May 7, 2007

Minutes of the

United States Environmental Protection Agency (EPA)

Human Studies Review Board (HSRB)

April 18-20, 2007 Public Meeting

Docket Number: EPA-HQ-ORD-2007-0216

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

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

Dates and Times:  	Wednesday, April 18, 2007, 10:00 AM – 5:30 PM

			Thursday, April 19, 2007, 8:30 AM – 5:30 PM

			Friday, April 20, 2007, 8:30 AM – 5:30 PM

(See Federal Register Notice – Attachment B)

Location: 	Environmental Protection Agency, One Potomac Yard (South
Bldg.), 2777 S. Crystal Drive, 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.

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

Board Members: 	Alicia Carriquiry, Ph.D.

Gary L. Chadwick, PharmD, MPH, CIP

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

Richard Fenske, Ph.D., MPH

Susan S. Fish, PharmD, MPH

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

KyungMann Kim, Ph.D., CCRP

Kannan Krishnan, Ph.D.

Michael D. Lebowitz, Ph.D., FCCP

Lois D. Lehman-Mckeeman, Ph.D.

Jerry A. Menikoff, M.D.

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 April 2007 HSRB meeting.  She thanked Board members for their
participation and called for introductions.  Dr. Fisher acknowledged the
efforts of Dr. Paul Lewis (Designated Federal Officer [DFO], HSRB,
Office of the Science Advisor [OSA], EPA) and members of EPA’s Office
of Pesticide Programs (OPP) in planning and preparing for this meeting.

Welcoming Remarks

Dr. Warren Lux (Human Subjects Research Review Official, OSA, EPA)
welcomed and thanked the Board on behalf of Dr. George Gray (Science
Advisor, EPA) and Dr. William H. Benson (Acting Chief Scientist, OSA.
EPA).  He commented that the last HSRB meeting represented the
culmination of a complete review cycle from submission of a protocol to
completion and use of the data in policies established by EPA.

Another Board activity of importance is education.  Regulatory matters
and protocol reviews are necessary to protect human subjects; however,
educational efforts also are needed to ensure appropriate protection.
Dr. Lux expressed appreciation for the Board’s efforts and requests
for education about matters pertinent to EPA and commended the Board’s
work to ensure its deliberations educate others, including OPP
personnel, third party sponsors, investigators, and interested members
of the public.  He especially wished to highlight the impact of the
Board’s efforts on investigators, because fully educated, informed
investigators will assure appropriate human subject protection.

Dr. Fisher thanked Dr. Lux for his comments and added that the Board
will continue to learn from Dr. Lux.  The Board expects input from EPA
staff to contribute to the consistency of its review of sponsors and EPA
in-house reviews, and may suggest ways to facilitate this exchange of
information in the future.

Mr. Jim Jones (Principal Deputy Assistant Administrator, Office of
Prevention, Pesticides, and Toxic Substances, EPA) welcomed Board
members to Washington, DC.  He stated that OPP continues to find Board
advice helpful to gain EPA acceptance of study results and improve the
quality of its feedback to investigators.  The Agency implemented new
rules for human subject studies in February 2006.  At that time, there
were controversies and doubts about whether the new rules would still
permit EPA to meet its deadlines and work within the statutory
framework.  The HSRB developed a framework for review, provided EPA with
sound advice, helped to settle controversies, and helped EPA adapt to
these changes.  Stakeholders are adjusting to the new rules and OPP is
meeting critical statutory deadlines.  Together, EPA and the HSRB have
made significant progress in ensuring that human subjects are protected.
 He introduced Dr. Debbie Edwards as the new Director of OPP.

Dr. Edwards described her previous work as Director of the Special
Review and Re-registration Division within OPP.  She commented that the
Board’s high-quality reviews have allowed OPP to be successful.  She
provided a brief overview of the meeting agenda, explaining that the
focus of the first day of the meeting would be devoted to a review of
recently conducted tick and mosquito repellency studies to support
regulatory decisions.  On April 19, 2007, the Board will discuss two
previously performed skin test studies that will raise new scientific
and ethical questions, as well as EPA’s framework for developing best
practices for subject recruitment for occupational exposure research.
On April 20, 2007, the Board will discuss follow-up on the Agricultural
Handlers Exposure Task Force (AHETF) and Antimicrobial Exposure
Assessment Task Force (AEATF) protocols and will review a summary of the
EPA Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Scientific Advisory Panel (SAP) January 2007 report “Worker Exposure
Methods.”  OPP also will present a draft framework for recruiting
subjects and ethical considerations for occupational exposure studies.

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 made available at a public docket—are met.  As DFO, he also
works with the appropriate officials to ensure that all applicable
ethics regulations are satisfied.  Each Board member has filed a
standard government financial disclosure form that has been reviewed by
Dr. Lewis and the 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.

Dr. Fisher thanked OPP members for their remarks and commended their
responsiveness to questions and requests from the Board for documents
and information.  She added that she was pleased to see the Board’s
recommendations incorporated into OPP analyses.

Dr. Fisher reviewed the meeting agenda.  For the last few meetings, the
Board has asked OPP to provide critiques of studies rather than
summaries.  Concerning discussion of the FIFRA SAP report, scheduled for
April 20, 2007, the Board requested this discussion because of questions
that arose during review of the handler protocol concerning why these
studies were necessary.

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.  A useful set of
criteria for assessing scientific validity has been developed for
sponsors and investigators providing protocols for review.  These
provide guidance for study design and materials needed for Board review
of protocols.  The Board assesses both the scientific and ethical
validity of a protocol, including procedures, dose selection, endpoint
selection, social value of the research, methods including statistical
analyses, selection of target populations, and derivation of sample
sizes.  In its ethics assessments, the Board considers both societal
benefit and participant risks.  It has worked to define prevalent
ethical standards and to develop additional ethics criteria.

EPA Follow-up on HSRB Recommendations

Mr. William Jordan (OPP, EPA) reviewed EPA follow-up on HSRB
recommendations for the completed IR3535 insect repellent efficacy
studies with lotion and pump spray formulations, EMD-003.1 and 003.2
(laboratory tick repellency) and EMD-004.1 and 004.2 (field mosquito
repellency).  EPA follow-up on the field mosquito repellent efficacy
protocol SCI-001 was also discussed.

Concerning the HSRB’s scientific recommendations for the completed
studies EMD-003.1 and 003.2 and EMD-004.1 and 004.2, the HSRB concluded
that the studies were scientifically sound and suggested alternative
statistical techniques for evaluating duration of efficacy.  The Board
also suggested that EPA consider the most appropriate way to conduct
dosimetry studies to determine typical consumer dose.  Based on these
recommendations, EPA will accept the IR3535 insect repellent efficacy
studies as adequate for the assessment of efficacy and will accept label
claims.

EPA continues to discuss the best statistical approaches for analyzing
data and determining duration of protection.  A challenge to this effort
is the existence of similar products on the consumer market that have
Complete Protection Times (CPTs) that were determined differently in
past studies.  EPA is considering the best ways to implement the
Board’s suggestions and manage the transition to new methods of
determining CPT.  Once EPA has developed an approach to implement new
statistical analysis methods, it will present the plan to the HSRB for
feedback.  EPA also plans to revise its draft repellent efficacy
guidelines to include discussion of methods for establishing doses,
based on typical consumer use.

Concerning ethics recommendations, HSRB concurred with EPA that these
studies met the applicable requirements of 40 Code of Federal Regulation
(CFR) 26, subparts K and L.  The Board noted some ethical deficiencies
and suggested that EPA recommend human research protection training for
investigators.  Based on this review, EPA will accept the IR3535
repellency studies.  Although EPA cannot require investigators to
complete human research protection training, it will informally
encourage such training.

HSRB also reviewed SCI-001 at the January 24, 2007, meeting and found
that the recommendations suggested by EPA and the Board were followed,
and that this protocol was likely to generate scientifically valid data
to assess the efficacy of the test products and to meet applicable
ethics requirements.  EPA agreed with the Board’s assessment, but has
not yet received a revised version of SCI-001 or the results of a
completed study conducted under this protocol.

Completed Repellent Efficacy Studies EMD-003.3 and EMD-004.3

Introduction

Mr. John Carley (OPP, EPA) provided background and context for insect
repellent efficacy studies EMD-003.3 and EMD-004.3.  These studies
tested the aerosol formulations of the IR3535 repellents tested as pump
spray and lotion.  Testing on the aerosol formulation was delayed
because of a manufacturing error.  EMD-003.3 tests repellency against
ticks in a laboratory setting.  EMD-004.3 tests repellency against
mosquitoes in two field settings.  Dosimetry testing for these
formulations was performed on October 25-26, 2006, in conjunction with
dosimetry testing for the other formulations.  The report relating the
results of EMD-003.4 and EMD-004.3 was submitted in December 2006, but
was not provided to the HSRB for discussion at the January 2007 meeting.
 These studies, which represent third-party research involving
intentional exposure of human subjects, were initiated after April 7,
2006, and were intended for submission to EPA under the pesticide laws.
Pre-review of the protocols and supporting materials by EPA and the HSRB
is required, as well as “substantial compliance” with 40 CFR 26
subparts K and L.

The execution and results of these protocols for the lotion and pump
spray formulations were the first completed studies reporting work under
post-rule protocols to be reviewed by the HSRB, and were reviewed
favorably at the January 24, 2007 meeting.  The HSRB review of both
protocols EMD-003.3 and 004.3 took place on October 19, 2006.  Subject
limb measurement and dosimetry testing of all three formulations
occurred between October 23 and November 1, 2006.  Revisions to the
protocols and informed consent forms (ICFs) were submitted to the
Independent Investigational Review Board (IIRB) on October 30, 2006, and
IIRB approval of final changes was granted on November 1, 2006.  Field
testing for protocol EMD-004.3 in Merced County, California,
(marsh/grassland) took place on November 15, 2006, and field testing in
Butte County, California, (forest/flooded marsh) occurred on
November 19, 2006.  Laboratory testing for EMD-003.3 took place on
November 18, 2006.  A final audit by the quality assurance (QA) unit was
performed on November 10, 2006, and final study reports for both
protocols were submitted on February 5, 2007.  The dosimetry phase of
these studies used the ICF changed by Dr. Scott Carroll (Carroll-Loye
Biological Research, Inc.); the efficacy phase used the final November
1, 2006 ICF.

The dosimetry phase involved 12 subjects.  Each subject’s limb surface
areas were calculated, subjects practiced application for “full
coverage,” four gauze “bracelet” dosimeters were placed on the
limbs, and the weight change in dosimeters after application was
measured.  The subject mean of three trials was determined and then the
grand mean of all 12 subject means was calculated.  Based on limb
surface area, the standard dose (gram per square centimeter [g/cm2]) was
converted to a volumetric standard dose (milliliter per square
centimeter [ml/cm2]) and scaled for each subject in the efficacy phase.

EMD-003.3, which tested tick repellency, involved 10 subjects in a
laboratory setting.  After application of a standard volumetric dose by
syringe to the arm, both arms were marked at the edge of the untreated
area and at the 3 centimeter (cm) mark on each side of the area.  New
ticks were placed near the wrist of the untreated arm and observed for
questing behavior.  Questing ticks then were placed at the lowest mark
of the treated arm and ticks crossing 3 cm or more into the treated area
were scored as “crossing.”  A fresh tick was applied every 15
minutes.  Time of efficacy failure was defined as the time of the first
of two crossings occurring within 30 minutes.

EMD-004.3, which tested mosquito repellency, involved 10 treated
subjects at each of two field sites.  Two untreated subjects were
present at each site to confirm mosquito biting pressure at the site.  A
standard volumetric dose scaled to the area of the subjects’ lower
legs was applied by syringe before traveling to the test site.  The
subjects wore Tyvek suits, head nets, and gloves and worked in pairs to
expose treated legs by rolling up their pants for 1 minute every
15 minutes.  The subjects watched for landings with intent to bite
(LIBes), and removed these mosquitoes with aspirators.  Landing
mosquitoes were reported to technicians and recorded.  Treated limbs
were re-covered with the Tyvek suit at the end of each 1-minute exposure
period.  Time of efficacy failure (time to first confirmed LIBe
[FCLIBe]) was defined as time post-treatment of the first of two LIBes
occurring within 30 minutes.

Scientific Considerations

Dr. Clara Fuentes (OPP, EPA) presented the science assessments for
EMD-003.3 and EMD-004.3.  These studies were executed in a manner
consistent with the revised protocols, with minor exceptions.  The study
designs produced scientifically sound data meeting the studies’
objectives to estimate typical consumer doses and quantify the duration
of repellency of the formulations tested against ticks and mosquitoes.

Deviations from the dosimetry phase of the protocol included a reduction
in the number of pre-test practice applications from three to one; there
were no data to suggest how this might have affected the dosimetry
phase.  Entry errors were not properly handled in all cases, but there
was no obvious ambiguity in the records and the data quality does not
appear to have been compromised.  The dosimetry data capture forms were
modified from those appended to the protocol, but the modification did
not compromise data quality.  The dosimeters were not backed with
impermeable layers but appeared to be sufficiently impermeable to the
test material without backing.  The aerosol spray dosimeter results were
not compared to those for the lotion and pump formulations, but these
comparisons were not required to determine typical consumer dose for
efficacy testing.

Half the subjects in EMD-003.3 withdrew from the study before a
confirmed crossing into the treated area (i.e., before failure of
efficacy) occurred.  The original analysis of pre-failure withdrawals
underestimated product performance.  Because of this, the data were
re-analyzed using the Kaplan-Meier method as suggested by the Board at
its January 2007 HSRB meeting.

For EMD-004.3, test material was applied 2 to 3 hours before beginning
field testing rather than at the site.  Because the materials were
effective for more than 8 hours, this was unlikely to have affected CPT
results, because CPT was estimated from the time of repellent
application to FCLIBe.  The subjects did not always cover treated limbs
between exposures, but stepped out of the test site or entered a
screened enclosure.  This was unlikely to have affected the results
because the treated limbs were not exposed to mosquitoes between
scheduled exposure periods.

Calculated doses from the dosimetry phase were 0.00134 g/cm2 for arms
and 0.000987 g/cm2 for legs.  For the efficacy phase, the calculated
dose for arms was 0.00143 ml/cm2, and for legs, 0.00105 ml/cm2; these
did not vary significantly from the calculated target doses.

The efficacy phase for EMD-003.3 found a mean CPT of 10.95 hours, +2.8
hours with a 95% confidence interval of 9 to 13 hours.  Range of subject
CPT was 4.25 to 13.5 hours.  After reanalysis using the Kaplan Meier
method, the median CPT was determined to be 13 hours and time to 25
percent failures was 10.75 hours.

The efficacy phase for EMD-004.3 found a CPT of 9.65 hours, ±0.32
hours, with a range of 8.75 to 9.75 hours and 95% confidence interval of
9.45 to 9.88 hours for testing at the forest site.  At the marsh/pasture
site, no confirmed landings occurred and all exposures were ended before
efficacy failure (10.25 hours).

Ethical Considerations

Mr. Carley described EPA’s ethics assessment of EMD-003.3 and
EMD-004.3.  The ethics assessment of these protocols involved review of
the revised submissions of February 5, 2007, (reports MRID 47045901 and
MRID 47045902), the EPA protocol review of September 15, 2006, and the
final report of the October 2006 HSRB meeting (dated
January 21, 2007).  Applicable ethical standards include 40 CFR
§26.1125 (requires prior submission of protocol and supporting
materials), 40 CFR §26.1601 (requires HSRB review of protocol and
supporting materials), 40 CFR §26.1303 (defines standards for
documenting ethical conduct of research), 40 CFR §26.1703 (forbids EPA
reliance on research involving intentional exposure of pregnant or
nursing women or children), and 40 CFR §26.1705 (forbids EPA reliance
on research unless EPA has “adequate information to determine the
research was conducted in substantial compliance with subparts A through
L”).

Deviations from the protocol included commencement of the dosimetry
phase before the IIRB approved final changes to the protocol and ICF;
this is a potentially serious violation of EPA and IIRB rules, but in
this case did not affect the quality of informed consent or subject
safety.  Data collection also preceded QA review; this was a technical
violation without ethical impact.  At its October 2006 meeting, the HSRB
recommended minor changes including designation of a physician on call
and clarification of potential adverse effects in the ICF (for EMD-003.3
only).  These changes were not properly implemented before subject
consent was obtained for the dosimetry phase.  Although the study was
conducted with haste and deviations from the protocol were found, the
research was substantially compliant with ethical standards; all
required documentation is available, and shows no evidence that subjects
were misled or endangered by the initiation of the research before IIRB
approval of changes suggested by the HSRB.  The studies were deemed to
be in compliance with all applicable ethics statutes.

Dr. Michael Lebowitz asked whether requiring ticks to cross at least 3
cm into the treated area and requiring at least 2 crossing within a
30-minute time period was standard for tick repellency studies.  Mr.
Carley answered that this is one of several different ways to test for
tick repellency.  The time to first confirmed crossing is adapted from
time to first bite or FCLIBe, but this concept was not included in the
draft guidelines from June 2006.  These are the first studies to use
this approach in an efficacy test.  EPA believes that this is a
legitimate way to measure failure of efficacy.

Dr. Fisher inquired whether the withdrawal of half of the subjects from
EMD-003.3 before efficacy failure meant only the data from six subjects
was analyzed.  Mr. Carley responded that the data from all 10 subjects
was analyzed.  The repellent was effective for more than 10 hours;
thus, some subjects needed to leave the test before the first confirmed
crossing.  The increased efficacy of insect repellents is leading to a
need for more sophisticated statistical analysis methods that were not
needed when CPTs were in the range of 2 to 3 hours.

Dr. Fisher asked about the rationale for applying the repellent 2 to 3
hours before field testing and whether this was anticipated to mimic
consumer use, given that the original protocol called for application at
the test site.  Dr. Janice Chambers suggested that since the field
testing was conducted in November, when the days are short, the
repellent may have been applied earlier to permit sufficient time to
test efficacy.  Dr. Fisher agreed that this may have been an issue, but
haste is not a reason to deviate from a protocol presumably designed
with scientific rationales.  Mr. Carley explained that if early failure
of efficacy occurred, the circumstances surrounding any difference in
application would be taken into account to determine if deviations from
the protocol had an impact.  Laboratories that perform repellent work do
not have different protocols to use at different times of the year to
accommodate mosquito activity and day length.  A solution to this
problem was to apply the test material immediately before exposure at
times of the year during which appropriate mosquito biting activity is
found, and earlier if the test is performed at times of less activity.
There is little concern that this deviates significantly from typical
consumer behavior.

Dr. KyungMann Kim commented that according to the summary of data
presented, the statistics calculated were inappropriate; means cannot be
calculated if subjects withdraw.  Additionally, the data was presented
as having no variability; however, variability cannot be estimated if
all subjects do not reach failure of efficacy. Although the mean can not
be calculated (due to missing data), it is possible to state that the
mean is at least 10 hours.  However, no determination of variability can
be made.

Dr. Fisher asked if the untreated controls also remained in the field
for 10 hours.  Mr. Carley explained that during the field trials,
untreated subjects underwent the same cycles and durations of exposure.
Addressing Dr. Kim’s comments on the statistical analysis, Mr. Carley
reminded Board members that these studies were conducted before the
Board’s January 2007 discussion on statistical analysis pertaining to
such studies; therefore, the studies cannot be expected to be in
compliance with the Board’s suggestions from the January 2007 meeting.
 Dr. Kim agreed, but added that EPA’s own analysis of the data was
troubling.

Public Comments

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

Dr. Carroll thanked the Board for its helpful input and acknowledged the
delay between feedback received and the ability to incorporate it into
scientific protocols.  He explained that the Board would be receiving
information on a protocol that, because of EPA scheduling requirements,
was submitted before the January 2007 HSRB meeting and thus they could
not incorporate Board recommendations.  Dr. Carroll commented that he
would explain how he will incorporate Board recommendations.  For
example, after receiving Dr. Kim’s advice regarding statistical
analysis of the data, Dr. Carroll performed survival analysis on his
data; however, the usefulness of this analysis is questionable because
EPA is currently developing guidelines for statistical analysis.  At
present, the data is reported as censored data, which is not a valid
approach in Dr. Kim’s estimation but does conform to current EPA
requirements.  Dr. Carroll requested feedback for implementing Dr.
Kim’s suggestions regarding statistical analysis, particularly in the
case of the mosquito repellency testing, because subjects were not
bitten.  Dr. Kim stated that because none of the 10 subjects received a
bite, there is no information with which to estimate time to event.  The
minimum CPT is greater than 10 hours, but there is no information for
statistical analysis, contrary to the results presented by EPA.

Dr. Sean Philpott requested the gender distribution for the completed
efficacy studies and whether the control subjects to measure biting
pressure were the same subjects at each site.  Dr. Carroll agreed to
provide this information.  Dr. Philpott broached the subject of
enrolling subjects using an unapproved revised protocol.  The Board
recommended, and what is obligatory by IIRB and regulatory statutes,
that Dr. Carroll report deviations to the IIRB and develop a plan to
correct the deviations.  He asked Dr. Carroll to describe progress on
this matter.  Dr. Carroll explained that he submitted the protocol
deviations to the IIRB and discussed them with the director of the IIRB.
 There is no formal plan to prevent the problem from occurring again,
aside from Dr. Carroll’s assurance that it would not.  He explained
that the problem arose in part based on his inexperience with
interactions with the IIRB and because the IIRB introduced some errors
to the protocol that Dr. Carroll corrected; the IIRB has acknowledged
making these errors.

Dr. Fisher commented that although Dr. Carroll has been very responsive
to the Board, not all registrants will be as responsive and the Board
must be careful not to set precedents regarding its response to
deficiencies in protocols.  She asked Dr. Carroll to clarify whether the
subject pools for the studies overlapped, and if so, whether there is
accommodation for variability among subjects, or any other problem
arising from subject overlap that the Board should be concerned about.
Dr. Carroll answered that there is some overlap among the studies.  He
stated that there is no reason to believe that there are aberrations
among subjects, and in fact it may be best to use the same 10 subjects
to allow comparison among studies.  He informed the Board that he would
be providing a flow chart to track subjects through studies in the
future.  Dr. Kim commented that for the mosquito repellency test, for
the two sites there is overlap of six subjects.  If data from the two
sites are analyzed separately, this is not a problem, but it could be if
the data from both sites are combined.

Dr. William Brimijoin expressed disappointment that the data do not
encompass the longest possible protection times.  The short days
probably are a problem, but so is the high efficacy of the products.  He
asked whether there was any way to obtain a more accurate CPT.  Dr.
Carroll acknowledged that he did not anticipate the high degree of
efficacy of the products, and that the tests were performed unusually
late in the year (which also was a reason for applying the test
materials before traveling to the sites).  He added that he did not
attempt to influence how long subjects remained in the study because the
renewed emphasis on subject rights and protection required him to
respect the desire of subjects to withdraw.  As part of the recruiting
process, Dr. Carroll will now inform subjects that the studies could
last for more than 12 hours and that the scientific quality of the data
relies on subject participation for extended periods of time.  Dr.
Brimijoin asked whether test material could be applied to subjects 12
hours before traveling to the test site.  Dr. Carroll responded that
this would result in assumptions and label claims based on data he does
not have; however, this approach has been used in the past.

No further public comments were made.

Board Discussion

Scientific Considerations—EMD-003.3

Dr. Chambers opened the science review of EMD-003.3.  This protocol
tested the active ingredient IR3535 in aerosol form.  This protocol was
similar to EMD-003.1 and EMD-003.2, previously reviewed by the Board.
The product used was produced using Good Manufacturing Practices (GMPs)
and experiments performed using Good Laboratory Practices (GLP).
Passive dosimetry experiments were recommended and performed; this
allowed a 7 percent lower dose to be tested compared to industry
standards.  Protocol deviations were minor and had no significant
effects on the result.  Four women and six men served as subjects.  Ten
subjects were justified as providing adequate statistical power while
exposing a small number of subjects to risk.  The study found a mean CPT
of 10.95 hours +2.8 hours and mean time to 25 percent failures, adjusted
for censoring, of 10.75 hours.  These are conservative estimates.

With respect to scientific criteria, existing data was not adequate to
test efficacy, thus new studies were required.  The benefits of this
work include identification of an effective tick repellent with better
efficacy and fewer adverse effects.  The risks to subjects included
irritation from tick bites and exposure to vector-borne diseases, but
these risks were minimized because laboratory-reared ticks were used and
were removed before biting occurred.  Regarding study design criteria,
the design was clearly defined and had specific hypotheses.  The study
involved appropriate controls, dosimetry experiments were performed to
quantify dosage, and plans for medical treatment were in place.  The
results are likely to be generalizable.  The subjects were
representative of the population, with respect to applicable ethical
statutes.  The sample did not include vulnerable groups.  Measurements
were accurate, reliable, and appropriate.  Experiments were appropriate
and stopping and safety plans were in place.  In conclusion, the study
is scientifically sound to test the efficacy of IR3535 in an aerosol
formulation for tick repellency.  Dr. Chambers commended Dr. Carroll for
his responsiveness to Board inquiries and the clarity of his data.

Dr. Lebowitz concurred with Dr. Chambers.  He found the dosimetry
testing to be appropriate and useful.  Concerning the efficacy study,
withdrawals would be expected in a study lasting more than 12 hours.
Comments on conclusions drawn from the data, particularly concerning the
Kaplan-Meier survival analysis, are appreciated.  He agreed with Dr.
Chambers’ conclusions regarding sample size.  Dr. Lebowitz asked about
requiring a second crossing 3 cm or more into the treated area as
failure of efficacy, or whether use of one crossing would give a
reasonable result.  He referred to the table in Figure 19 of the report,
which showed that a number of subjects had only one crossing, which
would change efficacy results if used as evidence of product failure.

Dr. Kim credited Dr. Carroll for trying a different type of analysis.
He continued Dr. Lebowitz’s line of questioning regarding the
requirement of 2 crossings as product failure.  If a consumer receives
one bite, the consumer would regard this as product failure.

The definition of CPT in both protocols is unsatisfactory.  He asked
whether the requirement for more than one bite or crossing was an EPA
standard.  Mr. Carley responded that current EPA guidelines and drafts
of new guidelines require a confirmed bite.  The first occurrence of a
bite or crossing is historically considered to be anomalous.  Requiring
a second event to confirm the first has historically been accepted as a
test of efficacy failure.  Dr. Kim remarked that given the raw data, a
different impression of efficacy is gained if the first bite is used as
failure of efficacy.  He recommended sensitivity analysis to determine
which approach was correct.  Dr. Gary Chadwick asked whether both
analyses could be used.  Dr. Chambers remarked that there are existing
products that used the second bite or crossing as efficacy failures, and
consistency with these products must be maintained.  Dr. Fisher
commented that using the second bite or crossing is a conservative
approach for measuring efficacy, but not consumer protection because it
extends the CPT.  To a consumer, one bite is one bite and would indicate
a lack of efficaciousness.  She added that given the apparent lack of
attractiveness to mosquitoes of the 10 test subjects, the question is
whether the judgments should be conservative in favor of protection or
increased efficacy.  The EPA may need to change its determination of
CPT, relative to the efficacy of the products.  Dr. Kim added that the
requirement for ticks to cross 3 cm into the treated area also may
artificially increase CPT.

Mr. Jordan stated that when EPA discussed the issue of the best way to
evaluate efficacy to the SAP, they agreed that there are problems with
using the first bite as an indicator of failure.  A more reliable basis
for assessing failure would be to determine a reduction in the number of
bites received; however, this requires subjects to be bitten numerous
times and compare the number of bites received by treated versus
untreated subjects.  Because of scientific and ethical concerns, this
approach was not used; instead, efficacy failure was used to determine
CPT.  EPA is mindful of the biological uncertainty of a single bite and
thus requires confirmation of the first bite with a second bite.  EPA
also acknowledges the high degree of variability in the population
regarding attractiveness to mosquitoes and how a repellent works for a
given person.  The CPTs indicated on labels are for informing about the
relative benefits of different products, not to guarantee a specific
CPT.

Dr. Lebowitz commented that, given individual variability, the large
numbers of withdrawals, and the requirement for multiple crossings or
bites, a solution to this problem would be to significantly increase
sample size to have sufficient observations to satisfy crossing
requirements and overcome variability issues.  Dr. Brimijoin reminded
him that the HSRB’s mandate is to ensure protection of research
subjects, not protection of the public.  The Board recognizes the
conflict between assuring good science and minimizing risk to subjects.
The best science requires many more subjects, and would require more
mosquito bites, but this would significantly increase the risk to
subjects.  Dr. Brimijoin stated that he would prefer a larger sample
size because he believes the risks of these experiments are low, but EPA
standards require minimization of subject exposure.

Dr. Brimijoin also stated that although it is appropriate for the Board
to ask questions outside its realm of expertise and it is legitimate to
question methods that are standard in the field, the Board must
recognize existing standards and why they exist.  For example, use of
the confirmed bite standard might reduce noise in the data.  Dr. Fisher
agreed that although the Board must consider the value of the knowledge
produced for public protection, the Board must focus primarily on
subject risk.  Regarding relative efficacy, Dr. Fisher commented that
consumers may rely on the 10+ hour CPT to know when the product would
need to be re-applied.

Regarding Dr. Carroll’s method as a resolution between other methods,
Mr. Carley stated that using LIBes would have no affect on design, and,
in Dr. Carroll’s view, an actual bite is not needed to confirm
failure; others in the field disagree.

Ethical Considerations—EMD-003.3

Dr. Philpott opened the ethics review by agreeing with the ethical
strengths and weaknesses of EMD-003.3 as detailed by Mr. Carley.  It is
clear that the likely societal benefits of this study justify the
potential risks, which are minimal because IR3535 has been commercially
available for a number of years.  Participants also are unlikely to be
at risk for vector-borne diseases from exposure to the
laboratory-raised, pathogen-free ticks.  Clear stopping rules and
medical management plans are in place.  The protocol has procedures to
minimize coercion during the recruitment process.  Compensation for
participation is reasonable, and children and pregnant women are
excluded from the study.  Because of potential stigmatization for
exclusion, Dr. Carroll has developed a well-designed approach to ensure
confidentiality.  In general, the study comports with the applicable
requirements of 40 CFR 26, subparts K and L.  There is no evidence that
the conduct of this research was unethical.

As noted previously, some serious deviations from accepted practices
occurred, namely using an unapproved ICF containing handwritten changes
during recruitment.  Dr. Philpott commended Dr. Carroll for reporting
this deviation to the IIRB.  Drs. Richard Sharp and Jerry Menikoff
agreed with Dr. Philpott’s assessment and had no further comments.

Dr. Fisher concluded that the Board recommends that the data from this
study can be used by EPA.  She commended Dr. Carroll for his clarity,
GLPs, and performing the dosimetry phase of the study.  The Board
recognized problems with generalizability of the results, but believed
Dr. Carroll has justification for the small sample size.  The reasons
for performing this study are sound (lack of efficacy data on this
formulation, potential societal benefit, and low risk to subjects).  The
deviations from the protocol do not affect the data.

The Board questioned the use of the second crossing to determine loss of
efficacy, but realizes this does not affect this study; however, the
Board recommended that this should be a matter for future consideration
by EPA.  There also were questions concerning comparing the amounts of
IR3535 used in the dosimetry phase to toxic benchmarks.  Regarding
ethics, there is minimal risk to the subjects because of the use of
pathogen-free ticks and removal of ticks before biting occurs.  The
Board reviewed the deviations that occurred and appreciated Dr.
Carroll’s responsiveness to this issue and his willingness to work
with the IIRB.

Scientific Considerations—EMD-004.3

Dr. Chambers opened the science review of EMD-004.3.  This protocol
tested the efficacy of IR3535 in aerosol formulation against mosquitoes
in two field settings (marsh/grassland and forest/flooded marsh).  An
alternate site was used as the second test site because of insufficient
biting pressure at the initial site.  There was no evidence of West Nile
Virus (WNV) or other vector-borne diseases at either site.  Ten subjects
were tested at each site, and untreated controls also were tested to
determine mosquito biting pressure.  The trial terminated after dark and
results allowed only a minimum performance (CPT) to be determined, thus
statistical analysis of variance was not possible.  The scientific
justification for this study was the same as that for EMD-003.3.  In
conclusion, the report on EMD-004.3 contains data that are sufficiently
sound to assess mosquito repellent efficacy of the aerosol formulation
of IR3535.

Dr. Brimijoin agreed with Dr. Chambers’ assessment of EMD-004.3 and
recognized the same issues surrounding statistical analysis of the data.
 Dr. Kim asked if there have been previous efforts to understand the
potency of the different preparations of IR3535.  He commented that the
aerosol formulation appeared to be more potent against mosquito biting
compared to the results for the lotion and pump spray formulations.  Dr.
Fisher agreed that the aerosol formulation appeared to be more potent
and asked whether it was typical that aerosols are more effective.  She
also asked whether perhaps the mosquitoes exhibited different behavior
in this study.  Dr. Chambers said that, in her opinion, questions on
comparison of formulations were beyond the purview of the Board and
added that biting pressure was adequate based on data from the controls.
 Dr. Brimijoin agreed that data from the control subjects showed that
there was substantial biting pressure at the site; therefore, failure to
bite is a treatment effect.  This effect would be more obvious if the
study had enrolled more controls, but this was not possible for ethical
reasons.

Ethical Considerations—EMD-004.3

Dr. Philpott opened the ethics review of EMD-004.3.  The process for
subject enrollment and maintenance of confidentiality was the same as
for EMD-003.3.  EMD-004.3 had a larger number of subjects because
testing was conducted at two field sites, although there was overlap
among some of the subjects at each site.  The two control subjects used
to determine biting pressure were experienced laboratory personnel.  The
study enrolled 26 to 28 volunteers, including alternative subjects to
replace any subjects who withdrew or were unable to participate; this
approach helped protect subject confidentiality.

EMD-004.3 presented some distinct concerns, namely the risk of disease
from infected mosquitoes.  Appropriate efforts were made to minimize
risk.  The studies were intended to be conducted in areas in which
arthropod-borne diseases had not been detected by vector control
agencies for at least one month prior to the study.  This precaution was
violated by the detection of WNV in a sentinel chicken prior to the
study.  The study proceeded because vector control agencies concluded
that there was no further disease activity at the site.

Other ethical issues included the use of an unapproved ICF.
Additionally, the untreated controls may not have received sufficiently
explicit descriptions of the risk.  Dr. Sharp asked whether, given the
protocol violations described by Dr. Philpott, this protocol could be
deemed to be in substantial compliance with ethics statutes.  Dr.
Menikoff reminded Dr. Sharp that the Board must be consistent with the
meaning of “compliant” as determined during the January 2007 HSRB
meeting.  Dr. Fisher agreed, and noted that further discussion of the
meaning of “compliant” would take place later in the meeting.  She
agreed that the Board should consider whether these protocol violations
were substantial deviations from ethical standards, and asked whether
subjects were informed of the issue with the informed consent documents.
 Mr. Carley responded that subjects participating in the dosimetry
phase signed the September 2006 version of the ICF that Dr. Carroll had
amended in writing to reflect HSRB suggestions.  The final changed
version was approved on November 1, 2006, and was used to consent
subjects for the efficacy phases of both the tick and mosquito studies.

Dr. Fisher inquired whether subjects had been informed about the
detection of WNV in a sentinel chicken.  Dr. Carroll answered that he
noted this information in his report, but the chicken in question was
not part of the flock closest to the site.  Instead this flock was far
enough from the site (approximately 30 miles) that its presence was not
considered a violation of the protocol.  Dr. Philpott expressed concern
that the term “regions,” as used in the ICF, to inform participants
about the possible presence of vector-borne disease is too vague.  If
the flock is in the same county as the test site, it could be considered
to be in the same region, and thus proceeding with the study was a
violation.  Dr. Carroll should remember this when planning similar
protocols that use this approach for minimizing exposure to vector-borne
diseases.  Dr. Carroll also should consider analyzing mosquitoes caught
at the test site.  Dr. Fisher added that at the April meeting approving
the January report the Board recommended that, for future protocols, if
the region tested is not pathogen-free for 30 days, post-study testing
of trapped mosquitoes should be performed.

Dr. Fisher concluded that the Board comments indicated the EMD-004.3 is
a valid study, regardless of issues with interpretation and analysis of
the data.  CPT could be related as at least 10 hours, rather than 10 or
more hours, in accordance with available data.  There were some issues
concerning the ICFs and the extent to which the study followed some
requirements.  The Board’s consensus was to approve this study.

Carroll-Loye Mosquito Repellent Efficacy Protocol WPC-001

Introduction

Mr. Carley provided background on a proposal for a field test of
mosquito repellency for a conditionally registered formulation
containing Oil of Lemon Eucalyptus (OLE) as its active ingredient.
Conditional registration means that EPA has the authority to approve
products similar to previously approved products when fewer than all
registration requirements have been satisfied; the unaddressed
requirements are made conditions of registration that must be resolved
within a specific timeframe.  This product was registered with specific
requirements to conduct product-specific studies.  OLE is used in other
similar products at ranges encompassing that used in this product.  The
protocol WPC-001 is adapted from and closely similar to Carroll-Loye
protocols EMD-004 and SCI-001, previously reviewed favorably by the
HSRB.  The few remaining deficiencies in this protocol can be easily
corrected and thus EPA believes this protocol is ready for HSRB review.

Scientific Considerations

Dr. Fuentes presented the scientific considerations for protocol
WPC-001.  The objectives of this study were to test the mosquito
repellent efficacy characteristics of the test material and to satisfy a
condition of registration imposed by EPA.  The test material, Repel 30
LE (EPA Reg. No. 305-62), contains 30 percent OLE in a pump spray
formulation.  The oral Lethal Dose (LD)-50 is less than 5,000 milligrams
per kilogram (mg/kg) and the dermal LD-50 is greater than 2,000 mg/kg.

The study includes a dosimetry phase with 10 subjects, to establish the
typical consumer dose for use in efficacy testing.  Subjects are trained
in the laboratory to aspirate landing mosquitoes before they bite, using
laboratory-reared, pathogen-free mosquitoes.  Because there is only one
treatment, the study is not blinded.  The study involves two field
trials, each enrolling ten treated subjects and two untreated
“experienced” control subjects.  Untreated subjects are included to
monitor biting pressure; each will be attended by two assistants to
aspirate mosquitoes before they can probe or bite.  Both treated and
untreated subjects are exposed to mosquitoes for 1 minute every 15
minutes.  Product efficacy is measured as average time from treatment to
FCLIBe.

The field sites are described in the report as the California Central
Valley or Florida Keys, depending on the season.  Expected wild mosquito
populations include Aedes vexans, Ochlerotatus melanimon, O.
taeniorhynchus, and Culex pipens.  Variables, including biting pressure
(threshold = 1 LIBe/minute), FCLIBe, and time to FCLIBe, will be
measured.  Test results will be analyzed by calculating the mean time to
first confirmed LIBe; untreated controls are not used for comparison of
treatment means.  Means will be reported with 95 percent confidence
interval of the mean and associated standard deviation; other analyses
may be used as appropriate to the results.

The sample size reflects a compromise between financial and ethical
concerns.  Sample size is difficult to predetermine without knowing the
distribution of outcome values.  EPA guidelines recommend six
replicates, which has been widely regarded as sufficient to show
statistical significance at P<0.05; 10 replicates slightly improves
accuracy in estimating the population mean.

Necessary protocol revisions include deletion of the reference in
§6.2.1 to untreated controls for the dosimetry assay; provision in the
statistical plan for diagnostic statistical tests for normality, and for
analysis of non-normally distributed data; inclusion of roughly equal
proportions of male and female subjects in the sample; and inclusion in
limb surface areas measuring procedures for recording the exact
locations of the four measured circumferences, so that dosimeters can be
placed at the same locations.

If further revised as suggested, this protocol is likely to comply with
scientific standards and yield scientifically reliable information
because it would produce important information that cannot be obtained
except by research with human subjects and it has clear scientific
objectives; the study design should produce adequate data to achieve
those objectives.

Ethical Considerations

Mr. Carley presented ethical considerations for WPC-001.  The proposed
study would field test the mosquito repellent efficacy of a single test
formulation, containing OLE as its active ingredient.  The test
formulation was conditionally registered with claims for “up to 6
hours” of protection; EPA requires product-specific efficacy testing
to maintain the product’s registration.  The proposed study presents
value to society by making available a potentially attractive
alternative to other available repellents, some of which are found
unpleasant by many users.

Subjects will be recruited among “communities of friends, neighbors
and scientists” near the investigator’s laboratory.  Exclusion
factors are students or employees of the investigator; children, or
pregnant or nursing women; those sensitive to repellents or to mosquito
bites; those in poor health or physical condition; and those unable to
speak and understand English.  No subjects come from vulnerable
populations.  More detail is needed about recruitment of the two
“experienced” subjects who will serve as untreated controls.

Risks include irritation of the eyes on contact with the repellent, the
repellent is harmful if swallowed, and possible exposure to biting
arthropods and/or arthropod-borne diseases.  Risk minimization
procedures specific to the repellent include exclusion of sensitive
candidates, closely monitoring use of the repellent during the dosimetry
phase, and having a technician apply the repellent.  Risks from mosquito
bites are minimized by excluding sensitive candidates, training subjects
to aspirate mosquitoes before they have time to bite, and minimizing
exposure of skin.  Risks of disease are minimized by conducting research
where no mosquito-borne viruses have been detected for at least a month,
and by minimizing bites.  The probability of risks is characterized as
“extremely small” because of the low acute and chronic hazard
profile of the product (although the product is a Toxicity Category II
eye irritant), design of the research to minimize exposures, training
subjects to aspirate landing mosquitoes before they have time to probe
or bite, and performing field testing in areas free of WNV.  An
additional way to reduce risk would be to perform post-study serological
testing of mosquitoes caught at the test site.

Regarding benefits, there are no direct benefits to subjects; the
primary direct beneficiary is the sponsor.  If the material is proven
effective, indirect beneficiaries will include repellent users who
prefer this product to other repellents.  No reasonable opportunities
have been overlooked to further reduce risk while maintaining scientific
robustness; the residual risks to subjects are very low and are
reasonable given the expected societal benefits to repellent users,
which are likely to be realized.

The IIRB of Plantation, Florida reviewed and approved the protocol and
informed consent materials on January 23, 2007.  This IIRB is
independent of the sponsors and investigators and is registered with the
Office for Human Research Protections (OHRP).  It is not accredited by
the Association for the Accreditation of Human Research Protection
Programs (AAHRPP) or any other accrediting organization as far as EPA
can determine.  EPA has determined that this IIRB’s procedures meet
regulatory standards.

Regarding the informed consent process, the description of subject
recruiting and consent processes in California is complete and
satisfactory; however, more detail is needed regarding the recruiting
process in Florida, especially concerning the role of the Mosquito
Control District administration.  The IIRB-approved ICF is appropriate
for both treated and untreated subjects and is included in the protocol,
but misleadingly suggests the test material is not yet registered with
EPA.

The protocol shows adequate respect for subjects through the methods
proposed for managing information about prospective and enrolled
subjects that will generally protect their privacy; however, subject
privacy would be better protected if subject names did not appear on
data collection forms.  Subjects will be free to withdraw at any time,
and will be reminded of this at several points.  Medical care for
research-related injuries will be provided at no cost to the subjects.

This is a proposal for third-party research involving intentional
exposure of human subjects to a pesticide, with the intention of
submitting the resulting data to EPA under the pesticide laws.  The
primary ethical standards applicable to this research are 40 CFR 26,
subparts K and L.  A point-by-point evaluation of how this protocol
addresses the requirements of 40 CFR 26 subparts K and L and the
additional criteria recommended by the HSRB appears as Attachment 1 to
the EPA Review.

Required revisions to this protocol include a description of how
untreated controls will be recruited, and how the process of informing
them will differ from that used for treated subjects.  It will also
include a detailed description of the recruiting process in Florida
equivalent to that used to describe the process used in California, with
particular attention to the role of the Mosquito Control District
administration.

Regarding the status of protocol WPC-001’s compliance with ethical
standards, all requirements of §26.1111, §26.1116, and §26.1117 are
met; with requested revisions, all requirements of §26.1125 are met;
all requirements of §26.1203 are met; all elements of National Academy
of Science (NAS) recommendation 5-1 are satisfied; and all elements of
NAS recommendation 5-2 are satisfied.  If further revised as suggested,
protocol WPC-001 will meet the applicable requirements of 40 CFR 26,
subpart K and L.

Dr. Fisher inquired whether FCLIBe was the same as first confirmed
crossing.  Mr. Carley explained that this was the equivalent of
crossing.  For EMD-004.3, the endpoint for failure of efficacy was the
average time from treatment to the FCLIBe.  Efficacy failure is measured
as the FCLIBe confirmed by another crossing within 30 minutes; CPT is
measured as time to efficacy failure.  Dr. Fisher asked whether data on
“rejected” bites are collected.  Mr. Carley responded that it is
collected as raw data.  An entry is made for every 15 minute time period
to record the numbers of LIBes.  Thus, unconfirmed landings are
recorded, but are not counted if a subsequent landing does not occur
within 30 minutes.  Dr. Fisher asked whether EPA could modify the way it
determines FCLIBe.  Mr. Carley answered that EPA could perform parallel
analyses (using first landing versus first confirmed landing) for this
study, but data from previous studies from which to do this sort of
analysis would not be available.  Dr. Fisher asked whether the Board
should recommend that other investigators record data this way to allow
for other analyses in the future.  Mr. Carley responded that the Board
may want to discuss this issue at the June 2007 meeting after they
review a similar protocol from another investigator.

Dr. Kannan Krishnan asked whether Repel 30 LE is registered.  Mr. Carley
answered that the product is conditionally registered.  Dr. Krishnan
inquired about the concentration of the active ingredient in Repel 30
LE.  Mr. Carley responded that this product has, at 30 percent OLE, a
lower concentration of OLE than in previously registered pump spray
products also containing OLE.  A higher concentration product is
registered with no conditions.  Repel 30 LE is conditionally registered
because data from product-specific test conditions was not available.
Dr. Krishnan questioned whether there was any concern about changing the
composition or the vehicle of the product.  Mr. Carley replied that the
product is similar enough to other products on the market to be
considered safe.  The product has already met a number of conditions and
the remaining questions strictly concern efficacy.  The results of this
study will be used to modify label claims.  Dr. Krishnan questioned
whether EPA has supporting data on file concerning the toxicity class of
the product.  Mr. Carley explained that EPA has data covering other
product requirements, including chemical and toxicity data.

Dr. Sharp requested clarification of the recommendation for revision of
the recruitment procedure for untreated controls and whether EPA was
asking for details beyond those provided to the Board.  Mr. Carley
explained that EPA wanted further detail on the process for soliciting
interested subjects, the process by which the investigators will apply
subject criteria, and how subjects will be offered the chance to serve
as untreated controls.

Public Comments

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

Dr. Carroll addressed questions concerning the subject recruitment
process, including subject influence on repellent performance, how
subjects may differ with respect to mosquito attractiveness, and how
study developers consider who might participate in the trial.

Although it is known that gender has a strong influence on mosquito
attractiveness, most studies are inconclusive regarding whether men or
women are more attractive to mosquitoes.  Thus, a gender balance
generally is used for mosquito repellency studies.  Regarding the
sampling frame for this study, comparison of the Carroll-Loye Biological
Research volunteer database to Davis, California, census data shows a
similar ethnic distribution.  Most individuals in the volunteer database
are between 20 and 40 years of age, with a smaller number between
40 and 55 years of age.  The individuals are relatively young,
well-educated, and likely to be life science researchers or students.
The subjects show substantial interest in participating, but this is not
likely to influence results of the study.  Carroll-Loye Biological
Research investigators do not actively or directly encourage
participation; instead, individuals in the database have requested that
investigators contact them when test subjects are needed.  Persons who
will serve as untreated control subjects are limited to experienced
technical personnel, who are screened with the same exclusion criteria
as are other subjects, and have additional inclusion requirements.

Dr. Carroll requested comments from the Board regarding language on the
ICF for informing untreated controls.  He presented his proposed
language, and added that he would like to use only one ICF for both
treated and untreated subjects.  He also asked whether the Board
recommend that he perform sampling for diseased organisms during
testing.  California has an intensive disease-sampling program and
California vector ecologists suggest a 2-week buffer to ensure the
absence of vector-borne diseases.

Dr. Fisher requested Dr. Carroll explain the size of the “region” as
described in the study protocol.  She said that the testing criteria
would be determined by the extent to which Dr. Carroll can ascertain
that there was no evidence of disease in a region relevant to the test
site for the past 30 days.  Dr. Carroll asked the Board to consider in
its discussion of this protocol how data from mosquito sampling would be
used.

Dr. Philpott inquired whether the recruitment protocol shown to the
Board was similar to the previous one described for testing at the
Florida site.  He expressed concern that flying study subjects from
California to the Florida site would represent undue inducement to
participate.  Dr. Carroll answered that the Florida recruitment process
was still being developed; protocol WPC-001 does not include testing in
Florida.  Dr. Fisher questioned EPA as to why the Board was reviewing a
protocol that appeared to be somewhat undeveloped.  Mr. Carley responded
that his concerns about the inadequate description of the Florida
recruitment procedure could be alleviated by deletion of the reference
to recruiting in Florida; Dr. Carroll informed the Board that this
protocol will be performed only in California.  Dr. Sharp added that, in
his opinion, the protocol is well-developed aside from the gap in the
Florida recruitment process.

Dr. Fisher requested clarification concerning the implications of season
or temperature on the effectiveness of products tested in mosquito
repellency field studies, and whether this would influence the need for
untreated controls.  Dr. Fuentes explained that season and temperature
influence the ability to locate mosquitoes.  The activity of the product
does not change, but the numbers and types of mosquitoes at a given site
do.  The control group provides information on this by providing a
measure of biting pressure.  If biting pressure is adequate, any
difference in the amount of bites received by controls compared to
treated subjects is a treatment effect.  Dr. Fisher asked whether a
control is compared to a treated subject at each of the described
15-minutes intervals.  Mr. Carley responded that data concerning
mosquito landings is collected for controls at the same intervals and
for the same duration as treated subjects.

Board Discussion

Scientific Considerations—WPC-001

Dr. Krishnan questioned why, given that EPA has sufficient data on the
safety of this product, human studies were required and justified.  He
added that although most of the essential elements for the protocol have
been adequately described and are appropriate, he has concerns regarding
sample size and statistical analysis.  The sample size justification is
not convincing.  Dr. Krishnan commented that he had hoped the results of
the completed mosquito repellent efficacy studies could be used to
inform sample size for this study.  Given the concerns of Drs. Alicia
Carriquiry and Kim regarding the confounding of CPT calculations by
subject withdrawal, perhaps guidelines need to be established concerning
how long subjects are required to remain in the study.  Dr. Krishnan
added that once dosimetry studies are complete, the dose should be
compared to a toxic benchmark.

Dr. Krishnan concluded that based on the available information, this
protocol can provide scientifically reliable data.  The protocol
approval is based only on activities in California, not for the Florida
site.  The investigators also should address issues pertaining to
statistical analysis, which should help obtain more reliable results.

Dr. Fisher related comments from Dr. Carriquiry regarding protocol
WPC-001.  Dr. Carriquiry noted a great deal of variability in the
dosimetry phase of previous studies, and asked if, given the variability
of consumer use, should more than one dose level be tested to obtain
data that are more meaningful for the consumer.  Mr. Carley responded
that EPA has accepted a single dose for as long as it has required and
reviewed such studies.  For most studies, the dose used is based on a
“rule of thumb” not on actual measurements.  At the last HSRB
meeting, the Board asked EPA to consider best methods for dose studies;
EPA is considering this but has not yet developed a consensus.  Dr.
Lebowitz reminded the Board that it had indicated satisfaction with
single dose protocols reviewed during the morning session of this
meeting.  He expressed dissatisfaction with the use of a single dose
because of inter- and intra-individual variation, but recognized that
adjusting sample size could resolve these issues and permit use of a
single dose.  Dr. Kim questioned whether the dose used was close to that
expected to be used by the consumer.  Mr. Carley explained that labels
for repellents usually informed consumers to “apply for full
coverage.”  Consumers tend to re-apply product if they are bitten.
Regardless of better ways to cope with the variability inherent in this
work, EPA is not trying to produce an accurate prediction of CPT for
each user.  CPT is used for comparison with products currently on the
market; these are not dose-response studies.

Dr. Brimijoin inquired whether, given the numbers of different
investigators performing these studies, data from different studies are
truly comparable.  Dr. Fisher added that she was surprised these studies
are not more informative concerning the duration of these products’
effectiveness.  Relative efficacy cannot be compared because the studies
are performed under different conditions, with different subjects, and
at different sites.  Dr. Chambers reminded Board members that these are
field studies, which will not be as clean as those performed in a
laboratory setting.  The studies do provide consumers with information
that will help them choose which product to use.  Using multiple doses
in a study would require more subjects and thus increase risk.

Dr. Carriquiry commented that there was no discussion in the protocol of
how CPT is determined if a subject withdraws before FCLIBe.  She asked
whether a power analysis had been performed to determine the number of
subjects needed to show that any effect is not due to chance.  These
calculations typically rely on previous study results.  She asked
whether the Board has given appropriate guidance for justification of
sample size.  Dr. Kim answered that the studies were essentially
descriptive and P-values cannot be appropriately calculated for them.
Dr. Fisher agreed that the Board had concerns about determining sample
size.  Mr. Carley explained that EPA is considering this issue, but at
present, the sample size of 10 is acceptable.  It is the responsibility
of EPA, not individual investigators, to address general questions
concerning EPA guidelines and standards and how to use results to
determine label language.  Mr. Jordan agreed with Mr. Carley, and added
that Dr. Kim’s comments are helpful for describing the purpose of
including more subjects to give more precision to estimates of CPT.
Investigators provide data for EPA use; EPA must decide how much
precision is required in this data to make label claims for products.
These issues are broad and cut across many fields, and will be used by
EPA to consider and perhaps revise its guidelines.  Transitioning from
old to new guidelines also will require planning.  The current rule of
thumb used by EPA, and the onus on investigators, is to determine
whether the current studies are as good as or better than previous
studies.  Dr. Fisher agreed, but added that the Board questions if
changes can be made at the present to achieve standards the Board
believes are necessary.  The Board believed EPA must address these
issues.  Mr. Carley reminded the Board that these protocols represent
regulatory science and regulatory standards.  Guidelines for these
studies must be consistent; a compromise must be reached between
refining the guidelines at every HSRB meeting and accepting protocols
because they follow historical, albeit perhaps less than optimal,
standards.

Dr. Brimijoin commented that it appeared that similar studies are being
held to progressively more rigorous standards.  This could be unnerving
to proponents, but the Board should continue to push for higher
standards, particularly if a given analysis is inappropriate or there is
an easy way to resolve an issue.  Dr. Kim acknowledged the obvious level
of frustration given that several of the Board’s recommendations have
not been implemented as the Board would like.  EPA does not provide
clear input to registrants (concerning sample size, CPT derivation,
etc.) and thus it may not be realistic to see changes in the protocols
reflecting the Board’s advice.  It is also clear that any change
implemented will have considerable and broad implications, given EPA’s
historical body of data.  Nonetheless, the Board must continue to push
for better science, and especially must address any “fatal flaws” it
discovers.  Mr. Carley clarified that Dr. Kim’s concerns had not been
implemented in the protocol reviewed at this meeting since the protocol
was written before the January 2007 HSRB meeting.  EPA will develop
guidelines based on Board suggestions and disseminate the guidelines to
investigators.  Dr. Chambers suggested that EPA provide the Board with
background about EPA data sets and regulatory constructs to help inform
the Board about insect repellents and regulations.  Mr. Jordan agreed
that this would be helpful and said he would try to provide such
materials for Board review of the occupational handler exposure studies.

Ethical Considerations—WPC-001

Dr. Sharp opened discussion on ethical considerations for WPC-001.  He
thanked Mr. Carley for his thorough review of this protocol.  The
social benefits for this study are well articulated.  OLE is an
important alternative repellent, especially for those sensitive to the
smell of other commercially available mosquito repellents.  The limited
risks inherent to this study were minimized appropriately.  Dr. Sharp
commended Dr. Carroll on the improvements Dr. Carroll made to the
protocol.  Recruitment in Florida could be a serious issue because there
was little definition of recruitment procedures to be used in that
state.  However, because the study will be conducted in California,
removal of references to recruitment in Florida could be removed from
the protocol.  In conclusion, this protocol, with minor revisions, meets
the applicable ethical requirements.

Dr. Menikoff agreed with Dr. Sharp’s assessment.  He expressed concern
that there was not a separate ICF for control subjects.  Control
subjects face higher risks than treated subjects and one ICF that does
not indicate whether the risks detailed are for treated subjects or
control subjects may not permit control subjects to recognize that they
are at higher risk.  An addendum should be made that control subjects
signature could be added to the ICF to ensure control subjects are
properly consented.  Dr. Susan Fish agreed with Drs. Menikoff’s and
Sharp’s assessments.

Concerning the ICF, Dr. Sharp questioned whether the Board wanted to
substantially change an ICF that had been reviewed and approved by an
IIRB, suggesting the Board should defer somewhat to the IIRB’s
assessment.  Dr. Gary Chadwick agreed, but maintained that whether
people have the information necessary to make an informed choice is a
significant ethical issue.  The Board recommended that this issue be
addressed.  Dr. Fisher agreed that it was a significant issue and that
the ICF did not distinguish between control and treated subjects.
Mr. Carley explained that part of the confusion surrounding this issue
arose from inclusion of the Florida site in the protocol reviewed by EPA
and the Board.  Dr. Carroll currently does not plan to conduct the study
in Florida, so issues surrounding recruitment in Florida may be solved
by reorganizing the protocol.

Dr. Fisher concluded that the Board found the protocol to meet
scientific criteria.  Concerning ethics, she agreed that subjects’
names should not be included on data forms, the ICFs need to be
finalized, and a clearer determination of how control subjects are
recruited and selected was needed.  The protocol also should clarify
that the study will not be performed in Florida.

Research Conducted After April 7, 2006:  Meaning of “Substantial
Compliance” with 40 CFR Part 26

Mr. Jordan presented EPA considerations on the meaning of “Substantial
Compliance” in 40 CFR §26.1705.  EPA has prohibited reliance on
unethical human research with non-pregnant, non-nursing adults conducted
after April 7, 2006, unless EPA has adequate information to determine
the research was conducted in substantial compliance with subparts A
through L of this statute.  Without adequate information, EPA cannot
make a determination of compliance.  An exception to this rule is that
if EPA has data that do not meet ethical standards, the data may be used
to support regulatory action leading to more stringent health protection
or improved public health

This rule was developed from NAS recommendations for “intentional
human dosage studies” (NAS Recommendation 5-6).  The recommendation
was modified slightly to clarify that EPA would consider refusing to
rely on a completed human study only if the study fails to
“substantially” comply with the applicable ethical standard.  This
addition reflects EPA’s judgment that relatively minor administrative
or record-keeping deficiencies in a researcher’s compliance with a
rule as complex as the Common Rule would not in themselves justify
rejecting otherwise scientifically valuable and ethically conducted
research.

The information contained within the presentation, “Compliance
Oversight in Human Subjects Protection” by Dr. Kristina C. Borror,
Director of Division of Compliance Oversight in Office of Human Research
Protection (OHRP), Department of Health and Human Services (DHHS)
(February 1, 2005) also informed EPA’s decision.  This report
demonstrates that deficiencies often occur in research involving human
subjects, but most are not serious.  The report describes 269
determination letters sent over a period of 4 years to more than
180 institutions.  Most letters were based on review of submitted
documents, although OHRP also conducted site visits at 18 institutions.
Within the 269 letters were 71,000 citations for non-compliance
(approximately four citations per letter); 142 institutions had at least
one citation; the median was four citations per institution.  During
this time, OHRP suspended or restricted assurances for only 20
institutions, indicating that only 20 institutions had serious or
numerous deficiencies.  This suggests a gradient in terms of the
seriousness of the citations, although the report does not contain
detailed information concerning the kind of violations cited.
Approximately 51 percent of all institutions cited had deficiencies in
IIRB documentation for informed consent processes, although most of
these deficiencies were not serious.

Public comment was permitted when EPA was in the final phases of
developing this regulation, and most comments indicated a lack of
clarity concerning the definition of key phrases (i.e., “fundamentally
unethical,” “significantly deficient,” or “substantial
compliance”).  Overall, although most investigators wanted EPA to
specifically state the number or types of comments that would lead to a
study being deemed “not in substantial compliance,” EPA believed
this was unnecessary.  EPA agreed with NAS that each study would require
case-by-case evaluation.  EPA also expected the terms to develop greater
clarity over time, through HSRB and public review of EPA decisions
concerning this matter.

The term “substantial compliance” has legal meaning and the phrase
appears in judicial review, often in disputes between two parties when
trying to determine if the complaining party’s requests were met as
detailed in a contract or in support of whether a regulation was met.
The term involves interpretation of the underlying intent of a
requirement and allows flexibility in judging the acceptability of
behavior.  For example, the way in which the HSRB approached review of
several insect repellent studies in January 2007 reflected good and
thoughtful judgment concerning substantial compliance of the protocols
with ethical standards.

EPA recommended that the Board not attempt to define a priori standards
for “substantial compliance” but instead build a record of specific
decisions taking into account such factors as the nature and number of
deficiencies, the investigator’s intent, any relevant past conduct,
prevailing practices in the field, and the likely significance of the
deficiency for subjects of the research.  The Board is also asked to
explain the reasoning regarding any HSRB conclusions concerning whether
compliance is “substantial.”

Dr. Chadwick discussed the definition of “substantial compliance.”
He commended EPA’s approach to soliciting HSRB input.  He cautioned
Board members to be sure to understand the difference between ethical
deficiencies and regulatory deficiencies.  Dr. Chadwick added that it
is unrealistic for the Board to determine an investigator’s intent,
and also may be unrealistic for the Board to determine and consider an
investigator’s past conduct.  Dr. Philpott agreed that determining
intent probably is not possible.  Dr. Fisher agreed that the Board
should avoid assessing intent, because intent is not provable.  EPA can
consider intent or relevant past conduct if it chooses, but the Board
determines only if regulations were followed and if not, were these
lapses likely to cause harm or violate subjects’ rights.  The phrase
“substantial compliance” is contradictory because it implies that
following all regulations is not necessary.  Regarding consideration of
relevant past conduct, Dr. Fisher stated that, at some point, sponsors
should be expected to be cognizant of applicable regulations and able to
develop solid ICFs.  The Board must consider precedent; behaviors that
may be acceptable now may not be acceptable in the future.

Dr. Lebowitz stated that the presentation provided legal definitions of
key terms.  The Board assesses whether a protocol is sufficiently
scientifically and ethically sound.  He expressed doubt considering
whether the Board ever used the term “substantial compliance.”  An
education process may be necessary for the Board to be able to define
“substantial compliance.”  Dr. Menikoff stated that he found the
criteria useful.  Intent cannot be directly measured, but assessing the
conduct of an investigator provides reasonable information concerning
what the investigator intended to do.  Problems with ICFs are usually
minor mistakes, such as typographical or version errors; in these cases,
the intent of the investigator was to comply with ICF guidelines.  Past
conduct also can offer clues concerning intent.  Dr. Brimijoin agreed
that EPA has taken a sensible approach to this issue.  It is unlikely
the Board will ever see a perfect protocol; it may have to make
judgments that a protocol is “close enough” to compliant.  EPA
consults the Board on whether it considers a protocol to be in
substantial compliance, but EPA makes the final decision regarding this
issue.

Dr. Richard Fenske requested to see the report discussed in the OHRP
presentation, if such a report exists.  He expressed discomfort with the
legal framework of the guidelines.  For example, identification of a
“complaining party” would be unclear for most scientific protocols.
A legal context may not be appropriate for a science and ethics advisory
board.  Overall, however, Dr. Fenske found the recommendations helpful
(especially those concerning the nature and number of deficiencies and
the likely significance of the deficiency for research subjects),
although the other suggestions could be amended.  He commented that the
Board acknowledges that errors, such as using the wrong version of an
ICF, may occur in field studies, which speaks to the intent and past
performance of the investigator.  He also recommended that EPA inform
the Board about investigators’ past performance when possible.

Dr. Fisher remarked that there may be differences in “substantial
compliance” when the Board is reviewing a proposed protocol compared
to a completed protocol.  If the HSRB makes recommendations concerning
compliance for a proposed protocol, the investigator should incorporate
the recommended changes.  The HSRB never concludes that it is
permissible for an investigator to disregard its recommendations.  Mr.
Jordan clarified that this rule applies only for EPA use of data from a
completed protocol.  Dr. Fisher agreed that when the Board reviews a
completed protocol, it can determine only the extent to which the
investigators followed the regulations and whether any deficiencies
resulted in harm to the research subjects.  She expressed concern about
using “intent” to decide compliance.  Additionally, past conduct
often is not admissible in legal situations.  The Board can evaluate
only how a protocol was conducted, if it was in compliance with
regulations, and if it violated human subject rights.  Dr. Chadwick
remarked that the Board must understand that no protocol will be 100
percent correct.  There needs to be allowances for accepting data from
studies with minor deficiencies.  Dr. Menikoff agreed that few protocols
would meet all requirements and regulations, and intent should be
considered.  He cited as an example Dr. Carroll’s additional language
to the ICF, which was technically in violation of regulations, but
resulted in a better, more informative ICF.  Dr. Fisher stated that the
Board did not know Dr. Carroll’s intent, but only found that the
changes did not violate subject rights or result in less information for
subjects.  Dr. Chadwick stated that although he agrees with the idea of
flexibility, the HSRB is not in a position to decide or comment
on intent.

Dr. Sharp also cited Dr. Carroll’s situation, stating that the Board
knew there was a consent violation and proceeded to obtain information
that allowed it to determine this was an honest mistake and not a
protocol violation.  Dr. Fisher responded that if the change to the ICF
had not provided sufficient protection, the HSRB would judge it to be
unethical.  Intent should not be considered in the Board’s assessment.
 Dr. Sharp reminded Dr. Fisher that this rule applied to previously
conducted studies, and the Board would be determining only if the data
was usable by EPA.  Dr. Philpott agreed with Dr. Fisher that determining
intent was not possible.  Mr. Jordan agreed that it could be difficult
to infer intent, but still may be worth pursuing.  Concerning Dr.
Sharp’s point that this consideration applied only to previously
conducted studies, Mr. Jordan explained that EPA’s goal for these
assessments is to try to prevent violations from occurring in the
future.  Having an understanding of an investigator’s motives or
intent that lead to deficiencies is relevant for predicting the type of
response from EPA that will lead to a change in behavior.  He clarified
that EPA operates in a regulatory context, and appreciates the
clarification of deficiencies as regulatory rather than ethical.  The
intent underlying the regulations is to ensure ethical treatment of
human subjects, thus, it is relevant to try to understand the ethical
impact of a regulatory deficiency.  The most powerful response EPA has
to address deficiencies is to inform a sponsor that their data are
unusable and they will have to repeat the study, leading to added
expenses and delays for the sponsor.  EPA also can impose civil or
criminal penalties, report an investigator to OHRP, or disqualify an
investigator from receiving EPA grants.  The choice of which measure to
use depends in part on how effective the measure will be in changing
behavior to avoid repetition of a mistake.

Dr. Brimijoin suggested that the Board not think of EPA’s
recommendations for determining “substantial compliance” as a
checklist, but rather as suggestions.  The first and last
recommendations are the most substantial; the HSRB likely will always
consider the nature and number of deficiencies and the likely
significance of the deficiency for research subjects.  The other
recommendations might have relevance occasionally and might consciously
or unconsciously influence decisions about the seriousness of a
violation.  Overall, the Board should not be rigid on these matters.
The final conclusion should make no reference to intent, only whether
the protocol achieves substantial compliance or not, the definition of
which likely will evolve over time.  Dr. Fisher agreed in principle with
Dr. Brimijoin, but stated that she would not adopt these recommendations
as HSRB guidelines if “intent” was included.  She agreed that
decisions on compliance would focus mainly on the nature and number of
deficiencies and the likely significance of the deficiency for subjects
of the research.

Dr. Fisher disagreed that the Board does not judge whether a protocol is
unethical after it has been conducted.  If the HSRB finds evidence of
harm, they must find that the protocol was not in substantial
compliance; the final decision for using the data rests with EPA.  If
the data will offer improved protection for the public, it must be
acknowledged that the study may have been unethical, but the benefits
outweigh this.  Dr. Sharp stated that he was not suggesting that the
HSRB cannot pass judgment if a past study was unethical; however, the
Board cannot protect these subjects from harm but can only perhaps
protect their dignity from harm by recommending against EPA use of the
data.  Dr. Fenske agreed, adding that if the study involves third party
research, such as use of a contractor who may not follow protocols
diligently, the HSRB’s judgment of the study and disapproval may
protect future subjects by bringing scrutiny to the contractor.  Dr.
Fisher agreed, adding that issues of justice apply–recognition of
unethical behavior is justice.  The regulations state that EPA will not
use the data if the data were obtained in an unethical manner.  Dr.
Menikoff suggested that evaluating “intent” may allow the Board to
reject data from a study that did not have egregious violations, but
failure to reject the data could mean that this violation is not taken
seriously by future investigators, which could lead to harm to future
subjects.

Dr. Fisher concluded that EPA recommendations concerning the nature and
number of deficiencies and the likely significance of the deficiency for
research subjects could be formally addressed by the Board.  Other
recommendations may arise during Board deliberations and can be
considered, but will not be formally adopted as guidelines.

Dr. Fisher returned discussion to WPC-001, regarding determination of a
pathogen-free region surrounding the test site.  Dr. Carroll must ensure
that the region is pathogen-free, or must trap mosquitoes during the
study for testing for pathogens.  Mr. Carley stated that the Board must
consider whether using sentinel flocks is the best indicator of a
pathogen-free region or if testing pools of mosquitoes is more
indicative of a pathogen-free region.  It is also critical to determine
the size of the “pathogen-free region.”  Dr. Lebowitz stated that it
is critical to determine that the mosquitoes collected during testing
are pathogen-free.  If this is not the case, a subject may have been
infected, which is a critical ethical issue.  The current standard is to
use pools of trapped mosquitoes.  Entomologists and infectious disease
experts likely have information concerning the region need to consider
an area to be free of potential risk, and also on the behavior of
mosquitoes that informs determination of the risk area.  Sentinel flocks
are a secondary measure of a pathogen-free area, but this information
can be obtained more quickly than mosquito testing.  Dr. Philpott
commented that the best approach may be to rely on experts in this area,
as Dr. Carroll did.  Procedures should be redefined to reflect that if
experts conclude that disease is absent from an area, this is
acceptable.  Dr. Carley asked whether inclusion of a letter from the
local mosquito control agency would suffice.  Dr. Fisher agreed that
this was permissible, or the investigator could include the agency’s
monthly report concerning the presence of pathogens.  She also suggested
that if there was concern because of detection of a pathogen in a
sentinel flock, serological testing of mosquitoes caught during the
study could be performed; a plan for alerting subjects if a pathogen is
found during mosquito testing should be developed.

Follow-up From Previous Day’s Discussion

Mr. Jordan had no follow-up comments from Wednesday’s discussions.
Mr. Carley verified that a product containing 40 percent OLE in a pump
spray formulation is registered with EPA.  He also reported that 100
percent of all human studies reviewed by the HSRB to date have been
subject to EPA audit.  All research records have been found to be
complete and there were no GLP issues.

Dr. Fisher introduced two consultants who participated in Board
deliberations at this meeting.  Dr. Yiliang Zhu is a professor and
directs the Biostatistics Ph.D. program and the Center for Collaborative
Research at the Department of Epidemiology and Biostatistics, College of
Public Health, University of South Florida.  He has served on several
advisory committees, including the NAS/National Research Council
committee on EPA’s reassessment of dioxin risks and serves on the
Organ Transplant Advisory Committee at DHHS.  His research focuses on
quantitative methodologies in health risk assessment.  Dr. David Hoel is
Distinguished University Professor in the Department of Biostatistics,
Bioinformatics, and Epidemiology at The Medical University of South
Carolina, Charleston, South Carolina.  Dr. Hoel worked at the National
Institute of Environmental Health Sciences as Director of the Division
of Environmental Risk Assessment.  He has served on a number of advisory
boards and has an interest in the modification of adverse health effects
caused by environmental factors such as chemicals and radiation.

HSRB Workgroup and EPA Process on Confidential Business Information
(CBI) Redacted Submissions

Mr. Jordan described two skin irritation studies which involved the
first claims of CBI for a study reviewed by the HSRB.  These studies
differ from those quantifying effect levels for hexavalent chromium
because they seek to categorize products within a range of irritators or
sensitizers.  Neither product is expected to cause irritation or
sensitivity; nonetheless, the studies excluded from the study population
those who might be sensitive to the products.  The hexavalent chromium
studies also employed a repeat open application testing procedure,
whereas these studies were conducted by application of the product via
patches placed in direct contact with the skin.

The products involved in these studies also were subject to CBI claims.
The Board had previously proposed a process for handling CBI issues,
with the goal of providing as much information to the HSRB as possible,
ensuring adequate information for a sound review, and permitting the
review to be conducted during a public meeting.  The Board did not
receive information deemed CBI by the sponsor.  The CBI process also
seeks to encourage sponsors to make CBI claims only when necessary and
to limit their scope, providing for an informal EPA assessment of the
appropriateness of CBI claims.  If EPA finds the claims to be
reasonable, EPA will provide redacted material to the HSRB Chair.  The
Chair will appoint members of the HSRB to a workgroup to review the
redacted material and inform EPA whether the material provided is
adequate for a sound review.  If concerns are raised by work group
members, EPA and the Chair will discuss whether the Board can have
access to additional non-CBI information that addresses the
workgroup’s concerns.

For the protocols discussed at this meeting, initial CBI claims were
broad, but after discussion, the sponsor agreed to limit the CBI claim.
The Board workgroup reviewed the materials and determined a need for
further information, which OPP has attempted to provide.  The most
important information requested by the work group was toxicity data; a
summary of toxicity information on three major active ingredients in
insect repellents was provided, but the ingredient(s) used in the
studies themselves was not identified.

Dr. Fisher provided further detail on how the process for working with
CBI claims was developed.  An overarching issue was the need for Board
deliberations to remain transparent to the public, and respect both the
CBI claims of the sponsor, and the responsibility of EPA to respect and
protect CBI.  In cases for which EPA believes CBI claims are invalid,
the Board wishes to support EPA.

As part of the process, EPA contacts registrants who may make a CBI
claim to inform them that materials and information not claimed as CBI
will be reviewed by the HSRB in a public session.  EPA encourages the
registrant to provide as much information to the Board as possible, to
facilitate accurate assessment of the scientific validity and value of
the study, the safety risks to subjects, and the human subjects’
protection.  The Board anticipates that toxicity data on an ingredient
whose identity is claimed as CBI and other forms of safety and efficacy
information will frequently be necessary for Board review.  One example
of potential CBI is the name of the sponsor, which could be redacted
from the Investigational Review Board (IRB) report and ICFs.
Additionally, EPA can provide the Board with a statement that EPA has
identified no unethical conflicts of interest between the sponsor,
investigator, and potential subjects.  The DFO can determine whether
there is a statutory conflict between Board members’ HSRB
responsibilities regarding the protocol and private interests and
activities.  If the active ingredient is claimed as CBI, the registrant
can provide animal or human toxicity data that will assist the Board
with safety and efficacy evaluations.

After completion of the prior tasks and gathering of redacted materials,
EPA holds an planning meeting with the Board Chair and DFO to discuss
the nature of the CBI claim, information the Board will not be able to
view because of the claim, and steps that will be taken to provide the
Board with sufficient information for its review.  After the planning
meeting, the Chair will identify Board science and ethics members who
would be most appropriate to serve as primary reviewers of the protocol.
 These HSRB members will receive the question(s) EPA will ask the Board
to address; a general description of the nature of the CBI and non-CBI
materials; and a description of supporting information regarding the CBI
claims that will be made available to the Board.  Drs. Fisher and Fenske
were chosen to serve as workgroup members for the protocols with CBI
claims discussed at this meeting.

The workgroup analyzes the available information and reports to Dr.
Fisher whether the information would be sufficient to help the Board
answer EPA's questions and if not, what additional non-CBI materials or
statements by EPA regarding the nature of the CBI information would be
required.  The Chair will review the workgroup’s analysis and
communicate to the HSRB DFO the Chair's evaluation of whether additional
information is needed for Board review.  The Chair will request that
EPA, to the extent legally permissible, provide the information to the
Board.

A description of the general nature of CBI and steps taken to provide
background information within legal limits will be included in the
materials submitted to the full Board for review.  A representative of
the registrant may make a presentation and answer questions at the
public meeting to ensure the Board has adequate information to advise
EPA and to ensure that CBI is protected at the open meeting.

The workgroup evaluation of the materials for the patch test studies
discussed during the meeting found an absence of toxicity data; no
rationale for the dose level selected; no information concerning whether
the experimental dose level is the level that consumers would use; an
informed consent document that indicates five insect repellents but
study reports for only two; and a lack of background information to
assess the risks to participants.  During the planning meeting, EPA
stated that this information could be obtained based on publicly
available information.  Dr. Fisher expressed surprise that most of this
information was not initially provided, and that EPA did not know it was
not provided.  A letter from EPA indicating what additional information
they can provide would be useful.

Completed Skin Patch Tests

Background

Mr. Carley presented background information on the completed skin patch
tests conducted with two insect repellent products.  The products tested
in this and the repeat insult patch test (RIPT) study are intended to be
applied repeatedly to large areas of skin and thus should be
non-irritating.  The sponsor has performed these tests to confirm
non-irritation and characterize any irritation or sensitization
potential.

The first submission of documentation occurred in May 2006.  While these
are pre-rule studies, 40 CFR §26.1303 still applies because further
documentation was submitted in November 2006.  The November 2006
submission contained broad claims of confidentiality.  In February 2007,
the sponsor resubmitted the study with narrowed claims of
confidentiality, in both complete and releasable redacted versions.
Responses to EPA reviewer questions were submitted in March 2007, in
both complete and releasable redacted versions.  These studies involved
third-party research with intentional exposure of human subjects,
intended for submission to EPA under the pesticide laws.  Because the
studies were initiated before April 7, 2007, pre-review of the
protocol was not required and applicable ethical standards are 40 CFR
§26.1703 and §26.1704.

The studies were submitted with supplemental claims of CBI.  FIFRA
§10(d)(1) requires EPA to protect from disclosure the identity or
concentration of pesticide inert ingredients in pesticide products, and
information concerning manufacturing or quality control processes for a
pesticide product.  The scope of supplemental claims can include the
identity of the sponsoring company, product name and form, or the
identity and concentration of the active ingredient.  Claims of
confidentiality must be substantiated.  In this case, the registrant
argued that making public the applicant’s name, trade name of the
proposed product and form, and composition of the new product prior to
registration approval would place the registrant at a competitive
disadvantage.

These studies underwent the pilot process on CBI redacted submissions as
described.  Concerns of the HSRB workgroup included a lack of
information concerning the identity and concentration of active and
inert ingredients in the tested products.  To address this concern, EPA
has received complete information on product composition in the
Confidential Statements of Formula submitted by the registrant and has
informed the HSRB that the active ingredient currently is registered as
a repellent by EPA and occurs in these products at concentration ranges
previously approved for other products containing this ingredient.  The
HSRB workgroup also expressed concern about the lack of toxicity
information provided for the product ingredients.  EPA received other
toxicity information on the formulated products, including toxicity
profiles of the component ingredients, published reports of irritation
and sensitization potential, and provided World Health Organization
(WHO) profiles of registered repellent active ingredients to the HSRB.
The HSRB workgroup also noted a lack of rationale for dose levels.  EPA
informed the work group that the dose used (0.2 ml of product on a
2 cm-by-2 cm patch) is standard practice in cosmetics and consumer
products patch testing.  Additionally, the patch dose of 0.2 ml/4 cm2 is
equivalent to 30 ml/600 cm2, which is approximately 30 times the typical
user repellent application rate; this elevated dose is appropriate for
these patch tests.  The work group’s final concern focused on the lack
of information reported for other materials included in the studies.
These studies represent multi-material, multi-sponsor patch studies,
with single-material reports, which is common practice in cosmetics and
consumer products testing.  The patches are separated during testing,
and thus no interference between test materials is expected.

Dr. Fisher questioned why FIFRA considers manufacturing or quality
control processes CBI.  Mr. Carley explained that the purpose behind
this provision was to protect pesticide registrants from being forced to
disclose information that would offer competitors an unfair competitive
advantage.  Dr. Fisher asked whether quality control processes could
impact the safety or quality of the ingredients.  Mr. Carley indicated
that this was not a concern.  He explained that the scope of these
protections actually is narrow.  The U.S. Supreme Court concluded that
the phrase “health and safety data” is broad, but information
concerning manufacturing and quality control processes must be made
public 30 days after registration, and that certain ingredients must be
listed on labels.

Dr. Fenske commented on the lack of rationale for dose.  If the
rationale for a given dose is “standard practice,” documentation
should be included.  For example, if the procedure is Food and Drug
Administration (FDA) approved, some statement to indicate that it is
approved by a government agency for cosmetic and consumer products would
be helpful.  Mr. Carley agreed, adding that EPA does not have
guidelines for accepted protocols for these studies.  Submitters have
attached articles from the Cosmetic, Toiletry and Fragrance Association
describing a range of practices, but the articles do not describe the
best way to perform such testing.  The most accurate way to consider
this is to understand there are different ways to perform these studies
that fall into several general categories; if done often enough by a
given laboratory, the protocols become routine, although they do not
really become standardized.  Dr. Roger Gardner (OPP, EPA) added that for
pesticide tests on animals, there are standard procedures with
recommended doses based on a large database of information.  The goal of
the studies is to determine if irritation can be induced; the criterion
calls for choosing a dose at which irritation is likely to occur.  Dose
also is only qualitatively related to anticipated consumer exposure;
most guidelines call for exceeding this dosage.  Dr. Fenske reiterated
that because there do not appear to be recommendations for human studies
available through EPA, information from other agencies, such as FDA,
would be helpful.  Dr. Gardner explained that late in the review process
for these studies, EPA found that FDA has draft guidelines; however,
insufficient time was available to ascertain the rationale for dosing.

Dr. Fish inquired whether the dose range was consistent with those used
in Dr. Carroll’s studies.  Mr. Carley responded that these are very
limited dose studies and are not appropriate for extrapolating dose to
the very different materials tested in the primary irritation studies.
For repellent testing, a dose of 1 g/600 or 650 cm2 is used, based on a
survey of DEET users, to approximate consumer dose of a repellent.

Dr. Menikoff noted that five compounds had been applied to subjects, but
the results of only two of these are reported.  He asked if EPA knew the
identity of the other three compounds.  Mr. Carley indicated that EPA
does not know the identity of the compounds; registrants indicated that
these were “developmental compounds.”  Dr. Menikoff remarked that
this had implications for informed consent and asked if it had been
verified that subjects received truthful information about the
compounds.  Mr. Carley explained that these questions would be addressed
during EPA’s review of the studies.  He added that five materials were
used in the 48-hour irritation study, but 16 were used in the RIPT
study; most of these materials were provided by other sponsors and EPA
does not have information on their identities.  Dr. Kim inquired how EPA
could rule out interference among materials if the identity of the other
materials is unknown.  Dr. Gardner responded that dermal effects are
specific and local.  The selection criterion of dosing for sensitization
is different from that of dose selection for irritation.  There also are
dermatologic indicators that differentiate between irritation and immune
responses indicating sensitization.  The effects of irritation studies
are local, similar to the effects of food allergy skin tests.

Dr. Lebowitz questioned if EPA asks toxicologists to verify information
from registrants concerning the toxicity of ingredients found in the
products.  Mr. Carley confirmed that this was the case.  Dr. Lebowitz
also asked whether animal toxicity skin testing literature was used to
determine if products had potential sensitization capabilities before
testing the products in humans.  Dr. Gardner explained that animal test
results (using guinea pigs) are available for sensitization potential of
active ingredients in pesticide products.  This information is required.
 EPA relies on background data as well as toxicity tables to assess
sensitization potential.  Dr. Fisher noted that these tests use the
assumption that each patch has independent effects.  She cautioned that
there are practices over which EPA has no control, such as the
participation of multiple sponsors and use of multiple materials in a
single study.  The Board must be alert to potential problems arising
from this situation.

48-hour Primary Dermal Irritation Study

Background

Mr. Carley presented background information on the 48-hour Primary
Dermal Irritation Study.  Documents were submitted covering product A
(MRID 47077101, Code 1000718-008) and product B (MRID 47093901, Code
1004006-005).  Supplements, both identical in content, were also
submitted for each product (MRIDs 47077201, 47077601 for products A and
B, respectively).  Products A and B are both repellents containing the
same EPA-registered active ingredient at concentrations within a
previously accepted range, and contain similar pesticide inert
ingredients.

Each of the two study reports describes results for one of five
substances tested in a single execution of the protocol with a single
subject panel; results have been submitted for two of the five
substances tested.  All subjects were non-pregnant, non-nursing
consenting adults, free of skin disease, not sensitive to similar
products, and not using medications.  The study enrolled 54 subjects; 53
completed the study.

The study schedule called for application of 0.2 ml of five test
materials to 2 cm-by-2 cm Webril patches (five patches per subject),
followed by air-drying for 30 minutes before application of the patches
to each subject’s back.  Forty-eight hours after application, the
patches are removed and sites evaluated.  If the first evaluation is
positive, a second reader re-evaluates the site.  Seventy-two hours
after application, the sites are evaluated again.

The dermal LD50 limit dose is greater than 2,000 mg/kg for the active
ingredient.  The margin of exposure (MOE) for an applied dose of 0.2 ml
to a 70 kg adult is greater than 350.  Skin loading of 0.2 ml/4 cm2 is
approximately 30 times loading at the “typical consumer dose” of a
repellent (1 g/600 cm2).

Science Assessment

Dr. Gardner presented EPA’s science assessment of the 48-hour Primary
Dermal Irritation Study.  EPA requires primary dermal irritation data
under 40 CFR Part 158 for registration of all products.  Guidance for
conducting animal tests of irritation is published under EPA’s Office
of Prevention, Pesticides and Toxic Substances Test Guideline 870.2500
and corresponds to Organisation for Economic Cooperation and Development
Test Guideline 404.  The results from such studies are used to identify
possible effects from exposure of the skin to the test substance and are
used to support precautionary labeling.

EPA classifies irritants according to toxicity category.  Category I
substances are corrosive and/or scarring; Category II substances can
cause severe irritation at 72 hours (severe erythema or edema); Category
III substances can cause moderate irritation at 72 hours (moderate
erythema); and Category IV substances cause only mild or slight
irritation (no irritation or slight erythema).  Standard precautionary
statements are based on the toxicity category.  For example, the label
for a Toxicity Category III substance might include language cautioning
consumers to avoid contact with skin or clothing and to wash thoroughly
with soap and water after handling.  Toxicity Category IV substances do
not require precautionary statements, but registrants may choose to use
Category III labeling standards.

EPA encourages minimization of unnecessary animal testing.  EPA does not
encourage human irritancy testing, but has accepted it in place of
animal testing in some cases.  The submitter of this study requested a
waiver of the usual requirements for animal testing of dermal
irritation, because each component in the products tested is discussed
in published literature, has a history of use as an intentional food
additive or in cosmetics products directly applied to human skin, and is
well-known to EPA.  The waiver request also argues that there is
published literature on product components that indicates most are mild
to slight irritants that would be classified as Toxicity Category IV.  A
few of the substances are moderate irritants that would be classified in
Toxicity Category III, with labeling to “avoid contact with skin.”

Subject inclusion criteria called for males or females who were at least
18 years old and in general good health; were free of any systemic or
dermatologic disorder which would interfere with the results of the
study or increase the risk of adverse events; were of any skin type or
race, given that the skin pigmentation allowed discernment of erythema;
had completed a medical screening procedure; and had signed an ICF.
Exclusion criteria excluded subjects who had any visible skin disease
which would interfere with the evaluation; were receiving systemic or
topical medication which would interfere with the study results; had
psoriasis or active atopic dermatitis or eczema; were pregnant, planned
to become pregnant during the study, or were breast-feeding; and/or had
a known sensitivity to cosmetics, skin care products, insect repellents,
or to topical drugs related to the material being evaluated.

The study enrolled 54 participants; one participant withdrew.  The
participants included 48 females and six males, ranging in age from 19
to 71 years (average age was 51 years).  Subjects were primarily
Caucasian.

The study protocol involved application of 0.2 ml of five test materials
to 2-by-2 cm Webril patches (five patches per subject), followed by
air-drying for 30 minutes before application of the patches to each
subject’s back.  Forty-eight hours after application, the patches are
removed and sites evaluated.  If the first evaluation is positive, a
second reader re-evaluates the site.  Seventy-two hours after
application, the sites are evaluated again.

Reactions were graded using a +/- system.  The reaction categories were
no reaction (-); minimal or doubtful response, slightly different from
surrounding skin (?); definite erythema, no edema (+); definite
erythema, definite edema (++); and definite erythema, definite edema,
vesiculation (+++).  The Primary Irritation Index (PII), used for
classification, was calculated as the higher mean score at either the
48-hour or 72-hour observation, calculated by dividing the sum of
reaction scores for all subjects at each observation time by the number
of subjects in the group.  A PII of 0.50 or less indicates that the
product is essentially non-irritating; these products are the equivalent
of Toxicity Category IV.

Results and Discussion

Most of the responses in this study were in the marginal category.  A
“?” was used when response effects were reversible, and thus
indicate irritation, not sensitization.  A high proportion of subjects
had marginal responses, which could be a result of having an occlusive
patch on the skin.  Two areas of concern include a lack of untreated
patches as negative controls, rendering questionable the association of
observed responses with the test substance.  Additionally, the patches
were dried before application, which resulted in a markedly different
pattern of exposure from typical use of a topically applied repellent.
The rationale for this approach was to ensure that the liquid product
remained at the test site so that a dose exceeding the typical consumer
dose was achieved.  Dr. Gardner expressed concern that this approach
resulted in a lack of skin contact by volatile components of the
products, which would evaporate before patch application.  Changes in
the products’ physical characteristics as they dry could affect the
irritation potential of the products.

The lack of negative controls and different pattern of exposure
represent significant scientific limitations; however, the data are
considered sufficiently reliable to be used in conjunction with other
information on the irritancy potential of product ingredients to support
the conclusion that these formulations do not cause more than mild skin
irritation.

Ethics Assessment

Mr. Carley presented EPA’s ethics review of the 48-hour Primary Dermal
Irritation Study.  He noted that the Board had expressed concern that if
the identity of the sponsor was subject to CBI, conflict of interest
issues could arise; he informed the Board that EPA had not identified
any conflicts of interest.

Applicable ethical standards include 40 CFR §26.1303 (defines standard
for documenting ethical conduct of research), 40 CFR §26.1703 (forbids
EPA reliance on research involving intentional exposure of pregnant or
nursing women or children), and 40 CFR §26.1704 (forbids EPA reliance
on research if there is “clear and convincing evidence” that its
conduct was fundamentally unethical or significantly deficient relative
to standards prevailing when it was conducted).  The initial submissions
did not address the requirement of 40 CFR §26.1303 to document ethical
conduct.  Resubmissions are adequate to support review; however,
discussions of risk, risk minimization, benefits, and risk/benefit are
weak, but acceptable for pre-rule studies.

The purpose of this study was to determine the ability of two
experimental repellent products (and three other unidentified materials)
to cause immediate irritation by application to human skin under
controlled patch conditions.  The sponsor’s policy is to avoid
“unnecessary use of animals in testing;” thus, this study was
submitted to support a request for waiving EPA’s normal requirement
for animal testing of irritancy.

The 54 subjects enrolled in the study (53 completed it) were selected
from among subjects who previously participated in research at this
laboratory; they were recruited as they completed a previous study.  The
subjects received $30 compensation for three visits, which was
considered likely to attract primarily economically disadvantaged
subjects.  There were no other indications that subjects were from
vulnerable groups.  The risks associated with participation were
described to subjects in generic terms; both the irritation and RIPT
studies were described identically.  Although identifying weak irritants
before marketing and use has potential societal benefit, this assay is
unable to identify weak irritants.  EPA concluded that, if
scientifically acceptable, the benefit of this study probably justifies
the low incremental risks to subjects.

The study was reviewed by the Allendale IRB (AIRB) of Allendale,
Pennsylvania, which is registered with OHRP but not known to be
accredited.  The submitted documentation of IRB composition, procedures,
and review meets regulatory requirements.  General compliance with FDA
rules was asserted by TKL Research, which performed the study.

Written consent was obtained from all subjects, using an ICF approved by
the AIRB.  This document was highly generic and sometimes unclear, and
the consent process emphasized reliance on frequent test subjects, and
on establishing their eligibility rather than their fully informed
understanding.  Review of applicable documentation found that subject
privacy was not compromised in the reports.  The subjects were paid only
upon completion of the study, which may have unduly influenced subjects
not to withdraw.  Subjects also were offered a “finder’s fee” for
referring others, but were paid only if the referral completed testing,
which also may have unduly influenced referral subjects not to withdraw.

Ethical concerns include recruitment of subjects from a population of
frequent test subjects, without explicit consideration of
representativeness.  The compensation was low and may have
disproportionately attracted economically disadvantaged subjects.
Compensation was tied to completion of the study, which may have
compromised freedom to withdraw.  Additionally, although possible
lasting effects (change in skin pigmentation, generation of allergies)
were acknowledged, treatment promised only “to relieve the immediate
problem,” and only for undefined “significant reactions.”  A
troubling qualified promise was made to identify the agent that induced
an allergic reaction.  There was unnecessary identification of subjects
by Social Security Number.  Because the assay may be inadequate for
identifying weak irritants, this study may be inappropriate for
determining irritation category.

There were some gaps in documentation of ethical conduct, but
documentation was relatively complete for pre-rule research.  There was
no clear and convincing evidence that the research was fundamentally
unethical and no intentional exposure of children or pregnant or nursing
women occurred.  EPA had many ethical concerns about this study, but
concluded that the research was consistent with common practice in
testing cosmetics and other consumer products not regulated as
pesticides.  There was no clear and convincing evidence that the
research was significantly deficient relative to prevailing standards.

The charge to the HSRB was to determine whether these studies are
sufficiently sound, from a scientific perspective, to be used as part of
a weight-of-evidence assessment to evaluate the potential of the
formulations tested to irritate human skin and to determine if there is
clear and convincing evidence that the conduct of these studies was
fundamentally unethical, or significantly deficient relative to the
ethical standards prevailing at the time the research was performed.

Mr. Jordan corrected the MOE for subjects in this trial as being greater
than 60,000 to 70,000, not 350 as previously reported.

Dr. Fisher inquired if the data, if used, would increase consumer
protection.  Mr. Carley explained that the basic requirement for
consumer protection is an animal study.  This protocol was submitted to
request EPA waive animal tests.  Thus, EPA cannot determine if testing
in humans would provide information significantly different from that
derived from animal testing.

Dr. Fish inquired whether readers of the dermal reaction were blinded.
Dr. Gardner responded that no information was provided on blinding.
Because control patches were not used, blinding would only mask the
identity of the different products.

Dr. Menikoff asked about the relationship between human and animal
testing, particularly whether a company could seek EPA approval for a
product based only on animal testing.  Mr. Carley explained that the
standard data requirement for these products is a standard animal test
of dermal irritation.  Dr. Gardner added that in the waiver rationale,
the registrant argues that because the products would be applied
directly to the skin, the results would confirm a body of evidence on
separate components that suggest no irritation.  With potentially
dangerous products, EPA labels reflect the most dangerous component,
regardless of product composition.  For these products, a person who
experiences irritation likely will discontinue use; further
consideration of consumer behaviors falls under risk management.

Dr. Brimijoin asked Mr. Carley to expand on concerns that the assay is
of dubious value because it does not identify minor irritants.  Mr.
Carley explained that the study report indicates the evaluation method
used will screen out strong irritants, but not weaker irritants that
require multiple exposures.  Dr. Brimijoin inquired if this affected the
Board’s response to the first charge question, concerning whether the
studies were sufficiently sound to evaluate the potential of the
products to irritate human skin.  He asked whether knowledge that the
registrants have excluded the possibility of major irritation could be
considered a major part of a weight-of-evidence assessment.  Dr. Fisher
questioned whether the purpose of the study was to identify all levels
of irritation or only severe levels; the registrants admit they cannot
evaluate low levels of irritation.  She requested clarification on the
value of the study claimed by registrants and the value of the study to
EPA.  Mr. Jordan explained that EPA has a large amount of information
about this formulation and its ingredient.  EPA requested the Board’s
opinion concerning the scientific soundness of the study, and to
describe its strengths and limitations.  EPA seeks to assign this
formulation to one of four irritant categories.  The product is likely
to fall into Category IV (non-irritant) or Category III (slightly or
mildly irritating).  EPA will make labeling decisions based on the
assigned category.

Dr. Philpott raised the issue of the registrant’s request for a waiver
for animal testing, and whether EPA believes there is sufficient
evidence from animal and in vitro testing to support this request.  Dr.
Gardner explained that data were provided as published literature.  EPA
has significant experience with these types of pesticide studies, and it
is not difficult to make extrapolations based on data from individual
components.  EPA takes a conservative approach to identifying risk;
labeling is based on the highest toxicity category of an ingredient in a
product.

Dr. Lois Lehman-McKeeman asked Dr. Gardner if EPA had confirmation of
product composition and whether, under standard clinical practices,
analytical verification of composition is required.  Dr. Gardner
responded that analytical verification was not required because the
products in the study are of known composition; product composition
information was supplied and certified by the registrants.  They
provided a confidential statement of the formula that reports a range of
ingredients and product chemistry characteristics, such as stability.

Dr. Krishnan inquired whether, given that five products were tested
simultaneously, there was concern that the actual MOE is lower than that
calculated.  Dr. Gardner stated that this was not a concern because the
products are already known to be of low toxicity.  If there is a direct,
acute effect; this effect will not extend to the other products unless
the other products are sensitizers, which this assay cannot determine.
The MOE for all the products likely is low, and aggregation of MOEs
would result in a low MOE.

Public Comments

Dr. James Milbauer and Ms. Milena Reckseit of TKL Research

Dr. James Milbauer (TKL Research consultant) explained that TKL Research
performed the patch testing for a corporate sponsor seeking
weight-of-evidence to address the issue of a waiver for animal testing.
The patch test protocol used is based on a long record of literature
published since the 1950s by academic dermatologists and others.
Despite this record, specific protocols for performing patch testing are
not available, although most investigators perform the testing
similarly.  The patch test commonly is used for diagnosis of contact
dermatitis.

The manufacturer performed preclinical testing before beginning human
testing to determine the safety of the product.  The sponsor believes
that, because different species react differently to substances, human
patch testing, although not required by EPA, would further ensure the
safety of those using the products.

Dr. Milbauer addressed the inability of this test to measure weak
irritants.  He commented that most irritants are distributed along a
gradient of irritation potential, and pre-clinical testing screens out
the greatest risk associated with the product.  This test widens the
sponsor’s “comfort level” concerning this product.  The sponsor
realizes that the weakest irritants that require repeat exposure to
induce irritation will not be identified in this test.  Additionally, no
test can ensure that no one in a population will react to a product, but
testing can determine that the product will be safe for most users.

Ms. Milena Reckseit (TKL Research) addressed the Board’s questions
concerning the attractiveness of the low amount of compensation ($30) to
primarily financially disadvantaged people.  She explained that most
subjects lived in New Jersey or in one of four New York metropolitan
areas and hale from a range of socioeconomic and demographic
populations.  The majority of the subjects (71.5 percent) are from towns
with average household incomes greater than $66,000, in contrast to the
average American household income of approximately $42,000.  On average,
60 percent of inhabitants of the areas from which subjects came are in
the labor force, and slightly more than 60 percent own their own home;
approximately 4.3 percent of the population live below the poverty
level.  Approximately 93 percent of study participants were white, were
largely female, and most ranged in age from 35 to 64 years.  Roughly 71
percent of study participants live in towns approximately 3 miles from
the site; the subject fee of $30 ($10 per visit) was considered
reasonable in part because participation required little travel.

Dr. Fisher asked Dr. Milbauer and Ms. Reckseit to clarify the AIRB’s
response to the lack of information on three of the five materials
tested in the 48-hour Primary Dermal Irritation Study.  Dr. Milbauer
explained that the AIRB received verbal communication from the sponsors
that the other three products are approved and marketed repellents.  The
sponsor wanted to ensure that the new products were no more or less
irritating than the other three products.  Dr. Fisher inquired whether
the AIRB received a risk-benefit analysis for all five products and how