Final Draft Dated September 2 , 2010

Page 1 of 17 EPA

- HSRB

- 10

- 01 1 2 Paul Anastas, PhD 3 EPA Science Advisor 4 Office of the Science Advisor 5 1200 Pennsylvania Avenue, NW 6 Washington, DC 20460 7 8 Subject: June 23, 2010 EPA Human Studies Review Board Meeting Report 9 10 Dear Dr. Anastas, 11 12 The United States Environmental Protection Agency (EPA or Agency) requested that the 13 Human Studies Review Board (HSRB ) review two completed repellent efficacy studies 14 conducted b y Carroll

- Lo ye Biological Research, Inc. (CLBR) of Davis, California. These two 15 studies involved intentional exposure of human volunteers to picaridin

- containing insect 16 repellents. The Agency proposes to rel y on these two studies, conducted after publication of the 17 EPA’s expanded final rule for protection of subjects in human research (40 CFR 26) on February 18 6, 2006 (71 Federal Register 24, 6137), for regulatory actions under the pesticide laws. 19 20 The Agency also provided the HSRB with additional information on two informative 21 topics: revised Agency guidelines for performance testing of topically applied repellent products, 22 to be released for use b y investigators and sponsors of new studies; and the recent settlement 23 agreement reached between the Agency and six external parties to resolve litigation related to 24 EPA’s 2006 rule for the protection of human subjects of research. 25 26 The enclosed report provides the Board’s response to EPA charge questions presented at 27 the June 23, 2010 meeting. In addition, the report includes some additional recommendations for 28 revising the Agency repellent testing guidelines before release. 29 30 Assessment of Completed Carroll

- Loye Biological Research Study LNX

- 002: Efficacy Test 31 of KBR 3023 (Picaridin, Icaridin)

- Based Personal Insect Repellents (20% Cream and 32 20% Spray) with Black Flies Under Field Conditions

. 33 34 Science 35 36

• The Board concurred with the Agency ’s assessment that this study provides scientifically 37 valid results to assess the repellent efficacy against black flies for the formulations tested. 38 39 Ethics 40 41

• The Board concurred with the Agency ’s assessment that the study submitted fo r review 42 was conducted in substantial compliance with subparts K and L of 40 CFR 26. 43Final Draft Dated July 28, 2010

Page 2 of 17 Assessment of Completed Carroll

- Loye Biological Research Study LNX

- 003: Efficacy Test 44 of KBR 3023 (Picaridin; Icaridin)

- Based Personal Insect Repellents (20% Cream and 45 2 0% Spray) with Ticks Under Laboratory Conditions. 46 47 Science 48 49

• The Board concurred with the Agency ’s assessment that this study provides scientifically 50 valid results to assess the repellent efficacy against ticks for the formulations tested. 51 However, the high frequency of participants for whom the repellent’s protection time 52 exceeded the long duration of the study creates statistical challenges in evaluating a 53 specific protection time. 54 55 Ethics 56 57

• The Board concurred with the Agency ’s assessment that the study s ubmitted for review 58 was conducted in substantial compliance with subparts K and L of 40 CFR 26. 59

Revised Agency Guidelines for Performance Testing of Topically Applied Insect Repellents 60 61 The Board was not given a charge for consideration of the revised guidelines, but did 62 have several comments designed to enhance the utility of the document. The Board felt that the 63 revised Agency

guidelines will provide sponsors and researchers with helpful guidance in the 64 design of future efficacy tests of topically

applied insect repellents. Before releasing these 65 revised guidelines publicly , however, the Board recommended several changes or clarifications, 66 including: 67 68

• Removal of the maximum

- likelihood method requirement in the data analy sis section; 69

• Clarification of recomm endations regarding the use of positive controls, particularly with 70 respect to the number of controls and the rationale for including them in the study ; 71

• Careful consideration of recommendations regarding the recruitment and inclusion of so

72 called ‘vulnerab le’ populations, including racial and ethnic minorities; and 73

• Encouraging the use of study designs that will enable investigators to collect data that will 74 allow quantitative measurement of the repellent efficacy during the complete protection 75 period. 76 77 Finally , as at previous meetings, the Board underscored that it would continue to evaluate 78 protocols submitted for review to the HSRB based on appropriate statistical assumptions and 79 anal ytic plans and thus might recommend rejection of a protocol even if it fo llowed the revised 80 Guidelines explicitly

. 81 82 Sincerel y, 83

84 Sean Philpott, PhD, MSBioethics 85 Chair 86 EPA Human Studies Review Board 87Final Draft Dated September 2 , 2010

Page 3 of 17 NOTICE 88 89 This report has been written as part of the activities of the EPA Human Studies Review 90 Board, a Federal advisory committe e providing advice, information and recommendations on 91 issues related to scientific and ethical aspects of human subjects research. This report has not 92 been reviewed for approval by the Agency

and, hence, the contents of this report do not 93 necessarily

rep resent the view and policies of the Environmental Protection Agency , nor of other 94 agencies in the Executive Branch of the Federal government, nor does the mention of trade 95 names or commercial products constitute a recommendation for use. You may obtain further 96 information about the EPA Human Studies Review Board from its website at 97 http://www.epa.gov/osa/hsrb

. You may also contact the HSRB Designated Federal Officer, via 98

e

- mail at phre@epa.gov 99 100 In preparing this document, the Board carefull y considered all information provided and 101 presented b y the Agency presenters, as well as information presented b y public commenters. 102 This document addresses the information provided and pre sented within the structure of the 103 charge b y the Agency

. 104Final Draft Dated July 28, 2010

Page 4 of 17 US ENVIRONMENTAL PROTECTION AGENCY 105 HUMAN STUDIES REVIEW BOARD 106 107 Chair 108 109 Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union 110 Graduate College and the Mount Sinai School of Medicine, Schenectady, NY 111 112 Vice Chair 113 114 Janice Chambers, PhD, DABT, William L . Giles Distinguished Professor, Director, Center for 115 Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University
, 116 Mississippi State, MS 117 118 Members 119 120 George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada

121 Reno Center for Research Design and Anal ys is, University of Nevada

- Reno, 1664 N. Virginia 122 Street, Reno, NV 123 124 Vanessa Northington Gamble, MD, PhD, Univers ity Professor of Medical Humanities, Professor 125 of Health Policy

and American Studies, The George Washington University , Washington, DC 126 127 Sidney

Green, Jr., PhD, Fellow of the ATS, Professor, Department of Pharmacology , Howard 128 University

College of Medicine, Washington, DC 129 130 Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University
, 131 Manhattan, KS 132 133 Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of 134 Arizona, Tucson, AZ 135 136

* Jose E. Manautou, PhD, Associate Professor of Toxicology , Department of Pharmaceutical 137 Science, University of Connecticut School of Pharmacy , 69 North Eagleville Road, Storrs, CT 138 139 Jerry

A. Menikoff, MD, JD, Director, Office of Human Subjects Research, Office of the 140 Director, National Institutes of Health, Bethesda, MD 141 142 *Rebecca Parkin, PhD, MPH, Associate Dean for Research and Public Health Practice, School 143 of Public Health and Human Services, The George Washington University, Washington, DC 144 145 William Popendorf, PhD, MPH , Professor, Department of Biology , Utah State University, 146 Lo gan, UT 147 148 Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of 149 Nebraska Medical Center, Omaha, NE 150Final Draft Dated September 2 , 2010

Page 5 of 17 151 Virginia Ashby

Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, 152 Veterans Health Administration 810 Vermont Ave., NW, Washington, DC 153 154 Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 155 Sciences, University of Florida, Gainesville, FL 156 157 Human Studies Review Board Staff 158 159 Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science 160 Advisor, United States Environmental Protection Agency , Washington, DC 161 162

* Not in attendance at June 23, 2010 Public Meeting 163Final Draft Dated July 28, 2010

Page 6 of 17 INTRODUCTION 164 165 On June 23, 2010, the United States Environmental Protection Agency ’s (EPA or 166 Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues 167 concerning: two completed repellent efficacy studies involving two registered insect repellents 168 containing picaridin conducted subsequent to publication of the EPA’s expanded final rule for 169 protection of subjects in human research. In accordance with 40 CFR 26.1602, EPA sought 170 HSRB review of these completed studies. Each of these completed studies is discu ssed more 171 fully

below. 172 173 In addition, the Agency provided the HSRB with additional information on two 174 informative topics: the revised Agency guidelines for performance testing of topically applied 175 repellent products, to be released for use b y investigators and sponsors of new studies; and a 176 recent settlement agreement reached between the Agency and six external parties to resolve 177 litigation related to EPA’s 2006 rule for the protection of human subjects of research. A 178
summary

of the Board’s conclusions conce rning the Agency ’s revised guidelines for 179 performance testing of topically applied repellent products is also provided below. 180 181 182 REVIEW PROCESS 183 184 On June 23, 2010, the Board conducted a public face

- to

- face meeting in Arlington, 185 Virginia. Advance notice of th e meeting was published in the Federal Register as “Human 186 Studies Review Board; Notice of Public Meeting” (75 Federal Register 109, 32461). 187 188 Following welcoming remarks from Agency officials, the Board heard presentations from 189 EPA on the following topics: two completed insect repellent efficacy studies involving 190 intentional human exposure to two registered insect repellents containing picardin (LNX

- 002 and 191 LNX

- 003) conducted b y Carroll

- Lo ye Biological Research, Inc. (CLBR) of Davis, CA. 192 193 The Board also aske d clarifying questions of several study sponsors and/or research 194 investigators, including: 195 196 Dr. Scott Carroll, Principal, Carroll

- Lo ye Biological Research 197 Mr. Shawn King, Director of Operations, Carroll

- Lo ye Biological Research 198 199 Oral comments were provided by : 200 201 Dr. Scott Carroll, Principal, Carroll

- Lo ye Biological Research 202 203 No written public comments were provided. 204 205 For their deliberations, the Board considered the materials presented at the meeting, oral 206 comments, and Agency background documents (e.g., pu blished literature, sponsor and 207 investigator research reports, study protocols, data evaluation records, and Agency science and 208Final Draft Dated September 2 , 2010

Page 7 of 17 ethics reviews of proposed protocols and completed studies). A comprehensive list of 209 background documents is available online at http://www.regulations.gov. 210 211 212 CHARGE TO THE BOARD AND BOARD RESPONSE 213 214 Assessment of Completed Carroll

- Loye Biological Research Study LNX

- 002: Efficacy Test 215 of KBR 3023 (Picaridin; Icaridin)

- Based Personal Insect Repellents (20% Cream and 216 20% Spray) wit h Black Flies Under Field Conditions. 217 218 Overview of the Study 219 220 LNX

- 002 was a field

- based study to measure the effectiveness of picaridin as a black fly 221 repellent when used in one of two compound formulations (20% picardin KBR 3032 All

- Family 222 Insect Repellent Cream and 20% picaridin KBR 3023 All

- Family Insect Repellent Spray). 223 224 A total of 25 participants (selected from a pool of 119 volunteers diverse in age and 225 ethnicity) participated in this study . There were 15 participants (8 female and 7 male) in the 226 dosimetry

phase. Twenty treated and two untreated volunteers participated in the efficacy test, 227 with three more subjects serving as alternates. Ten participants tested each product formulation. 228 229 Dosimetry data accumulated in a previous Carroll

- Lo ye study ( LNX

- 001), along with 230 additional dosimetry data collected from 15 volunteers in LNX

- 002, were used for dose 231 selection. For the spray product each participant received 0.97μl/cm2 of product, equivalent to 232 0.9312 mg product/μl. For the cream product, the volumetric dose rate was 1.94 μl/cm2

, 233 equivalent to 1.9012 mg product/μl. For the spray product the mean picaridin dose was 98 mg 234 per participant and 202 mg/participant for the cream product. MOE calculations were based on 235 an assumed 70 kg participant and the acute dermal LD50 value for picaridin at the limit dose of 236 greater than 2,000 mg/kg. For the cream product the MOE = 690 and for the spray product the 237 MOE = 1429, both values exceed the target MOE = 100. 238 239 The efficacy of picaridin as a black fly repellent was determined in a study conducted at a 240 field site in the Mojave Desert of Southeastern California. Ten participants each were randoml y 241 assigned to one of two repellent treatments at the site for a total of ten volunteers per treatment. 242 Each treatment wa s applied to an equal number of males and females. Participants were treated 243 approximately

2.5 hours before field exposure. Untreated controls and participants treated with 244 repellent were exposed to black flies for one minute every 15 minutes until the rep ellent failed. 245 Treated participants were partnered in groups of two and each partner monitored the front of 246 their own exposed forearm and the back of their partner’s forearm. Black flies landing with 247 intent to bite (LIBe) were recorded, aspirated into containers, and identified in the laboratory

. 248 Participants remained in the test until the repellent failed as determined b y the first confirmed 249 LIBe, or until the end of the test period, whichever came first. The time at which the repellent 250 failed equaled the Complete Protection Time (CPT) for each subject. 251 252 Eleven of the 20 volunteers experienced a confirmed LIBe. Mean CPT values were not 253 significantl y different for the two formulations, with mean CPT calculated at 9.9 h for both 254Final Draft Dated July 28, 2010

Page 8 of 17 products. Median CPT values also were calculable for both products and were nearl y the same, 255 10.1 h for the cream product and 9.8 h for the spray product. 256 257 Science 258 259 Charge to the Board 260 261 Is the CLBR study L NX

- 002 sufficiently

sound, from a scientific perspective, to be used 262 to estim ate the duration of complete protection against black flies provided by the test repellents? 263 264 Board Response to the Charge 265 266 HSRB Recommendation 267 268 The Board concurred with the Agency ’s assessment (Sweeney 2010a) that this study 269 provides scientificall y vali d results to assess the repellent efficacy against black flies for the 270 formulations tested. 271 272 HSRB Detailed Recommendations and Rationale 273 274 This study (Carroll 2010a; Carroll 2010c) was conducted according to a protocol that had 275 been amended to take into ac count recommendations of the EPA and the HSRB (EPA HSRB 276 2009a). 277 278 The conduct of the dosimetry study and the field study

were very

similar to the conduct 279 of previous field repellent efficacy studies conducted by

Carroll

- Lo ye Biological Research. 280 281 The study

was carefully

conducted, with both sexes represented among the participants 282 and the endpoint being the first confirmed landing with intent to bite (LIBe) for each participant. 283 The margins of exposure (MOE) were high enough to not be a significant factor in the use of 284 either formulation. 285 286 The protocol had one scientific deviation that was considered minor. Namely , a black fl y 287 species not named in the protocol was present during field testing. Board members felt that this 288 deviation did not materially affe ct the scientific integrity and validity of the study

. 289 290 Ethics 291
Charge to the Board 292
Does available information support a determination that study L NX

- 002 was conducted 293 in substantial compliance with subparts K and L 40 CFR Part 26? 294Final Draft Dated September 2 , 2010

Page 9 of 17 Board Response to th e Charge 295

HSRB Recommendation 296
The Board concurred with the Agency ’s assessment (Carley 2010a) that the study 297 submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 298 26. 299

HSRB Detailed Recommendation and Rationale 300

The documents provided by Carroll

- Lo ye (Carroll 2010a; Carroll 2010c) state that the 301 study

was conducted in compliance with the requirements of the US EPA Good Laboratory 302 Practice Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; 303 FIF RA § 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study 304 was reviewed and approved by a commercial human subjects review committee, Independent 305 Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL . Documentation p rovided to the 306 EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule 307 (45 CFR Part 46, Subpart A) and found it in compliance. IIRB, Inc. also reviewed and approved 308 Amendment 1 of October 30, 2009 (Carley 2010a; IIRB, In c. 2010). 309 310 1. The Board concurred with the conclusions and factual observations relating to the study , as 311 detailed in the EPA’s Ethics Review (Carley 2010a). Specifically : 312 313

a. Prior HSRB and Agency Review. The requirements of 40 CFR §26.1125 for prior 314 submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol 315 were satisfied. The study (Carroll 2010a; Carroll 2010c) was conducted in accordance 316 with the protocol previously approved b y the HSRB (EPA HSRB 2009a). The Agency’s 317 ethics review of May 18, 2009 identified no deficiencies requiring correction relative to 318 40 CFR 26, subparts K and L , or to FIFRA § 12(a)(2)(P) (Carley 2010a). Because the 319 study

was conducted in California, the approval of CDPR was also required before the 320 study could be initiated. CDPR granted final approval of the amended protocol and 321 supporting documents on September 14, 2009. 322

b. Responsiveness to HSRB and Agency Reviews. Following the HSRB review, the protocol 323 and consent form were modified through Amendment 1 of August 13, 2009 (Carley 324 2010a; Carroll 2010c). This amendment incorporated changes responsive to the 325 comments of EPA, the HSRB, and California Department of Pesticide Regulation 326 (CDPR), as well as additional corrections initiated by the investigators and, at the request 327 of the sponsor, provision for collecting additional dose

- determination data for the cream 328 formulation, to be pooled with that originall y collected in study LNX

- 001. Agency 329 suggestions were also addressed satisfactorily in Amendment 1. The reference to third 330 party

coverage of costs of medical treatment noted by the HSRB was revised in 331 Amendment 1. IIRB, Inc. granted approval to Amendment 1 and supporting documents 332 on August 18, 2009 (Carley 2010a; Carroll 2010c). 333

c. Substantial Complianc e with Reporting Requirements (40 CFR §26 subpart M). The 334 primary

study report initially

failed to address the requirement of 40 CFR §26 subpart M, 335 §26.1303(b) to submit copies of “official notification to the sponsor or investigator ... that 336Final Draft Dated July 28, 2010

Page 10 of 17 research invo lving human subjects has been reviewed and approved by an IRB.” This 337 omission was corrected by the submission of a supplemental document catalogued as 338 MRID 48071301 (Carroll 2010c). Taking the two submissions together, along with the 339 separately

submitted documents reporting the roster and procedures of the IIRB, Inc., 340 (2010), the requirements of 40 CFR §26.1303 to document the ethical conduct of the 341 research were fully satisfied. Several Board members also remarked that, while current 342 regulations only require “substantial” compliance with these reporting requirements, the 343 submitted documents and supplementary materials from IIRB, Inc. met fully the 344 regulatory reporting requirements. 345

2. The Board concluded that this study met all applicable ethical requirements for research 346 involving human participants, in accordance with the following criteria that had been stated 347 in the Board’s prior review of this study protocol: 348 349

a. Acceptable risk

- benefit ratio. The risks to study participants were minimized 350 appropriatel y and were justified by the potential societal benefits, particularly data on the 351 efficacy

of these new formulations as personal insect repellents. 352 353

• Minors and pregnant or lactating women were excluded from participation, with 354
pregnancy confirmed by

over

- th e

- counter pregnancy testing on the day

of study or b y 355 opt

- out. The potential of stigma resulting from study exclusion was also appropriatel y 356 minimized. 357 358

• Based on toxicological data currentl y available for picaridin, coupled with appropriate 359 exclusion crit eria, study participants were unlikely to be at risk of adverse side effects 360 with exposure. 361 362

• Clear stopping rules and medical management procedures were in place, and no adverse 363 events related to product exposure were reported. 364 365

• The study was designed to minimize the likelihood of black fl y bites. 366 367 368 b. Voluntary and informed consent of all participants 369 370

• The study protocol included several mechanisms designed to minimize coercive 371 recruitment and enrollment. Monetary compensation was not so high as to undul y 372 influence participation. 373 374 3. There were three minor protocol deviations reported, including: 1) use of a superseded data 375 collection form; 2) The presence of a second species of biting black fl y at the field test site; 376 and 3) a gap of greater than 60 day s between dose determination and field testing. The Board 377 concluded, however, that these three deviations from the protocol were minor and did not 378 affect on the integrity of the research or the safety of participants. 379 380 381Final Draft Dated September 2 , 2010

Page 11 of 17 Assessment of Completed Carroll

- Loye Biological Research Study LNX

- 003: Efficacy Test 382 of KBR 3023 (Picaridin; Icaridin)

- Based Personal Insect Repellents (20% Cream and 383 20% Spray) with Ticks Under Laboratory Conditions. 384 385 Overview of the Study 386 387 LNX

- 003 was a laboratory

- based study to measure the effectiveness of picaridin as a tick 388 repellent when used in one of two compound formulations (20% picardin KBR 3032 All

- Family 389 Insect Repellent Cream and 20% picaridin KBR 3023 All

- Family Insect Repellent Spray). The 390 efficacy

of picaridin as a tick repellent was determined in a controlled laboratory setting by 391 placing laboratory

- raised, pathogen

- free Western black

- legged ticks ( Ixodes pacificus ) and 392 American dog ticks ( Dermacentor variabilis ) on picaridin

- treated and untreated forearms of 393 study

volunte ers, and then measuring the speed and distance that moving ticks would penetrate 394 into the treated area at 15

- minute intervals. Each treated participant served as their own untreated 395 control. Tick questing behavior was confirmed on the untreated arm of each subject before the 396 tick was used for repellency testing. 397 398 Dosimetry data accumulated in previous Carroll

- Loye studies (LNX

- 001 and L NX

- 002) 399 were used for dose selection. For the spray product each participant received 0.97μl/cm2 of 400 product, equivalent to 0.9312 mg product/μl. For the cream product, the volumetric dose rate was 401 1.94μl/cm2 , equivalent to 1.9012 mg product/μl. For the spray product the mean picaridin dose 402 was 100 mg per participant and 192 mg/participant for the cream product. MOE calculations 403 were based on an assumed 70 kg subject and the acute derm al LD50 value for picaridin at the 404 limit dose of greater than 2,000 mg/kg. For the spray product the mean picaridin dose was 100 mg 405 per subject and 192 mg/subject for the cream product. For the cream product the MOE = 741 and 406 for the spray

product the MOE = 1429, both values exceed the target MOE = 100. 407 408 A total of 23 participants (selected from a pool of 119 volunteers diverse in age and 409 ethnicity) participated in this study . Three were alternate participants; twenty were treated. In the 410 test phase, ten subjects participated in each product treatment test on each day . Treatments were 411 randomized within each gender. There were an equal number of male and female test subjects. 412 Each volunteer participated on only one day of the test, but testing included both tick species. All 413 ticks repelled or not, were removed from the arm of the participant before they had time to bite. 414 Exposure to each tick was for a period of 3 minutes on each arm. Further exposures to each 415 species were stopped for any subject who experienced a “crossing” b y that species into the 416 treated area of the forearm confirmed b y another crossing in either of the subsequent two 417 exposure periods. This endpoint was used to calculate the Complete Protection Time (CPT) for 418 each subject. 419 420 Despite an extremel y long duration of testing (15.25 h), more than half the study 421 participants did not experience a confirmed crossing. Thus, it was not possible to calculate a 422 median time to failure for the 20% cream. Although there was also significant right

- censorship 423 of the data for the 20% spray , there were enough data points to support calculation of the 424 Kaplan

- Meier (K

- M) median. The 20% cream had a mean CPT = 12.6 h against Ix. scapularis 425 and 15.3 h against D. variabilis . Most of these data were right

- censored an d a median could not 426 be calculated. For the 20% spray product, data collected with Ix. scapularis resulted in a median 427Final Draft Dated July 28, 2010

Page 12 of 17 CPT of 15 h while the mean CPT equaled 14.1 h. The mean CPT against D. variabilis was 14 h 428 and the median CPT was 14.1 h. 429 430 Science 431 432 Charg e to the Board 433 434 Is the CLBR study L NX

- 003 sufficiently

sound, from a scientific perspective, to be used 435 to estimate the duration of complete protection against ticks provided by the tested repellents? 436 437 Board Response to the Charge 438 439 HSRB Recommendation 440 441 The Board concurred with the Agency ’s assessment (Sweeney 2010b) that this study

was 442 conducted in accordance with Good Laboratory Practices as described in 40 CFR §160, the draft 443 EPA Guidelines §810.3700, and its own previously approved protocols and that i ts results 444 provide scientificall y sound data that can be used to estimate the duration of complete protection 445 against ticks. However, the high frequency of participants for whom the repellent’s protection 446 time exceeded the long duration (15.25 hours) of the study creates statistical challenges in 447 evaluating a specific protection time. 448 449 HSRB Detailed Recommendations and Rationale 450 451 This study (Carroll 2010b) was conducted according to the protocol previously approved 452 by the HSRB (HSRB 2009b). The protocol full y addressed the EPA’s comments in its review of 453 the protocol and responded to HSRB comments at the meeting in October 2009. The study 454 incorporated the results of prior dosimetry studies and lessons learned from previous laboratory 455 tick repellent effic acy studies conducted b y Carroll

- Lo ye Biological (Carroll 2010b). The study 456 seems to have been carefully conducted with twenty

participants (10 male and 10 female), two 457 formulations of one repellent at the same concentration (a cream and spray , tested on separate 458 day s), and exposures to two genera of ticks (ny mphal deer ticks (

Ixodes scapularis ) and ny mphal 459 American dog ticks ( Dermacentor variabilis )) during each 15

- minute interval for as long as 460 15.25 hours. The MOE’s were very high (741 and 1429 for the cream and spray , respectivel y) 461 and therefore protective of the participating volunteers. The report was clearly written and 462 detailed. 463 464 There was interest expressed by some Board members regarding the possible influence of 465 subjective differences in the manipulations (the “guiding” of the ticks shortly after they

were 466 placed on each participant) upon the results; however, discussion revealed that the time scale of 467 these manipulations was sufficiently short in relation to the three minutes they were allowed t o 468 remain on the arm to not be of concern. 469 470 There was concern expressed by some Board members regarding the high rates of right 471 censorship (especiall y the 60% and 80% rate in the cream formulation) caused by the lack of 472 confirmed crossings b y either tick species within the study duration (despite it lasting just over 473Final Draft Dated September 2 , 2010

Page 13 of 17 15 hours). It was not possible to calculate a median CPT for the cream formulation using 474 Kaplan

- Meier survival analy sis. The Agency may wish to consider the importance of these 475 computations and the use of Kaplan

- Meier median comple te protection time and its 95% l ower 476 confidence interval when making decision regarding the efficacy of insect repellents in future 477 studies. 478 479 Ethics 480 481 Charge to the Board 482 483 Does available information support a deter mination that study

L NX

- 003 was conducted 484 in substantial compliance with subparts K and L 40 CFR Part 26? 485 486 Board Response to the Charge 487 488 HSRB Recommendation 489 490 The Board concurred with the Agency ’s assessment that the study submitted for review 491 was conducted in substantial compliance with subparts K and L of 40 CFR 26. 492 493 HSRB Detailed Recommendations and Rationale 494 495 The document provided by Carroll

- Lo ye (Carroll 2010b) states that the study was 496 conducted in compliance with the requirements of the US EPA Good La boratory Practice 497 Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; FIFRA § 498 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study was 499 reviewed and approved by a commercial human subjects review c ommittee, Independent 500 Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL . Documentation provided to the 501 EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule 502 (45 CFR Part 46, Subpart A) and found it in c ompliance (c.f. Carley 2010b). 503 504 1. The Board concurred with the conclusions and factual observations relating to the study , as 505 detailed in the EPA’s Ethics Review (Carley 2010b). 506 507 2. The Board concluded that this study met all applicable ethical requirements for research 508 involving human participants, in accordance with the following criteria that had been stated 509 in the Board’s prior review of this study : 510 511

a. Acceptable risk

- benefit ratio. The risks to study participants were minimized 512 appropriatel y and wer e justified by the potential societal benefits, particularly data on the 513 efficacy

of these new formulations as personal insect repellents. 514 515

• Minors and pregnant or lactating women were excluded from participation, with 516
pregnancy confirmed by

over

- the

- counter pregnancy testing on the day

of study or b y 517 opt

- out. The potential of stigma resulting from study exclusion was also appropriatel y 518 minimized. 519Final Draft Dated July 28, 2010

Page 14 of 17 520

• Based on toxicological data currentl y available for picaridin, coupled with appropriate 521 exclusion criteria, st udy participants were unlikely to be at risk of adverse side effects 522 with exposure. 523 524

• Clear stopping rules and medical management procedures were in place, and no adverse 525 events related to product exposure were reported. 526 527

• The study was designed to minimize the likelihood of tick bites. 528 529

• Finally , the efficacy trial was conducted with laboratory

- raised ticks free of known 530 pathogens. 531 532 b. Voluntary and informed consent of all participants 533 534

• The study protocol included several mechanisms designed to minimize co ercive 535 recruitment and enrollment. Monetary compensation was not so high as to unduly 536 influence participation. 537 538 539 Revised Agency Guidelines for Performance Testing of Topically Applied Insect Repellents 540 (Product Performance Test Guidelines. OPPTS 810.3700: Insect Repellents to be Applied 541 to Human Skin). 542 543 In order to improve the quality and reliability

of repellent data submitted to the Agency
, 544 the EPA has developed a non

- binding guidance document (Product Performance Test 545 Guidelines. OPPTS 810.3700: Insect Repellents to be Applied to Human Skin) describing the 546 methodology

recommended by

the Agency

for collection of the necessary data to support 547 registration and labeling of topically applied products (Office of Chemical Safety and Pollution 548 Prevention 2010). These revised guidelines will replace the current “Product Performance Test 549 Guidelines. OPPTS 810.3700: Insect Repellents for Human Skin and Outdoor Premises” 550 released b y the Agency in December 1999. 551 552 A draft version of these guidelines was first reviewed b y the Board at its June 2006 553 meeting, and again at its October 2008 meeting (EPA HSRB 2006; EPA HSRB 2008). In these 554 reviews the Board made many suggestions for strengthening the scientific and ethical conduct of 555 this kind of research, and has encouraged E PA to further revise and publish its guidelines for 556 researchers considering this ty pe of study. 557 558 The EPA is expected to announce in the Federal Register the availability of these new 559 draft guidelines, for immediate use for sponsors and investigators. 560 561 HS RB Evaluation 562 563 While the Board was not given a charge for consideration of the guidelines, it did have 564 several comments to enhance the utility of the document. Specificall y, the Board felt that the 565Final Draft Dated September 2 , 2010

Page 15 of 17 document was well written and will provide sponsors and re searchers with helpful guidance in 566 the design of future efficacy tests of topicall y applied insect repellents. Before releasing these 567 revised guidelines publicly , however, the Board recommended the following changes or 568 clarifications: 569 570 1. Currently

(as de scribed in the revised Guidelines’ Objectives (c)(1)(i)), the preferred measure 571 of repellent efficacy is the duration of the Complete Protection Time (CPT). CPT is 572 important, but it is not the only (and perhaps not alway s the best) measure of effectivenes s. A 573 quantitative measure of the repellent’s effectiveness during the CPT might also be useful. 574 For example, if opportunities to make re

- applications are limited but less protection is 575 acceptable, then consumers may wish to use a repellant with a long CPT . If the repellant can 576 easily

be re

- applied however, consumers may want to choose a product with higher 577 effectiveness. The Agency thus may want to encourage the use of study designs that yi eld a 578 valid measure of repellent effectiveness within the CPT. 579 580 2. The revised Guidelines strongl y encourage the use of “positive [repellent] controls” (such as 581 DEET) in the design of repellent studies (c.f. Sec. (c)(viii) in the context of scientific study 582 design and in each of the specific guidance sections (j), (k), and (l)). The Board felt that the 583 justification for the use of positive controls seemed weak. It was not clear from a scientific 584 perspective just how such data would be used to interpret a given study or what value it 585 would add, while increasing the number of additional human participants exposed to the 586 DEET control without a clear scientific benefit would raise ethical concerns. The Board thus 587 recommended that the Agency clarify how and when positive controls should be included in 588 the study

design, either in the revised Guidelines or in the accompanying Standard 589 Evaluation Procedures (SEPs). 590 591 3. Maximum likelihood methods, as described in the Guidelines’ statistical analysis section, 592 require that the distribution of data be known. The Agency thus should remove from this 593 section the recommendation that maximum likelihood estimates be used if this distribution is 594 not known and the data cannot be transformed to fit an underlying distribution. Use of 595 maximum likelihood methods would, in this case, be inappropri ate. 596 597 4. The revised Guidelines, as currentl y written, intermingle scientific and ethical considerations. 598 The Board recommended that the Agency reexamine the organization and wording of the 599 document in order to distinguish between the two. 600 601 5. The Board al so recommended that, with respect to discussions of participant recruitment and 602 vulnerability , the following changes be made: 603 604

a. The term “race/ethnicity” should be used instead of just “race.” 605 b. When considering issues of participant vulnerability, the p rimary concern is not just 606 arbitrary exclusion of potentially vulnerable populations if provisions can be made to 607 ensure the safety of the participants. There is also the concern of potential benefits from 608 research participation for vulnerable groups. The Guidelines should be revised to address 609 this fact. 610Final Draft Dated July 28, 2010

Page 16 of 17 c. The Board also suggested that the EPA reexamine issues of language in recruitment and 611 consent materials in the Guidelines, referring the Agency specificall y to the Board’s 612 October 2009 report (EPA HSRB 2009b), which explicitly discusses such issues of 613 language. Investigators should also be urged to examine the recruitment population in 614 advance so that speakers of other languages are present as needed. 615 616 617 REFERENCES 618 619 Carley , J.M. 2010a. Ethics Review of Co mpleted Carroll

- Lo ye Black Fl y Repellent Field 620 Efficacy

Study L NX

- 002. Dated May

20, 2010. Unpublished document prepared b y the Office of 621 Chemical Safety and Pollution Prevention, United States Environmental Protection Agency. 622 623 Carley , J.M. 2010b. Request for Additional Documentation. Email Exchange between United 624 States Environmental Protection Agency and Independent Institutional Review Board, Inc. Dated 625 April 20, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution 626 Preventio n, United States Environmental Protection Agency

. 627 628 Carley , J.M. 2010c. Ethics Review of Completed Carroll

- Lo ye Tick Repellent Laboratory 629 Efficacy

Study L NX

- 003. Dated May

20, 2010. Unpublished document prepared b y the Office of 630 Chemical Safety and Pollutio n Prevention, United States Environmental Protection Agency

. 631 632 Carroll, S. 2010a. Efficacy Test of KBR3023 (Picaridin; I caridin)

- Based Personal 633 Insect Repellents (20% Cream and 20% Spray) with Black Flies under Field Conditions. Dated 634 April 5, 2010. Unpubli shed document prepared b y Carroll

- Lo ye Biological Research. MRID 635 48053802. 636 637 Carroll, S. 2010b. Efficacy Test of KBR3023 (Picaridin; Icaridin)

- Based Personal 638 Insect Repellents (20% Cream and 20% Spray) with Ticks Under Laboratory Conditions. Dated 639 April 5, 2010. Unpublished document prepared b y Carroll

- Lo ye Biological Research. MRID 640 48053801. 641 642 Carroll, S. 2010c. Supplemental Submission to EPA MRID 40853802. Dated April 19, 2009. 643 Unpublished document amendment prepared b y C arroll

- Lo ye Biological Research. MRID 644 48071301. 645 646 EPA Human Studies Review Board. 2006. June 27

- 30, 2006 Human Studies Review Board 647 Meeting Report. 648 649 EPA Human Studies Review Board. 2008. October 21

- 22, 2008 Human Studies Review Board 650 Meeting Report. 651 652 EPA Human Studies Review Board. 2009a. Jun e 24

- 25, 2009 Human Studies Review Board 653 Meeting Report. 654 655 EPA Human Studies Review Board. 2009b. October 20

- 21, 2009 Human Studies Review Board 656 Meeting Report. 657Final Draft Dated September 2 , 2010

Page 17 of 17 658 Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster and Procedures. 659 Unpubli shed materials prepared b y IIRB. 660 661 Office of Chemical Safety and Pollution Prevention. 2010. Product Performance Test Guidelines. 662 OPPTS 810.3700: Insect Repellents to be Applied to Human Skin. Draft document prepared by 663 the Office of Chem ical Safety and Pollution Prevention, United States Environmental Protection 664 Agency

. 665 666 Sweeney , K.J. 2010a. Science Review of Human Study of Black Fl y Repellent Performance. 667 Dated May

24, 2010. Unpublished document prepared b y the Office of Chemical Safety and 668 Pollution Prevention, United States Environmental Protection Agency

. 669 670 Sweeney , K.J. 2010b. Science Review of Human Study of Tick Repellent Performance. Dated 671 May

24, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution 672 Prevention, United States Environmental Protection Agency

. 673