2/16/07

Minutes of the

United States Environmental Protection Agency (EPA)

Human Studies Review Board (HSRB)

January 24, 2007 Public Meeting

Docket Number: EPA-HQ-ORD-2006-0998

HSRB Web Site:  http://www.epa.gov/osa/hsrb/

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

Dates and Times:  	Wednesday, January 24, 2007, 8:30 AM – 4:30 PM

(See Federal Register Notice – Attachment B)

Location: 	Sheraton Crystal City Hotel, 1800 Jefferson Davis Highway,
Arlington, VA  22202

Purpose: 	The EPA Human Studies Review Board (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.

Board Members: 	David C. Bellinger, Ph.D.

Alicia Carriquiry, Ph.D.

Gary L. Chadwick, PharmD, MPH, CIP

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

Susan S. Fish, PharmD, MPH

Suzanne C. Fitzpatrick, Ph.D., D.A.B.T.

KyungMann Kim, Ph.D., CCRP

Kannan Krishnan, Ph.D.

Michael D. Lebowitz, Ph.D., FCCP

Sean M. Philpott, Ph.D.

Richard Sharp, 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 (HSRB Chair) welcomed Board members, U.S. Environmental
Protection Agency (EPA or Agency) staff, and members of the public to
the first HSRB meeting of 2007.  She thanked Board members for their
participation and called for introductions.  Dr. Fisher acknowledged
Dr. Paul Lewis (Designated Federal Officer [DFO], HSRB, Office of the
Science Advisor [OSA], EPA) for his assistance with and contributions to
Board activities.  She informed Board members of planning meetings she
had with EPA officials and commended the Agency’s helpfulness and
responsiveness to issues raised during previous Board meetings.

Welcoming Remarks

Dr. George Gray (EPA Science Advisor) thanked the HSRB for its efforts
in this review process.  He introduced Mr. Jim Jones (Director, Office
of Pesticide Programs [OPP], EPA).  He expressed appreciation for Board
efforts on its previous reports, which have been useful for EPA as EPA
considers its approach to regulatory decisions and for decision making
regarding research performed and funded by EPA.  He commented that this
meeting represents the first meeting at which the entire review
process—submission of a protocol, identification of Board concerns,
response to those concerns and adjustment of the protocol by study
sponsors, presentation of study results and Board review has been
completed.  EPA appreciates the timeliness of the Board’s efforts.
Today provides an opportunity for Board members to see the impact their
work has had on the process.

Dr. Gray thanked his EPA colleagues for their work in support of the
HSRB.  He welcomed public comments at today’s meeting.  The HSRB is an
open and transparent board and the advice of the HSRB helps EPA make
sound decisions based on strong science.  Dr. Gray concluded that he
looks forward to future open and thoughtful analysis and advice from the
HSRB.

Opening Remarks

Mr. Jones re-iterated the value of the HSRB’s work to EPA staff.  He
informed Board members that EPA has found the new approval process for
pesticide studies involving humans to be effective and result in
excellent advice useful for decision making.  He indicated that results
would be presented from studies on tick and mosquito repellent products
that have undergone the entire Agency and HSRB review process, including
assessment of both scientific and ethical issues.  HSRB advice has been
invaluable for informing EPA of ways to perform these studies while
assuring protection of the participants, which is of significant
importance to EPA’s function as a regulatory agency.

Meeting Administrative Procedures

Dr. Lewis welcomed Board members and thanked them for their work.  He
welcomed members of the public and his EPA colleagues.  As DFO, Dr.
Lewis serves as liaison between the HSRB and EPA and ensures that
Federal Advisory Committee Act (FACA) requirements -open meetings,
timely meeting announcements in the Federal Register, and meeting
materials are made available at a public docket.  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 Office of the Science Advisor Deputy Ethics Officer in
consultation with EPA’s Office of General Counsel (OGC) to ensure that
all ethics disclosure requirements have been met.  Dr. Lewis reminded
participants that meeting times would be approximate and that public
comments would be limited to five minutes.

Meeting Process

Dr. Fisher reviewed the process for meeting operations, HSRB
responsibilities, the HSRB Charter, Board process, and major objectives.
 She stated that the Board seeks to clarify and develop criteria to
evaluate the science and ethics of different types of completed research
and protocols, allowing for fairness and consistency.  She commented
that initial review of protocols is not a priori approval of studies
already performed; the Board examines completed studies as carefully as
proposed studies.  The Board takes seriously its responsibility to
review protocols and determine the sponsors’ responsiveness to issues
raised during the initial review, as well as the caliber of the data.

The HSRB review begins with a presentation by EPA of the scientific and
ethical considerations on the studies under review.  This presentation
is followed by clarifying questions from the HSRB and then public
comments on the issues being discussed.  Dr. Fisher explained that
particular Board members are assigned to be primary reviewers of the
studies; their reviews are presented and then deliberated upon by the
entire Board.

Scientific considerations would precede ethical considerations because
to be ethical, a study must be scientifically valid.  Dr. Fisher stated
that the Board would assess both the scientific and ethical validity of
a protocol, including procedures, dose selection, endpoint selection,
social value of the research, appropriateness of control and
experimental groups, methods including statistical analyses, and
selection of target populations and derivation of sample sizes.  The
Board would review how well established protocols were followed and also
examine the handling of unexpected events from both a scientific and
ethical perspective.

Dr. Fisher commended EPA’s effort in fitting protocols to HSRB
guidelines and in informing sponsors of HSRB and EPA information needs
in order to conduct a thorough review.  She also commended efforts to
justify the use of human subjects and thoroughly document potential
risks.

Update on EPA Follow-up of HSRB Recommendations

Mr. William Jordan (OPP, EPA) introduced Mr. John Carley (OPP, EPA),
lead for the ethical review; Dr. Clara Fuentes (OPP, EPA), lead for the
scientific review; and Dr. Warren Lux, (Human Subjects Research Review
Official [HSRRO], OSA, EPA).  Dr. Lux ensured that EPA’s efforts are
compatible, consistent, and compliant with its responsibility to protect
subjects of human research.

Mr. Jordan reported how EPA used the Board’s recommendations
concerning studies reviewed at meetings held in the summer and fall of
2006:

(1)	The HSRB reviewed the Chromium Repeat Open Application Test (ROAT)
study with Acid Copper Chromate (ACC), which provided EPA with useful
scientific information for risk assessment activities and assurance that
the study met acceptable ethical standards.  The Board recommended that
EPA combine both irritant and sensitization reactions to determine the
10 percent (%) minimum elicitation threshold value (MET10) for this
substance and recommended against a proposed normalization protocol of
test subjects to subjects in the North American Contact Dermatitis Group
(NACDG).  EPA used these recommendations and the results of the study to
develop a risk assessment for dermal exposure of workers and the general
public who could come into contact with ACC-treated wood used in
residential construction.  EPA concluded that the potential for
sensitization and irritation associated with contact with ACC-treated
wood was sufficient to warrant EPA regulatory action to deny an
application for residential use of ACC-treated wood.

(2)	Insect Repellent Efficacy Protocols EMD-003 and EMD-004 were
originally assessed in June 2006.  The lead investigator on these
protocols, Dr. Scott Carroll (Carroll-Loye Biological Research, Inc.),
revised the protocols based on Board advice and the protocols were again
reviewed by the Board at its October 2006 meeting.  The Board deemed the
protocols to be scientifically sound, likely to produce reliable data,
and to meet ethical standards.  Mr. Jordan stated that Dr. Carroll has
since completed the research and submitted the results to EPA.  He
reported that EPA had reviewed the research and would present the
reviews to the Board during this meeting.

(3)	The Board reviewed draft EPA guidance to submitters of protocols for
proposed new human research and suggested several changes.  Mr. Jordan
stated that EPA plans to revise the draft guidance in the coming months,
incorporating the HSRB’s suggestions, and seek to engage stakeholders
by soliciting general public comment on the draft.  He explained that as
EPA has gained experience in these processes, the Agency has realized
the competing needs to provide sufficient information for review while
considering confidential business information (CBI) claims; issues of
timing of studies; and problems associated with serial submissions of
supporting documents, rather than one complete package.

(4)	The HSRB also offered suggestions for how EPA and researchers can
submit materials requiring HSRB review when some of the materials are
subject to CBI claims.  Mr. Jordan indicated that EPA will work with
Drs. Fisher and Lewis and the OGC to resolve this issue.  EPA also will
work with submitters to ensure that materials claimed confidential are
protected from unlawful disclosure and will work with the HSRB to
promote the greatest degree of transparency in the Board’s review of
materials allowed under the statute.

The Board previously reviewed several protocols developed by the
Agricultural Handlers Exposure Task Force (AHETF) and provided extensive
comments on both the study design from a scientific perspective and on
ethical issues that arise in the conduct of such studies.  EPA analyzed
their database used for assessing exposure of pesticide handlers and
presented their analysis at the January 2007 meeting of the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory
Panel (SAP).  Dr. Janice Chambers participated in this meeting and
provided advice on scientific issues.  Discussion at the SAP meeting
focused on the benefits of obtaining new data on handler exposures; the
reliability of passive dosimetry versus biomonitoring; and various
methodological issues, including the proportionality of exposure to the
active ingredient, hand rinse efficiency, sample size, and cluster
selection, among others.  Mr. Jordan commented that the process of
preparing for the meeting and receiving feedback from the SAP was
useful, and has allowed EPA to be better prepared to present the AHETF
protocols to the HSRB for review later in 2007.  Mr. Jordan specifically
thanked Dr. Chambers for her suggestions regarding the presentations of
research and protocols at the SAP meeting.

Mr. Jordan informed Board members that the Board’s workload probably
would remain heavy and that a number of topics are under consideration
for presentation at the April 2007 meeting.  EPA will endeavor to use
Board resources efficiently.

Dr. Fisher expressed her appreciation for the presentations and
commented that the Board received useful feedback on its efforts.  She
asked Mr. Jordan about a statistical question raised during the
Board’s June 2006 meeting reviewing the AHETF protocols AHETF meeting
concerning a proposed meta-analysis and inquired if SAP had any comments
or advice on this issue that might be useful to the Board and study
sponsors.  Mr. Jordan explained that the SAP addressed three sets of
questions related to statistical issues.  The first related to
establishing sample size, such as how many subjects should be included
to develop a robust database that EPA can use for handler exposure
assessment.  The second concerned whether to take samples repeatedly
from the same subject (within-worker variability) or from a larger
number of different subjects (between-worker variability).  There are
advantages to both approaches.  The SAP provided useful advice
concerning this matter, but EPA will continue to consider both
approaches and will develop a concrete proposal and justification with
regard to the number of subjects and advantages and disadvantages of
each approach.  The third issue concerned cluster selection.  The AHETF
presented essentially identical application protocols performed in
different parts of the country at different times of the year.  Although
the protocols are essentially identical, performing the experiments at
different times and places could be a source of variability.  The SAP
provided information concerning how to select sampling sites to be
representative of the exposed worker population.  This information will
influence the design of the studies.  The SAP meeting covered
agricultural handler scenarios but also raised questions about the
design of exposure studies for those handling antimicrobial
disinfectants.  The use patterns of agricultural and antimicrobial
substances are different, but similar statistical issues apply.

Dr. Fisher thanked Mr. Jordan for informing the Board of the review
process procedures and commended EPA on its efforts to seek and
effectively use the advice they receive.  She recommended that
independent consultants or reviewers external from agricultural groups
be included in the review process.  Mr. Jordan clarified that EPA’s
presentation to SAP was part of a larger group that included the
California Department of Pesticide Regulation, scientists responsible
for assuring pesticide safety, and scientists from the Canadian
Pesticide Regulatory Authority.  This approach allows EPA to draw on
resources unique to each organization.  EPA has worked with Canada’s
Pesticide Management Regulatory Agency, which has access to useful
scientific expertise.  EPA pushes the boundaries to obtain current data
to address scientific issues and for regulatory assessment; the same
applies for ethics assessments.

Dr. Fisher expressed appreciation for EPA’s efforts to address issues
raised by the Board.  She commented that Board members wish to develop
criteria for addressing scientific and ethical issues before their
meeting with the AHETF in October 2007.  HSRB members wish to discuss
criteria prior to receiving protocols, so that sponsors will know how
their protocols will be reviewed.  She asked whether the HSRB would
receive the recommendations developed by SAP to use to develop their own
criteria.  Mr. Jordan informed Dr. Fisher that minutes from the SAP
meeting would be available in late March 2007.  He will deliver a copy
to the HSRB DFO for subsequent delivery to the Board as soon as possible
and will consider Dr. Fisher’s request to discuss criteria for these
reviews at the April 2007 HSRB meeting.  Mr. Jordan added that he
believes the AHETF hopes to have its protocols reviewed in October 2007.
 The Antimicrobial Exposure Task Force  (AETF) does not yet have a
review schedule and does not have to consider the growing season.  The
Board might wish, however, to review AEATF protocols in June 2007.  Dr.
Fisher thanked EPA for its efforts and added that she was impressed with
the level of detail in the EPA reviews.

Insect Repellent Completed Efficacy Studies EMD-003 and EMD-004

Introduction

Mr. John Carley provided background and context for insect repellent
efficacy studies EMD-003 and EMD-004.  Protocol EMD-003 proposed testing
3 formulations of repellent (lotion, pump spray, and aerosol) containing
the active ingredient IR-3535 for efficacy in repelling ticks under
laboratory conditions.  Protocol EMD-004 tested the same 3 formulations
for efficacy in repelling mosquitoes under field conditions in two
habitats (dense forest and moist pasture or marshland).  Guidelines
recommended testing in two habitats to assess efficacy in the presence
of different mosquito species with different behaviors.  Both protocols
had a dosimetry phase to establish a “typical consumer dose” that
would be used in the efficacy phases of the trials.  The same 12
subjects participated in dosimetry testing of the 3 formulations for
both protocols.  An error in formulation of the aerosol test material
caused a delay in testing this formulation, and the reports considered
during this meeting addressed testing of only the lotion and pump spray
formulations.  Separate reports for each formulation (lotion and pump
spray) were submitted for each protocol, and then a subsequent report
including both formulations was re-submitted.

Since the protocols are third-party research involving intentional
exposure of human subjects, intended for submission to EPA under the
pesticide laws, and initiated after April 7, 2006, pre-review of the
protocol and supporting materials by EPA and the HSRB was required, as
was substantial compliance with 40 Code of Federal Regulations (CFR) 26
Subparts K and L.  These protocols were among the first considered by
the HSRB (in June 2006), were the first protocols reviewed favorably by
the HSRB (October 2006), and are the first completed studies as
presented here to the HSRB.

Mr. Carley described the series of review cycles the protocols
underwent.  Review Cycle 1 took from April 18 to October 6, 2006; it
began with Independent Investigational Review Board (IIRB) approval of
the protocols and submission of the protocols for EPA and HSRB review
and discussion.  It concluded with delivery of a final report by the
HSRB on October 6, 2006.  Review Cycle 2 began with submission of the
first revision of the protocols to EPA on July 12, 2006, followed by
IIRB approval of the revised protocols, submission of second and third
revisions and subsequent IIRB approval, EPA review, and concluded with
the HSRB draft HSRB meeting report on December 8, 2006.  Review Cycle 3
began with data collection between October 23 and November 1, 2006,
followed by report submission to EPA on November 9, 2006, EPA science
and ethics reviews, submission of supplemental materials, and concluded
at the January 24, 2007 meeting with the HSRB discussion of EPA reviews.
 The research itself, including the dosimetry phase, mosquito repellent
efficacy phase (laboratory and field studies) took place between October
23 and November 1, 2006.  The study reports were submitted to EPA on
November 9, 2006.  Mr. Carley noted that the efficacy phase for the
aerosol study was conducted on November 18 and 19, 2006; although these
reports had been received by EPA, they would not be discussed during
this meeting.

Scientific Considerations

Dr. Fuentes presented the science assessment of protocols EMD-003 and
EMD-004.  The purpose of the science assessment was to evaluate the
validity of the revised protocols, assess their consistency with
recommendations made by EPA and the HSRB, and to provide a scientific
review of the reported studies.  Both protocols were revised consistent
with the recommendations, except for minor exceptions.  The studies both
produced sound data meeting the studies’ objective to estimate typical
consumer doses and quantify the duration of repellency of the
formulations tested against ticks and mosquitoes.

The deviations from the recommended protocols were minor.  During the
dosimetry phase, the number of practice applications was dropped from 3
to 1, because 3 practice applications were deemed unnecessary.  This did
not affect the grand mean of the dosimetry phase, because subjects
nonetheless performed 3 applications of product.  Entry errors were
not properly handled in all cases, primarily because data were
collected by the subjects themselves, with assistance from a trained
technician during the collection process.  The errors in the entries
were not significant and did not compromise the validity of the results.
 The dosimeters were not backed with impermeable layers because the
dosimeters themselves were sufficiently impermeable.  The temperature of
the laboratory rose 1oC above expected (to 26oC) for two testing
periods, but this did not affect the results.  During the dosimetry
phase of the protocol, a proposed Friedman 2-way analysis of variance
(ANOVA) for comparison between formulations and for assessing possible
interaction of formulations with subjects’ application differences was
omitted, but this analysis was not essential for estimating the typical
consumer dose for use in the efficacy evaluation.  Similar deviations
occurred during the efficacy phase and also did not affect the results.
Testing of the aerosol formulation was not included in the protocols at
this time.

During the performance phase of EMD-004, product performance was
underestimated, which likely contributed to subjects (three treated with
pump spray, two treated with lotion) terminating exposure before
efficacy failure.  The early departure times of these subjects were
treated as equivalent to a failure of repellency, leading to a
conservative estimate of complete protection time (CPT).  Subjects also
did not always cover treated limbs between exposures, but because they
stepped out of the test site or entered a screened enclosure, no
exposure of treated limbs to mosquitoes occurred between one-minute
exposure periods.

Determination of grand means from the dosimetry phase for the lotion
formulation gave values of 0.001158 grams per square centimeter (g/cm2)
for arms and 0.001108 g/cm2 for legs.  These numbers represent the
arithmetic means of the subject means presented in the report.  The text
of the report lists these values as 0.0115 g/cm2 and 0.001114 g/cm2 for
arms and legs, respectively.  There was no explanation for this
discrepancy or for why the arms and legs had a single target dose.  Dr.
Fuentes stated that EPA believed that differences at this level of
precision can be attributed to differences in documentation.  The target
dose for the protocol testing the tick repellency of the lotion
formulation, EMD-003.1, was 0.00115 milliliters per square centimeter
(ml/cm2) for both arms and legs; this was within the range of standard
deviation for the grand means of the dose.

Dr. Fuentes noted that the report of the efficacy phase for EMD-003.1
had an error in transcribing the treatment dose from spreadsheets to the
table in the report, but recalculation of the data indicated that all 10
test arms received the correct 0.0011 ml/cm2 dose.  The efficacy phase
for EMD-004.1, testing mosquito repellency of the lotion formulation had
two testing sites, Butte County (woods) and Glenn County (marsh), CA.
The protocol was accurately performed and reported for the Butte County
site.  For the Glenn County site, the table in Appendix 3 contained
errors.  One arm appeared to receive a higher dose of the lotion, but
recalculation showed that this was due to a transcribing error (arm
entered instead of leg).  One leg was underdosed (0.008 ml/cm2) and one
was overdosed (0.012 ml/cm2).

The grand means for the dosimetry phase of the pump spray formulation
were 0.00067 g/cm2 for arms and 0.00051 g/cm2 for legs.  The target
doses for the efficacy phase of this formulation were 0.00071 ml/cm2
(arms) and 0.00054 ml/cm2 (legs).  The difference between the grand
means and the target dose were within the standard deviations range.
The actual dosing for testing tick and mosquito repellent efficacy for
pump spray formulations were correctly calculated and within the
standard deviations of the target dose.

The results of the efficacy phase for tick repellency indicated a mean
CPT of 9.1 hours ± 2.5 hours for the lotion (EMD-003.1), with a range
of 5 to 12 hours, and a mean CPT of 12.1 hours ± 2.8 hours with a
range of 6.5 to 15 hours for the pump spray formulation (EMD-003.2).
The results of the efficacy phase for mosquito repellency for the lotion
formulation (EMD-004.1) indicated a mean CPT of 7.3 hours ± 0.93 hours
at the forest site and 8.5 hours ± 0.84 hours for the marsh pasture
site.  The results of the pump spray formulation (EMD-004.2) were mean
CPTs of 7.1 hours ± 0.99 hours for the forest site and 8.4 hours ±
0.84 hours for the marsh/pasture site.

EPA concluded that the dosimetry phase of the study to determine typical
consumer dose is a strength of the revised protocol and the repellency
studies.  The minor deviations from the protocols did not compromise the
validity of the data or the results of the tests, and both EMD-003 and
EMD-004 study designs produced scientifically reliable data that met the
studies’ objectives.

Dr. Fisher expressed skepticism that the deviations from the recommended
procedures were minor, as stated in the Agency’s summary.  The study
enrolled only 12 subjects, and some over- or under-applied the lotion.
Any means or efficacy scores will be evaluated based on this, so it is
surprising that the effects of this error were minor.

Dr. Fisher also advised that the language, “guided by or in response
to” be used instead of “consistent with” recommendations.
“Consistent with” implies that the study was perfectly designed and
well-implemented; however, if data analysis of the 12 subjects in the
study included subjects who did not apply the repellent properly, the
study was not perfectly implemented.  She also inquired how, if the same
12 subjects were used repeatedly in this study, the results would apply
to the general population, and if this sample size was truly sufficient
to be considered representative of consumer application techniques and
to support risk assessment activities.  Dr. Fisher added that many
errors in data collection and analysis occurred, despite the small
sample size, and wondered why the onus was on EPA to correct these
errors.

Mr. Carley clarified that 12 subjects were used for the dosimetry study
and 10 subjects for each formulation for the repellent phase; this did
not necessarily include the same 12 subjects.  He explained that the
historical rule of thumb for dosimetry states that a typical application
is 1 gm/600cm2, which is assumed to be appropriate regardless of the
formulation or concentration of the formulation.  These studies showed
that there are important differences in application that vary with the
site of application (leg versus arm) and formulation (spray versus
lotion).  He commented that each of the 12 subjects in the trial were
appropriately representative.  Each subject applied the material 3
times, the mean application amount was determined, and the grand mean
calculated for the group.  Dosage errors occurred only at Site 2 for
efficacy testing against mosquitoes; all other errors were errors in
reporting.  Mr. Carley stated that he did not believe the study was
performed carelessly.

Dr. Susan Fish commented that if the grand mean of the means is used as
a recommended dose, and this is generalized to the population as a
whole, half of the general public will likely apply half the dose
tested.  She acknowledged that although there may be historical reasons
for using this calculation, using the lower quartile to determine
recommended dose may more effectively account for people who apply less
product.  Mr. Carley recommended that the HSRB discuss this issue when
reviewing the new protocol (SCI-001) that would be presented in the
afternoon.  The proposal to perform the dosimetry experiments using the
described method was reviewed at the last two HSRB meetings, although
the level of variability in the results was unanticipated.

Dr. Alicia Carriquiry inquired about the effect of individuals serving
as their own internal control in the tick repellency study.  Mr. Carley
clarified that in the tick study, the untreated arm is used to confirm
that the ticks showed active questing behavior and were appropriate to
use for testing the effect of the repellent applied to the subject’s
other arm.  Dr. Carriquiry asked why the CPT was not calculated as the
difference between the distances the tick traveled on the treated arms
compared to the untreated arms.  Mr. Carley explained that the
repellency on the untreated arm would be 0.

Dr. Gary Chadwick questioned the relatively high withdrawal rate
(20-30%) of subjects before efficacy failure and asked about the reasons
for withdrawal, as well as the effects this had on the results.  Dr.
Fish clarified that because the subjects did not complete the entire 10
hours of testing, their withdrawal times, for example, 8 to 9 hours into
the testing session, were considered their CPT; this would underestimate
product performance.  Dr. Chambers asked how the CPT data would be used
to develop labels for the products.  Dr. Fisher explained that a
minimal time based on the CPT average would be used, if standard
deviation is used, the minimal time may be less than the CPT average.

Dr. Kannan Krishnan expressed concern about the toxicity of the
products.  He commented on the lack of comparison between the dosages
received in the dosimetry studies compared to a toxicity benchmark, such
as the lowest observed adverse effect level (LOAEL).  Dr. Fisher
answered that toxicity information for this test material was available
before commencement of the study.  Mr. Carley explained that most
subjects were treated with approximately 1 gram of product.  Assuming an
average weight of 75 kilograms (kg), most subjects would receive
approximately 14 milligrams (mg)/kg.  The acute oral toxicity for
IR-3535 is more than 5,000 mg/kg, dermal toxicity is more than 2,000
mg/kg.  Mr. Carley stated that the materials tested are intended for
continuous skin contact, are designed to be innocuous, and have been
tested in toxicity studies.  He reported that EPA is comfortable with
the use of these formulations for continuous skin contact, and the
levels used in these studies did not represent a serious toxicity risk.
Dr. Krishnan recommended including a statement to this effect in the
report.

Dr. KyungMann Kim asked for clarification of the data collection
process, particularly concerning the deviation from the protocol stating
that each subject collected his or her own data , in contrast to the
study report stating that the study director recorded the data.  Dr.
Fuentes explained that each subject was trained to collect data with the
supervision of a trained technician.  Dr. Fisher added that although
subjects collected data in the field, the report of the data was written
by the investigators.  Dr. Lebowitz commented that it would be useful
for the HSRB to have the evidence used by EPA to determine that the
deviations did not affect the study results.  Because the number of
subjects was small, any deviations could affect both the within-subject
means and the between-subject grand means.

	Dr. Fisher commented that the variability observed in the dosage study
was unanticipated.  She asked whether the study gave EPA sufficient
information despite the variability and whether another step besides
determination of grand means was needed.  Dr. Fuentes answered that the
purpose of the dosimetry study was to ensure the safety of the subject.
If the dosage values were determined to be below the LOAEL, EPA
considered the product to be safe.

Dr. Janet Andersen (OPP, EPA) explained how EPA reports efficacy.  If a
product is determined to work for a given number of hours, EPA uses a
conservative analysis of the data to label the product.  If CPT is
determined to be 9 hours ± 2.5 hours, EPA would label the product as
effective for 6 hours.  Dr. Andersen indicated that the labels usually
include comments cautioning that efficacy can vary based on individual
human characteristics (for example, sweating) and would state that the
product should be reapplied as often as necessary.  She noted that EPA
recognizes that this number would not be precise because of the
variability among humans.  EPA provides this sort of guidance to help
registrants decide how to label their products.  Dr. Anderson added that
EPA has a Label Review Manual used by regulatory staff for guidance;
this manual is publicly available on EPA’s Web site.  Mr. Carley
clarified that the labels provide information for consumers to make
informed decisions about which product to use.  The label does not
provide a prediction of how long a product will work for a given
individual, given that different people respond differently to the
product and pests are of different species and behave differently in
different environments.

Ethical Considerations

Mr. Carley described the EPA’s ethics assessment of EMD-003 and
EMD-004.  The documents considered in this review included the initial
submissions received on November 9, 2006, revised submissions received
on December 15, 2006, EPA’s protocol review dated September 15, 2006,
and the HSRB final draft meeting report dated December 8, 2006.
Additional information included in the review was an email dated
December 19, 2006 from Dr. Carroll concerning dates the study was
conducted and use of the September 12, 2006 informed consent form (ICF),
and correspondence between Dr. Carroll and the IIRB in September 2006.

Protocols EMD-003 and EMD-004 met the applicable ethical standards 40
CFR §26.1125, 40 CFR §26.1601, 40 CFR §26.1303, 40 CFR §26.1703, and
40 CFR §26.1705.  These protocols also met the requirements for
completeness of documentation (40 CFR §26.1303).  Although all required
documents were submitted, no single complete report exists (documents
were submitted serially).

Deviations from the protocol did not present ethical problems.  Data
collection began before IIRB approval of the revised protocol and the
ICF.  However, data collection was performed under a prior,
IIRB-approved protocol (dated September 12, 2006) and thus does not
constitute an ethical violation.  Data collection preceding quality
assurance (QA) review was considered a technical violation without
ethical impact.  Dropping of the aerosol testing phase was reported only
in the transmittal document, but the effect was only to confuse the
reader and did not have an ethical effect.

In response to the HSRB recommendations, the investigators designated an
on-call physician, clarified potential adverse effects in the ICF
(EMD-003 only), and moved ICF discussion of compensation out of the
“Benefits” section.  These changes were not implemented before
subjects were recruited, consented, and tested using the lotion and pump
spray formulations.

In summary, there was no evidence that the procedures of the IIRB were
violated.  Although data collection preceded IIRB approval of final
changes to the protocol and ICF, these changes were minor and the
protocol and ICF used had been approved by the IIRB in September 2006,
and favorably reviewed by the HSRB in October 2006.  Some of these
irregularities might have resulted from the haste of the process;
nonetheless, the research was compliant with ethical standards.  All
required documentation was provided, and there was no evidence that the
subjects were misled or endangered by the delay in implementing the
changes suggested by the HSRB.  The study is in compliance with the
applicable statutes.

EMD-003 and EMD-004 generated large numbers of documents and large
amounts of information.  The protocols and reports were more complete in
both design and execution than those usually reviewed by EPA and the
HSRB.  The investigator has worked in good faith to understand and
incorporate the new rules implemented by EPA to ensure that research
involving humans meets the highest ethical and human standards.  Many of
the discrepancies observed arose because the record of these studies is
so extensive.  The main criticisms to these studies include some
difficulties in QA that likely arose because of the haste with which the
studies were performed and reported.

Public Comment

Dr. Scott Carroll of Carroll-Loye Biological Research, Inc.

          Dr. Carroll expressed his appreciation for the input and
guidance provided by the HSRB.  To address the question of dosimetry
errors, Dr. Carroll confirmed that in 2 of 60 applications for
efficacy, errors were made in dosing.  In one case, 0.0008 ml/cm2
instead of 0.011 ml/cm2 was applied, in the other 0.012 ml/cm2 was
applied.  The subject dosed at the lower rate had a lower CPT, and the
subject who received a higher dose had a longer CPT, although this
subject had a mosquito land earlier than other subjects.  These errors
did not impact the quality of the data.

Because the studies were performed on a tight schedule, Dr. Carroll used
previously approved ICFs.  He reviewed the compensation plan with the
subjects and discussed HSRB-recommended alterations to the ICF, inserted
or crossed out language to reflect these alterations, and both he and
the subject initialed the changes.  This allowed the studies to proceed
on schedule.

Dr. Carroll informed the HSRB and EPA staff that industry sponsors are
concerned about the delays caused by the new review structure.  He added
that he also is concerned with the logistics of the situation and by the
burden this structure places on EPA.  He proposed as a more reasonable
research cycle:  15 days for IRB protocol review and submission; 75 days
for EPA and HSRB protocol reviews, including a HSRB meeting; 105 days
for research and report submission; 75 days for subsequent EPA and HSRB
reviews including a second HSRB meeting.   This results in a total time
of 270 days, which is the briefest timeframe appropriate to perform this
research.  The current procedure requires protocol revisions and
re-reviews that place burdens on EPA staff, laboratories, and IRBs.
Potential solutions to these issues include more lead time from
sponsors, more research and regulatory staff, and more experience with
the review procedure itself.

Dr. Fisher thanked Dr. Carroll for informing the Board about the
challenges presented by the review process to sponsors and
investigators, and asked Board members if they had questions for Dr.
Carroll.

Dr. Sean Philpott asked Dr. Carroll to clarify who signed the new ICF.
Dr. Carroll explained that subjects participating in the November 3,
2006 study at the marsh site signed the revised and original forms.  Dr.
Philpott commented that the HSRB did not receive documentation of tick
handling training.  Dr. Carroll assured him that he had documentation
for training of all subjects and explained that Visit 1 for the subjects
covered tick handling and the dosimetry study.  Not all subjects who
participated in the efficacy study participated in the dosimetry phase.
He added that similar documentation was maintained for training subjects
in aspiration of mosquitoes.

Drs. Fisher and Philpott requested clarification on whether the same
subjects were involved in both the tick and mosquito studies.  Mr.
Carley explained that the same 12 subjects participated in the efficacy
study for each of the 3 formulations of the product.  Dr. Carroll
offered to provide a flow chart that would document the movement of each
subject through the study protocols.  He added that he also would try to
convince sponsors to combine the sub-reports into one report, to
alleviate the problems and confusion arising from serial submissions of
documents.  Dr. Fisher stated that the HSRB would not make a
recommendation concerning collapsing of studies, but would recommend a
more accurate and informative portrayal of study participants.

Dr. Fisher questioned whether the participants in the study were
representative of the general population, given that many of these
people are from the same community, may have participated in a number of
similar studies, and thus may be more experienced with applying insect
repellents.  Dr. Carroll answered that there is no historical art or
practice in the field of dosimetry concerning how to define
“representative.”  He sought information from investigators in the
cosmetics industry and toxicology field to learn about dose monitoring.
EMD-003 and EMD-004 enrolled subjects from a college-educated,
field-oriented group.  He acknowledged that these subjects may be more
familiar both with the data collection process and with repellent
application.

Dr. Philpott asked whether Dr. Carroll had monitored for arboviruses
other than West Nile Virus, and whether the mosquitoes had been tested
for the presence of transmissible viruses.  Dr. Carroll responded that
mosquitoes were not tested because this would have to be funded by study
sponsors, but that material collected by abatement personnel was sent to
the Centers for Disease Control and Prevention (CDC) for screening and
no viruses were found.

Dr. Richard Sharp asked whether all protocol deviations had been
reported to the IRB.  Dr. Carroll replied that not all of the deviations
had been reported.  Dr. Chadwick expressed concern that crossing out a
section on a consent form may be considered by some to be merely an
editorial change; but, it is not acceptable according to regulations to
do this without IRB approval.  Under these circumstances, this was a
minor change.  However, he cautioned Dr. Carroll against repeating the
activity.  Dr. Carroll assured Dr. Chadwick he would not perform ad hoc
revisions to a consent form.  Dr. Carroll explained that in some cases,
the changes requested from, and approved by, the IRB were not made on
the forms the IRB returned as scans.

Dr. Lebowitz requested clarification of entry errors and whether these
errors compromised the data.  Dr. Carroll explained that entry errors
refer to instances, such as incorrect crossing-out of mis-entered
values.  EPA staff could see the improperly entered value, and note that
the replacement values were logical.  Dr. Carroll added that during the
tick data collection process, there was direct oversight by a trained
technician of subject data collection and entry.

Dr. Lebowitz asked Dr. Carroll to explain the impact of a change of 1oC
above expected temperatures for two testing periods.  Dr. Carroll
explained that the original temperature values were based on his
experience with a West Coast tick population, which is active in winter.
 These experiments used a Northeastern population that is more active at
higher temperatures.  No change in questing behavior was observed on the
untreated arm when the temperature rose.

Dr. Lebowitz inquired why the two-way ANOVA analysis was not performed
in the dosimetry phase to analyze within-subject variability and
between-subject variability.  Dr. Carroll explained that because the
design was balanced, little information is lost by using the standard
deviation of the grand mean instead of ANOVA.  ANOVA was not performed
because of a lack of time; however, the analysis was conducted on the
aerosol study a couple of weeks later.

Dr. Philpott questioned why there were no data on dosimetry or efficacy
for three subjects.  Dr. Carroll explained that these subjects were
either excluded for confidential reasons or participated only in the
aerosol study.  Dr. Fisher clarified that confidential refers only to
information that could be used to identify a subject.  The reason for
exclusion can be given as long as it does not permit identification.
Dr. Carroll remarked that he wished to avoid mentioning a class of
people who might be excluded.  Dr. Fisher stated that identifying a
subject as a member of a class does not affect confidentiality or
identification.  Dr. Suzanne Fitzpatrick disagreed.  Because this
discussion took place at a public meeting, some of the original subjects
might be attending and, because the subject pool was quite small, may
have known who was excluded, and descriptions of reasons for exclusion
could result in identification of subjects.  Dr. Carroll offered to
provide in the study report whether a person was excluded for personal
reasons or voluntarily dropped out of the study.  Dr. Fisher agreed that
this would be useful, and thanked Dr. Carroll for his participation.

No further public comments were made.

Board Discussion

Scientific Considerations—EMD-003

Dr. Chambers reviewed the study EMD-003, in which two formulations
(lotion and pump spray) containing the active ingredient IR-3535 were
tested for the ability to repel ticks according to the protocol
presented and modified, based on suggestions and input from EPA and the
HSRB, by Carroll-Loye Biological Research, Inc.  As suggested by the
HSRB, passive dosimetry experiments were used to determine the amount of
product typically used by consumers.  This dose was calculated using the
grand mean of 12 subjects tested and was used as the dose for the
repellency tests for each product.  The dosimetry protocol was common
for this and the mosquito repellency experiment, EMD-004.

The EMD-003 protocol was performed in a laboratory setting with only
minor deviations, none of which affected safety or the quality of the
data.  A sample size of 10 subjects was justified as leading to
sufficient statistical power while exposing only a small number of
people to risk.  Laboratory-reared, disease-free ticks were first tested
on the untreated limb to confirm normal questing behavior.  The first
confirmed crossing was used to calculate the CPT.  This study identified
a range of 5 to 12 hours with a mean CPT of 9.1 hours for lotion, and
6.5 to 12 hours with a mean of 12.1 hours CPT for spray.  These values
probably are conservative, because some subjects terminated the
experiment before the first confirmed crossing.

EMD-003 met scientific criteria established by the HSRB.  Existing data
were not adequate to answer questions concerning efficacy for the new
formulations, thus new studies involving human subjects were warranted.
Potential benefits to this study include identification of repellents
with greater efficacy and/or fewer drawbacks than products currently on
the market.  Risk was minimal because the tested products were of low
toxicity and ticks were laboratory-raised and pathogen-free.  The most
likely risk was irritation from tick bites, but this risk was low
because subjects were instructed to remove the ticks before bites
occurred.  EMD-003 met study design criteria, including a clearly
defined purpose (test efficacy), and specific hypotheses and objectives.

The study enrolled suitable subjects and study investigators anticipated
that the findings would be generalizable to the general population;
however, there was some question of how representative the study
population was of the general population.  The inclusion and exclusion
criteria were appropriate and study subjects were not members of
vulnerable groups.

Concerning measurement criteria, the measurements were accurate,
reliable, and appropriate to the questions asked.  QA was addressed,
although some issues arose in this area.  Appropriate statistical
methods were used to calculate the CPT with a range of variability.  The
data generated using these methods (such as mean with a range of
variability) were suitable for use by EPA for making regulatory
decisions.  Measures of uncertainty were addressed using standard
deviation.  Laboratory experiments were appropriate for testing tick
repellency.  The study included a medical management plan and safety
monitoring.

According to data presented at this meeting, the dosimetry study
indicated that subjects used more of the lotion formulation than the
pump spray formulation, but better tick protection was found for the
pump spray formulation.  Protection time may be less related to dose
than to how long the product lasts before evaporation or product
deterioration results in loss of efficacy.

Dr. Chambers concluded that the reported study EMD-003 is sufficiently
sound from a scientific perspective to assess repellent efficacy of the
lotion and pump spray formulations against ticks.

Dr. Fitzpatrick agreed with Dr. Chambers’ conclusions.  She clarified
that the levels of active ingredient in the pump spray and lotion
formulations differed and were in line with observed protection times.
She agreed that deviations from the protocol were minor and presented no
risk to study participants.  Deviations, such as entry errors, are
common in field studies.  She agreed that the sample was representative,
within the confines of the exclusion criteria.  The study population
included people likely to use the products.  The dosimetry experiments
were a commendable attempt to introduce dosing precision to this field.
Although the average consumer might use more product, this is not a
cause for concern because the formulations are already known to be safe
and efficacious; these studies simply clarify a time range of
effectiveness.

Dr. Lebowitz noted that Drs. Chambers and Fitzpatrick satisfied his
concerns about generalizability.  His concerns about the use of the
grand mean were reduced by EPA’s explanation that a CPT range will be
used to develop the use label, with appropriate statements about
individual variability.

Dr. Carriquiry agreed with Drs. Chambers, Fitzpatrick, and Lebowitz.
She clarified that the negative control referenced in the protocol is
not a true negative control, and references to this should be removed
from the report or language should be added to clarify this.

Dr. Fisher asked meeting participants if there were any dosimetry models
concerning adequate methodology for insect repellents.  Mr. Carley
responded that these were the first repellency studies with a specific
dosimetry phase.  Traditionally, 1 gm/600 cm2 is used as an approximate
typical consumer dose.  The result of the dosimetry phase of this study
indicated a lower typical dose; the impact of this would be a more
conservative estimate of protection time.  Dr. Fisher suggested that EPA
might wish to provide guidance concerning whether this was a valid way
to determine dose.

Ethical Considerations—EMD-003

Dr. Philpott opened discussion of ethical considerations of EMD-003.  He
stated that the benefits to this study were clearly defined.  There were
no direct individual benefits, but there is a societal benefit arising
from identification of a new repellent product.  Individual risk was
clearly defined and the protocol included adequate attempts to minimize
risks associated with toxicity, reactions to the compound, exposure to
insect-borne diseases, and other unanticipated events.  The likelihood
of adverse reactions was minimal, a medical management plan was in
place, stopping rules were clearly defined, and laboratory-raised ticks
were used.

The study population had clear inclusion and exclusion criteria,
although this was a population of convenience, composed of study
subjects who had participated in previous Carroll-Loye Biological
Research, Inc studies, members of Dr. Carroll’s department at the
University of California (UC)-Davis, and people with an interest in
entomology.  This raised questions concerning the representativeness of
the population and questions of vulnerability because Dr. Carroll is
academically affiliated with the UC-Davis.  However, efforts were made
to minimize vulnerability were adequate.  Clear exclusion criteria and
interviews of subjects by Dr. Carroll to assess their motivation for
participating minimized the vulnerability.  Subjects were compensated at
a rate of $15 per hour for their participation; this could amount to
several hundred dollars if subjects participated in dose and efficacy
studies for both formulations.  This was not considered to be unduly
excessive compensation.

A significant concern is the alteration and use of the ICF prior to IIRB
approval.  Although the intent was to improve the informed consent
process and did not impede the process or harm participants, this was
nonetheless a regulatory violation and Dr. Carroll should review IRB
protocols and procedures.  The study was in compliance with the criteria
of 40 CFR 26 Subparts K and L and all necessary documents for review
were submitted.

Dr. Fish agreed that all ethical concerns had been addressed.  She added
that because this is a new procedure for researchers and registrants,
researchers should consider reviewing IRB requirements.  Regulatory
breaches in the protocol occurred; although no harm resulted, these were
nonetheless breaches.  EPA should consider requiring training in human
subject protection.

Dr. Sharp clarified the two deviations from standards of clinical
research ethics.  First, minor protocol deviations and changes to ICFs
occurred, but did not compromise subject protection.  Second, the
failure to report these deviations to the IRB perhaps presents a larger
problem.  Only the IRB can decide if an infraction is minor or requires
corrective action, such as additional training or auditing.  Dr.
Fitzpatrick remarked that regulations require that deviations be
“reported in a timely manner,” which could mean 3 months for a minor
deviation (based on Food and Drug Administration FDA practices).  Dr.
Fish countered that the IRB might wish deviations to be reported sooner.
 Dr. Fisher clarified that although the changes occurring during this
study they did not result in harm, such changes could be harmful in
other circumstances; the HSRB does not wish to downplay the potential
seriousness of deviations of this sort.

Dr. Fisher presented the conclusion of the HSRB discussion of EMD-003:

Dr. Carroll and Mr. Carley adequately answered HSRB questions about
dose, variability, and subjects.  The HSRB consensus is that the data
were valid and could  be used for the indicated purpose.

Concerning ethics, some deviations occurred but did not place subjects
at risk.  The Board recognized that many deviations were introduced to
provide more protection.

The Board discussed whether to recommend EPA develop a policy that
investigators demonstrate ethics training similar to National Institutes
of Health (NIH) policies.  Dr. Chadwick stated that in his opinion, the
Board should strongly recommend that EPA consider requiring ethics and
human protection training to those investigators performing human
subjects research.

Mr. Carley asked the Board for clarification.  Application forms sent to
the IIRB included responses to questions concerning the investigator’s
training in human studies and ethical standards.  He asked whether this
was adequate or if EPA should develop its own requirements and training.
 Dr. Fish added that not all IRBs ask whether investigators have been
trained in human subject protection; NIH and a few other sources of
federal funding require training.  Dr. Fitzpatrick noted that NIH
requires training to receive funding.  If EPA does not fund a study, it
may have less authority to require investigator training.  Dr. Fisher
summarized that the Board could recommend that EPA develop guidelines to
ensure adequate training of investigators in human research protection,
rather than relying on IRBs.  EPA also should determine the content of
required training based on models such as those used by NIH.

Dr. Kim raised a technical issue concerning data analysis of EMD-003 and
EMD-004.  He commented that the CPT was determined as time to event
(tick crossing or mosquito landing).  However because some subjects
dropped out before the event occurred, the actual time to event was not
available.  The investigators assumed that the true CPT would be longer
than the time to drop out, but this may not be a valid assumption.  He
suggested that the investigators consider using the Kaplan-Meier
estimate, which will give a correct unbiased median estimate of CPT
along with the appropriate standard deviation, which will be much larger
than what was reported in the study.  The Kaplan-Meier estimate also can
account for censored data, such as loses from the sample before the
final outcome is observed.  Dr. Fisher requested that information
regarding the Kaplan-Meier estimate be forwarded to Dr. Lewis, who will
forward it to EPA staff.

Scientific Considerations—EMD-004

Dr. Chambers reviewed the protocol, EMD-004, a field study in which the
active ingredient IR-3535 in two formulations was tested for the ability
to repel mosquitoes according to the protocol presented and modified,
per EPA and HSRB input, by Carroll-Loye Biological Research, Inc.  Data
were reported for the pump spray and lotion formulations; the aerosol
formulation would be presented at a later date.  The formulations were
made according to Good Manufacturing Practices and laboratory
experiments performed using Good Laboratory Practices.  The dosimetry
phase was performed as reported and discussed for EMD-003.

EMD-004 was a field study conducted according to approved protocols with
only very minor deviations, none of which affected the quality of data
or compromised the safety of the subjects.  Two locations in California
were used, dense forest and moist pasture/marsh, which had differences
in the composition and relative abundance of mosquito species.  Neither
site showed evidence of West Nile Virus.

A sample size of 10 subjects per product was justified as generating
sufficient statistical power while exposing only a small number of
people to potential risk.  Each subject had one limb treated and the
remaining limbs covered with impervious material.  Two experienced
persons served as negative controls (no repellent product) to confirm
mosquito biting pressure and biting pressure was maintained throughout
the period of the study; which was defined as at least one landing with
an intent to bite (LIBe) or one LIBe per minute.  Experimental subjects
worked in pairs to monitor the LIBe during 1-minute intervals occurring
each 15 minutes until the first confirmed LIBe was determined and
stopping rules were applied.  The CPT was calculated as the mean CPT of
all participants for each product.  The mean CPTs for the lotion were
7.3 hours for forest and 8.5 hours for marsh.  Mean CPTs for the pump
spray were 7.1 hours for forest and 8.4 hours for marsh.  The
calculated CPTs likely are conservative because a number of subjects
reported no LIBes and some terminated the experiment before the first
confirmed LIBe.

EMD-004 met general scientific criteria and had a clear scientific
question—testing the efficacy of IR-3535 in repelling mosquitoes.
Existing data were not adequate to answer questions of efficacy of the
new formulations.  Therefore a new study involving human subjects was
necessary.  The potential benefits of the study included identification
of an effective repellent with greater efficacy.  Risk was minimal
because the formulation products had low toxicity, mosquitoes were
aspirated before they could bite, and test sites had no evidence of West
Nile Virus.

The study design criteria were met.  The study purpose was clearly
defined, there were specific objectives and hypotheses, and an adequate
sample size was used.  There was justification for selection of the
target population, which was appropriate and reasonable and met
appropriate inclusion and exclusion criteria; vulnerable group subjects
were not used.

Measurements were accurate, reliable, and appropriate to the question
being asked.  QA issues were addressed.  The statistical methods used to
calculate the CPT with a range of variability were appropriate.  Field
experiments were appropriate and the study included a medical management
plan and safety monitoring.

Dr. Chambers concluded that EMD-004 was sufficiently sound from a
scientific perspective to assess mosquito repellent efficacy of two
formulations containing IR-3535.

Dr. Lebowitz agreed that the review was accurate.  He had concerns about
statistical questions, generalizability, and the number of subjects
used.  He stated that despite some shortcomings and deviations from
protocol, the results could be used for the purposes suggested.  Dr.
Lebowitz concluded that the study was sufficiently sound to assess the
repellant efficacy of the formulations tested against mosquitoes.

Dr. Kim agreed that the study was sound, but there were problems with
the methods used to define the CPT, especially given the subject
drop-out rate and methods used to estimate CPT for these subjects.  The
methods used would overestimate the repellency of the formulations and
would artificially reduce the standard deviations.  Using the
Kaplan-Meier estimate would give a correct unbiased estimate of the
median CPT and standard deviations larger than those reported, which
would affect the label EPA develops for this product, because standard
deviation is used to determine a CPT range.  He expressed disappointment
that no statistician at EPA had reviewed the data.

The Board discussed the statistical analysis method used in the study.
Dr. Kim argued that the current protocol included data that did not
exist (such as CPT, if the subject left before a mosquito landed), which
could lead to underestimated standard deviations, and has implications
for the product label.  Dr. Fish questioned whether this was a standard
method in repellant studies for measuring efficacy or determining time
to a confirmatory event.  If the same method is used in all studies, the
impact should be the same and the relationship between different
products remains constant.  Dr. Kim pointed out that the degree of data
censoring varies between studies.  Thus there would be an impact on
relative comparisons.  Using the Kaplan-Meier estimate to calculate the
median and standard deviation is appropriate when data that does not
exist is imputed.  Using the current approach results in biased means
and standard deviations.  Dr. Carriquiry agreed that re-analyzing the
data using the Kaplan-Meier estimate likely would result in large
standard deviations.  The practical consequence of this is wide
confidence intervals, which will negatively impact efficacy estimates.

Dr. Fisher concluded that the Board would not reject the data, but would
include in its recommendations that EPA should be aware that using
arithmetic mean and standard deviation to determine the CPT is
incorrect, and should consider different ways to determine mean and
standard deviation. This comment is applicable to both EMD-003 and
EMD-004.   Mr. Carley stated that this data was analyzed in accordance
with EPA guidelines; changes may be needed but should not affect this
study.  Dr. Fisher remarked that introducing new analysis methods could
affect EPA’s ability to compare products and deliver information to
consumers concerning product performance relative to other products.
She agreed, however that EPA should be given information about different
statistical analysis techniques from Drs. Kim and Carriquiry and should
consider applying these techniques to future studies.  Mr. Jordan agreed
with Dr. Fisher’s suggestion and stated that EPA is trying to move
toward more sophisticated ways of analyzing data.  EPA follow-through on
this advice is challenging because their database contains studies
performed over decades ago with different designs and ways of
calculating CPTs.  EPA needs to balance regulatory considerations of
label value based on different statistical approaches.

Dr. David Bellinger inquired whether the Board wished to revise the
scientific criteria to include specification of the sampling frame (such
as, definition of eligible subjects based on inclusion and exclusion
criteria) used to enroll subjects; the current report does not describe
the population from which subjects were drawn.  Dr. Fisher agreed that
definition of eligible subjects and sampling frame would strengthen
justifications for generalizability and should be included in the
report.

Dr. Fisher summarized the Board’s discussion of the scientific
criteria for EMD-004:

EMD-004 met scientific criteria with some minor deviations.

The Board had some concerns with respect to data usability, given the
statistical methods used to analyze the data.  EPA should consider
alternate ways to analyze and evaluate the data.  The Board is aware
that EPA must consider relevance to other studies and how changes would
affect consumer information.

The Board recommended inclusion of a description of the sampling frame
and definition of eligible subjects to help justify subject
generalizability.

Ethical Considerations—EMD-004

Dr. Philpott opened the ethics discussion by noting that ethics
considerations for EMD-004 were similar to those of EMD-003.  EMD-004
has similar societal benefits but no direct individual benefits.  Clear
stopping rules and a medical management plan were in place to protect
subjects.  Two anticipated risks to subjects are reactions to the
compound (unlikely because of the toxicity profile of the active
ingredient and history of its use in Europe) and risk of exposure to
arboviruses.  This risk was mitigated by the plan to conduct the trial
only in a region with no evidence of West Nile Virus or Eastern Equine
Encephalitis for one month, based on monitoring of chicken sentinels.  A
deviation to this protocol was the report of a single case of West Nile
Virus in a single flock prior to the trial.  The justification to
continue was that the chicken was not geographically close to the study
site.  In CDC’s opinion, the West Nile Virus season was over in this
region. However the geographical location of the flock site relative to
the test site was not clear.  The Board recommended reporting this as a
potential deviation.

Concerning the study population, there are some questions as to whether
this is a representative sample.  Vulnerability issues also are a
concern because some subjects may have had ties to Dr. Carroll, but as
with EMD-003, sufficient safeguards were in place to eliminate coercion
and vulnerability fears.  Compensation for the subjects was not
considered unreasonable.  In accord with 40 CFR 26 Subparts K and L, no
children or pregnant or nursing women were included in the study.

Two deviations exist concerning modification of the ICF approved on
September 12, 2006.  The first is the unapproved modification and use
of the ICF, the second is the failure to report this deviation to the
IIRB, although questions of timeliness of reporting have been raised.
With respect to the EPA charge, EMD-004 is not unethical and comports
with 40 CFR 26 Subparts K and L.

Dr. Chadwick commented that the charge asks if the protocol is in
substantial compliance with applicable statutes.  EPA needs to define
“substantial” and determine the level of noncompliance it is willing
to tolerate.

Dr. Fisher added that the detection of West Nile Virus in a sentinel
flock is a QA issue that should have been reported to the IRB before the
experiment began, although she agreed with CDC’s opinion regarding
subject safety.  She agreed that the study presented no substantial
ethical problems and subjects were not exposed to unacceptable risk or
an increase in risk by these deviations.

Insect Repellent Efficacy Protocol SCI-001

Introduction

Mr. Carley and Mr. Kevin Sweeney (OPP, EPA) presented EPA’s science
and ethics reviews of protocol SCI-001, a proposal to field test
mosquito repellency for four EPA-registered formulations containing
DEET.  These reviews were December 30, 2006, and were based on initial
protocol submission as supplemented by additional documents received by
December 13, 2006.  A further revised version of the protocol, with IRB
approval and revised ICF (and supporting correspondence) was received on
January 3, 2007.  SCI-001 is adapted from and similar to EMD-004, which
was previously approved by the HSRB.

Scientific Considerations

Mr. Sweeney presented the science assessment of SCI-001.  He explained
that the objectives of this study are to test the mosquito repellent
efficacy characteristics of three test materials, to compare them to one
another, reinforce measurements of time for which they are effective,
and to contrast them with the U.S. military issue topical insect
repellent.  Test Material #1 is LipoDEET, which contains 30% DEET that
has lipid spheres and inhibits evaporation, improved field, and reduced
plasticizing and odor.  Test Material # 2, Coulston’s Duranon, is 20%
DEET in a controlled-release, low-odor formulation.  Test Material #3 is
Insect Guard II, which contains as active ingredients 17.5% DEET, 5%
N-octyl bicycloheptane dicarboximide (synergist), and 2.5% Di-n-propyl
isocinchomerate (fly repellent).  Test Material # 4, 3M Ultrathon
(military issue repellent), contains 34.34% DEET in a polymer-based
lotion to extend efficacy and reduce plasticizing.

This study was similar to EMD-003 and EMD-004 in terms of the dosimetry
phase, efficacy measurements (time to “first confirmed landing with
intent to bite”), and training of subjects in aspirating mosquitoes
before they bite.  The field conditions and timing of exposure also were
similar (subjects work in pairs with 2 assistants to aspirate
mosquitoes, and both treated and untreated subjects would be exposed to
the mosquitoes for 1 minute every 15 minutes).  The field testing sites
are the California Central Valley or Florida Keys, with expected wild
mosquito populations of Aedes vexans, Ochlerotatus melanimon, O.
taeniorhynchus, and Culex pipens.  The test results would be analyzed
using unspecified statistics.  Measurements would be reported with 95%
confidence intervals of the mean and associated standard deviations.
The efficacy of each treatment would be compared to that of Ultrathon.
The sample size reflects a compromise between financial and ethical
concerns, although it is difficult to pre-determine sample size without
knowing the distribution of outcome values.  EPA guidelines recommends 6
replicates, which is considered sufficient to show statistical
significance at P<0.05.

EPA recommended changes to the protocol including developing a full
description of the statistical analysis plan to compare means and assess
within-treatment variability, and to define a testable hypothesis.  If
these revisions are completed, this protocol likely would yield
scientifically reliable information and will satisfy the scientific
criteria recommended by the HSRB, namely, producing important
information that cannot be obtained except by research with human
subjects, and having a clear scientific objective, and a study design
that should produce adequate data to test the hypothesis.

Dr. Chambers questioned whether the study would compare the same amount
of active ingredient or the same amount of material applied.  Mr. Carley
responded that the dose rate in the efficacy phase would be determined
by a preliminary dosimetry phase.  The grand mean of the subject mean
will be calculated to obtain a standard dose for each product.  These
could be different for each product, resulting in variation in the DEET
dose.  Mr. Sweeney added that the DEET dose likely would be reported.

Dr. Fisher commented that to quantify the CPT, if subjects can drop out
of the study at will, criteria will be needed to establish how long a
subject must remain in the study to use their data, or if data from
another subject can be substituted.  Subject drop-out can influence the
confidence interval.  She also commented on the lack of dosimetry
standards in the field, and asked whether the dosimetry method employed
in EMD-003 and EMD-004 was satisfactory.  If the dose is based on how
much product the person applies, this could lead to confusion concerning
how to compare the formulations with different amounts of DEET.  Mr.
Carley replied that the dosimetry phase would help to determine the
typical consumer dose for each formulation.  Subjects would be
instructed to apply the product until they believe they have achieved
complete coverage, and, because different formulations have a different
feel, different amounts likely would be applied.  Dr. Fisher commented
that this emphasizes how experienced subjects, or knowledgeable
subjects, may not be representative of the general population in terms
of product use.

Ethical Considerations

Mr. Carley presented the ethics assessment of SCI-001.  The proposed
study would test the field efficacy of 3 registered test formulations
and one ‘comparison article’, all containing the active ingredient
DEET as a mosquito repellent.  Demonstration of long-term efficacy for
the test products may lead to more attractive alternatives to the
comparison article, which is found unpleasant by many users.  The
military issued Ultrathon is not used as widely as it should be because
of these unpleasant characteristics.  If the other formulations are
found to be as effective as Ultrathon, a potential societal benefit lies
in the increased use by those at risk for arthropod-borne diseases, such
as members of the military.

Subjects will be recruited among “communities of friends, neighbors
and scientists” near the investigator’s laboratory, excluding
students or employees of the investigator, or members of vulnerable
populations, such as children and pregnant or nursing women.

Risks include possible irritation, headache, dizziness or temporary
stomach distress from exposure to the test materials, and exposure to
biting arthropods and arthropod-borne disease.  These risks were are
considered small because the materials have low acute and chronic hazard
profiles, the research had been designed to minimize exposure, subjects
were trained to aspirate mosquitoes before they bite, and field testing
would be performed in areas free of West Nile Virus.  The risk-benefit
ratio is acceptable, because although there is no direct benefit to
subjects, there is a low level of risk that is acceptable in view of the
expected societal benefit of the identification of alternative,
effective, long-lasting mosquito repellents.

The IIRB reviewed and approved the protocol and informed consent
materials.  The description of the recruiting and consent processes has
been deemed satisfactory and the IRB-approved ICF is included in the
protocol; a few editorial changes are needed in the ICF.  Methods have
been proposed for ensuring subject privacy.  Subjects would be free to
withdraw at any time, and medical care for research-related injuries
would be provided at no cost to the subjects.

The primary ethical standards applicable to this research are 40 CFR 26,
Subparts K and L.   An evaluation of how this protocol addressed the
requirements of these standards and the additional criteria recommended
by the HSRB appears as Attachment 1 to the EPA Review.  Further
revisions to the protocol include provision of the fax and set-up form
cited in the IIRB/Carroll correspondence; correction of the erroneous
reference in the ICF to EMD as a sponsor and in §10.1 to gauze
bracelets in the dosimetry phase; deletion of the reference in §12 to
conducting research in the Florida Keys or an explanation in §9.1.5
describing how subjects will be recruited in Florida; and provision of
documentation of all calculations of subject skin area and of individual
doses in the efficacy phase.

This protocol was in compliance with ethical standards § 26.1111,
26.1116, 26.1117, 26.1125, 26.1203, all elements of the National Academy
of Sciences (NAS) recommendation 5-1, and all elements of NAS
recommendation 5-2.  If further revised as suggested, protocol SCI-001
would meet the applicable requirements of 40 CFR part 26, subparts K and
L.  The various parts of the protocol need to be consolidated,
proofread, and submitted as a single document for review.

Public Comment

Dr. Scott Carroll of Carroll-Loye Biological Research, Inc.

Dr. Carroll explained that SCI-001 was developed while collecting data
for EMD-003 and EMD-004.  Development of the protocol required a great
deal of input from EPA, which Dr. Carroll would like to be able to
reduce in the future.

Concerning the statistical analysis, Dr. Carroll’s goal, based on the
sponsor’s wishes, is to determine how each formulation compares to
Ultrathon.  This involves a pairwise comparison approach and comparative
survival analysis was determined to be appropriate, based on
Dr. Carroll’s discussions with a colleague familiar with this type of
analysis.  The data would be used to provide a value to justify label
changes by EPA and to provide the military with information they can use
to identify a suitable and effective replacement for Ultrathon.
Concerning subjects who dropped out of EMD-003 and EMD-004, this issue
arose because the products remained efficacious for longer than
anticipated, and subjects were thus not informed that the study could
last for more than 7 hours.  For SCI-001, Dr. Carroll has proposed
increasing compensation to $20 per hour and informing the subjects that
they may be in the field for more than half a day (12 hours).  If
drop-outs continue to be a problem, the approach as described previously
by HSRB member Dr. Kim would be used to analyze the data.

Dr. Carroll discussed the issue of subject recruitment in Florida from a
pool of vector professionals.  This group may not constitute a
representative sample.  The Florida site was chosen as an alternate for
when California is off-season.  Dr. Fisher inquired why, if for any
given month there are appropriate sites around the country for this
experiment, there was a rush for the HSRB to review this protocol.  Dr.
Carroll replied that since the advent of the new review system, many
sponsors were concerned that the process would lead to delays in
registration of products.  Dr. Fisher commented that this issue had been
raised at a previous meeting, and the HSRB had asked EPA to provide a
justification for the urgency of review.

In response to Dr. Fisher’s question concerning substitution of
subjects, Dr. Carroll explained that this would incur additional
expenses given the increased exposure time needed.  Dr. Fisher replied
that the experiment did not appear to be costly and wondered how
substantial the increase in cost would be to use a substitute.  She also
commented on the lack of criteria for establishing how long a subject
needs to remain in the field to include their data in the analysis.  Dr.
Carroll responded that for this protocol, subjects would be asked to
remain in the field for 12 hours.  Although EPA approved a claim of 4
hours of efficacy for the products being tested, this value is based on
extrapolation from other formulations with similar percentages of DEET.
The manufacturers believe the products would last longer.  Additionally,
Ultrathon has previously been demonstrated to last 12 hours.

Dr. Chambers commented that substitution also would require inclusion of
untreated controls, which may present an ethical issue.  Dr. Fitzpatrick
suggested that it might be more effective to include more subjects than
called for in the original protocol.  Dr. Carroll agreed, but added that
it has been difficult to increase the sample size from 6 to 10.

Dr. Fish asked why the inclusion criteria for this protocol specified an
age range of 18 to 55 years, compared to the EMD-003 and EMD-004
protocols, which specified older than 18 years.  Dr. Carroll explained
that the upper limit of 55 years was recommended by the CDC, which
considers West Nile Virus to present a more serious health risk for
those over the age of 55.  Dr. Fish inquired about whether a sentence in
the protocol stating that “subjects may obtain data” meant that the
subjects could remove their data or obtain a copy.  Dr. Carroll replied
that subjects would be given a copy of their data.  Dr. Fish commented
that the ICF stated that the amount of product used would not be greater
than one-quarter teaspoon and asked if this could be confirmed prior to
the dosimetry phase.  Dr. Carroll agreed that this statement should be
changed to read “approximately one-quarter teaspoon.”

Dr. Krishnan inquired if the experiments would run for 12 hours per day,
given the claims of up to 12 hours of effectiveness for Ultrathon.  Dr.
Carroll explained that individual subjects would be occupied for more
than 12 hours because of travel to and from the research site.  He
suspected that the products likely would last between 8 and 12 hours.
He stated that he intends to explain to the subjects that the products
could be efficacious for more than 12 hours; this is the rationale for
the higher rate of compensation.  Dr. Krishnan inquired if the results
concerning variability from the EMD-003 and EMD-004 studies would be
used to estimate sample size for this protocol.  Dr. Carroll replied
that this presented a good basic research question, although probably
not one appropriate for the sponsors to pursue.

Dr. Krishnan remarked that he was struck by errors that the IRB did not
catch regarding this protocol.  Dr. Carroll stated that, in the past, he
has noticed that the IRB did not always thoroughly examine the materials
he provided to them.  However he is now observing that this IRB appears
to be reviewing materials more thoroughly.

Dr. Lebowitz questioned whether other arthropod-borne diseases, such as
Dengue Fever or Eastern Equine Encephalitis could be present at the test
site and asked if Dr. Carroll would use the same precautions outlined in
EMD-003 and EMD-004 to reduce the risk of exposure to these diseases.
Dr. Carroll explained that those precautions would be used.  Dr.
Lebowitz inquired if the timeframe for exposure would include times at
which mosquitoes with different habits (i.e., night active or daylight
active) were present.  Dr. Carroll responded that he could expose
subjects at times during which mosquitoes found at that site are most
active.  Another approach is to divide the 12 hours of exposure time to
incorporate different times of day.

Dr. Kim commented that because there was no hypothesis concerning
expected differences between the formulations, an estimate of the needed
sample size could not be made.  Dr. Carriquiry agreed that the
justification for a sample size of 10 was not adequate from a
statistical perspective.  The justification for not increasing the
sample size above 10 is not compelling.

Board Discussion

Scientific Considerations

Dr. Krishnan stated that the SCI-001 protocol was valid and likely to
generate valid data.  It is unclear whether information on comparative
efficacy can be obtained.  EPA does not permit statements of comparative
efficacy, so the rationale for this research was questionable.  A
clearer statement of how comparisons would be made is needed.  It is
apparent from the documentation that the formulations have low chronic
toxicity and the typical consumer dose is likely to be below toxicity
benchmarks.  Nonetheless, toxicity values are needed.  Dr. Krishnan
expressed surprise and concern that the response variability from
EMD-003 and EMD-004 would not be used to determine sample size for
SCI-001.  He also expressed concern about the proposed data analysis.

Dr. Carriquiry commented that the protocol needs significant revision as
related to statistical analysis.  The proposed calculation of means
makes comparisons across products difficult; an exponential model might
be more suitable.  She also expressed concern that the subjects were not
representative of typical users.  She agreed that with modifications,
the protocol would generate valid data.

Dr. Fisher summarized the Board’s comments on SCI-001.  Given that
subjects would be asked to remain in the field for up to 12 hours, the
Board should consider a risk-benefit analysis in terms of the number of
subjects tested, so that if too many drop out before evidence of loss of
product efficacy, substitutions can be made.  The Board also recommended
the investigator consider using the Kaplan-Meier estimate for endpoint
analysis as suggested by Dr. Kim for EMD-003 and EMD-004.  A rationale
and appropriate analysis for the endpoint chosen should be developed.

Dr. Fisher discussed differences between training subjects to aspirate
mosquitoes and training to criteria for subjects recording data.
Standard practice is to train to criteria before the study begins.  The
protocol also should provide a more thorough explanation of how the
reviewers can be confident of the reliability of self-report by
subjects.

The Board believed that, from a statistical perspective, there was no
evidence that comparative efficacy is possible.  There was no clear
hypothesis, so power analysis would be difficult.  However, if a
hypothesis was developed, the protocol could provide data that could be
used to determine variability and estimate the needed sample size.

Because study participants were drawn from a population of friends and
colleagues of the investigator, they are unlikely to represent a random
sample.  A response bias could occur based on subjects’ familiarity
with the products.  The protocol should address the need to obtain a
random, naïve sample of participants.

Dr. Fish expressed concerns about using the grand mean of means and
asked whether the Board should consider recommending the investigator
use the lower quartile instead of midpoint for determining dose.  Dr.
Lebowitz commented that there is a tendency to use geometric means to
normalize data, but investigators should not assume a priori an
appropriate distribution of data for use of this approach.  Use of the
Kaplan-Meier estimate for statistical analysis should be considered.
Dr. Chambers asked whether using the lower quartile to determine dose
for efficacy would hinder the ability to compare the results of this
study to other studies.  Dr. Fish replied that dosimetry experiments for
this field were first performed in protocols EMD-003 and EMD-004, so
consistency would be an issue no matter which approach is used to
determine dose.  Dr.   Fisher suggested that the investigator perform
both analyses.  It may be necessary for EPA to use the results of
traditional analyses for comparisons, but EPA also should collect
results from different analyses for possible use in the future.

Ethical Considerations

Dr. Sharp thanked Mr. Carley for his review of the ethical
considerations of this protocol and commended him on the level of data
provided.  He commented that the existence of multiple versions of the
same trial made tracking and review difficult.  Dr. Sharp noted four
deficiencies in the protocol:

The protocol does not give an adequate description of recruitment of
controls.  Assuming that targeted calls would be made to potential
volunteers, or flyers will be posted seeking volunteers, these materials
(including scripts for the calls) should be submitted to the IRB.

The description of risk attributed to DEET exposure in the ICF refers to
sprays containing alcohol.  Lotions are used in the study; thus, this
statement should be corrected.

The ICF is inapplicable to controls and should be corrected.

The ICF indicates that 40 subjects would participate.  This should be
changed to “48 or more subjects” to avoiding capping the number of
permitted subjects at too low a level to allow appropriate statistical
analysis.

Dr. Sharp also commented that he had concerns about the quality of the
IRB review in general.  In addition, the training, experience and
qualification of IRB members should be included in each submission.

Dr. Philpott agreed that the proposed number of subjects should be
changed to reflect a possible need for more subjects.  He also
recommended including a description of procedures to monitor for
arthropod-borne disease other than West Nile Virus, both in the protocol
and in the ICF.

Dr. Fisher summarized that more information was needed concerning
recruitment of controls, such as a script for telephone calls.  A
different ICF also will be needed for the controls.  The error
concerning risk based on alcohol-containing formulations should be
corrected.  The protocol and ICF also should describe with greater
accuracy the need for a specific number of subjects.  The risk to
controls concerning diseases other than West Nile Virus should be more
clearly explained.

Dr. Fisher suggested that the HSRB consider comments addressing the
adequacy of the IRB information received by EPA, and recommended that
EPA remind the HSRB about the availability of information concerning the
IRB’s qualifications.

Dr. Lewis thanked Board members, EPA staff, and Dr. Carroll for their
participation.  He informed Board members that the next HSRB meeting is
scheduled for April 18-20, 2007, at EPA’s Potomac Yard facility.  The
next teleconference is planned for March 22, 2007, at approximately 1
p.m. EDT for the Board to review its draft report from today’s
meeting.  He will send Board members a list of dates for meetings and
teleconferences planned for 2007.

Dr. Fisher adjourned the meeting.

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 for
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 		List of 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

David C. Bellinger, Ph.D.

Professor of Neurology

Harvard Medical School

Professor in the Department of Environmental Health

Harvard School of Public Health

Children's Hospital

Boston, MA

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

Associate 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

KyungMann Kim, Ph.D., CCRP

Professor and Associate Chair

Department of Biostatistics & Medical Informatics

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, WI

Kannan Krishnan, Ph.D.

Professor

Département de santé environnementale et santé au travail

Faculté de médicine

Université de Montréal

Montréal, QC  Canada

Michael D. Lebowitz, Ph.D., FCCP

Professor of Public Health & 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. *

Associate Professor of Law, Ethics & Medicine

Director of the Institute for Bioethics, Law and Public Policy

University of Kansas Medical Center

Kansas City, KS

Sean M. Philpott, Ph.D.

Associate Professor of Clinical Ethics

Albany Medical College

Associate Director

Alden March Bioethics Institute

Albany Medical Center

Albany, NY

Richard Sharp, Ph.D.

Assistant Professor of Medicine

Center for Medical Ethics and Health Policy

Baylor College of Medicine

Houston, TX

* Not in attendance

** Participated via phone

Attachment B

Federal Register Notice Announcing Meeting

Human Studies Review Board; Notice of Public Meeting

[Federal Register: December 28, 2006 (Volume 71, Number 249)]

[Notices]

[Page 78200-78202]

[DOCID:fr28de06-73]

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

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2006-0998'; FRL-8262-7]

Human Studies Review Board; Notice of Public 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 reviews of human subjects' research.

DATES: The public meeting will be held January 24, 2007 from 8:30 a.m.
to approximately 5:30 p.m., Eastern time.

LOCATION: Sheraton Crystal City Hotel, 1800 Jefferson Davis Highway,
Arlington, VA  22202. The telephone number for the Sheraton Crystal City
Hotel is<PHONE_NUMBER>.

MEETING ACCESS: Seating at the meeting will be on a first-come basis. To
request accommodation of a disability please contact the person listed
under

FOR FURTHER INFORMATION CONTACT at least 10 business days prior to the
meeting, to allow EPA as much time as possible to process your request.

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 Unit I.D.
of this notice.

FOR FURTHER INFORMATION CONTACT: Any member of the public who wishes
further information should contact Lu-Ann Kleibacker, EPA, Office of the
Science Advisor, (8105R), Environmental Protection Agency, 1200
Pennsylvania Ave., NW, Washington, DC 20460; telephone number:
(202)564-7189; fax:<PHONE_NUMBER>; e-mail address:   HYPERLINK
<EMAIL_ADDRESS><EMAIL_ADDRESS>. General
information concerning the EPA HSRB can be found on the EPA Web site at
 HYPERLINK "http://www.epa.gov/osa/hsrb/"  http://www.epa.gov/osa/hsrb/
.

ADDRESSES: Submit your written comments, identified by Docket ID No.

EPA-HQ-ORD-2006-0998, by one of the following methods:

    Internet:   HYPERLINK "http://www.regulations.gov"
http://www.regulations.gov  Follow the on-line instructions for

	submitting comments.

    E-mail:   HYPERLINK<EMAIL_ADDRESS><EMAIL_ADDRESS>.

    Mail: Environmental Protection Agency, EPA Docket Center (EPA/DC),

ORD Docket, Mailcode: 28221T, 1200 Pennsylvania Ave., NW, Washington, DC
 20460.

    Hand Delivery: The EPA/DC Public Reading Room is located in the EPA

Headquarters Library, Room Number 3334 in the EPA West Building, located
at 1301 Constitution Ave., NW, Washington DC. The hours of

	operation are 8:30 AM to 4:30 PM Eastern Standard Time (EST), Monday

	through Friday, excluding Federal holidays. Please call<PHONE_NUMBER>

or email the ORD Docket at   HYPERLINK<EMAIL_ADDRESS><EMAIL_ADDRESS>for instructions. Updates to Public Reading Room
access are available on the website

	(  HYPERLINK "http://www.epa.gov/epahome/dockets.htm"
http://www.epa.gov/epahome/dockets.htm ).

    Instructions: Direct your comments to Docket ID No.
EPA-HQ-ORD-2006-0998. EPA's policy is that all comments received will be
included in the public docket without change and may be made available
online at   HYPERLINK "http://www.regulations.gov"
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   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  or e-mail. The
  HYPERLINK "http://www.regulations.gov"  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   HYPERLINK "http://www.regulations.gov"
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.

SUPPLEMENTARY INFORMATION:

I. Public Meeting

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,
including such 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   HYPERLINK
"http://www.epa.gov/fedrgstr/"  http://www.epa.gov/fedrgstr/

Docket: All documents in the docket are listed in the

  HYPERLINK "http://www.regulations.gov"  http://www.regulations.gov
index. Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is restricted
by statute. Certain other material, such as copyrighted material, will
be publicly available only in hard copy.  Publicly available docket
materials are available either electronically in   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  or in hard
copy at the ORD Docket, EPA/DC, Public Reading Room. The EPA/DC Public
Reading Room is located in the EPA Headquarters Library, Room Number
3334 in the EPA West Building, located at 1301 Constitution Ave., NW,
Washington DC. The hours of operation are 8:30 AM to 4:30 PM EST, Monday
through Friday, excluding Federal holidays. Please call<PHONE_NUMBER>
or email the ORD Docket at   HYPERLINK<EMAIL_ADDRESS><EMAIL_ADDRESS>for instructions. Updates to Public Reading Room
access are available on the website (  HYPERLINK
"http://www.epa.gov/epahome/dockets.htm"
http://www.epa.gov/epahome/dockets.htm ).

    EPA's position paper(s), charge/questions to the HSRB, and the
meeting agenda will be available by late December 2006. In addition, the
Agency may provide additional background documents as the materials
become available. You may obtain electronic copies of these documents,
and certain other related documents that might be available
electronically, from the regulations.gov website and the HSRB Internet
Home Page at   HYPERLINK "http://www.epa.gov/osa/hsrb/"
http://www.epa.gov/osa/hsrb/ . For questions on document availability or
if you do not have access to the Internet, consult the person listed
under FOR FURTHER INFORMATION CONTACT.

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

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

    a. Explain your views as clearly as possible.

    b. Describe any assumptions that you used.

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

    d. Provide specific examples to illustrate your concerns and suggest
alternatives.

    e. 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. To ensure proper receipt by EPA, it is imperative that you
identify docket ID number EPA-HQ-ORD-2006-

0998 in the subject line on the first page of your request.

    a. Oral comments. Requests to present oral comments will be accepted
up to January 17, 2007. 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 email) to the person listed under
FOR FURTHER INFORMATION CONTACT no later than noon, Eastern time,
January 17, 2007 in order to be included on the meeting agenda and to
provide sufficient time for the HSRB Chair and HSRB Designated Federal
Officer (DFO) to review the agenda to provide an appropriate public
comment period. The request should identify the name of the individual
making the presentation, the organization (if any) the individual will
represent, and any requirements for audiovisual equipment (e.g.,
overhead projector, LCD projector, chalkboard). Oral comments before the
HSRB are limited to five minutes per individual or organization. Please
note that this limit applies to the cumulative time used by 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 these 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. Each speaker should bring 25 copies of his or her
comments and presentation slides for distribution to the HSRB at the
meeting. b. 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, Eastern time, January 17, 2007. You should submit your
comments using the instructions in Unit I.C. of this notice. In
addition, the Agency also requests that person(s) submitting comments
directly to the docket also provide a copy of their comments to the
person listed under FOR FURTHER INFORMATION CONTACT. There is no limit
on the length of written comments for consideration by the HSRB.

 E. Background

A. Topics for Discussion

    The EPA will present for HSRB review the results of two completed
insect repellent efficacy studies on which it intends to rely in making
registration decisions. In addition, EPA will present for HSRB review a
proposal for new research involving a field study to evaluate the
efficacy of a mosquito repellent. The Board may also discuss planning
for future HSRB meetings.

B. Meeting Minutes and Reports

    Minutes of the meeting, summarizing the matters discussed and
recommendations, if any, made by the advisory committee regarding such
matters will be released within 90 calendar days of the meeting. Such
minutes will be available at   HYPERLINK "http://www.epa.gov/osa/hsrb/"
http://www.epa.gov/osa/hsrb/  and   HYPERLINK "

http://www.regulations.gov"

http://www.regulations.gov .  In addition, information concerning a
Board meeting from the person listed under FOR FURTHER INFORMATION
CONTACT.

Dated: December 21, 2006.

George M. Gray,

Science Advisor

[FR Doc. E6-22300 Filed 12-27-06; 8:45 am]

BILLING CODE 6560-50-P

Attachment C

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD (HSRB)

PUBLIC MEETING

JANUARY 24, 2007*

SHERATON CRYSTAL CITY HOTEL

ARLINGTON, VA

HSRB	Web Site: http://www.epa.gov/osa/hsrb/

Docket Telephone:<PHONE_NUMBER>

Docket number: EPA-HQ-ORD-2006-0998

8:30 a.m.	Introduction and Identification of Board Members

			Celia Fisher, Ph.D. (HSRB Chair)

8:45 a.m.	Welcome

			George Gray, Ph.D. (EPA Science Advisor)

8:55 a.m.	Opening Remarks

			Mr. Jim Jones (Director, Office of Pesticide Programs, [OPP], EPA)

9:05 a.m.	Meeting Administrative Procedures

			Paul Lewis, Ph.D. (Designated Federal Officer [DFO], HSRB, OSA, EPA)

9:10 a.m.	Meeting Process

			Celia Fisher, Ph.D. (HSRB Chair)

9:25 a.m.	Update on EPA Follow-up of HSRB Recommendations

			Mr. William Jordan (EPA, OPP)

Insect Repellent Completed Efficacy Studies EMD-003 and EMD-004

9:35 a.m.	Science and Ethics of Insect Repellent Completed Efficacy
Studies EMD-003

and EMD-004

			Clara Fuentes, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA)

10:15 a.m.	Break

10:30 a.m.	Public Comments

11:00 a.m.	Board Discussion

EMD-003.1 and EMD-003.2: Tick Repellency with Lotion and Pump Spray
Formulations

Are these studies sufficiently sound, from a scientific perspective, to
be used to

assess the repellent efficacy of the formulations tested against ticks
and mosquitoes?

Does available information support a determination that these studies
were

conducted in substantial compliance with subparts K and L of EPA
regulations at 40 CFR part 26?

EMD-004.1 and EMD-004.2: Mosquito Repellency with Lotion and Pump Spray
Formulations

Are these studies sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy of the formulations tested
against ticks and mosquitoes?

Does available information support a determination that these studies
were conducted in substantial compliance with subparts K and L of EPA
regulations at 40 CFR part 26?

12:30 p.m.	Lunch

Insect Repellent Efficacy Protocol SCI-001

1:30 p.m.	Science and Ethics of Insect Repellent Efficacy Protocol
SCI-001

			Mr. Kevin Sweeney (OPP, EPA) and Mr. John Carley (OPP, EPA)

2:30 p.m.	Public Comments

3:00 p.m.	Break

3:15 p.m.	Board Discussion

If the proposed research described in Protocol SCI-001 from Carroll-Loye
Biological Research is revised as suggested by EPA, does the research
appear likely to generate scientifically reliable data, useful for
assessing the efficacy of the test substances for repelling mosquitoes?

If the proposed research described in Protocol SCI-001 from Carroll-Loye
Biological Research is revised as suggested by EPA, does the research
appear to meet the applicable requirements of 40 CFR part 26, subparts K
and L?

4:30 p.m.	Adjournment

* Please be advised that agenda times are approximate.  For further
information, please contact the Designated Federal Officer for this
meeting, Paul Lewis via telephone:<PHONE_NUMBER> or email:
<EMAIL_ADDRESS>
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