Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 EPA-HSRB-09-01
2
3 Kevin P. Teichman, Ph.D.
4 Acting Science Advisor
5 Office of the Science Advisor
6 1200 Pennsylvania Avenue, NW
7 Washington, DC 20460
8
9 Subject: February 17, 2009 EPA Human Studies Review Board Meeting Report
10
11 Dear Dr. Teichman:
12
13 The United States Environmental Protection Agency (EPA or Agency) requested the
14 Human Studies Review Board (HSRB) to review scientific and ethical issues addressing: a
15 completed Carroll-Loye Biological Research Mosquito Repellent Efficacy Study (SPC-001) and
16 a completed Carroll-Loye Biological Research Tick Repellent Efficacy Study (SPC-002).
17 In addition, the HSRB explored several technical aspects of spatial/area repellent testing, to help
18 familiarize the Board with the technology as it prepares to review spatial repellent protocols at a
19 future HSRB meeting. A summary of the Board's conclusions concerning these topics is provided
20 below.
21
22 Assessment of Completed Carroll-Love Biological Research Study SPC-001: Efficacy Test
23 of Picaridin-Based Personal Repellants with Mosquitoes Under Field Conditions
24
25 Science
26
27 The Board concurred with the Agency' s assessment that this study provides scientifically
28 valid results to assess the repellent efficacy against mosquitoes of the formulations tested.
29 However, from a statistical perspective, EPA may wish to reevaluate how the data should
30 be used to inform conclusions regarding specific protection times.
31 Ethics
32
33 The Board concurred with the Agency's assessment that the study submitted for review
34 was conducted in substantial compliance with subparts K and L of 40 CFR 26.
35
36
37 Assessment of Completed Carroll-Love Biological Research Study SPC-002: Efficacy Test
38 of Picaridin-based Personal Tick Repellents.
39
40 Science
41
42 The Board concurred with the Agency' s assessment that this study provides scientifically
43 valid results to assess the repellent efficacy against ticks of the formulations tested.
44 However, from a statistical perspective, EPA may wish to reevaluate how the data should
45 be used to inform conclusions regarding specific protection times.
46
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
2 Ethics
3 The Board concurred with the Agency's assessment that the study submitted for review
4 was conducted in substantial compliance with subparts K and L of 40 CFR 26.
5
6 Space Insect Repellent Testing
7
8 Because the HSRB may be reviewing spatial/area repellent protocols in the future, the
9 Board desired to be familiar with such technology. The HSRB considered four factors as part of
10 its educative process of spatial insect repellents technology: environmental aspects, study design,
11 sample size/statistics, and human subjects. The Board noted the following points:
12
13 Environmental aspects
14 Environmental and human factors are important aspects to address in spatial insect
15 repellent testing.
16
17 Study design
18 Setting some type of minimal allowable pest density should be required in the study
19 design.
20 Investigators should provide some statement regarding the efficacy they are trying to
21 determine (number of pests, duration, etc.).
22 The nature of the spatial dispensing device and the standard use conditions should be
23 carefully described.
24
25 Sample size/statistics
26 Issues such as the allocation of units (humans) to groups and the balance of other relevant
27 factors are absolutely critical and greatly affect the statistical analysis of the resulting
28 data.
29 Censoring, if unaccounted for, can seriously bias results.
30 It is crucial to know enough about the response variable and the factors that affect it so
31 that a reasonable experiment can be designed and the proportion of censored observations
32 can be kept to a minimum.
33
34 Human subjects
35 Justification for the involvement of humans (as "bait") must provide sufficient
36 information to allow the HSRB to determine that the involvement is appropriate from
37 both scientific and ethical perspectives.
38
39 Sincerely,
40
41
42 Sean Philpott, Ph.D.
43 Chair
44 EPA Human Studies Review Board
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 NOTICE
2
3 This report has been written as part of the activities of the EPA Human Studies Review
4 Board, a Federal advisory committee providing advice, information and recommendations on
5 issues related to scientific and ethical aspects of human subjects research. This report has not
6 been reviewed for approval by the Agency and, hence, the contents of this report do not
7 necessarily represent the view and policies of the Environmental Protection Agency, nor of other
8 agencies in the Executive Branch of the Federal government, nor does the mention of trade
9 names or commercial products constitute a recommendation for use. Further information about
10 the EPA Human Studies Review Board can be obtained from its website at
11 http://www.epa.gov/osa/hsrb/. Interested persons are invited to contact Paul Lewis, Designated
12 Federal Officer, via e-mail at lewis.paul@epa.gov.
13
14 In preparing this document, the Board carefully considered all information provided and
15 presented by the Agency presenters, as well as information presented by public commenters.
16 This document addresses the information provided and presented within the structure of the
17 charge by the Agency.
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 U. S. ENVIRONMENTAL PROTECTION AGENCY
2 HUMAN STUDIES REVIEW BOARD
O
4 Board Members
5
6 Celia B. Fisher, Ph.D., Marie Ward Doty Professor of Psychology, Director, Center for Ethics
7 Education, Fordham University, Department of Psychology, Bronx, NYi
8
9 William S. Brimijoin, Ph.D., Chair and Professor, Molecular Pharmacology and Experimental
10 Therapeutics, Mayo Foundation, Rochester, MN 2
11
12 Alicia Carriquiry, Ph.D., Professor, Department of Statistics, Iowa State University
13 Snedecor Hall, Ames, IA 3
14
15 Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office for Human Subjects
16 Protection, University of Rochester, Rochester, NY 3
17
18 Janice Chambers, Ph.D., D.A.B.T., William L. Giles Distinguished Professor, Director, Center
19 for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State
20 University, Mississippi State, MS
21
22 Richard Fenske, Ph.D., MPH, Professor and Associate Chair, Department of Environmental and
23 Occupational Health Sciences, University of Washington, Seattle, WA 3
24
25 Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology, Boston University
26 School of Public Health, Co-Director, MA in Clinical Investigation, Boston University School of
27 Medicine, Boston, MA 3
28
29 Dallas E. Johnson, Ph.D., Professor Emeritus, Department of Statistics, Kansas State University,
30 Manhattan, KS
31
32 Michael D. Lebowitz, Ph.D., FCCP, Retired Professor of Public Health & Medicine, University
33 of Arizona, Tucson, AZ
34
35 Lois D. Lehman-Mckeeman, Ph.D., Distinguished Research Fellow, Discovery Toxicology,
36 Bristol-Myers Squibb Company, Princeton, NJ
37
38 Rebecca Parkin, Ph.D., MPH, Associate Dean for Research and Public Health Practice, School
39 of Public Health and Human Services, The George Washington University, Washington, DC 4
40
41 Sean Philpott, Ph.D., MS Bioethics, Science and Ethics Officer, Global Campaign for
42 Microbiocides, PATH, Washington, DC
43
44 Ernest D. Prentice, Ph.D., Associate Vice Chancellor for Academic Affairs, University of
45 Nebraska Medical Center, Omaha, NE
46
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 Richard R. Sharp, Ph.D., Director of Bioethics Research, Department of Bioethics
2 Cleveland Clinic, Cleveland, OH 4;5
O
4 Linda J. Young, Ph.D., Professor, Department of Statistics, Institute of Food and Agricultural
5 Sciences, University of Florida, Gainesville, FL
6
7 Consultant to the Human Studies Review Board
8 Daniel Strickman, Ph.D., National Program Leader, Veterinary and Medical Entomology,
9 Agricultural Research Service, United States Department of Agriculture, Beltsville, MD
10
11 Human Studies Review Board Staff
12
13 Paul I. Lewis, Ph.D., Executive Director, Human Studies Review Board Staff, Office of the
14 Science Advisor, United States Environmental Protection Agency, Washington, DC
15
16 1 Membership and Chairpersonship expired effective March 27, 2009
17 2 Membership and Vice Chairpersonship expired effective March 27, 2009
18 3 Membership expired effective March 27, 2009
19 4 Not in attendance
20 5 Resigned from the HSRB Effective March 9, 2009
21
22
23 Board Members 4
24 INTRODUCTION 6
25 CHARGE TO THE BOARD AND BOARD RESPONSE 6
26 Carley JM. 2009a. Ethics Review of Completed Carroll-Loye Field Mosquito Repellent
27 Efficacy Study SPC-001. Dated January 23, 2009. Unpublished document prepared by Office
28 of Pesticide Programs, United States Environmental Protection Agency 22
29 Carley JM. 2009b. Ethics Review of Completed Carroll-Loye Field Tick Repellent Efficacy
30 Study SPC-002. Dated January 23, 2009. Unpublished document prepared by Office of
31 Pesticide Programs, United States Environmental Protection Agency 22
32 Carroll S. 2008a. Efficacy Test of Picaridin-Based Personal Repellants with Mosquitoes Under
33 Field Conditions. MRID 47535201. Dated August 19, 2008. Unpublished study prepared by
34 Carroll-Loye Biological Research 22
35 Carroll S. 2008b. Efficacy Test of Picari din-Based Personal Repellants with Mosquitoes Under
36 Field Conditions (Protocol SPC-001). Email to John M. Carley transmitting supplemental
37 correspondence between Carroll-Loye Biological Research and Independent Investigations
38 Review Board, Inc., concerning SPC-001, with enclosures. Dated November 7, 2008.
39 Unpublished document prepared by Carroll-Loye Biological Research 22
40 Carroll S. 2008c. Efficacy Test of Picari din-Based Personal Tick Repellants. MRID 47535202.
41 Dated August 19, 2008. Unpublished study prepared by Carroll-Loye Biological Research. 22
42 Carroll S. 2008d. Efficacy Test of Picari din-Based Personal Tick Repellants (Protocol SPC-
43 002). Email to John M. Carley transmitting supplemental correspondence between Carroll-
44 Loye Biological Research and Independent Investigations Review Board, Inc., concerning
45 SPC-002, with enclosures. Dated November 7, 2008. Unpublished document prepared by
46 Carroll-Loye Biological Research 22
Page 5 of22
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 INTRODUCTION
2
3 On February 17, 2009, United States Environmental Protection Agency's (EPA or
4 Agency) Human Studies Review Board (HSRB) conducted a teleconference meeting via
5 telephone. Advance notice of the meeting was published in the Federal Register "Human
6 Studies Review Board (HSRB): Notice of a Public Teleconference Meeting" (74 Federal
7 Register 19, 5653).
8
9 During the public teleconference meeting, following welcoming remarks from Agency
10 officials, the Board heard presentations from the Agency on the following topics: a completed
11 Carroll-Loye Biological Research Mosquito Repellent Efficacy Study (SPC-001) and a
12 completed Carroll-Loye Biological Research Tick Repellent Efficacy Study (SPC-002). The
13 Board also explored several technical aspects of spatial/area repellent testing. Each of these
14 topics is discussed more fully below.
15
16 Oral comments
17 The following oral comments were presented at the meeting:
18
19 Dr. Scott Carroll, Director, Carroll-Loye Biological Research, 711 Oak Avenue, Davis, CA
20
21 For their deliberations, the Board considered the materials presented at the meeting,
22 written public comments and Agency background documents (e.g., the published literature,
23 Agency data evaluation record, weight of evidence review, ethics review, pesticide human study
24 protocols and Agency evaluation of the protocol or study). For a comprehensive list of
25 background documents visit www.regulations.gov.
26
27 Written comments
28 No written comments were provided.
29 CHARGE TO THE BOARD AND BOARD RESPONSE
30
31 Assessment of Completed Carroll-Love Biological Research Study SPC-001: Efficacy Test
32 of Picaridin-Based Personal Repellants with Mosquitoes Under Field Conditions
33
34 Overview of the Study
35
36 SPC-001 was a field-based study of repellency to mosquitoes of three picardin-based
37 products (7% Picaridin Pump Spray [data will be bridged to 7% Pump Spray and 5.75%
38 Towelette], 15% Picaridin Pump Spray [data will be bridged to 15% Pump Spray and 12%
39 Towelette], and 15% Picaridin Pump Spray formulated with sunscreen). All but one of these
40 products - the formulation with sunscreen - were registered with the EPA prior to testing.
41 Registration of the sunscreen-containing formulation has since been approved.
42
43 After HSRB review in October 2007, the protocol was further modified to: (1) clarify the
44 composition of the 15% formulation with sunscreen and to add the two towelette formulations to
45 the dose-determination phase, and (2) to correct minor errors and respond to EPA comments.
Page 6 of22
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 The study was conducted by Carroll-Loye Biological Research of Davis, CA between March 15th
2 and June 14th, 2008. The study was sponsored by Spectrum Brands, Inc. of Bridgeton, MO, a
3 division of United Industries Corporation. The study was required by EPA to support registration
4 of these products.
5
6 As submitted to the EPA, the completed study consisted of two interdependent analyses:
7 (1) a dosimetry study designed to determine the amount of repellent that users would typically
8 apply (a single dosimetry experiment was used to provide this information both for SPC-001 and
9 a related laboratory-based study of tick repellency, SPC-002 discussed later), and (2) an efficacy
10 study designed to measure the effectiveness of each compound as repellent for those species of
11 mosquitoes likely to be vectors for West Nile Virus (WNV) in the United States. The efficacy
12 study was conducted at two field sites in Butte and Glenn Counties, CA.
13
14 Dosimetry was determined by direct measurement of compound application. The
15 dosimetry study enrolled a total of 10 individuals (5 female and 5 male), each of whom tested all
16 three formulations. The dosimetry study was performed at a laboratory site in Davis, CA. Based
17 on the findings of the dosimetry phase, it was determined that the margin of exposure (MOE) for
18 dermal toxicity ranged from a low of 1197 for the 15% spray on legs to a high of 6623 for the
19 7% spray on arms.
20
21 The efficacy of each formulation as a mosquito repellent was determined by measuring
22 the ability of the formulations to prevent mosquito landings (defined as "Landing with Intent to
23 Bite"; LIBe) under field conditions at two environmentally distinct sites in Butte and Glenn
24 Counties, CA. Each efficacy study enrolled 10 participants (5 female and 5 male) for each
25 formulation at each of the two field sites. Two experienced participants (1 male and 1 female)
26 served as untreated controls to measure ambient mosquito pressure. Several volunteers
27 participated in multiple analytic phases, dosimetric and efficacy; a total of 56 volunteers
28 participated in at least one analytic phase of SPC-001. Prior to initiation of the efficacy study, all
29 volunteers were trained in a controlled laboratory setting using lab-reared, pathogen-free insects
30 to recognize a mosquito landing with the intent to bite, and to remove such mosquitoes with an
31 aspirator.
32
33 During the field study, treated participants and untreated controls exposed their limbs to
34 mosquitoes for one minute at fifteen-minute intervals, for 10 hours (40 exposure periods) post-
35 treatment or until failure of efficacy, whichever occurred first. Failure of efficacy was defined as
36 the two confirmed LIBes within a single exposure period, or a single LIBe within each of two
37 consecutive exposure periods. Participants worked in pairs to facilitate identification of LIBes
38 and to aspirate mosquitoes during exposure periods. No actual bites were reported, and aspirated
39 mosquitoes were stored for later identification and arboviral testing.
40
41 Based on these data, mean complete protection time (CPT) for the 7% pump spray was
42 calculated to be 8.4 ± 2.1 h at the Butte County site and 7.0 ± 2.2 h at the Glenn County site.
43 Mean CPT for the 15% pump spray was 10.1 ± 4.0 h at the Butte County site and 10.7 ± 0.8 h at
44 the Glenn County site. Mean CPT for the 15% pump spray with sunscreen was 12.7 ± 4.9 h at
45 the Butte County site and 10.9 ± 1.3 h at the Glenn County site. Kaplan-Meier survival analyses
46 yielded similar results: median CPT for the 7% pump spray was 9.4 h at the Butte County site
Page 7 of22
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 and 7.4 h at the Glenn County site; for the 15% pump spray it was 10.3 h at the Butte County site
2 and 10.4 h at the Glenn County site; for the 15% pump spray with sunscreen it was 13.3 h at the
3 Butte County site and 11.7 h at the Glenn County site.
4
5 Science
6
1 Charge to the Board
8
9 Is study SPC-001 sufficiently sound, from a scientific perspective, to be used to assess
10 the repellent efficacy against mosquitoes of the three formulations tested?
11
12 Board Response to the Charge
13
14 HSRB Recommendation
15
16 The Board concurred with the Agency's assessment that this study provides scientifically
17 valid results that meet to assess the repellent efficacy against mosquitoes of the formulations
18 tested. However, from a statistical perspective, EPA may wish to reevaluate how the data should
19 be used to inform conclusions regarding specific protection times.
20
21 HSRB Detailed Recommendations and Rationale
22
23 This study was conducted according to the protocol previously approved by the HSRB,
24 with only one minor deviation. The conduct of the dosimetry study and the field study were very
25 similar to the conduct of previous field mosquito repellent efficacy studies conducted by Carroll-
26 Loye Biological. The study seems to have been carefully conducted with both sexes represented
27 among the subjects and, in the field study, a mixture of 3 genera of mosquitoes was represented.
28 The MOE's were very high and therefore protective of the participating subjects. The report was
29 clearly written and detailed.
30
31 The only deviation was the use of historical limb measurements for those subjects who
32 had previously participated and who indicated that they had not changed weight or muscle mass
33 appreciably since the prior limb measurement. This deviation would not have affected the
34 integrity of the resultant data.
35
36
37 There was concern expressed by some Board members regarding EPA's specific
38 conclusions for times of protection afforded by the three repellents. As an example, for site two,
39 the mean complete protection was 10.9 hours for the spray with sunscreen and 15% picaridin.
40 The 12 hours of repellency calculated is not in the 95% confidence interval for the mean
41 protection time, lying above the upper limit of 11.7 hours. The study was not designed to
42 specifically test a CPT of 12 hours or any other time periods, and the results from this study do
43 not support such conclusions. The Board suggests that EPA reevaluate its conclusions on specific
44 protection times in light of the limitations and the variability of these data.
45
46 Ethics
Page 8 of22
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1
2 Charge to the Board
3
4 Does available information support a determination that study SPC-001 was conducted in
5 substantial compliance with subparts K and L 40 CFR Part 26?
6
7 Board Response to the Charge
8
9 HSRB Recommendation
10
11 The Board concurred with the Agency's assessment that the study submitted for review
12 was conducted in substantial compliance with subparts K and L of 40 CFR 26.
13
14 HSRB Detailed Recommendations and Rationale
15
16 The documents provided by Carroll-Loye (Carroll 2008a, 2008b) state that each study
17 was conducted in compliance of the requirements of the US EPA Good Laboratory Practice
18 Regulations for Pesticide Programs (40 CFR 160). Additional regulations - 40 CFR 26 subparts
19 K and L; FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710 -
20 are also applicable. The study was reviewed and approved by a commercial human subjects
21 review committee, Independent Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL.
22 Documentation provided to the EPA by IIRB, Inc. indicated that it reviewed these studies
23 pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A) and found them in
24 compliance.
25
26 1. The Board concurred with the conclusions and factual observations of the ethical strengths
27 and weaknesses of the study, as detailed in the EPA's Science and Ethics Review (Carley
28 2009a).
29
30 2. The Board concluded that this study met all applicable ethical requirements for research
31 involving human participants, in accordance to the following criteria:
32
33 a. Acceptable risk-benefit ratio. The risks to study participants were minimized
34 appropriately and were justified by the potential societal benefits, particularly data on the
35 efficacy of these new formulations as personal insect repellents.
36
37 Minors and pregnant or lactating women were excluded from participation, with
38 pregnancy confirmed by self-administered pregnancy testing on each "day of
39 study". The potential of stigma resulting from study exclusion was minimized by
40 enrolling three 'alternate' participants, allowing volunteers to withdraw or be
41 excluded without compromising confidentiality.
42
43 Based on toxicological data currently available for picaridin, study participants
44 were unlikely to be at risk of adverse side effects with exposure.
45
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 The study was designed to minimize the likelihood of insect bites, but when they
2 occur they are usually mild and readily treated with steroidal creams. The study
3 excluded individuals with a history of severe reactions to bites
4
5 Clear stopping rules and medical management procedures were in place, and no
6 adverse events related to product exposure were reported.
7
8 Finally, the field-based trials were conducted only in areas where known vector-
9 borne diseases like WNV had not been detected by county and state health or
10 vector/mosquito control agencies for at least one month. Mosquitoes collected
11 during the field studies also were subjected to molecular analyses to confirm that
12 they were free of known pathogens.
13
14 b. Voluntary and informed consent of all participants
15
16 The study protocol included several mechanisms designed to minimize coercive
17 recruitment and enrollment. Monetary compensation was not so high as to unduly
18 influence participation.
19
20 One protocol deviation occurred, as previously reported to the HSRB during its
21 review of completed Carroll-Loye study LNX-001 (EPA HSRB 2008). Contrary
22 to the HSRB-reviewed (EPA HSRB 2007) and IIRB, Inc.-approved protocol,
23 Carroll-Loye researchers used previously recorded limb measurements, rather
24 than collect physical data from all trial participants. This deviation occurred
25 inadvertently when a Carroll-Loye researcher, acting upon an EPA suggestion
26 that use of archival limb measurements was scientifically valid and would
27 minimize study procedure invasiveness, implemented this protocol change
28 without consulting Carroll-Loye management or IIRB, Inc. The result of an error
29 in communication, this deviation again did not place study participants at
30 increased risk or compromise the informed consent process.
31
32 Assessment of Completed Carroll-Love Biological Research Study SPC-002: Efficacy Test
33 of Picaridin-based Personal Tick Repellents
34
35 Overview of the Study
36
37 SPC-002 was a laboratory-based study of repellency to ticks of three picari din-based
38 products (7% Picari din Pump Spray [efficacy data will be bridged to 7% Pump Spray and 5.75%
39 Towelette], 15% Picaridin Pump Spray [efficacy data will be bridged to 15% Pump Spray and
40 12% Towelette], and 15% Picaridin Pump Spray formulated with sunscreen). All but one of
41 these products - the formulation with sunscreen - were registered with the EPA prior to testing.
42 Registration of the sunscreen-containing formulation has since been approved.
43
44 After HSRB review in October 2007, the protocol was further modified to: (1) clarify the
45 composition of the 15% formulation with sunscreen and to add the two towelette formulations to
46 the dose-determination phase, and (2) to correct minor errors and respond to EPA comments.
Page 10 of 22
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 The study was conducted by Carroll-Loye Biological Research of Davis, CA on March 22nd and
2 23rd, 2008. The study was sponsored by Spectrum Brands, Inc. of Bridgeton, MO, a division of
3 United Industries Corporation. The study was required by EPA to support registration of these
4 products.
5
6 As submitted to the EPA, the completed study consisted of two interdependent analyses:
7 (1) a dosimetry study designed to determine the amount of repellent that users would typically
8 apply (a single dosimetry experiment was used to provide this information both for SPC-002 and
9 a related field-based study of mosquito repellency, SPC-001 discussed previously); and (2) an
10 efficacy study designed to measure the effectiveness of each compound as repellent for two
11 species of ticks: nymphal deer ticks (Ixodes scapularis) and nymphal dog ticks (Dermacentor
12 variabilis). Both the dosimetry and the efficacy study were conducted at the Carroll-Loye
13 research laboratory in Davis, CA.
14
15 Dosimetry was determined by direct measurement of compound application. The
16 dosimetry study enrolled a total of 10 individuals (5 female and 5 male), each of whom tested all
17 three formulations. Based on the findings of the dosimetry phase, it was determined that the
18 margin of exposure (MOE) for dermal toxicity ranged from a low of 1197 for the 15% spray on
19 legs to a high of 6623 for the 7% spray on arms.
20
21 The efficacy of each formulation as a tick repellent was determined by placing ticks on
22 picaridin-treated and untreated forearms for 3-minute periods, at 15-minute intervals. Failure of
23 repellency occurred when a particular species of tick "crossed" into the treated area of the
24 forearm, confirmed by another crossing of the same species of tick in either of the subsequent
25 two exposure periods. The untreated forearm of each volunteer served as an untreated control,
26 and was used to establish active questing behavior of each tick used. Prior to starting the efficacy
27 study, participants were trained to handle ticks safely and to monitor their movements and all
28 ticks were removed from participants' arms before biting. Volunteers also worked in groups of
29 three and were attended by technicians at all times.
30
31 The efficacy study enrolled 10 participants (5-6 female and 4-5 male) for each
32 formulation. Several volunteers participated in multiple analytic phases, dosimetric and efficacy;
33 a total of 33 volunteers participated in at least one analytic phase of SCI-002.
34
35 Based on these data, mean CPT calculated for the 7% pump spray was 5.67 ± 2.09 h
36 (range 3.25 - 9.75 h) forD. variabilis and 7.88 ± 1.43 h (range 5.75 - 11.25 h) for/, scapularis.
37 Mean CPT calculated for the 15% pump spray was 9.65 ± 4.03 h (range 4.0 - 14.25 h; 3
38 instances of right-censoring) for D. variabilis and 11.80 ± 3.34 h (range 6.5 - 14.25 h; 6
39 instances of right-censoring) for /. scapularis. Mean CPT calculated for the 15% pump spray
40 with sunscreen was 8.17 ± 4.86 h (range 1.0 - 14.25 h; 3 instances of right-censoring) for D.
41 variabilis and 8.65 ± 4.31 h (range 3.25 - 14.25 h; 3 instances of right-censoring) for/.
42 scapularis. Kaplan-Meier survival analyses yielded similar results: median CPT for the 7%
43 pump spray was 5.50 h for D. variabilis and 8.25 h for/, scapularis; for the 15% pump spray it
44 was 10.25 h for D. variabilis but could not be calculated for /. scapularis because of data
45 censoring; for the 15% pump spray with sunscreen it was 7.0 h for D. variabilis and 8.25 h for/.
46 scapularis.
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1
2 Science
3
4 Charge to the Board
5
6 Is study SPC-002 sufficiently sound, from a scientific perspective, to be used to assess
7 the repellent efficacy against ticks of the three formulations tested?
8
9 Board Response to the Charge
10
11 HSRB Recommendation
12
13 The Board concurred with the Agency's assessment that this study provides scientifically
14 valid results to assess the repellent efficacy against ticks of the formulations tested. However,
15 from a statistical perspective, EPA may wish to reevaluate how the data should be used to inform
16 conclusions regarding specific protection times.
17
18 HSRB Detailed Recommendations and Rationale
19
20 This study was conducted according to the protocol previously approved by the HSRB,
21 with only one minor deviation. The conduct of the dosimetry study and the field study were very
22 similar to the conduct of previous laboratory tick repellent efficacy studies conducted by Carroll-
23 Loye Biological. The study seems to have been carefully conducted with both sexes represented
24 among the subjects and with the use of 2 genera of ticks. The MOE's were very high and
25 therefore protective of the participating subjects. The report was clearly written and detailed.
26
27 The only deviation was the use of historical limb measurements for those subjects who
28 had previously participated and who indicated that they had not changed weight or muscle mass
29 appreciably since the prior limb measurement. This deviation would not have affected the
30 integrity of the resultant data.
31
32 There was concern expressed by some Board members regarding EPA's specific
33 conclusions for times of protection afforded by the three repellents. Two tick species were
34 studied. For one of these, Dermacentor variabilis, the mean CPT of 5.7 and 9.7 hours for the 7%
35 and 15% spray, respectively, were below the claims of tick repellency of 7 and 11 hours,
36 respectively. Although the 5.7 and 9.7 hours fall within the 95% confidence interval, mean
37 protection time is not equal to CPT. The study was not designed to specifically test a CPT of 7 or
38 11 hours, and the results do not support such conclusions. The Board suggests that EPA
39 reevaluate its conclusions on complete protection times for these repellents in light of the
40 limitations and the variability of these data.
41
42 Ethics
43
44 Charge to the Board
45
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Proposed Final Draft Dated May 15, 2009; Do Not Cite or Quote
1 Does available information support a determination that study SPC-002 was conducted in
2 substantial compliance with subparts K and L 40 CFR Part 26?
O
4 Board Response to the Charge
5
6 HSRB Recommendation
7
8 The Board concurred with the Agency' s assessment that the study submitted for review
9 was conducted in substantial compliance with subparts K and L of 40 CFR 26.
10
11 HSRB Detailed Recommendations and Rationale
12
13 The documents provided by Carroll-Loye (Carroll 2008c, 2008d) state that each study
14 was conducted in compliance the requirements of the US EPA Good Laboratory Practice
15 Regulations for Pesticide Programs (40 CFR 160). Additional regulations - 40 CFR 26 subparts
16 K and L; FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710 -
17 are also applicable. The study was reviewed and approved by a commercial human subjects
18 review committee, Independent Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL.
19 Documentation provided to the EPA by IIRB, Inc. indicated that it reviewed these studies
20 pursuant to the standards of the Common Rule (45 CFR Part 46, Subpart A) and found them in
21 compliance.
22
23 1. The Board concurred with the conclusions and factual observations of the ethical strengths
24 and weaknesses of the study, as detailed in the EPA's Science and Ethics Review (Carley
25 2009b).
26
27 2. The Board concluded that this study met all applicable ethical requirements for research
28 involving human participants, in accordance to the following criteria:
29
30 b. Acceptable risk-benefit ratio. The risks to study participants were minimized
31 appropriately and were justified by the potential societal benefits, particularly data on the
32 efficacy of these new formulations as personal insect repellents.
33
34 Minors and pregnant or lactating women were excluded from participation, with
35 pregnancy confirmed by self-administered pregnancy testing on each "day of
36 study". The potential of stigma resulting from study exclusion was minimized by
37 enrolling three 'alternate' participants, allowing volunteers to withdraw or be
38 excluded without compromising confidentiality.
39
40 Based on toxicological data currently available for picaridin, study participants
41 were unlikely to be at risk of adverse side effects with exposure.
42
43 Clear stopping rules and medical management procedures were in place, and no
44 adverse events related to product exposure were reported.
45
46 The study was designed to minimize the likelihood of tick bites.
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1
2 Finally, the efficacy trial was conducted with laboratory-raised ticks free of
3 known pathogens.
4
5 c. Voluntary and informed consent of all participants
6
1 The study protocol included several mechanisms designed to minimize coercive
8 recruitment and enrollment. Monetary compensation was not so high as to unduly
9 influence participation.
10
11 One protocol deviation occurred, as previously reported to the HSRB during its
12 review of completed Carroll-Loye study LNX-001 (EPA HSRB 2008). Contrary
13 to the HSRB-reviewed (EPA HSRB 2007) and IIRB, Inc.-approved protocol,
14 Carroll-Loye researchers also used previously recorded limb measurements,
15 rather than collect physical data from all trial participants. This deviation occurred
16 inadvertently when a Carroll-Loye researcher, acting upon an EPA suggestion
17 that use of archival limb measurements was scientifically valid and would
18 minimize study procedure invasiveness, implemented this protocol change
19 without consulting Carroll-Loye management or IIRB, Inc. The result of an error
20 in communication, this deviation again did not place study participants at
21 increased risk or compromise the informed consent process.
22
23
24 Space Insect Repellent Testing
25
26 Because the HSRB may be reviewing spatial/area repellent protocols in the future, the
27 Board desired to be familiar with such technology. A HSRB workgroup was created that
28 generated a list of questions to assist the Board when evaluating future protocols. To assist the
29 Board in their understanding of spatial repellents, the Board asked Dr. Dan Strickman to serve as
30 a Consultant to the Board to address such questions. The HSRB considered four factors as part
31 of its educative process of spatial insect repellents technology: environmental aspects, study
32 design, sample size/statistics, and human subjects.
33
34 HSRB Workgroup Questions:
35
36 Environmental Aspects
37
38 1. What are the environmental (temperature, wind, time of day, humidity, proximity to
39 water/plants, size and type of space) and human factors (height/weight; gender, age,
40 ethnicity, density of humans in space) that can affect insect behavior and repellent efficacy
41 relevant to space treatment studies?
42
43 Dr. Strickman's reply discussed the strong effect that environmental factors, especially
44 wind (i.e. dispersal), may have on the avidity of the insects, while acknowledging such
45 differences can be species specific. As many of these repellents are released in gaseous or
46 particulate form, temperature and humidity will affect the dispersal behavior in any outdoor
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1 space as well. This may alter the size and clumping of the dry or droplet particulate, producing
2 greater deposition, all of which might affect their repellent properties (see EPA air quality
3 criteria documents; Fradin and Day 2002). The presence of other particulates and gases may also
4 affect repellent and insect behavior. Spatial factors and human density within the space may be a
5 factor affecting dispersion and deposition as well. Finally, the effect of the environment on
6 repellent characteristics may have an impact on human inhalation and adsorption as well (see
7 EPA air quality criteria documents for physical-chemical changes due to environmental and
8 spatial factors on human health). Thus, environmental factors, including the characteristics of
9 the test spaces, need to be rigorously controlled.
10
11 Dr. Strickman also highlighted the strong effect of human factors on insect attractiveness,
12 noting the four-fold variation in attractiveness due to diet, gender, age, etc. (see, e.g., Qiu et al.
13 2006), and the overall relevance of using human subjects for repellent testing. He believes such
14 factors could affect the performance of active ingredients. The density and behavior of humans
15 will also affect insect behavior and thus efficacy of the spatial repellents. What has not been
16 considered herein is the impact of human activity behavior on repellent dispersion (Fradin and
17 Day 2002), the impact of deposition of the repellents on clothes, or the reduction of repellents
18 gaseous or parti culate repellents.
19
20 2. What factors need to be considered for test spaces with respect to size of area in which the
21 test is conducted? How is the most appropriate test area determined?
22
23 Dr. Strickman commented that "The test area should exceed the label claim for area
24 protected. An ideal test would evaluate the area protected by measuring the occurrence of pests
25 [sic] across a transect." It is assumed that the specifications on space protected for each type of
26 repellent would be different.
27
28 The test area would need to be free of other factors, as mentioned above. One can also
29 speculate that odors due to other chemicals might interfere or enhance the odiferous actions of
30 the repellents on insect behavior.
31
32 EPA indicated that the products will probably be volatile pyrethroids, and that past tests
33 using them have involved test areas of 100-700 square feet. EPA goes on to state in their
34 response: "Ideally, testing of a spatial repellent would generate results that could be used
35 modularly to generate directions for usei.e., if efficacy testing shows the size and shape of the
36 area of protection relative to the location of an emitting device and the direction and strength of
37 the wind, then an array of similar shapes covering the entirety of a larger area to be protected
38 would show where multiple emitters should be placed." They also stated: "Most consumer use
39 of spatial repellents is expected to be in relatively small areas containing at least several people.
40 It is thus appropriate to test them with subjects placed closer together than might be acceptable in
41 a test of a topically applied repellent, for which separation of subjects is needed to minimize
42 interaction." EPA states in its Product Performance Test Guidelines (4.v) that the test area size
43 and its preparation are discussed, and (in 4.vi) that the number and placement of the candle, coil
44 or mat should be consistent with label directions. "Test subjects should be located at the
45 maximum distance from the candle, coil, or mat that the label recommends. If the label states
46 that the candle, coil, or mat should be placed upwind, then test subjects should remain
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1 downwind. Otherwise, test subjects should move around the circumference of the test area
2 periodically. Report this time interval with study results." These are important additions to Dr.
3 Strickman's response.
4
5 3. Does the number of human subjects within testing environments of different sizes affect insect
6 activity? Does the number of subjects in a given area affect product efficacy or the
1 measurement of product efficacy?
8
9 Dr. Strickman responded by stating: "In general, results from field tests are unaffected by
10 the number of subjects as long as the density of pests is sufficient. Often, the local population of
11 pests is so high that additional traps or subjects do not affect results from each device or person.
12 In the laboratory or large cage trials, where populations are limited and controlled, additional
13 traps or human bait subjects might reduce the number collected by each trap or person." This
14 statement may be a sufficient answer to the question, though one could add that the density of
15 subjects will affect their behavior (if not still), and such behavior will affect the repellent
16 dispersion. One could speculate, probably inadequately, that sufficient human density might
17 affect insect activity as well.
18
19 The EPA response states: "If testing were to show that efficacy varies with the number of
20 people in a test area, this would probably be reflected on the label. But because most testing uses
21 only one number of peoplei.e., one sample size for all replicatesthis kind of information is
22 unlikely to be available. EPA does not require it." EPA states in its Product Performance Test
23 Guidelines (4.iv) that the number of test subjects is discussed, and if more that one test subject
24 are exposed to the space repellent that the number of bites should be averaged.
25
26 4. Are there any other special considerations regarding insect behavior in such studies that
27 require inclusion in protocols?
28
29 No additional Board comments on either Dr. Strickman's or EPA's response.
30
31 Study Design
32
33 1. How is the location of open spaces typically selected? How many different or similar sites
34 are appropriate to assess generalizability?
35
36 Issues relevant to location and generalizability include the availability of the desired
37 species and the abundance of the pest. For consistency in experimental design and interpretation,
38 setting some type of minimal allowable pest density should be required in the study design (this
39 level can be determined after expert consultation). The locations and the number of different
40 kinds of pests should be typical of the attended use so as to make any results more generalizable.
41
42 The investigators should provide some description of the efficacy endpoints they are
43 planning to measure (i.e. number of pests, duration, etc). That will help to assess whether the
44 study design, including location and sites, are adequate.
45
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1 Finally the Board suggested that there should be some standard conditions set for
2 allowable wind speed, minimum pest density, and pest diversity.
O
4 2. What are common spatial dispensing devices? How are they related to the nature of the
5 product dispenses (e.g. gas, suspended liquid, smoke)? What are the design or measurement
6 challenges for different dispensing devices and products?
1
8 Regarding study design aspects, some type of data should be collected to ensure proper
9 operation and/or dispersion. These might include: (1) determination of ambient concentrations
10 of active product over time and area; and (2) operation of physical devicesto ensure that they
11 are emitting levels of agent as specified in the protocol. Environmental conditions (discussed
12 previously) including wind, temperature and humidity would also need to be accurately recorded
13 for all types of spatial repellents.
14
15 3. What type ofdosimetry data is required to determine amount of product application used in
16 the testing? How is discharge time determined? What are the relative design merits of the
17 experimenter or subject discharging the repellent?
18
19 For these products, the physicochemical characteristics of the active ingredient in the
20 specified formulation need to be determined. This would include measures of volatility, lipid
21 solubility and vapor pressure of the active ingredient and determination of whether any of these
22 properties are altered by the formulation. The characteristics would determine the extent to
23 which an ingredient may saturate the air.
24
25 To address this question requires specifying what is meant by dosimetry data. If ambient
26 levels of compound are at issue, then these should be determined empirically. If by dosimetry
27 one means exposure in humans, then the physicochemical properties coupled with some
28 constants for skin penetration and inhalation would be required.
29
30 If the discharge rate is not adjustable, then general issues could be addressed in a
31 laboratory setting prior to field testing. This could include: (1) typical time of discharge under
32 controlled conditions as related to product design (i.e. how long does a candle burn?); (2) effect
33 of environmental conditions on discharge (practical matters like failure of candles to burn if wind
34 speed exceeds some maximum); and (3) duration of time in the environment after completion of
35 discharge. Protocols should specify if discharge is a single or repeated event, and if repeated,
36 some standardization to when discharge is repeated should be specified.
37
38 It is likely that discharge directed by the experimenter would be more consistent than
39 discharge by the subject. If one or more subjects are allowed to discharge a product, then all
40 variables relative to dosimetry would be extremely difficult to control.
41
42 For physical devices, the number of knockdowns seems like a reasonable endpoint.
43
44 4. How are outcomes measured in these studies? How are insect knockdown and mortality
45 effects measured? Are both knockdown and landings/bites usually measured in the same
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1 study? What is the difference between knockdowns and bites in terms of information
2 regarding product efficacy/effectiveness?
O
4 The ability of a product to disrupt the pest on its way to the host is what should be
5 measured, suggesting that assessment of insect landings should be sufficient. This would seem
6 to require subjects determining number of landings in a specified time period, with criteria for
7 "failure" established. For physical devices, it would seem that the same criteria would apply,
8 and the number of knockdowns can be determined as an associated finding (i.e. do higher
9 knockdowns correlate to decreased landings?).
10
11 5. What is the difference with respect to measurement in assessing efficacy of the active
12 ingredient and effectiveness of the formulation ?
13
14 These tests must focus on the intended formulation. Characteristics of the active
15 ingredient serve to identify those compounds that might work for repellency, but the final test
16 must be on the formulation. Data relating to physicochemical properties, dosimetry, etc. should
17 be collected using the formulation. For physical agents, how the device functions should also be
18 evaluated.
19
20 Sample Size and Statistics
21
22 1. Depending on the outcome measure, what are best practices with respect to human sample
23 size? What is the sample size norm in the field? How is determination of sample size related
24 to square feet of test area? What is the best way to determine the power of these studies?
25
26 The general design of experiments to test efficacy of space or area repellents depends on
27 a number of factors, and thus it is a challenge to provide specific answers to the questions
28 focusing on sample size and statistics. The Board attempted to provide some general best
29 practice principles that will require more specific definitions in different situations.
30
31 It has been noted that it is possible to test the efficacy of space repellents without using
32 humans as bait. This appears to be the case for repellents such as coils, candles, lamps and
33 others which are designed to either create a chemical barrier that repels flying insects from an
34 area, or which are designed to have a knockdown or even lethal effect on those insects. In this
35 case, efficacy can be tested using devices such as traps and require no human exposure. Every
36 effort should be made to design and implement these types of studies that do not expose humans
37 to potentially harmful bites. Since these studies would no longer be subject to review by the
38 HSRB, no further comments on this matter are relevant.
39
40 In spatial/area studies, the experimental unit to which repellents are being applied is a
41 particular space and/or area. Thus the sample size questions must address the number of
42 different spaces/areas that should be included, and not the number of subjects or traps within
43 each space. For a given response variable, determination of sample size can be addressed using
44 many different approaches. Two of the common ones include:
45
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1 Selecting a sample size that will ensure adequate statistical power (probability of detection of
2 an effect of a desired size).
3 Selecting a sample size that will ensure estimation of an effect of a desired size with desired
4 accuracy.
5
6 In either case, sample size calculations will depend on:
7
8 The response variable: in efficacy studies, several different response variables can be
9 plausibly justified. These include, for example, number of bites during a given period, time to
10 first bite, or proportional reduction in number of bites. Each of these response variables
11 corresponds to a different probabilistic model and thus the actual size calculations would
12 need to be modified accordingly.
13 The size of the effect we wish to detect: Detection of a very small effect requires a much
14 larger sample than detection of a bigger effect. If, for example, we wish to be able to detect a
15 reduction as small as 20% in the number of bites of individuals exposed to a repellent relative
16 to those exposed to a placebo, we will need to design a larger experiment than if we wish to
17 detect reductions of at least 80%.
18 The heterogeneity (in terms of relevant differences) in the target population and other factors:
19 if we know that the efficacy of a product depends on gender, ethnicity, and other individual
20 attributes, but also on wind speed, humidity and other environmental factors, then the sample
21 size needs to be large enough to permit randomizing over these attributes or designing an
22 experiment in which these factors can be used, e.g., to define blocks. In any event, it is very
23 important to account for differences across experimental units that are known to affect the
24 response; these may confound results if not appropriately addressed. The possibility of
25 generalizing results from the trial to public usage depends greatly on whether systematic
26 effects on the response (other than the treatment itself) have been accounted for either
27 through randomization or through blocking.
28 The anticipated uncertainty associated with the estimated effect size: once every known
29 confounder has been accounted for, all other sources of uncertainty in the estimated model
30 parameters must be known or approximated. The size of this uncertainty is directly related to
31 the required sample size in the experiment.
32
33 2. What are best practices with respect to statistical analysis? How is censored data handled?
34
35 Implementing an analysis that is technically sound and consistent with the design of the
36 study (which in turn must be consistent with the stated goals of the study) is critical. For
37 example, the standard assumption of normality typically is not appropriate when the response
38 variable is time to an event or when it is a count variable (such as the number of bites in a given
39 period).
40
41 In the case of space repellents, experiments are typically designed so that a treatment
42 group can be compared to a control group and relative efficacy can be estimated. Issues such as
43 the allocation of units (humans) to groups and of balance of other relevant factors become
44 absolutely critical and greatly affect the statistical analysis of the resulting data.
45
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1 3. What are the pros and cons of various endpoints (e.g., ending the study after a set number of
2 hours, waiting until the first landing/bite, other) to assess product efficacy (e.g., to meet
3 assumptions for appropriate statistical analyses) ?
4
5 Censoring, if unaccounted for, can seriously bias results. Most statistical methods can be
6 extended to account for some proportion of censored observations, but they tend to fail when the
7 proportion of unobserved responses is large. Thus, it is crucial to know enough about the
8 response variable and the factors that affect it so that a reasonable experiment can be designed
9 and the proportion of censored observations can be kept to a minimum. Minimizing the
10 proportion of censored responses should be an element in the design of the experiment.
11
12 Human Subjects
13
14 1. Why are human subjects necessary for such studies if the outcome measures are knockdowns
15 or mortality?
16
17 As with other areas of human subject research, environmental factors and study design
18 features play a large role in determining the ethical considerations and safety of human subjects.
19 The Belmont Report principles of respect for persons, beneficence and justice will serve well as
20 a guide in determining the ethical acceptability of any study that may presented to the HSRB.
21
22 Justification for the involvement of humans (as "bait") must provide sufficient
23 information to allow the HSRB to determine that the involvement is appropriate from both
24 scientific and ethical perspectives. Why the study design (including outcome measures) dictates
25 the need for human exposure should be explained. Information provided should include
26 alternative study designs, including a justification why those alternative approaches were ruled
27 out. The types of population(s) to be tested should be explained and justified. While it is
28 presumed that it is unlikely that issues relating to vulnerable populations will arise in this type of
29 testing, consent issue should be adequately presented in the proposals.
30
31 2. What are the potential risks to treated subjects (e.g. inhalation, dermal effects)? What are
32 exclusion criteria in subject selection to avoid such risks? How is the degree of risk related
33 to dosage, ingredient, formulations, and aerosol pressure?
34
35 Details about possible risks from inhalation and contact routes will be important, as will
36 the steps taken to mitigate or minimize those risks. Inclusion and exclusion criteria for the study
37 need to be included. General steps such as not exposing persons with asthma, other breathing
38 problems and product or class sensitivity would be appropriate, but each product protocol would
39 have to adequately answer questions such as these before the test (Note: this raises a similar
40 "justice/beneficence" issue that FDA faces; namely, if products are tested in a study population
41 that excludes persons likely to react negatively to the product, but the product will be used by
42 those persons or groups after approval, then they may be exposed to risks that are unquantified).
43
44 If protective clothing is proposed, a description of the protection afforded and the impact
45 on the study design (e.g., decrease in ability to attract insects) should be included. Duration of
46 exposure needs to be described and the potential risks - including fatigue and heat-related
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1 illness, agent exposure (dosage, ingredient, etc.) and vector exposure (lab-raised versus wild) -
2 adequately addressed. Prior testing (e.g., laboratory, animal, human, computer modeling)
3 information may be required to adequately assess welfare concerns. References to EPA agent
4 approval and other known agent information will be important for determining safety and
5 assessing risk. This risk information will be considered in relation to the societal benefit, hence
6 scientific validity and the soundness of study design will be important in these studies as they
7 have been in other studies considered by the HSRB.
8
9 3. What is the methodological rationale for continuous versus intermittent exposure? How do
10 human risk differ for these types of exposures? Will exposure start at the beginning of the test
11 period immediately after release of the product?
12
13 No additional Board comments on either Dr. Strickman's or EPA response.
14
15 4. If the test agent has properties to repel or destroy an insect, what is the relationship (if any) to
16 a related mechanism of action to humans?
17
18 No additional Board comments on either Dr. Strickman's or EPA response.
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1 REFERENCES
2
3 Carley JM. 2009a. Ethics Review of Completed Carroll-Loye Field Mosquito Repellent Efficacy
4 Study SPC-001. Dated January 23, 2009. Unpublished document prepared by Office of Pesticide
5 Programs, United States Environmental Protection Agency.
6
7 Carley JM. 2009b. Ethics Review of Completed Carroll-Loye Field Tick Repellent Efficacy
8 Study SPC-002. Dated January 23, 2009. Unpublished document prepared by Office of Pesticide
9 Programs, United States Environmental Protection Agency.
10
11 Carroll S. 2008a. Efficacy Test of Picaridin-Based Personal Repellants with Mosquitoes Under
12 Field Conditions. MRID 47535201. Dated August 19, 2008. Unpublished study prepared by
13 Carroll-Loye Biological Research.
14
15 Carroll S. 2008b. Efficacy Test of Picari din-Based Personal Repellants with Mosquitoes Under
16 Field Conditions (Protocol SPC-001). Email to John M. Carley transmitting supplemental
17 correspondence between Carroll-Loye Biological Research and Independent Investigations
18 Review Board, Inc., concerning SPC-001, with enclosures. Dated November 7, 2008.
19 Unpublished document prepared by Carroll-Loye Biological Research.
20
21 Carroll S. 2008c. Efficacy Test of Picari din-Based Personal Tick Repellants. MRID 47535202.
22 Dated August 19, 2008. Unpublished study prepared by Carroll-Loye Biological Research.
23
24 Carroll S. 2008d. Efficacy Test of Picari din-Based Personal Tick Repellants (Protocol SPC-002).
25 Email to John M. Carley transmitting supplemental correspondence between Carroll-Loye
26 Biological Research and Independent Investigations Review Board, Inc., concerning SPC-002,
27 with enclosures. Dated November 7, 2008. Unpublished document prepared by Carroll-Loye
28 Biological Research.
29
30 EPA HSRB. 2008. October 24-26, 2007 EPA Human Studies Review Board Meeting Report.
31
32 EPA HSRB. 2009. October 21-22, 2008 EPA Human Studies Review Board Meeting Report.
33
34 Fradin MS, Day JF. 2002. Comparative Efficacy Of Insect Repellents Against Mosquito Bites.
3 5 New England Journal of Medicine 347(l):13-8.
36
37 Qiu YT, Smallegange RC, Van Loon JJ, Ter Braak CJ, Takken W. 2006. Interindividual
38 variation in the attractiveness of human odours to the malaria mosquito Anopheles gambiae s. s.
39 Medical and veterinary entomology 20(3):280-7.
40
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