a final report is completed at
a public meeting or teleconference.  Board discussions held during the
meeting serve as a foundation for recommendations, but do not represent
a formal consensus; no consensus vote is taken at the meeting.  The
meeting minutes provide a summary of the meeting, but these are not
approved by the Board, nor are they a substitute for the Board final
consensus.  Board members write their report after each meeting and
integrate meeting materials and discussions into a summary of issues and
recommendations.  A draft report is posted for public review.  The
public meeting held after the public review period allows an additional
opportunity to modify the draft report based on public comment and Board
discussion/consensus.  At the conclusion of the public meeting, the
report is finalized.  

	Dr. Fisher thanked EPA for sending the EPA presentations prior to the
teleconference meeting as previously requested.  She requested that,
given the advance availability of the presentation materials, EPA
abbreviate its presentations during the teleconference.  Mr. John Carley
(OPP, EPA) explained that the tick study would be reviewed first because
it was conducted first; descriptions of events occurring during the tick
study would make the mosquito study somewhat easier to understand.

Background and Context

	Mr. Carley provided an overview of completed tick repellent study
SPC-002.  The protocol was approved by the Independent Investigational
Review Board, Inc. (IIRB) on July 17, 2007, and submitted to EPA by
Carroll-Loye Biological Research in August 2007.  EPA’s science and
ethics review of September 24, 2007 was based on the initial protocol
submission.  The Board reviewed this protocol favorably at its meeting
on October 25, 2007.  The protocol was amended in January 2008 based on
review of the protocol by the HSRB as detailed in its draft final report
of the October 2007 meeting; the amendments were approved by IIRB, Inc.
in January 2008.  The protocol also was submitted to the California
Department of Pesticide Regulation (CDPR) for review and was approved as
amended in March 2008.  The first amendment to the protocol:

identified the Centers for Disease Control and Prevention as the source
of the ticks used in the protocol

described pathogen screening of the ticks

broadened the scope of the dose determination phase to include two
towelette formulations

corrected the description of the 15-percent spray with sunscreen

clarified the extrapolation plan for other formulations

added an efficacy data collection form

appended the draft label for the 15-percent spray with sunscreen.  

	The second amendment was submitted to IIRB, Inc. in February 2008 and
approved on March 6, 2008.  This amendment included:

a revised consent form (which addressed EPA concerns)

a revised Subjects’ Bill of Rights

a revised tick handling training sheet

an appended Materials Safety Data Sheet for the 15-percent spray with
sunscreen

a treatment allocation form

a revised tick crossing data capture form

a table to clarify the extrapolation plan.  

	Dose determination for SPC-001 and SPC-002 was executed under SPC-002
and shared by both protocols.  Dose determination took place March
15-19, 2008.  Efficacy testing for SPC-002 was conducted March 22-23,
2008.  A deviation regarding the use of limb measurements from previous
studies was reported to IIRB, Inc. on July 6, 2008.  IIRB, Inc. accepted
the deviation report on July 14, 2008.  The study report was completed
on August 19, 2008.  The primary submission of the report to EPA
occurred on September 9, 2008, and a supplemental submission was made on
November 7, 2008.

EPA Science Assessment of Carroll-Loye Biological Research Tick
Repellent Efficacy Study (SPC-002)

	Mr. Kevin Sweeney (OPP, EPA) provided EPA’s science review of
SPC-002.  The objective of this protocol was to test five repellent
formulations containing picaridin for the ability to repel ticks in a
laboratory setting.  Each test used two species of ticks, which were
tested in the nymphal stage because these ticks are most likely to
harbor disease-causing pathogens.  Efficacy was reported as Complete
Protection Time (CPT).

	Dose determination was performed to estimate typical consumer dosing
behavior for the five repellent formulations.  These were a
5.75-percent towelette (121-90), a 7-percent pump spray (121-89), a
12-percent towelette (121-93), a 15-percent pump spray (121-91), and a
15-percent pump spray with sunscreen (121-OT).  The dosimetry phase
included 10 subjects and established a typical consumer dose for each
of the five formulations; however, the towelette formulations were
excluded from the testing phase.  The lower mean dose for each pair of
“equivalent liquid formulations” was selected for use in efficacy
testing.  Typical arm doses determined for equivalent liquid
formulations (grand mean dose) were 1.38 ± 0.40 milligrams per
square centimeter (mg/cm2) for the 5.75-percent towelette,
0.59 ± 0.32 mg/cm2 for the 7-percent pump spray, 1.26 ± 0.42 mg/cm2
for the 12-percent towelette, and 0.93 ± 0.50 mg/cm2 for the 15-percent
pump spray.  Leg doses determined for the mosquito repellency testing
were lower than those for the arm.  Only three of the products (the
7-percent pump spray, 15-percent pump spray, and 15-percent pump spray
with sunscreen) were used in efficacy testing.  The standard dose rates
for these products for arms and legs were 0.59 mg/cm2 and 0.48 mg/cm2
for the 7-percent pump spray; 0.93 mg/cm2 and 0.65 mg/cm2 for the
15-percent pump spray; and 0.75 mg/cm2 and 0.46 mg/cm2 for the
15-percent pump spray with sunscreen, respectively. 

	The three pump spray formulations were tested to determine CPT in the
laboratory against two species of nymphal ticks to satisfy a condition
of registration imposed by EPA.  To execute this protocol, 30 subjects
were trained in the laboratory to handle laboratory-reared,
pathogen-free ticks and to remove them before they could bite and bury. 
Ten subjects were treated on the arms with each test material.  The
treatments were not distinguishable from each other and neither subjects
nor technicians recording the results knew who received which treatment.
 Fifteen subjects were tested on each of two successive days.  The
untreated arm of each treated subject served as a control to ensure that
only actively questing ticks were used in efficacy testing.  Each
subject tested one nymphal tick of each species in each 15-minute
exposure period until efficacy failure or approximately 15 hours
post-treatment.  CPT was calculated as the mean time from treatment to
“First Confirmed Crossing” or FCC, e.g., the time at which a tick
first crossed into the treated area on the subject’s arm.

	Standard doses determined during dosimetry testing were applied to
subjects’ forearms.  Using a standard 70-kilogram (kg) body weight to
determine the dose rates (milligrams per kg [mg/kg]), Margins of
Exposure (MOEs) for each formulation were 6,623 (7-percent pump spray),
1,881 (15-percent pump spray), and 2,265 (15-percent pump spray with
sunscreen).  These exceed the target MOE of 100, so risk to subjects was
low.

	There was considerable variability in the test results and some right
censoring of data for the products containing 15 percent picaridin. 
Mean CPT and standard deviation for testing using Ixodes scapularis were
7.9 ± 1.4 hours for the 7-percent pump spray, 11.8 ± 3.3 hours for the
15-percent pump spray, and 8.7 ± 4.3 hours for the 15-percent spray
with sunscreen.  For testing using Dermacentor variabilis, mean CPTs and
standard deviations were 5.7 ± 2.1 hours for the 7-percent pump spray,
9.7 ± 4.0 hours for the 15-percent pump spray, and 8.2 ± 4.9 hours for
the 15-percent spray with sunscreen.

	The primary protocol deviation occurring for this study was the use of
some subject limb measurements on file from previous studies.  The same
deviation was reported for protocol LNX-001, which was reviewed by the
HSRB in October 2008.  The deviation was reported to and accepted by
IIRB, Inc., and did not affect the scientific integrity of the study or
the results.  In response to comments from EPA, the “lotion” product
was more completely characterized in the protocol, the source of ticks
was identified, and steps taken to ensure that the ticks were disease
free were described.  In response to the HSRB, the protocol clarified
that subject allocation to treatments would ensure that no subjects
tested more than one repellent to ensure consistency with the stated
statistical design.

	EPA has found that the study provides scientifically valid results that
meet Agency standards.  For purposes of labeling, the data are adequate
to support the following claims of tick repellency:  7 hours for the
7-percent spray (product 121-89 Cutter Insect Repellent 7K), 11 hours
for the 15-percent spray (product 121-91 Cutter Insect Repellent 15 KP),
and 8 hours for the 15-percent spray with sunscreen (product 121-OT
Cutter Insect Repellent SS).

	Clarifying Questions 

	Dr. Linda Young opened the discussion by stating that, in her opinion,
the data do not support the label claims proposed by EPA.  Dr. Janice
Chambers commented that this was a policy issue outside the Board’s
purview, but Dr. Fisher countered that although EPA decides how to use
the data for labeling decisions, the Board has the responsibility to
advise on whether the data are sufficient to support CPT claims that
will be included on the label.

	Dr. Young complimented EPA for clearly describing the research
objective for this protocol.  Study design, analysis, and data
interpretation all are created based on the research objective; however,
Dr. Young expressed concern that any one study of an insect repellent
could suffice for label information that will be used on a nationally
marketed product.  Diverse mosquito, tick, and human populations exist
across the United States as do differences in the susceptibility of
species to repellents and attractiveness of humans to insects.  The
results from the tick protocol show mean protection times of less than 7
hours for one of the two species; therefore, the EPA label claims that
were included in the materials sent to the Board are inconsistent with
study results.  This protection time is within the confidence interval,
but taking protection time from the lower band of the confidence
interval would account for most resistant species.  In addition, if the
time at first bite was reported, rather than the second confirming bite,
which would result in a CPT closer to 3 hours.  Mean protection time is
not equal to CPT and the uncertainty inherent to these observations
should be conveyed to the consumer.  The public has become increasingly
literate in matters related to statistics and probability and should be
provided with margin of error information.

	Dr. Fisher explained that the Board must make two decisions related to
the completed study:  (1) whether the investigator followed HSRB
recommendations related to the study design and data collection, and
whether the data were reliably collected; and (2) whether there are
limitations to the use of the data for its intended purpose as stated in
conclusions by EPA.  In 2008, the Board decided that CPT was
inappropriate for right-censored data and EPA should not rely on this
measure for judging efficacy.  During this teleconference, the Board was
provided with additional information related to the way that EPA
interprets and uses the data and thus the Board should comment on this
issue.

	Dr. Young agreed that there were no marked departures from the approved
protocol; however, the data do not support the claims made by EPA.  Dr.
Stephen Brimijoin stated that the Board was confusing policy decisions
with scientific determinations.  He agreed with Dr. Young’s
statements regarding matching study design to study objective and being
aware of how the data will be used; however, he disagreed that the
protocol was flawed because it was not performed using more insect
species, more field sites, and much larger numbers and diversity of
subjects.  He remarked that he would not agree with a decision stating
that the data are not sufficiently scientifically sound to be relied on
by EPA.  This would be inappropriate, particularly given the efforts of
EPA and Carroll-Loye Biological Research to address issues raised by the
Board concerning these matters.  He agreed with Dr. Young that the
studies were not designed to produce a CPT of 7 hours, and that an
absolute CPT of 7 hours was invalid.  The Board charge question asks if
the data are scientifically sound to be used for the intended purpose. 
These data will be used to devise a label; the Board can recommend that
the label refer to the variability and error inherent in this measure;
however, the Board must focus on whether the data are scientifically
sound.

	Dr. Michael Lebowitz suggested that there was confusion between the
Board charge question and EPA conclusions.  The Board charge pertains
only to the scientific soundness of the data.  The conclusions presented
by Mr. Sweeney refer to how EPA would use the data if the Board agrees
that the data are sound.  The Board can answer the charge question and
then respond to EPA conclusions presented in the SPC-002 presentation as
an advisory note stating that the data could be more appropriately used.

	Dr. Alicia Carriquiry agreed with Dr. Young’s opinion that the label
claims for CPT were too optimistic.  In addition, it is unclear whether
these laboratory results can be applied to the entire United States.  It
is unlikely that the participants were diverse enough to support
application of the results to all people in the United States and to all
tick species.  The Board should consider whether the data are
sufficiently scientifically sound to be extrapolated to the entire
country.  

	Dr. Fisher asked why tick repellency was studied under laboratory
conditions.  Mr. Sweeney answered that tick studies are not performed in
the field because of the diseases carried by ticks and the likelihood
that a participant would not notice a tick bite in the field.  Dr.
Dallas Johnson requested clarification on the use of mean crossings per
subject to determine CPT.  Mr. Sweeney explained that lines are drawn
on the participants’ arms and ticks are observed to determine when
they cross the lines.  A confirmed crossing requires the initial
crossing to be confirmed by another crossing within 15 minutes; this
indicates product failure.  

	Dr. Fisher noted that the use of limb measurements taken previously
seems to have occurred several times.  Mr. Carley clarified that this
protocol deviation occurred for the first time when the tick protocol
was conducted in March 2008.  In October 2008, the Board reviewed a
study conducted in June 2008.  The episode was noted in the
summer 2008; two mosquito and one tick protocol were conducted at the
same time using the same methods.  The protocol deviation discussed at
the October 2008 HSRB meeting is the same occurrence reported during
this discussion of the completed protocol.

EPA Ethics Assessment of Carroll-Loye Biological Research Tick Repellent
Efficacy Study (SPC-002)

	Mr. Carley provided EPA’s ethics review of SPC-002.  EPA found this
study to be well conducted and designed and it was modified to
incorporate HSRB and EPA recommendations.  One protocol deviation
occurred, namely the use of previously recorded limb measurements for
some subjects.  This deviation was unintentional, reported to the IIRB,
Inc. in a timely manner, and had no ethical consequences.

	In its September 24, 2007 review of SPC-002, EPA asked the investigator
to incorporate an appropriate data collection form for recording
efficacy test results; this was addressed in Amendment 1 and refined in
Amendment 2.  EPA also requested inclusion of product labels in the
protocol and that the labels be provided to subjects during the dose
determination phase.  A draft label for the 15-percent spray with
sunscreen thus was attached to the protocol via Amendment 1.  EPA asked
that the investigator address in the consent form the risk of tick bites
and diseases and measures taken to prevent bites; these issues were
addressed in the consent form revisions provided with Amendment 2.  In
its March 6, 2008 report, the HSRB had no additional recommendations for
refinements to this protocol.  

	EPA has found that SPC-002 meets the applicable standards, namely 40
Code of Federal Regulations (CFR) § 26.1303, 26.1703, 26.1705, and
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
§12(a)(2)(P).  The requirements of 40 CFR § 26.1303 to document the
ethical conduct of SPC-002 were met in the supplemental submission of
November 7, 2008.  SPC-002 did not involve intentional exposure of
pregnant or nursing women or of children less than 18 years of age.  The
only protocol deviation was unintentional, promptly reported, and of no
ethical significance.  The subjects were fully informed and participated
voluntarily.  SPC-002 thus was conducted in substantial compliance with
the requirements of 40 CFR part 26, subparts A-L.  Assuming SPC-002 is
determined to be scientifically acceptable; EPA finds no limitations in
law or regulation to reliance on it in actions under FIFRA.

Charge Questions

	The Board was asked to consider whether SPC-002 was sufficiently sound,
from an ethical perspective, to be used to assess the repellent efficacy
against ticks for the three formulations tested.  The Board also was
asked to address whether the available information supports a
determination that the study was conducted in substantial compliance
with subparts K and L of 40 CFR part 26.

Public Comments

	Dr. Scott Carroll, on behalf of Carroll-Loye Biological Research

	Dr. Scott Carroll acknowledged that the Board’s concerns regarding
statistical analysis and interpretation of the data and how EPA uses the
data have been persistent issues.  He explained that the studies
conducted by Carroll-Loye Biological Research are more thorough and
incorporate much larger sample sizes compared to prior work.  The
reliability of the data also has been improved.  He agreed that in other
fields, experiments involving human subjects have much larger sample
sizes; however, work in the field of medical entomology has a history of
obtaining reliable results with relatively small sample sizes.  DEET
labeling, for example, is remarkably accurate.  Dr. Carroll also
informed the Board that a Carroll-Loye Biological Research protocol was
recently published in the Journal of Medical Entomology, thus
demonstrating that this work meets peer review standards.  He expressed
appreciation for the Board’s input on various Carroll-Loye Biological
Research protocols and stated that he will continue to work to improve
these studies.

	Dr. Brimijoin noted that laboratory research protocols often are
repeated a number of times, but that this might be more difficult when
the work is being performed in the field or for a commercial entity to
support labeling requirements.  He commented that the costs of
experimentally addressing all Board concerns related to multiple
species, different field conditions, and diverse human populations,
would likely be prohibitive.  

	Dr. Fisher remarked that her impression is that picaridin was safer
than DEET, but DEET was a more effective repellent; however, DEET
protection times appear to be lower than those obtained in the picaridin
studies.  Dr. Carroll agreed that picaridin appears to be safer than
DEET, but there is no evidence that it is less effective.  The published
literature on picaridin indicates that it is slightly to moderately more
effective than DEET.  Dr. Fisher stated that the CPT for picaridin
appeared to be twice as long as that for DEET.  Dr. Carroll commented
that CPT will vary because of differences in studies with respect to
insect species and subjects.  Picaridin also is known to be more
effective against Anopheles sp. than DEET.  Dr. Fisher noted that data
from a large number of studies should be considered before making strong
statements regarding the relative effectiveness of these products.  

Board Discussion

	Scientific Considerations – Study SPC-002

	Dr. Chambers opened the science discussion for SPC-002.  She noted that
the label for the pump spray with sunscreen will indicate 5 hours of
protection time, not 8 hours.  She stated that the study was
scientifically valid.  The protocol was clearly written, and the
deviation, which was done to reduce inconvenience to participants, had
no impact on data quality.  The data are scientifically valid and the
study accomplished its objective.  Labeling decisions made by EPA are
beyond the purview of the Board.

	Dr. Carriquiry agreed that the protocol was followed, but the data do
not support the label claims made by EPA, which also could be considered
an objective of the study.  It is difficult to determine whether the
study is scientifically valid in the absence of a clear objective.  If
the data are to be used for developing a label, the label should include
caveats related to the lack of generalizability of the data.  Dr.
Carriquiry disagreed with the conclusions drawn by EPA regarding the
protection times it developed based on the data.

	Dr. Fisher reminded Board members that they should assess the protocol
based on whether execution of the study followed the protocol, the data
were reliably collected, and whether statistical analyses were
appropriate and sufficient with respect to EPA’s conclusions.  Board
members agreed that the execution of the study followed the protocol and
that the data were reliably collected.

	Dr. Carriquiry agreed that the statistical analyses were correctly
executed, but there were problems with the interpretation of the
analyses results.  Dr. Johnson noted that this was not the first meeting
at which the Board had been presented with EPA conclusions regarding the
use of the data to establish protection times for a label and suggested
disregarding this information.  Dr. Fisher responded that the Board has
often asked EPA to provide information on how it will use data from
these protocols to inform labels.  EPA is drawing conclusions that the
study sufficiently addresses product protection time and no further
studies are needed.  Dr. Johnson stated that if EPA wishes the Board to
address its use of the data for labels, this should be included in the
Board’s charge questions.

	Dr. Lois Lehman-Mckeeman stated that the experiment was reasonably
well-conducted and had been improved; however, the conclusions were
somewhat puzzling.  She agreed with Dr. Chambers regarding the purview
of the Board for determining appropriate use of the data by EPA.  The
Board has previously assessed data without knowing how EPA intended to
use the data.  She indicated that she was reluctant to conclude that
the study could not be used because of the Board’s disagreement with
EPA conclusions.  Dr. Brimijoin agreed with Dr. Lehman-Mckeeman and
noted that the Board has previously concluded that if a study is not
scientifically valid, it is not ethically valid and the data cannot be
used by EPA.  In his opinion, finding that a study is not scientifically
valid should be reserved for studies with serious flaws.  He encouraged
Board members with reservations about the statistical analyses and
designs of the protocols to state their reservations for the record and
offer advice; however, the Board must conclude that SPC-002 is
scientifically valid and that EPA can use the data.

	Dr. Fisher, drawing on the Board’s October 2008 written report on
these protocols, reminded the Board that it had approved the study
design, but was troubled by and noted in the report the lack of
generalizability of the data.  Recommending that generalizability be
improved is not inconsistent with approving the conduct of the study. 
She agreed that the study was well conducted and provided reliable data,
but the data are useable only in a limited sense.

	Drs. Chambers and Lebowitz recommended that the Board find the study
scientifically valid as conducted.  Dr. Fisher asked whether the Board
would address the EPA conclusions.  Dr. Brimijoin responded that the
Board was not asked to address this issue and that he would not agree
to any conclusion other than that the study was valid.  Dr. Fisher
disagreed that the data from the study was adequate to support the
specific protection times presented in the EPA’s conclusions.  Dr.
Chambers noted that the conclusions were not drawn by those conducting
the study and were not part of the study.  Dr. Lewis suggested that
these concerns be included in the Board’s response to the charge
questions in its report.

	Ethical Considerations – Study SPC-002

	Dr. Sean Philpott opened the ethics discussion by noting that the study
meets the applicable ethical requirements.  There is an acceptable
balance of risks and benefits, participation was voluntary, informed
consent was obtained, and justice issues were addressed.  The risks to
the subjects were minimal and justified by the potential societal
benefits of marketing new tick repellent formulations.  He commended Dr.
Carroll’s respect for subject privacy regarding possible unexpected
results of pregnancy tests by using alternate subjects.  The study had
clear medical stopping rules, the risk of tick bites was low, and
pathogen-free ticks were used.  The protocol was designed to ensure
voluntary informed consent and mechanisms to avoid coercion were in
place.

	The protocol deviation that was reported occurred when a laboratory
manager acted on EPA’s suggestion for using archived measurements. 
The manager used archived measurements without consulting Dr. Carroll or
IIRB, Inc.  Dr. Carroll has acknowledged that this was a result of a
communication error and has assured EPA and the Board that it will not
happen again.  The deviation posed no increase in risk to the study
participants and thus is not a serious issue.  Dr. Philpott concluded
by stating that the study was ethically conducted and EPA therefore can
use the data generated by it.  Dr. Ernest Prentice agreed with Dr.
Philpott’s conclusions.  SPC-002 was conducted in compliance with 40
CFR subparts K and L.  He expressed some concern about the statistical
analyses and EPA conclusions regarding these data, but agreed that these
matters should be discussed at the next Board meeting; however, he
concluded that the study was well conducted and the data can be used by
EPA.  Dr. Susan Fish agreed with Drs. Philpott and Prentice.

	Dr. Fisher summarized that the study was well conducted and generated
the appropriate data.  She recommended that the Board note in its report
the importance of addressing issues raised at this meeting at the next
Board meeting, particularly statistical matters broached by
Drs. Carriquiry and Young.

 

Carroll-Loye Biological Research Mosquito Repellent Efficacy Study
(SPC-001)

Background

	Mr. Carley provided an overview of the mosquito repellent efficacy
study SPC-001.  This study underwent the same EPA and HSRB protocol
review process as SPC-002, with some differences in the amendment
process.  SPC-001 was submitted to CDPR and then amended in
mid-May 2008 after comments were received from CDPR and the HSRB. 
Final CDPR approval was received on May 29, 2008.  The first amendment
to the protocol was similar to that for SPC-002, including adding dose
determination for the two towelette formulations, correcting the
description of the 15-percent pump spray with sunscreen product,
clarifying the extrapolation plan, and clarifying allocation of subjects
to treatments.  Amendment 2 clarified terminology and language, added a
table to further clarify the extrapolation plan, further clarified
allocation of subjects to treatments, clarified timing of pregnancy
testing, and updated the demographic description of the pool from which
subjects were recruited.  Field testing for SPC-001 was conducted June
8-14, 2008.  The deviation report to IIRB, Inc. regarding the use of
limb measurements from previous studies was submitted on July 6, 2008.

EPA Science Assessment of Carroll-Loye Biological Research Mosquito
Repellent Efficacy Study (SPC-001)

	Mr. Sweeney provided EPA’s review of the science of SPC-001.  The
dose determination phase for this study was shared with that for
SPC-002.  The objectives of this study were to measure CPT in the field
against mosquitoes for three repellent formulations containing
picaridin:  7-percent pump spray (121-89), 15-percent pump spray
(121-91), and 15-percent pump spray with sunscreen (121-OT).  This study
was performed to satisfy a condition of registration imposed by EPA.

	This study was similar to other recent Carroll-Loye Biological Research
field studies.  Subjects were trained in the laboratory to aspirate
landing mosquitoes before they bite.  Laboratory-reared, pathogen-free
mosquitoes were used.  Neither subjects nor technicians recording
results knew who received which product.  Untreated subjects were used
to monitor mosquito pressure; each subject was attended by two
technicians to aspirate landing mosquitoes.  The study involved 10
subjects treated with one of the three tested formulations and 2
untreated control subjects who participated in each of 2 field trials;
some subjects participated on both days.  Both treated and untreated
subjects were exposed to mosquitoes for 1 minute at 15-minutes
intervals, until efficacy failure or up to 17 hours post-treatment.  CPT
was calculated as the mean time from treatment to “First Confirmed
Landing with intent to bite” or FCLibe.

	Standard doses were applied to subjects’ arms and legs and a standard
70-kg body weight was used to determine the dose rates.  The MOEs for
arms were the same as for SPC-002.  The MOEs for legs were 3,597
(7-percent pump spray), 1,197 (15-percent pump spray), and
1,682 (15-percent pump spray with sunscreen).  Since these are in
excess of the target MOE of 100, risk to subjects was low.

	The field sites used were located in the California Central Valley. 
Site 1 was located in Butte County and was a grassy lakeside with
shrubs.  Site 2 was located in Glenn County and was a tall native forest
understory.  Various Aedes and Anopheles sp. were present at the sites,
as was Culex tarsalis.  The investigator ensured that neither West Nile
Virus (WNV) nor other pathogens had been detected at the sites by
various monitoring agencies.

	The median CPT values were close to the mean CPT values and the
variability was not as great as in SPC-002.  Mean CPT and standard
deviations at Site 1 were 8.4 ± 2.1 hours for the 7-percent spray,
10.1 ± 4.0 hours for the 15-percent spray, and 12.7 ± 4.9 hours for
the 15-percent spray with sunscreen.  At Site 2, mean CPTs and standard
deviations were 7.0 ± 2.2 hours for the 7-percent spray, 10.7 ± 0.8
hours for the 15-percent spray, and 10.9 ± 0.8 hours for the
15-percent spray with sunscreen.

	The deviation reported for study LNX-001 and SPC-002 regarding the use
of subject limb measurements on file from previous studies was reported
for this protocol.  The deviation was reported to and accepted by IIRB,
Inc.  The deviation did not affect the scientific integrity or the
results of the study.  In response to a comment in the EPA review, the
investigator added a more thorough description of the 15-percent pump
spray with sunscreen to the protocol through Amendment 1.

	EPA has concluded that the study provides scientifically valid results
that meet EPA standards.  For purposes of labeling, this study supports
claims of repellency of 8 hours for the 7-percent spray (product
121-89), 10 hours for the 15-percent spray (product 121-91), and 12
hours for the 15-percent spray with sunscreen (product 121-OT).

EPA Ethics Assessment of Carroll-Loye Biological Research Mosquito
Repellent Efficacy Study (SPC-001)

	Mr. Carley provided EPA’s review of the ethics of protocol SPC-001. 
The study was well designed, executed properly, and clearly reported. 
The submission of the report of the completed study meets regulatory
standards for completeness.  The same protocol deviation in protocol
SPC-002 (use of previously recorded limb measurements) was properly
reported to IIRB, Inc. and was of no ethical consequence.  In response
to EPA and the HSRB ethics reviews, the investigator incorporated an
appropriate data collection form for recording field test results, and
provided product labels in the protocol and to subjects during the dose
determination phase.  In its March 6, 2008 report on its review of this
protocol, the HSRB made no additional recommendations for refinements.

	The applicable standards for this protocol are 40 CFR § 26.1303,
26.1703, 26.1705, and FIFRA §12(a)(2)(P).  The investigator documented
the ethical conduct of SPC-001 as required.  SPC-001 did not involve
intentional exposure of pregnant or nursing women or of children less
than 18 years of age.  The only protocol deviation (which was
unintentional) was reported promptly and was of no ethical significance.
 Subjects were fully informed and participated voluntarily.  SPC-001 was
conducted in substantial compliance with the requirements of 40 CFR part
26, subparts A-L.  Assuming SPC-001 is determined to be scientifically
acceptable, EPA finds no barrier in law or regulation to the Agency’s
reliance on it in actions under FIFRA.

Charge Questions

	The Board was asked to consider whether SPC-001 was sufficiently sound,
from a scientific perspective, to be used to assess the repellent
efficacy against mosquitoes for the three formulations tested.  The
Board also was asked to address whether the available information
supports a determination that the study was conducted in substantial
compliance with subparts K and L of 40 CFR part 26.

Public Comments

	Dr. Scott Carroll, on behalf of Carroll-Loye Biological Research

	Dr. Scott Carroll offered to respond to questions from the Board.  No
comments were provided.

Board Discussion

	Scientific Considerations – Study SPC-001

	Dr. Chambers opened the science review by stating that her opinion of
this protocol was the same as that for SPC-002.  The report was clear,
the study was well conducted, the MOE was acceptably high; therefore,
the study is scientifically sound.  Dr. Carriquiry agreed that the study
was well conducted, the data are valid, and the analyses were correct;
however, she remarked that EPA had overstated its conclusions.  The
Agency’s presentation indicated the median CPT to be slightly longer
than the mean, which implies that the distribution of CPTs is not
symmetric.  This suggests that the mean is probably not the best value
to use when making label recommendations.  In response to a question
from Dr. Fisher, Dr. Carriquiry agreed that this implied limitations to
conclusions drawn about protection times.  Dr. Lehman-Mckeeman agreed
with Dr. Chambers’ assessment.  

	Dr. Fisher summarized that the Board consensus was that the study had
been conducted according to the protocol and the data were reliably
collected, but that some Board members concluded there were statistical
limitations to the generalizability of the data.  She also noted that
the Board did not wish to discourage EPA from seeking the Board’s
advice on how data from completed protocols might contribute to the
Agency’s labeling decisions, especially since this information
provided a context within which to better judge the adequacy of the data
for the Agency’s needs. However, the Board viewed the current language
of the charge questions as potentially limiting the scope of its
recommendations.  Further general discussion at the next face-to-face
Board meeting regarding the wording of the charges was suggested.

	Ethical Considerations – Study SPC-001

	Dr. Philpott opened the ethics review by noting that the study was
similar to SPC-002.  Given the available information, SPC-001 is in
substantial compliance with the pertinent regulations.  The main
difference between this study and SPC-002 is the conduct of SPC-001 in
the field rather than laboratory and in its study of efficacy against
mosquitoes rather than ticks.  Appropriate stopping rules were used and
medical assistance was available.  Although field testing is accompanied
by possible exposure to vector-borne diseases, the studies were
conducted at sites at which neither WNV nor other pathogens had been
detected for at least 1 month prior to the study.  Molecular analyses of
mosquitoes captured during the study showed that no pathogens were
present.  Follow-up with the participants found no adverse effects
attributable to pathogens or to the products themselves.  Dr. Philpott
concluded that the data could be used by EPA.  Drs. Fish and Prentice
agreed with Dr. Philpott’s review.  Dr. Fisher concluded that the
Board consensus was that SPC-001 had been ethically conducted.

Spatial/Area Insect Repellent Testing

Introduction

	Dr. Fisher explained that because the HSRB will for the first time
review protocols for spatial repellent testing at a future HSRB meeting,
the Board needs to be educated about such protocols.  A working group
was created that generated a list of questions for EPA concerning these
protocols.  In response, EPA asked Dr. Dan Strickman to serve as
consultant to the Board and address these questions.  Both Dr. Strickman
and EPA addressed the questions posed by the Board working group and
provided guidelines and other useful information.  Drs. Fisher and Lewis
also targeted additional areas to address.  EPA did not orally present
information from the meeting materials; however, Dr. Strickman provided
a review of spatial/area insect repellent testing and addressed some
issues raised by the Board.  

Technical Aspects of Spatial/Area Repellent Testing

	Dr. Strickman described differences between testing spatial/area
repellents versus topical repellents.  Topical repellants operate at the
last stages of the biting process and are highly targeted to protect
subjects.  Spatial repellents exert their effects on the insect at a
distance from the subject, and these effects are different than those of
topical repellants.  This category of repellents includes devices that
emit repellent chemicals and also physical barriers, such as bed nets
and screened suits.

	Spatial repellent testing often uses a human “surrogate,” such as a
carbon dioxide-baited trap.  Spatial repellents function by stopping
insect movement through irritating, intoxicating, or killing the insect
before it reaches a human; therefore, determining the proportion of
insects whose movements are stopped before reaching the trap can be used
to test efficacy, rather than counting numbers of landings or bites. 
However, if the spatial repellent works by interfering with mechanisms
involved in attraction of insects to humans, humans must be used in
testing.

	Complete protection time is not appropriate as a measure of efficacy
for spatial repellents because spatial repellents do not offer
100-percent protection.  Duration of effect and percent efficacy are
used instead; for example, a spatial repellent may be characterized as
reducing bites by 60 percent for up to 2 hours.  The percent
effectiveness should not vary over time for emitting devices.  Once the
device has emitted the targeted dose of chemical, effectiveness should
remain the same until the device stops emitting.

	Spatial repellent devices are often tested under controlled conditions
to avoid confounding effects of wind.  These tests are performed in
large, house-sized cages, which allow testing to be conducted at any
site within the United States and allow investigators to choose which
insect species to test.  Because of variables, such as the presence of
various species and, especially, wind, it is essentially impossible to
gather truly representative data in the field.

	Clarifying Questions

	Dr. Johnson asked how cage studies were used to judge efficacy of a
spatial repellent.  Dr. Strickman explained that the use of cages
allows investigators to pre-determine the number of mosquitoes present,
which permits determination of a true measure of protection.  This
approach also avoids the use of human subjects.  An emitting device can
be placed in a large cage between the mosquito release point and a trap,
and the number of mosquitoes that travel through the emitted repellent
to the trap can be counted.  Dr. Fisher asked whether the lack of human
subjects meant that the effect of differences in attractiveness to
mosquitoes on repellent efficacy could not be judged.  Dr. Strickman
explained that this depends on the mode of action of the device.  Most
devices emit a pyrethroid chemical that is emitted as small particles
and gas vapors.  Most mosquitoes do not pass through the cloud because
it is irritating, although those that do enter the cloud become
immobilized and do not bite.  In this case, the ability of the device to
stop mosquito movement is being tested, rather than its effect on
mosquito-human interactions.  In contrast, human subjects would be
needed to test devices that emit compounds that block mosquito receptors
to human attractants.  These do not stop mosquito movement, but instead
render the mosquitoes unable to detect humans.  Dr. Fisher inquired if
such studies would involve use of protective clothing.  Dr. Strickman
responded that protective clothing that allows odor and heat to escape
can be used, but problems arise with catching the mosquitoes to
determine the number that are not affected by the blocking compound.  An
assistant could aspirate landing mosquitoes, but this approach is not
standardized.  Bed nets with reverse funnels that prevent a connection
with the net interior also could be used to catch mosquitoes as they
seek the host.

	Dr. Johnson questioned how experimental results would be extrapolated
to real-life conditions.  Dr. Strickman replied that a study that
compared the number of bites received in the presence and absence of the
device could be performed.  Although this approach might be more
accurate, determining the percentage protection over time by monitoring
mosquito movement is considered accurate and avoids exposing human
subjects to mosquito bites.  Dr. Strickman acknowledged that
effectiveness under laboratory conditions differs from real-life
effectiveness.  For example, a 50-percent reduction in bites might seem
impressive in a controlled situation, but would not satisfy the
consumer.  Dr. Fisher inquired if labels for these products indicated
protection as percent reduction in bites.  Dr. Strickman explained that
EPA decides how this information is conveyed on the label.  Dr.
Strickman added that current spatial/area repellents are not 100-percent
effective.

	Dr. Carriquiry noted that, when extrapolating from a controlled study
to real-life conditions, a number of assumptions must be made.  Wind is
likely to be a significant factor affecting efficacy, but is not a
factor under controlled conditions.  She asked if these products were
tested under controlled conditions to permit comparison between
products.  Dr. Strickman answered that performing the tests under
controlled conditions does allow comparison to be made.  It might be
possible to generate laminar flow of a specific speed for the tests, but
not including wind provides a more straightforward approach.  Dr.
Carriquiry inquired if wind should be incorporated into the tests
because it does not affect all products the same way.  Dr. Strickman
acknowledged that the public might prefer a more accurate measure of
protection under real-life conditions, but it is not realistic to gather
all the information that would be needed to do so.  Variations among
people, including use of sunscreen or deodorant, and variations among
mosquito species are vast.  The controlled tests are primarily used to
compare products and determine if one product offers better protection
than another under controlled conditions.  Dr. Johnson questioned if
the Board would review studies that compare products or studies that are
used to make a protection claim.  Mr. Sweeney explained that the
products make protection claims, but the claims are often compared
across products; thus, similar test conditions that offer better
comparison are needed.  Dr. Fisher inquired how, given that labels are
used to provide relative information for the consumer, EPA ensures that
the data are consistent and collected under consistent conditions.  Mr.
Sweeney replied that the Agency offers guidance on data use and also has
established study requirements.

	Dr. Fisher explained that Board members had been assigned to discuss
questions that will arise when the HSRB evaluates spatial/area repellent
studies; these questions also will serve to provide EPA with an overview
of Board concerns and will allow sponsors to learn how the Board has
been educated in matters related to these types of studies, which should
help them tailor their protocols.  This discussion also was designed to
help the Board develop criteria for assessing scientific validity of
such studies when presented to the Board.  

Public Comments

	

Dr. Fisher invited oral public comment on spatial/area repellent
testing.  No oral public comments were presented.  

Board Discussion

	Environmental Aspects

	Dr. Lebowitz opened the discussion by noting that many studies of
spatial/area repellents do not involve humans and thus will not be
reviewed by the Board.  Significant differences in the behavior of
repellents under different conditions, or in the presence of different
insect species or individuals exist and will affect efficacy.  It is
difficult to test these variables because there is little existing data
from work performed under controlled conditions that tests the effects
of laminar flow, turbulence, temperature, humidity, and other factors to
allow extrapolation of repellent efficacy under controlled conditions to
real-life situations.  He acknowledged that the amount of testing that
would be required to account for all possible environmental conditions
is unrealistically large.  Thus, Dr. Lebowitz recommended that better
protocol guidelines be established, or that the Board recommend that EPA
develop more rigorous standards for testing these repellents to improve
comparisons among different repellents.  The mode of application and the
kind of chemical used also will be important for comparing efficacy
tests.  Dr. Lebowitz noted that certain kinds of emitters, such as
candles and coils, may have health effects; therefore, proper
determination of MOEs is crucial.  He recommended that the Board draft a
report of their concerns related to spatial/area repellent testing and
provide it to Dr. Strickman and EPA for review.

	Dr. Richard Fenske agreed that much of the testing of these repellents
will not be reviewed by the HSRB, because the tests do not involve
humans.  He also agreed that excluding humans from testing will allow
flexibility for more experimental scenarios, but some repellents, such
as those that affect human attractiveness for insects, will require
human testing.  Dr. Fisher stated that although the Board will not
review studies that do not involve humans, the Board may need to
consider why humans are included in a study and whether this is
appropriate.  She added that the Board should consider whether studies
that include humans are likely to generate data that will result in
labeling that offers greater protection for humans.  The HSRB’s charge
is to consider whether testing in human subjects is necessary or needed
to provide the best possible information for the consumer.  Dr. Lebowitz
agreed that scenarios may exist in which human testing is desirable, but
a series of cage experiments or use of sentinel species may be safer and
adequate.  He stated that the Board may not have sufficient experience
with this type of testing to determine when human testing is needed. 
There is a great deal of variability across studies of spatial/area
repellent testing and thus it is difficult to determine the most
appropriate type of testing.

	Study Design

	Dr. Lehman-Mckeeman opened discussion of study design by stating that
because the Board will review a number of different kinds of devices and
products, all protocols must include a clear description of the product,
the compound it delivers, and how the product delivers the compound. 
Protocols should include specific details concerning how devices will be
operated and how correct operation will be determined.  She agreed that
justification of the inclusions of humans in such studies will be
needed.  Standards also should be established.  For example, if testing
is conducted outdoors, minimal acceptable criteria for allowable
environmental conditions are needed; these might cover a range of
acceptable conditions.  Dr. Fisher suggested that the Board also may
wish to be educated about the need for field testing versus testing in a
controlled setting.

	Dr. Lehman-Mckeeman commented that design or measurement standards for
dispensing devices should be explained.  Determination of the ambient
concentration of the active ingredient should occur during testing to
determine whether the device functioned properly and to calculate MOE. 
Regarding dosimetry data, physical and chemical characteristics of the
active ingredient for any volatile product will need to be specified
because these characteristics will determine how the active ingredient
permeates the space.  The Board also will need to understand parameters
such as skin penetration and inhalation exposure related to the active
ingredient.  Physical devices with non-adjustable discharge rates could
be tested under laboratory conditions to determine the time of discharge
and chemical duration in the environment after completion of discharge;
these matters should be specified in the protocol.  In response to a
question from Dr. Fisher, Dr. Strickman explained that chemical release
by repellent emitters is usually expressed as ambient concentration. 
Dr. Lehman-Mckeeman remarked that determining ambient concentration
should be based on formulation, because formulation could alter the
behavior of the active ingredient.

	Dr. Lehman-Mckeeman concluded by stating that standardization of a
testing paradigm for spatial/area repellents is needed.  Devices that
discharge a compound will differ from products such as candles that emit
a repellent.  Physical and chemical properties of all formulations will
need to be known.

	Dr. Brimijoin agreed with Dr. Lehman-Mckeeman’s conclusions.  He
commented that given the apparent mismatch between study design and
study objective (informing labeling practice) in the topical repellent
studies, sponsors of spatial/area repellent studies should be aware of
this issue and its importance to the Board.  He agreed that specific
justification of the use of humans in spatial/area repellent testing
will be needed.  It is not always ethically more defensible to perform
such studies only in animals; spatial/area repellents will be used by
humans and the studies are low risk.  Humans should be involved in
testing earlier rather than later, given appropriate basic scientific
data to justify use of human subjects.

	Regarding controlled indoor studies versus variable outdoor studies,
the purpose for performing the studies (labeling purposes) should be
kept in mind.  The Board will need to consider the types of statements
that can be justified using the results from testing in controlled
environments.  Because the results will be used to create labels meant
to inform consumers, a reference point is needed—it is not sufficient
to state that Product A is stronger than Product B.  In addition,
results obtained under unrealistic conditions cannot be used to state
that a specific degree of protection will occur in a real-life
situation.  The Board must consider how the products will be used by
the consumer.

	Sample Size and Statistics

	Dr. Carriquiry agreed that the objective of the study, including how it
will be used to inform EPA labeling practices, must be clearly stated
because this will inform study design.  Response variables, such as
human or non-human subjects, first approach, first bite, or a median
lethal dose (LD50) measure need to be clearly defined and justified. 
Sample size calculations will depend on response variables, the size of
effect the investigators wish to detect, and the uncertainty associated
with the estimated effect size.  Examples for calculating sample size
under different conditions exist and should be considered by
investigators.  The investigators also must understand sources of
variability in the experiment, such as the product, environment, or
human subjects.  Statisticians also should be consulted to ensure that
an effective study design is developed.  Fractional factorial design
might call for 4 fractions at 2 levels (16 different fractions) but
studies that require only half this number of levels can be designed. 
By carefully designing the experiment, investigators may be able to
develop designs that more effectively support label claims for
protection for more specific circumstances, such as for a certain number
of hours under specific wind conditions.  She noted that extrapolating
from controlled to real-life conditions can be very difficult and may
not be necessary if the study is properly designed.

	Dr. Johnson reminded the Board that sample size in these experiments
refers to replicates of the testing area, whether it is a cage or a
real-life setting, such as a patio.  Variations in the number of
subjects inside the test area will not affect study results.  Better
data will be obtained if the number of areas in which testing occurs is
increased.

	Dr. Fish commented that investigators should include justification for
the use of humans and for any other experimental choices in protocols
and guidelines.  Various statements have been made concerning
variability in human attractiveness for insects related to age, gender,
and race; these differences will affect study design.  Dr. Lebowitz
added that EPA statements concerning exposure (e.g., brief periods of
consistent exposure versus exposure to continuous release) need to be
clarified.  Mr. Carley clarified that use of continuous versus
intermittent exposure will depend on the test.  Subject exposure will
begin shortly after placement of the emitter, after which exposure will
be continuous.

	

Human Subjects

	Dr. Gary Chadwick began by stating that justification for the use of
humans in a spatial/area repellent study is required for all protocols. 
Information on possible non-human studies and how these results will be
compared and used together with data from the human studies also should
be provided.  Justification for the use of humans should address any
possible alternative methods.  Investigators also should consider human
behavior during a test; the effectiveness of a spatial/area repellent
may be different when people are sitting still versus moving around and
perhaps exiting and re-entering the area covered by the repellent.  EPA
has stated that humans used as bait in such studies will wear full
coverage protective clothing.  If such protective clothing is used, the
HSRB should be provided with a description or picture of the clothing
and information on how it is worn.

	Risks and exclusion criteria will vary depending on the type of study,
chemical used, and method of dispersal.  Regarding the methodological
rationale for continuous versus intermittent exposure, again,
investigators must consider “real world” behavior such as moving in
and out of the area in which the repellent is released.  The effect of
such behaviors on repellent effectiveness could have implications for
labeling.  The manner in which the repellent agent is released and the
mechanism by which it repels insects (e.g., through irritation or
blocking the insects’ ability to detect humans) will likely inform
exclusion criteria.

	EPA should consider whether it requires both laboratory (or cage) tests
and field tests; if products are to be compared, laboratory tests would
be appropriate, but generating data for label claims might call for
field testing.

	Dr. Prentice agreed with Dr. Chadwick’s conclusions.  He commended
Dr. Strickman on his explanation of reasons why human subjects may be
needed for these tests, e.g., to test repellents that disrupt insect
behavior with respect to humans.  He emphasized that there must be
significant justification for using humans in this research and
investigators also must thoroughly explain how they have minimized
risks.  Drs. Fish and Philpott agreed with Drs. Chadwick and Prentice.

	Dr. Fisher commented that the goal of this discussion was to educate
Board members and also provide guidance to EPA and sponsors who may be
submitting such protocols about the questions the Board may have and the
justifications that are expected.  She advised Board members to keep in
mind that they will be setting standards for required experimental
justifications as they write their summaries of the discussions.  She
summarized several main points made by the Board.  

The need for human subjects must be justified.  This justification
should include description of any preceding laboratory studies, whether
or not animal studies would suffice, risk mitigation procedures, and
whether human testing actually would result in less information about
repellent properties than if humans were not used.  

Study design and objective, which includes the analyses used in making
labeling decisions, are highly important.  The Board wishes to emphasize
this point and its importance to the Board’s ability to evaluate
whether the studies are sufficient for EPA’s goals for use of the
data.  

Empirical evidence for environmental and gender differences and the
effects of area size on repellent effectiveness is needed.  

Information on ambient concentration and how it is determined should be
provided.  

Investigators should justify use of field or controlled laboratory
conditions, which will require clear statements regarding why testing is
being performed and whether the data will be used to determine relative
protection or other measures of effectiveness.

The extent to which protective garments interfere with accurate
assessment of repellent efficacy.

	At the next HSRB meeting, the Board will discuss issues raised during
this teleconference, particularly how charge questions should be defined
to allow the Board to clearly address potential protocol deviations,
statistical analyses, and generalizability of data.  The Board also will
address how previously published data should be used to judge the
validity of a proposed study, and the usefulness of EPA labeling
information for Board decisions.  Dr. Fisher will meet with Drs. Whung,
Lux and Lewis (OSA, EPA) in March 2009 to organize this session at a
future HSRB meeting.  Prior to this EPA meeting, small working groups
will be formed to help develop discussion topics.

Concluding Remarks

	Mr. Jordan described the agenda for the March-April 2009 HSRB meeting. 
A Carroll-Loye Biological Research protocol testing field efficacy of
two picaridin formulations against black flies will be reviewed.  This
protocol will be similar to protocols testing efficacy against
mosquitoes.  The AHETF will present scenario design documents and
protocols for analyzing exposure for workers involved in mixing and
loading pesticide products in water soluble packets.  Testing will be
conducted at five locations around the United States.  Because mixing
and loading is being assessed, rather than pesticide application,
recruiting practices will differ from those the Board has previously
reviewed.  An ICR, Inc. protocol for a field study testing the efficacy
of a spatial insect repellent against mosquitoes also will be evaluated.
 The protocol is now under review at EPA, and the discussions that took
place during this call will be considered as the review moves forward.

	Dr. Lewis thanked Board members and the public for their participation
in the teleconference.  He also thanked Dr. Strickman for serving as a
consultant and providing insight on spatial/area repellents.  The next
HSRB meeting is scheduled for the week of March 31, 2009.  Dr. Lewis is
working with OPP and OSA to finalize the agenda.  Because the Board has
agreed to release an initial draft of their report 2 weeks before the
next Board meeting, Dr. Lewis asked lead discussants to complete drafts
of their section of the Board report for today’s teleconference by
February 27, 2009.

	Dr. Brimijoin informed Board members that this was his last official
HSRB meeting.  He thanked his colleagues for providing an enjoyable and
stimulating experience and thanked EPA for inviting him to participate
in the HSRB process.  The Chair and Board members thanked Dr. Brimijoin
for his contributions and indicated he would be missed.

The meeting was adjourned by the Chair.

Respectfully submitted:

Paul I. Lewis, Ph.D.

Designated Federal Officer

Human Studies Review Board

United States Environmental Protection Agency

Certified to be true by:

Celia B. Fisher, Ph.D.

Chair

Human Studies Review Board

United States Environmental Protection Agency

NOTE AND DISCLAIMER:  The minutes of this public meeting reflect diverse
ideas and suggestions offered by Board members during the course of
deliberations within the meeting.  Such ideas, suggestions, and
deliberations do not necessarily reflect definitive consensus advice
from the Board members.  The reader is cautioned to not rely on the
minutes to represent final, approved, consensus advice and
recommendations offered to the Agency.  Such advice and recommendations
may be found in the final report prepared and transmitted to the EPA
Science Advisor following the public meeting.

Attachments 

	

Attachment A 		HSRB Members 

Attachment B 		Federal Register Notice Announcing Meeting 

Attachment C 		Meeting Agenda 

Attachment A

EPA HUMAN STUDIES REVIEW BOARD MEMBERS 

Chair

Celia B. Fisher, Ph.D.

Marie Ward Doty Professor of Psychology

Director, Center for Ethics Education

Fordham University

Bronx, NY 

Vice Chair

William S. Brimijoin, Ph.D.

Chair and Professor 

Molecular Pharmacology and Experimental Therapeutics

Mayo Foundation

Rochester, MN 

Members

Alicia Carriquiry, Ph.D.

Professor 

Department of Statistics

Iowa State University

Ames, IA 

Gary L. Chadwick, PharmD, MPH, CIP

Associate Provost

Director, Office for Human Subjects Protection

University of Rochester

Rochester, NY 

Janice Chambers, Ph.D., D.A.B.T.

William L. Giles Distinguished Professor

Director, Center for Environmental Health Sciences

College of Veterinary Medicine

Mississippi State University

Mississippi State, MS 

Richard Fenske, Ph.D., MPH 

Professor

Department of Environmental and Occupational Health Sciences

University of Washington

Seattle, WA 

Susan S. Fish, PharmD, MPH

Professor, Biostatistics & Epidemiology

Boston University School of Public Health

Co-Director, MA in Clinical Investigation

Boston University School of Medicine

Boston, MA 

Suzanne C. Fitzpatrick, Ph.D., DABT*

Senior Science Policy Analyst

Office of the Commissioner

Office of Science and Health Coordination

U.S. Food and Drug Administration

Rockville, MD 

Dallas E. Johnson, Ph.D.

Professor Emeritus

Department of Statistics

Kansas State University

Manhattan, KS

Michael D. Lebowitz, Ph.D., FCCP

Retired Professor of Public Health and Medicine

University of Arizona

Tucson, AZ 

Lois D. Lehman-Mckeeman, Ph.D.

Distinguished Research Fellow, Discovery Toxicology

Bristol-Myers Squibb Company

Princeton, NJ 

Jerry A. Menikoff, M.D.*  

Director, Office for Human Research Protections

Office of the Secretary

Department of Health and Human Services (HHS)

Rockville, MD 

Rebecca Parkin, Ph.D., MPH

Associate Dean for Research and Public Health Practice

School of Public Health and Health Services

The George Washington University

Washington, DC

Sean Philpott, Ph.D., M.Bioethics

Science and Ethics Officer

Global Campaign for Microbicides

PATH

Washington, DC  

Ernest D. Prentice, Ph.D.

Associate Vice Chancellor for Academic Affairs

Professor of Genetics, Cell Biology and Anatomy

Professor of Preventive and Societal Medicine

University of Nebraska Medical Center

Omaha, NE 

Richard R. Sharp, Ph.D.*

Director of Bioethics Research

Department of Bioethics

Cleveland Clinic

Cleveland, OH 

Linda J. Young, Ph.D.

Professor

Department of Statistics

Institute of Food and Agricultural Sciences

University of Florida

Gainesville, FL

Consultant to the Board

Daniel Strickman, Ph.D.

National Program Leader

Veterinary, Medical, and Urban Entomology

USDA Agricultural Research Service

Beltsville, MD

* Not in attendance at the February 17, 2008 teleconference

Attachment B

Federal Register Notice Announcing Meeting

Human Studies Review Board (HSRB); Notification of Public Teleconference
Meeting   

[Federal Register: January 30, 2009 (Volume 74, Number 19)]

[Notices]

[Page 5653-5655]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

------------------------------------------------------------------------
-------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2009-0030; FRL-8769-9]

 

Human Studies Review Board (HSRB); Notice of a Public Teleconference
Meeting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

------------------------------------------------------------------------
-------------------------------------------------------

SUMMARY: The U.S. Environmental Protection Agency’s (EPA or Agency)
Office of the Science Advisor (OSA) announces a public meeting of the
Human Studies Review Board (HSRB) to advise the Agency on EPA’s
scientific and ethical review of human subjects research. The HSRB will
hold a Public teleconference to discuss two completed field studies by
Carroll-Loye Biological Research of mosquito repellent efficacy, and
spatial insect repellent technology.

DATES: The teleconference will be held on February 17, 2009, from 11:30
to approximately 4 p.m. (Eastern Time). 

Location: The meeting will take place via telephone only. 

Meeting Access: For information on access or services for individuals
with disabilities, please contact Lu-Ann Kleibacker prior to the meeting
using the information under FOR FURTHER INFORMATION CONTACT, so that
appropriate arrangements can be made. 

Procedures for Providing Public Input: Interested members of the public
may submit relevant written or oral comments for the HSRB to consider
during the advisory process. Additional information concerning
submission of relevant written or oral comments is provided in section
D. of this notice.

FOR FURTHER INFORMATION CONTACT: Members of the public who wish to
obtain the call-in number and access code to participate in the
telephone conference, or who wish further information may contact Lu-Ann
Kleibacker, EPA, Office of the Science Advisor (8105), Environmental
Protection Agency, 1200 Pennsylvania Avenue, NW., Washington, DC 20460;
or via telephone/voice mail at (202) 564–7189 or via e-mail at
kleibacker.lu-ann@epa.gov. General information concerning the EPA HSRB
is on the EPA Web site at http://www.epa.gov/osa/ hsrb/.

ADDRESSES: Submit your written comments, identified by Docket ID No.
EPA–HQ–ORD–2009–0030, by one of the following methods: 

http://www.regulations.gov: Follow the on-line instructions for
submitting comments. 

E-mail: ORD.Docket@epa.gov. 

Mail: ORD Docket, Environmental Protection Agency, Mailcode: 28221T,
1200 Pennsylvania Ave., NW., Washington, DC 20460. 

Hand Delivery: EPA Docket Center (EPA/DC), Public Reading Room,
Infoterra Room (Room Number 3334), EPA West Building, 1301 Constitution
Avenue, NW., Washington, DC 20460, Attention Docket ID No.
EPA–ORD–2009–0030. Deliveries are only accepted from 8:30 a.m. to
4:30 p.m., Monday through Friday, excluding legal holidays. Special
arrangements should be made for deliveries of boxed information. 

Instructions: Direct your comments to Docket ID No.
EPA–HQ–ORD–2009– 0030. EPA’s policy is that all comments
received will be included in the public docket without change and may be
made available online at http://www.regulations.gov, including any
personal information provided, unless the comment includes information
claimed to be Confidential Business Information (CBI) or other
information whose disclosure is restricted by statute. Do not submit
information that you consider to be CBI or otherwise protected through
http:// www.regulations.gov or e-mail. The http://www.regulations.gov
Web site is an “anonymous access” system, which means EPA will not
know your identity or contact information unless you provide it in the
body of your comment. If you send an e-mail comment directly to EPA,
without going through http://www.regulations.gov, your e-mail address
will be automatically captured and included as part of the comment that
is placed in the public docket and made available on the Internet. If
you submit an electronic comment, EPA recommends that you include your
name and other contact information in the body of your comment and with
any disk or CD–ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA may
not be able to consider your comment. Electronic files should avoid the
use of special characters, any form of encryption, and be free of any
defects or viruses.

A. Does This Action Apply to Me? 

This action is directed to the public in general. This action may,
however, be of interest to persons who conduct or assess human studies
on substances regulated by EPA or to persons who are or may be required
to conduct testing of chemical substances under the Federal Food, Drug,
and Cosmetic Act (FFDCA) or the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). Since other entities may also be interested,
the Agency has not attempted to describe all the specific entities that
may be affected by this action. If you have any questions regarding the
applicability of this action to a particular entity, consult the person
listed under FOR FURTHER INFORMATION CONTACT.

B. How Can I Access Electronic Copies of This Document and Other Related
Information? 

In addition to using regulations.gov, you may access this Federal
Register document electronically through the EPA Internet under the
Federal Register listings at http://www.epa.gov/fedrgstr/. 

Docket: All documents in the docket are listed in the index under the
docket number. Even though it will be listed by title in the index, some
information is not publicly available, e.g., CBI or other information
whose disclosure is restricted by statute. Copyright material, will be
publicly available only in hard copy. Publicly available docket
materials are available either electronically in
http://www.regulations.gov or in hard copy at the ORD Docket, EPA/DC,
Public Reading Room, Infoterra Room (Room Number 3334), 1301
Constitution Ave., NW., Washington, DC. The Public Reading Room is open
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal
holidays. The telephone number for the Public Reading Room is (202)
566–1744, and the telephone number for the ORD Docket is (202)
566–1752.

C. What Should I Consider as I Prepare My Comments for EPA? 

You may find the following suggestions helpful for preparing your
comments: 

Explain your views as clearly as possible. 

Describe any assumptions that you used. 

Provide copies of any technical information and/or data you use that
support your views. 

Provide specific examples to illustrate your concerns and suggest
alternatives. 

To ensure proper receipt by EPA, be sure to identify the docket ID
number assigned to this action in the subject line on the first page of
your response. You may also provide the name, date and Federal Register
citation. 

D. How May I Participate in This Meeting? 

You may participate in this meeting by following the instructions in
this section. For information on access to the teleconference, please
contact Lu-Ann Kleibacker prior to the meeting using the information
under FOR FURTHER INFORMATION CONTACT. 

1. Oral Comments 

Requests to present oral comments will be accepted up to February 9,
2009. To the extent that time permits, interested persons who have not
pre-registered may be permitted by the Chair of the HSRB to present oral
comments at the meeting. Each individual or group wishing to make brief
oral comments to the HSRB is strongly advised to submit their request
(preferably via e-mail) to Lu-Ann Kleibacker listed under FOR FURTHER
INFORMATION CONTACT in order to be included on the meeting agenda and to
provide sufficient time for the HSRB Chair and HSRB DFO to review the
meeting agenda to provide an appropriate public comment period. The
request should identify the name of the individual making the
presentation and the organization (if any) the individual will
represent. Oral comments before the HSRB are limited to 5 minutes per
individual or organization. Please note that this includes all
individuals appearing either as part of, or on behalf of an
organization. While it is our intent to hear a full range of oral
comments on the science and ethics issues under discussion, it is not
our intent to permit organizations to expand the time limitations by
having numerous individuals sign up separately to speak on their behalf.
If additional time is available, there may be flexibility in time for
public comments. 

2. Written Comments 

Although you may submit written comments at any time, for the HSRB to
have the best opportunity to review and consider your comments as it
deliberates on its report, you should submit your comments at least five
business days prior to the beginning of the meeting. If you submit
comments after this date, those comments will be provided to the Board
members, but you should recognize that the Board members may not have
adequate time to consider those comments prior to making a decision.
Thus, if you plan to submit written comments, the Agency strongly
encourages you to submit such comments no later than noon, EST, February
9, 2009. To ensure proper receipt of all written material by EPA, it is
imperative that you identify docket ID number
EPA–HQ–ORD–2009–0030 in the subject line on the first page of
your submission. In addition, the Agency also requests that person(s)
submitting comments directly to the docket also provide a copy of their
comments to Lu-Ann Kleibacker listed under FOR FURTHER INFORMATION
CONTACT. There is no limit on the length of written comments for
consideration by the HSRB.

E. Background 

1. Human Studies Review Board 

The HSRB is a Federal advisory committee operating in accordance with
the Federal Advisory Committee Act (FACA) 5 U.S.C. App.2 section 9. The
HSRB provides advice, information, and recommendations to EPA on issues
related to scientific and ethical aspects of human subjects research.
The major objectives of the HSRB are to provide advice and
recommendations on: a. Research proposals and protocols; b. reports of
completed research with human subjects; and c. how to strengthen EPA’s
programs for protection of human subjects of research. The HSRB reports
to the EPA Administrator through EPA’s Science Advisor. 

The EPA will present for HSRB review scientific and ethical issues
surrounding the reports from a completed field study of mosquito
repellent efficacy (SPC–001) and a completed laboratory study of tick
repellent efficacy (SPC–002) conducted by Carroll-Loye Biological
Research using multiple skin-applied repellent products containing
picaridin. In addition, the HSRB will consider and discuss general
information about ‘‘spatial’’ or ‘‘area’’ insect
repellent products and their testing, in preparation for expected future
reviews of proposals for field efficacy testing of spatial repellents.
Insect repellent testing reviewed by the Board in past meetings has
concerned only skin-applied repellents, which differ in important ways
from spatial repellents. Finally, the HSRB may also discuss planning for
future HSRB meetings. 

2. Meeting Minutes and Reports 

Minutes of the meeting, summarizing the matters discussed and
recommendations made, if any, by the advisory committee regarding such
matters will be released within 90 calendar days of the meeting. Such
minutes will be available at http:// www.epa.gov/osa/hsrb/ and http://
www.regulations.gov. In addition, information concerning a Board meeting
report, if applicable, can be found at http://www.epa.gov/osa/hsrb/ or
from the person listed under FOR FURTHER INFORMATION CONTACT. 

Dated: January 26, 2009. 

Kevin Teichman, 

EPA Acting Science Advisor. 

[FR Doc. E9–2037 Filed 1–29–09; 8:45 am] 

BILLING CODE 6560–50–P

Attachment C

2/12/2009

 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

HUMAN STUDIES REVIEW BOARD (HSRB) 

FEBRUARY 17, 2009

PUBLIC TELECONFERENCE MEETING 

HSRB WEB SITE  http://www.epa.gov/osa/hsrb/ 

Docket Telephone: (202) 566 1752 

Docket Number: EPA–HQ–ORD–2009–0030 

Meeting by Teleconference

Call 202 564 7189 for the teleconference number

 

• 12:30 PM 	Convene Meeting and Identification of Board Members –
Celia Fisher, Ph.D. (HSRB Chair) 

• 12:40 PM 	Meeting Administrative Procedures – Paul Lewis, Ph.D.
(Designated Federal Officer [DFO], HSRB, Office of the Science Advisor
[OSA], EPA) 

• 12:45 PM 	Welcome – Pai-Yei Whung, Ph.D. (Chief Scientist, OSA,
EPA) 

• 12:55 PM 	EPA Follow-up on Pesticide Specific HSRB Recommendations
– Mr. William Jordan (Office of Pesticide Programs [OPP], EPA) 

Carroll-Loye Biological Research Tick Repellent Efficacy Study (SPC-002)

• 1:05 PM 	Carroll-Loye Biological Research Tick Repellent Efficacy
Study (SPC-002) – Mr. Kevin Sweeney (OPP, EPA) and Mr. John  Carley
(OPP, EPA)

• 1:25 PM 	Public Comments

• 1:35 PM 	Board Discussion

Is study SPC-002 sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy against ticks of the three
formulations tested? 

Does available information support a determination that study SPC-002
was conducted in substantial compliance with subparts K and L 40 CFR
Part 26? 

Carroll-Loye Biological Research Mosquito Repellent Efficacy Study
(SPC-001) 

• 1:55 PM 	EPA Science and Ethics Assessment of Carroll-Loye
Biological Research Mosquito Repellent Efficacy Study (SPC-001) – Mr.
Kevin Sweeney (OPP, EPA) and Mr. John Carley (OPP, EPA) 

• 2:15 PM 	Public Comments 

• 2:25 PM 	Board Discussion 

Is study SPC-001 sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy against mosquitoes of the three
formulations tested?

Does available information support a determination that study SPC-001
was conducted in substantial compliance with subparts K and L 40 CFR
Part 26? 

• 2:45 PM 	Break 

Spatial/area Insect Repellent Testing

 

• 2:50 PM 	Introduction – Celia Fisher, Ph.D. (HSRB Chair) 

• 2:55 PM 	Technical Aspects of Spatial/Area Repellent Testing –
HSRB Consultant 

• 3:15 PM 	Board Discussion 

Environmental Aspects 

What are the environmental (temperature, wind, time of day, humidity,
proximity to water/plants, size and type of space) and human factors
(height/weight; gender, age, ethnicity, density of humans in space) that
can affect insect behavior and repellent efficacy relevant to space
treatment studies? 

2.	What factors need to be considered for test spaces with respect to
size of area in which the test is conducted? How is the most appropriate
test area determined? 

3. 	Does the number of human subjects within testing environments of
different sizes affect insect activity? Does the number of subjects in a
given area affect product efficacy or the measurement of product
efficacy? 

4. 	Are there any other special considerations regarding insect behavior
in such studies that require inclusion in protocols? 

Study Design 

1.	How is the location of open spaces typically selected? How many
different or similar types of sites are appropriate to assess
generalizability? 

2.	What are common spatial dispensing devices? How are they related to
the nature of the product dispensed (e.g., gas, suspended liquid,
smoke)? What are design or measurement challenges for different
dispensing devices and products? 

3. 	What type of dosimetry data is required to determine amount of
product application used in testing? How is discharge time determined?
What are the relative design merits of the experimenter or subject
discharging the repellent? 

4. 	How are outcomes measured in these studies? How are insect knockdown
and mortality effects measured? Are both knockdown and landings/bites
usually measured in the same study? What is the difference in knockdowns
vs bites in terms of information regarding product
efficacy/effectiveness?

5. 	What is the difference with respect to measurement in assessing
efficacy of the active ingredient and effectiveness of the formulation? 

Sample Size and Statistics 

Depending on the outcome measure, what are best practices with respect
to human sample size? What is the sample size norm in the field? How is
determination of sample size related to square feet of test area? What
is the best way to determine power for these studies? 

What are best practices with respect to statistical analysis? How is
censored data handled? 

What are the pros and cons of various endpoints (e.g. ending the study
after a set number of hours, waiting until the first landing/bite,
other) to assess product efficacy (e.g. to meet assumptions for
appropriate statistical analyses)? 

Human Subjects 

Why are human subjects necessary for such studies if the outcome
measures are knockdowns or mortality? 

What are the potential risks to treated subjects (e.g. inhalation,
dermal effects)? What are exclusion criteria in subject selection to
avoid such risks? How is the degree of risk related to dosage,
ingredient, formulations, aerosol pressure? 

What is the methodological rationale for continuous versus intermittent
exposure? How do human risk differ for these types of exposures? Will
exposure start at the beginning of the test period immediately after
release of the product? 

If the test agent has properties to repel or destroy an insect, what is
the relationship (if any) to a related mechanism of action to humans? 

• 4:45 PM 	Concluding Remarks – Mr. William Jordan (OPP, EPA) 

• 4:50 PM 	Adjournment – Celia Fisher, Ph.D. (HSRB Chair) and Paul
Lewis, Ph.D. (HSRB DFO) 

* Please be advised that agenda times are approximate and subject to
change. For further information including the teleconference phone
number please contact Lu-Ann Kleibacker via telephone at 202 564 7189 or
email: kleibacker.lu-ann@epa.gov

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