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1 EPA-HSRB-10-01

2

3 Paul Anastas, PhD

4 EPA Science Advisor

5 Office of the Science Advisor

6 1200 Pennsylvania Avenue, NW

7 Washington, DC 20460 

8

9 Subject: June 23, 2010 EPA Human Studies Review Board Meeting Report

10

11 Dear Dr. Anastas,

12

13 The United States Environmental Protection Agency (EPA or Agency) requested that the 

14 Human Studies Review Board (HSRB) review two completed repellent efficacy studies 

15 conducted by Carroll-Loye Biological Research, Inc. (CLBR) of Davis, California. These two 

16 studies involved intentional exposure of human volunteers to picaridin-containing insect 

17 repellents. The Agency proposes to rely on these two studies, conducted after publication of the 

18 EPA’s expanded final rule for protection of subjects in human research (40 CFR 26) on February

19 6, 2006 (71 Federal Register 24, 6137), for regulatory actions under the pesticide laws. 

20

21 The Agency also provided the HSRB with additional information on two informative 

22 topics: revised Agency guidelines for performance testing of topically applied repellent products, 

23 to be released for use by investigators and sponsors of new studies; and the recent settlement 

24 agreement reached between the Agency and six external parties to resolve litigation related to 

25 EPA’s 2006 rule for the protection of human subjects of research. 

26

27 The enclosed report provides the Board’s response to EPA charge questions presented at 

28 the June 23, 2010 meeting. In addition, the report includes some additional recommendations for 

29 revising the Agency repellent testing guidelines before release.

30

31 Assessment of Completed Carroll-Loye Biological Research Study LNX-002: Efficacy Test 

32 of KBR 3023 (Picaridin, Icaridin) - Based Personal Insect Repellents (20% Cream and 

33 20% Spray) with Black Flies Under Field Conditions.

34

35 Science

36

37 • The Board concurred with the Agency’s assessment that this study provides scientifically

38 valid results to assess the repellent efficacy against black flies for the formulations tested. 

39

40 Ethics

41

42 • The Board concurred with the Agency’s assessment that the study submitted for review 

43 was conducted in substantial compliance with subparts K and L of 40 CFR 26.
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44 Assessment of Completed Carroll-Loye Biological Research Study LNX-003: Efficacy Test 

45 of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 

46 20% Spray) with Ticks Under Laboratory Conditions. 

47

48 Science

49

50 • The Board concurred with the Agency’s assessment that this study provides scientifically

51 valid results to assess the repellent efficacy against ticks for the formulations tested. 

52 However, the high frequency of participants for whom the repellent’s protection time 

53 exceeded the long duration of the study creates statistical challenges in evaluating a 

54 specific protection time.

55

56 Ethics

57

58 • The Board concurred with the Agency’s assessment that the study submitted for review 

59 was conducted in substantial compliance with subparts K and L of 40 CFR 26.

60 Revised Agency Guidelines for Performance Testing of Topically Applied Insect Repellents

61

62 The Board was not given a charge for consideration of the revised guidelines, but did 

63 have several comments designed to enhance the utility of the document. The Board felt that the 

64 revised Agency guidelines will provide sponsors and researchers with helpful guidance in the 

65 design of future efficacy tests of topically applied insect repellents. Before releasing these 

66 revised guidelines publicly, however, the Board recommended several changes or clarifications, 

67 including:

68

69 • Removal of the maximum-likelihood method requirement in the data analysis section;

70 • Clarification of recommendations regarding the use of positive controls, particularly with 

71 respect to the number of controls and the rationale for including them in the study;

72 • Careful consideration of recommendations regarding the recruitment and inclusion of so73 called ‘vulnerable’ populations, including racial and ethnic minorities; and

74 • Encouraging the use of study designs that will enable investigators to collect data that will 

75 allow quantitative measurement of the repellent efficacy during the complete protection 

76 period.

77

78 Finally, as at previous meetings, the Board underscored that it would continue to evaluate 

79 protocols submitted for review to the HSRB based on appropriate statistical assumptions and 

80 analytic plans and thus might recommend rejection of a protocol even if it followed the revised 

81 Guidelines explicitly.

82

83 Sincerely,

84

85 Sean Philpott, PhD, MSBioethics

86 Chair

87 EPA Human Studies Review Board
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88 NOTICE

89

90 This report has been written as part of the activities of the EPA Human Studies Review 

91 Board, a Federal advisory committee providing advice, information and recommendations on 

92 issues related to scientific and ethical aspects of human subjects research. This report has not 

93 been reviewed for approval by the Agency and, hence, the contents of this report do not 

94 necessarily represent the view and policies of the Environmental Protection Agency, nor of other 

95 agencies in the Executive Branch of the Federal government, nor does the mention of trade 

96 names or commercial products constitute a recommendation for use. You may obtain further 

97 information about the EPA Human Studies Review Board from its website at 

98 http://www.epa.gov/osa/hsrb. You may also contact the HSRB Designated Federal Officer, via 

99 e-mail at phre@epa.gov

100

101 In preparing this document, the Board carefully considered all information provided and 

102 presented by the Agency presenters, as well as information presented by public commenters. 

103 This document addresses the information provided and presented within the structure of the 

104 charge by the Agency.
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105 US ENVIRONMENTAL PROTECTION AGENCY

106 HUMAN STUDIES REVIEW BOARD

107

108 Chair

109

110 Sean Philpott, PhD, MSBioethics, Director for Research Ethics, The Bioethics Program of Union 

111 Graduate College and the Mount Sinai School of Medicine, Schenectady, NY

112

113 Vice Chair

114

115 Janice Chambers, PhD, DABT, William L. Giles Distinguished Professor, Director, Center for 

116 Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, 

117 Mississippi State, MS

118

119 Members

120

121 George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada122 Reno Center for Research Design and Analysis, University of Nevada-Reno, 1664 N. Virginia 

123 Street, Reno, NV

124

125 Vanessa Northington Gamble, MD, PhD, University Professor of Medical Humanities, Professor 

126 of Health Policy and American Studies, The George Washington University, Washington, DC

127

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

129 University College of Medicine, Washington, DC

130

131 Dallas E. Johnson, PhD, Professor Emeritus, Department of Statistics, Kansas State University, 

132 Manhattan, KS

133

134 Michael D. Lebowitz, PhD, FCCP, Retired Professor of Public Health & Medicine, University of 

135 Arizona, Tucson, AZ 

136

137 *Jose E. Manautou, PhD, Associate Professor of Toxicology, Department of Pharmaceutical 

138 Science, University of Connecticut School of Pharmacy, 69 North Eagleville Road, Storrs, CT

139

140 Jerry A. Menikoff, MD, JD, Director, Office of Human Subjects Research, Office of the 

141 Director, National Institutes of Health, Bethesda, MD

142

143 *Rebecca Parkin, PhD, MPH, Associate Dean for Research and Public Health Practice, School 

144 of Public Health and Human Services, The George Washington University, Washington, DC

145

146 William Popendorf, PhD, MPH, Professor, Department of Biology, Utah State University, 

147 Logan, UT 

148

149 Ernest D. Prentice, PhD, Associate Vice Chancellor for Academic Affairs, University of 

150 Nebraska Medical Center, Omaha, NE
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151

152 Virginia Ashby Sharpe, PhD, Medical Ethicist, National Center for Ethics in Health Care, 

153 Veterans Health Administration 810 Vermont Ave., NW, Washington, DC

154

155 Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural 

156 Sciences, University of Florida, Gainesville, FL 

157

158 Human Studies Review Board Staff

159

160 Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science 

161 Advisor, United States Environmental Protection Agency, Washington, DC 

162

163 * Not in attendance at June 23, 2010 Public Meeting
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164 INTRODUCTION

165

166 On June 23, 2010, the United States Environmental Protection Agency’s (EPA or 

167 Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues 

168 concerning: two completed repellent efficacy studies involving two registered insect repellents 

169 containing picaridin conducted subsequent to publication of the EPA’s expanded final rule for 

170 protection of subjects in human research. In accordance with 40 CFR 26.1602, EPA sought 

171 HSRB review of these completed studies. Each of these completed studies is discussed more 

172 fully below.

173

174 In addition, the Agency provided the HSRB with additional information on two 

175 informative topics: the revised Agency guidelines for performance testing of topically applied 

176 repellent products, to be released for use by investigators and sponsors of new studies; and a 

177 recent settlement agreement reached between the Agency and six external parties to resolve 

178 litigation related to EPA’s 2006 rule for the protection of human subjects of research. A 

179 summary of the Board’s conclusions concerning the Agency’s revised guidelines for 

180 performance testing of topically applied repellent products is also provided below.

181

182

183 REVIEW PROCESS

184

185 On June 23, 2010, the Board conducted a public face-to-face meeting in Arlington, 

186 Virginia. Advance notice of the meeting was published in the Federal Register as “Human 

187 Studies Review Board; Notice of Public Meeting” (75 Federal Register 109, 32461).

188

189 Following welcoming remarks from Agency officials, the Board heard presentations from 

190 EPA on the following topics: two completed insect repellent efficacy studies involving 

191 intentional human exposure to two registered insect repellents containing picardin (LNX-002 and 

192 LNX-003) conducted by Carroll-Loye Biological Research, Inc. (CLBR) of Davis, CA.

193

194 The Board also asked clarifying questions of several study sponsors and/or research 

195 investigators, including:

196

197 Dr. Scott Carroll, Principal, Carroll-Loye Biological Research

198 Mr. Shawn King, Director of Operations, Carroll-Loye Biological Research

199

200 Oral comments were provided by: 

201

202 Dr. Scott Carroll, Principal, Carroll-Loye Biological Research

203

204 No written public comments were provided.

205

206 For their deliberations, the Board considered the materials presented at the meeting, oral 

207 comments, and Agency background documents (e.g., published literature, sponsor and 

208 investigator research reports, study protocols, data evaluation records, and Agency science and 
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209 ethics reviews of proposed protocols and completed studies). A comprehensive list of 

210 background documents is available online at http://www.regulations.gov. 

211

212

213 CHARGE TO THE BOARD AND BOARD RESPONSE

214

215 Assessment of Completed Carroll-Loye Biological Research Study LNX-002: Efficacy Test 

216 of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 

217 20% Spray) with Black Flies Under Field Conditions.

218

219 Overview of the Study

220

221 LNX-002 was a field-based study to measure the effectiveness of picaridin as a black fly

222 repellent when used in one of two compound formulations (20% picardin KBR 3032 All-Family

223 Insect Repellent Cream and 20% picaridin KBR 3023 All-Family Insect Repellent Spray). 

224

225 A total of 25 participants (selected from a pool of 119 volunteers diverse in age and 

226 ethnicity) participated in this study. There were 15 participants (8 female and 7 male) in the 

227 dosimetry phase. Twenty treated and two untreated volunteers participated in the efficacy test, 

228 with three more subjects serving as alternates. Ten participants tested each product formulation. 

229

230 Dosimetry data accumulated in a previous Carroll-Loye study (LNX-001), along with 

231 additional dosimetry data collected from 15 volunteers in LNX-002, were used for dose 

selection. For the spray product each participant received 0.97μl/cm2232 of product, equivalent to 

0.9312 mg product/μl. For the cream product, the volumetric dose rate was 1.94 μl/cm2233 , 

234 equivalent to 1.9012 mg product/μl. For the spray product the mean picaridin dose was 98 mg 

235 per participant and 202 mg/participant for the cream product. MOE calculations were based on 

236 an assumed 70 kg participant and the acute dermal LD50 value for picaridin at the limit dose of 

237 greater than 2,000 mg/kg. For the cream product the MOE = 690 and for the spray product the 

238 MOE = 1429, both values exceed the target MOE = 100. 

239

240 The efficacy of picaridin as a black fly repellent was determined in a study conducted at a 

241 field site in the Mojave Desert of Southeastern California. Ten participants each were randomly 

242 assigned to one of two repellent treatments at the site for a total of ten volunteers per treatment. 

243 Each treatment was applied to an equal number of males and females. Participants were treated 

244 approximately 2.5 hours before field exposure. Untreated controls and participants treated with 

245 repellent were exposed to black flies for one minute every 15 minutes until the repellent failed. 

246 Treated participants were partnered in groups of two and each partner monitored the front of 

247 their own exposed forearm and the back of their partner’s forearm. Black flies landing with 

248 intent to bite (LIBe) were recorded, aspirated into containers, and identified in the laboratory. 

249 Participants remained in the test until the repellent failed as determined by the first confirmed 

250 LIBe, or until the end of the test period, whichever came first. The time at which the repellent 

251 failed equaled the Complete Protection Time (CPT) for each subject. 

252

253 Eleven of the 20 volunteers experienced a confirmed LIBe. Mean CPT values were not 

254 significantly different for the two formulations, with mean CPT calculated at 9.9 h for both 
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255 products. Median CPT values also were calculable for both products and were nearly the same, 

256 10.1 h for the cream product and 9.8 h for the spray product.

257

258 Science

259

260 Charge to the Board

261

262 Is the CLBR study LNX-002 sufficiently sound, from a scientific perspective, to be used 

263 to estimate the duration of complete protection against black flies provided by the test repellents?

264

265 Board Response to the Charge

266

267 HSRB Recommendation

268

269 The Board concurred with the Agency’s assessment (Sweeney 2010a) that this study

270 provides scientifically valid results to assess the repellent efficacy against black flies for the 

271 formulations tested.

272

273 HSRB Detailed Recommendations and Rationale

274

275 This study (Carroll 2010a; Carroll 2010c) was conducted according to a protocol that had 

276 been amended to take into account recommendations of the EPA and the HSRB (EPA HSRB 

277 2009a). 

278

279 The conduct of the dosimetry study and the field study were very similar to the conduct 

280 of previous field repellent efficacy studies conducted by Carroll-Loye Biological Research.

281

282 The study was carefully conducted, with both sexes represented among the participants 

283 and the endpoint being the first confirmed landing with intent to bite (LIBe) for each participant. 

284 The margins of exposure (MOE) were high enough to not be a significant factor in the use of 

285 either formulation.

286

287 The protocol had one scientific deviation that was considered minor. Namely, a black fly 

288 species not named in the protocol was present during field testing. Board members felt that this 

289 deviation did not materially affect the scientific integrity and validity of the study. 

290

291 Ethics

292 Charge to the Board

293 Does available information support a determination that study LNX-002 was conducted 

294 in substantial compliance with subparts K and L 40 CFR Part 26?
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295 Board Response to the Charge

296 HSRB Recommendation

297 The Board concurred with the Agency’s assessment (Carley 2010a) that the study

298 submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 

299 26. 

300 HSRB Detailed Recommendation and Rationale

301 The documents provided by Carroll-Loye (Carroll 2010a; Carroll 2010c) state that the 

302 study was conducted in compliance with the requirements of the US EPA Good Laboratory

303 Practice Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; 

304 FIFRA § 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study

305 was reviewed and approved by a commercial human subjects review committee, Independent 

306 Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL. Documentation provided to the 

307 EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule 

308 (45 CFR Part 46, Subpart A) and found it in compliance. IIRB, Inc. also reviewed and approved 

309 Amendment 1 of October 30, 2009 (Carley 2010a; IIRB, Inc. 2010).

310

311 1. The Board concurred with the conclusions and factual observations relating to the study, as 

312 detailed in the EPA’s Ethics Review (Carley 2010a). Specifically:

313

314 a. Prior HSRB and Agency Review. The requirements of 40 CFR §26.1125 for prior 

315 submission of the protocol to EPA and of §26.1601 for HSRB review of the protocol 

316 were satisfied. The study (Carroll 2010a; Carroll 2010c) was conducted in accordance 

317 with the protocol previously approved by the HSRB (EPA HSRB 2009a). The Agency’s 

318 ethics review of May 18, 2009 identified no deficiencies requiring correction relative to 

319 40 CFR 26, subparts K and L, or to FIFRA § 12(a)(2)(P) (Carley 2010a). Because the 

320 study was conducted in California, the approval of CDPR was also required before the 

321 study could be initiated. CDPR granted final approval of the amended protocol and 

322 supporting documents on September 14, 2009.

323 b. Responsiveness to HSRB and Agency Reviews. Following the HSRB review, the protocol 

324 and consent form were modified through Amendment 1 of August 13, 2009 (Carley

325 2010a; Carroll 2010c). This amendment incorporated changes responsive to the 

326 comments of EPA, the HSRB, and California Department of Pesticide Regulation 

327 (CDPR), as well as additional corrections initiated by the investigators and, at the request 

328 of the sponsor, provision for collecting additional dose-determination data for the cream 

329 formulation, to be pooled with that originally collected in study LNX-001. Agency

330 suggestions were also addressed satisfactorily in Amendment 1. The reference to third 

331 party coverage of costs of medical treatment noted by the HSRB was revised in 

332 Amendment 1. IIRB, Inc. granted approval to Amendment 1 and supporting documents 

333 on August 18, 2009 (Carley 2010a; Carroll 2010c). 

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

335 primary study report initially failed to address the requirement of 40 CFR §26 subpart M, 

336 §26.1303(b) to submit copies of “official notification to the sponsor or investigator ... that 
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337 research involving human subjects has been reviewed and approved by an IRB.” This 

338 omission was corrected by the submission of a supplemental document catalogued as 

339 MRID 48071301 (Carroll 2010c). Taking the two submissions together, along with the 

340 separately submitted documents reporting the roster and procedures of the IIRB, Inc., 

341 (2010), the requirements of 40 CFR §26.1303 to document the ethical conduct of the 

342 research were fully satisfied. Several Board members also remarked that, while current 

343 regulations only require “substantial” compliance with these reporting requirements, the 

344 submitted documents and supplementary materials from IIRB, Inc. met fully the 

345 regulatory reporting requirements.

346 2. The Board concluded that this study met all applicable ethical requirements for research 

347 involving human participants, in accordance with the following criteria that had been stated 

348 in the Board’s prior review of this study protocol:

349

350 a. Acceptable risk-benefit ratio. The risks to study participants were minimized 

351 appropriately and were justified by the potential societal benefits, particularly data on the 

352 efficacy of these new formulations as personal insect repellents.

353

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

355 pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by 

356 opt-out. The potential of stigma resulting from study exclusion was also appropriately 

357 minimized. 

358

359 • Based on toxicological data currently available for picaridin, coupled with appropriate 

360 exclusion criteria, study participants were unlikely to be at risk of adverse side effects 

361 with exposure. 

362

363 • Clear stopping rules and medical management procedures were in place, and no adverse 

364 events related to product exposure were reported.

365

366 • The study was designed to minimize the likelihood of black fly bites. 

367

368

369 b. Voluntary and informed consent of all participants

370

371 • The study protocol included several mechanisms designed to minimize coercive 

372 recruitment and enrollment. Monetary compensation was not so high as to unduly 

373 influence participation.

374

375 3. There were three minor protocol deviations reported, including: 1) use of a superseded data 

376 collection form; 2) The presence of a second species of biting black fly at the field test site; 

377 and 3) a gap of greater than 60 days between dose determination and field testing. The Board 

378 concluded, however, that these three deviations from the protocol were minor and did not 

379 affect on the integrity of the research or the safety of participants. 

380

381
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382 Assessment of Completed Carroll-Loye Biological Research Study LNX-003: Efficacy Test 

383 of KBR 3023 (Picaridin; Icaridin) - Based Personal Insect Repellents (20% Cream and 

384 20% Spray) with Ticks Under Laboratory Conditions.

385

386 Overview of the Study

387

388 LNX-003 was a laboratory-based study to measure the effectiveness of picaridin as a tick 

389 repellent when used in one of two compound formulations (20% picardin KBR 3032 All-Family

390 Insect Repellent Cream and 20% picaridin KBR 3023 All-Family Insect Repellent Spray). The 

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

392 placing laboratory-raised, pathogen-free Western black-legged ticks (Ixodes pacificus) and 

393 American dog ticks (Dermacentor variabilis) on picaridin-treated and untreated forearms of 

394 study volunteers, and then measuring the speed and distance that moving ticks would penetrate 

395 into the treated area at 15-minute intervals. Each treated participant served as their own untreated 

396 control. Tick questing behavior was confirmed on the untreated arm of each subject before the 

397 tick was used for repellency testing. 

398

399 Dosimetry data accumulated in previous Carroll-Loye studies (LNX-001 and LNX-002) 

were used for dose selection. For the spray product each participant received 0.97μl/cm2400 of 

401 product, equivalent to 0.9312 mg product/μl. For the cream product, the volumetric dose rate was 

1.94μl/cm2402 , equivalent to 1.9012 mg product/μl. For the spray product the mean picaridin dose 

403 was 100 mg per participant and 192 mg/participant for the cream product. MOE calculations 

404 were based on an assumed 70 kg subject and the acute dermal LD50 value for picaridin at the 

405 limit dose of greater than 2,000 mg/kg. For the spray product the mean picaridin dose was 100 mg 

406 per subject and 192 mg/subject for the cream product. For the cream product the MOE = 741 and 

407 for the spray product the MOE = 1429, both values exceed the target MOE = 100.

408

409 A total of 23 participants (selected from a pool of 119 volunteers diverse in age and 

410 ethnicity) participated in this study. Three were alternate participants; twenty were treated. In the 

411 test phase, ten subjects participated in each product treatment test on each day. Treatments were 

412 randomized within each gender. There were an equal number of male and female test subjects. 

413 Each volunteer participated on only one day of the test, but testing included both tick species. All 

414 ticks repelled or not, were removed from the arm of the participant before they had time to bite. 

415 Exposure to each tick was for a period of 3 minutes on each arm. Further exposures to each 

416 species were stopped for any subject who experienced a “crossing” by that species into the 

417 treated area of the forearm confirmed by another crossing in either of the subsequent two 

418 exposure periods. This endpoint was used to calculate the Complete Protection Time (CPT) for 

419 each subject.

420

421 Despite an extremely long duration of testing (15.25 h), more than half the study

422 participants did not experience a confirmed crossing. Thus, it was not possible to calculate a 

423 median time to failure for the 20% cream. Although there was also significant right-censorship 

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

425 Kaplan-Meier (K-M) median. The 20% cream had a mean CPT = 12.6 h against Ix. scapularis 

426 and 15.3 h against D. variabilis. Most of these data were right-censored and a median could not 

427 be calculated. For the 20% spray product, data collected with Ix. scapularis resulted in a median 
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428 CPT of 15 h while the mean CPT equaled 14.1 h. The mean CPT against D. variabilis was 14 h 

429 and the median CPT was 14.1 h.

430

431 Science

432

433 Charge to the Board

434

435 Is the CLBR study LNX-003 sufficiently sound, from a scientific perspective, to be used 

436 to estimate the duration of complete protection against ticks provided by the tested repellents?

437

438 Board Response to the Charge

439

440 HSRB Recommendation 

441

442 The Board concurred with the Agency’s assessment (Sweeney 2010b) that this study was 

443 conducted in accordance with Good Laboratory Practices as described in 40 CFR §160, the draft 

444 EPA Guidelines §810.3700, and its own previously approved protocols and that its results 

445 provide scientifically sound data that can be used to estimate the duration of complete protection 

446 against ticks. However, the high frequency of participants for whom the repellent’s protection 

447 time exceeded the long duration (15.25 hours) of the study creates statistical challenges in 

448 evaluating a specific protection time.

449

450 HSRB Detailed Recommendations and Rationale 

451

452 This study (Carroll 2010b) was conducted according to the protocol previously approved 

453 by the HSRB (HSRB 2009b). The protocol fully addressed the EPA’s comments in its review of 

454 the protocol and responded to HSRB comments at the meeting in October 2009. The study

455 incorporated the results of prior dosimetry studies and lessons learned from previous laboratory

456 tick repellent efficacy studies conducted by Carroll-Loye Biological (Carroll 2010b). The study

457 seems to have been carefully conducted with twenty participants (10 male and 10 female), two 

458 formulations of one repellent at the same concentration (a cream and spray, tested on separate 

459 days), and exposures to two genera of ticks (nymphal deer ticks (Ixodes scapularis) and nymphal 

460 American dog ticks (Dermacentor variabilis)) during each 15-minute interval for as long as 

461 15.25 hours. The MOE’s were very high (741 and 1429 for the cream and spray, respectively) 

462 and therefore protective of the participating volunteers. The report was clearly written and 

463 detailed.

464

465 There was interest expressed by some Board members regarding the possible influence of 

466 subjective differences in the manipulations (the “guiding” of the ticks shortly after they were 

467 placed on each participant) upon the results; however, discussion revealed that the time scale of 

468 these manipulations was sufficiently short in relation to the three minutes they were allowed to 

469 remain on the arm to not be of concern. 

470

471 There was concern expressed by some Board members regarding the high rates of right 

472 censorship (especially the 60% and 80% rate in the cream formulation) caused by the lack of 

473 confirmed crossings by either tick species within the study duration (despite it lasting just over 
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474 15 hours). It was not possible to calculate a median CPT for the cream formulation using 

475 Kaplan-Meier survival analysis. The Agency may wish to consider the importance of these 

476 computations and the use of Kaplan-Meier median complete protection time and its 95% lower 

477 confidence interval when making decision regarding the efficacy of insect repellents in future 

478 studies.

479

480 Ethics

481

482 Charge to the Board 

483

484 Does available information support a determination that study LNX-003 was conducted 

485 in substantial compliance with subparts K and L 40 CFR Part 26?

486

487 Board Response to the Charge

488

489 HSRB Recommendation

490

491 The Board concurred with the Agency’s assessment that the study submitted for review 

492 was conducted in substantial compliance with subparts K and L of 40 CFR 26.

493

494 HSRB Detailed Recommendations and Rationale

495

496 The document provided by Carroll-Loye (Carroll 2010b) states that the study was 

497 conducted in compliance with the requirements of the US EPA Good Laboratory Practice 

498 Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K, L and M; FIFRA § 

499 12(a)(2)(P); and the California Code of Regulations Title 3, Section 6710. The study was 

500 reviewed and approved by a commercial human subjects review committee, Independent 

501 Institutional Review Board Inc. (IIRB, Inc.) of Plantation, FL. Documentation provided to the 

502 EPA indicated that IIRB, Inc. reviewed this study pursuant to the standards of the Common Rule 

503 (45 CFR Part 46, Subpart A) and found it in compliance (c.f. Carley 2010b).

504

505 1. The Board concurred with the conclusions and factual observations relating to the study, as 

506 detailed in the EPA’s Ethics Review (Carley 2010b). 

507

508 2. The Board concluded that this study met all applicable ethical requirements for research 

509 involving human participants, in accordance with the following criteria that had been stated 

510 in the Board’s prior review of this study:

511

512 a. Acceptable risk-benefit ratio. The risks to study participants were minimized 

513 appropriately and were justified by the potential societal benefits, particularly data on the 

514 efficacy of these new formulations as personal insect repellents.

515

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

517 pregnancy confirmed by over-the-counter pregnancy testing on the day of study or by 

518 opt-out. The potential of stigma resulting from study exclusion was also appropriately 

519 minimized. 
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520

521 • Based on toxicological data currently available for picaridin, coupled with appropriate 

522 exclusion criteria, study participants were unlikely to be at risk of adverse side effects 

523 with exposure. 

524

525 • Clear stopping rules and medical management procedures were in place, and no adverse 

526 events related to product exposure were reported.

527

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

529

530 • Finally, the efficacy trial was conducted with laboratory-raised ticks free of known 

531 pathogens. 

532

533 b. Voluntary and informed consent of all participants

534

535 • The study protocol included several mechanisms designed to minimize coercive 

536 recruitment and enrollment. Monetary compensation was not so high as to unduly

537 influence participation.

538

539

540 Revised Agency Guidelines for Performance Testing of Topically Applied Insect Repellents 

541 (Product Performance Test Guidelines. OPPTS 810.3700: Insect Repellents to be Applied 

542 to Human Skin).

543

544 In order to improve the quality and reliability of repellent data submitted to the Agency, 

545 the EPA has developed a non-binding guidance document (Product Performance Test 

546 Guidelines. OPPTS 810.3700: Insect Repellents to be Applied to Human Skin) describing the 

547 methodology recommended by the Agency for collection of the necessary data to support 

548 registration and labeling of topically applied products (Office of Chemical Safety and Pollution 

549 Prevention 2010). These revised guidelines will replace the current “Product Performance Test 

550 Guidelines. OPPTS 810.3700: Insect Repellents for Human Skin and Outdoor Premises” 

551 released by the Agency in December 1999.

552

553 A draft version of these guidelines was first reviewed by the Board at its June 2006 

554 meeting, and again at its October 2008 meeting (EPA HSRB 2006; EPA HSRB 2008). In these 

555 reviews the Board made many suggestions for strengthening the scientific and ethical conduct of 

556 this kind of research, and has encouraged EPA to further revise and publish its guidelines for 

557 researchers considering this type of study. 

558

559 The EPA is expected to announce in the Federal Register the availability of these new 

560 draft guidelines, for immediate use for sponsors and investigators. 

561

562 HSRB Evaluation

563

564 While the Board was not given a charge for consideration of the guidelines, it did have 

565 several comments to enhance the utility of the document. Specifically, the Board felt that the 
Final Draft Dated September 2, 2010

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566 document was well written and will provide sponsors and researchers with helpful guidance in 

567 the design of future efficacy tests of topically applied insect repellents. Before releasing these 

568 revised guidelines publicly, however, the Board recommended the following changes or 

569 clarifications:

570

571 1. Currently (as described in the revised Guidelines’ Objectives (c)(1)(i)), the preferred measure 

572 of repellent efficacy is the duration of the Complete Protection Time (CPT). CPT is 

573 important, but it is not the only (and perhaps not always the best) measure of effectiveness. A 

574 quantitative measure of the repellent’s effectiveness during the CPT might also be useful. 

575 For example, if opportunities to make re-applications are limited but less protection is 

576 acceptable, then consumers may wish to use a repellant with a long CPT. If the repellant can 

577 easily be re-applied however, consumers may want to choose a product with higher

578 effectiveness. The Agency thus may want to encourage the use of study designs that yield a 

579 valid measure of repellent effectiveness within the CPT. 

580

581 2. The revised Guidelines strongly encourage the use of “positive [repellent] controls” (such as 

582 DEET) in the design of repellent studies (c.f. Sec. (c)(viii) in the context of scientific study

583 design and in each of the specific guidance sections (j), (k), and (l)). The Board felt that the 

584 justification for the use of positive controls seemed weak. It was not clear from a scientific 

585 perspective just how such data would be used to interpret a given study or what value it 

586 would add, while increasing the number of additional human participants exposed to the 

587 DEET control without a clear scientific benefit would raise ethical concerns. The Board thus 

588 recommended that the Agency clarify how and when positive controls should be included in 

589 the study design, either in the revised Guidelines or in the accompanying Standard 

590 Evaluation Procedures (SEPs).

591

592 3. Maximum likelihood methods, as described in the Guidelines’ statistical analysis section, 

593 require that the distribution of data be known. The Agency thus should remove from this 

594 section the recommendation that maximum likelihood estimates be used if this distribution is 

595 not known and the data cannot be transformed to fit an underlying distribution. Use of 

596 maximum likelihood methods would, in this case, be inappropriate.

597

598 4. The revised Guidelines, as currently written, intermingle scientific and ethical considerations. 

599 The Board recommended that the Agency reexamine the organization and wording of the 

600 document in order to distinguish between the two.

601

602 5. The Board also recommended that, with respect to discussions of participant recruitment and 

603 vulnerability, the following changes be made:

604

605 a. The term “race/ethnicity” should be used instead of just “race.”

606 b. When considering issues of participant vulnerability, the primary concern is not just 

607 arbitrary exclusion of potentially vulnerable populations if provisions can be made to 

608 ensure the safety of the participants. There is also the concern of potential benefits from 

609 research participation for vulnerable groups. The Guidelines should be revised to address 

610 this fact.
Final Draft Dated July 28, 2010

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611 c. The Board also suggested that the EPA reexamine issues of language in recruitment and 

612 consent materials in the Guidelines, referring the Agency specifically to the Board’s 

613 October 2009 report (EPA HSRB 2009b), which explicitly discusses such issues of 

614 language. Investigators should also be urged to examine the recruitment population in 

615 advance so that speakers of other languages are present as needed.

616

617

618 REFERENCES

619

620 Carley, J.M. 2010a. Ethics Review of Completed Carroll-Loye Black Fly Repellent Field 

621 Efficacy Study LNX-002. Dated May 20, 2010. Unpublished document prepared by the Office of 

622 Chemical Safety and Pollution Prevention, United States Environmental Protection Agency.

623

624 Carley, J.M. 2010b. Request for Additional Documentation. Email Exchange between United 

625 States Environmental Protection Agency and Independent Institutional Review Board, Inc. Dated 

626 April 20, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution 

627 Prevention, United States Environmental Protection Agency.

628

629 Carley, J.M. 2010c. Ethics Review of Completed Carroll-Loye Tick Repellent Laboratory 

630 Efficacy Study LNX-003. Dated May 20, 2010. Unpublished document prepared by the Office of 

631 Chemical Safety and Pollution Prevention, United States Environmental Protection Agency.

632

633 Carroll, S. 2010a. Efficacy Test of KBR3023 (Picaridin; Icaridin)-Based Personal

634 Insect Repellents (20% Cream and 20% Spray) with Black Flies under Field Conditions. Dated 

635 April 5, 2010. Unpublished document prepared by Carroll-Loye Biological Research. MRID 

636 48053802.

637

638 Carroll, S. 2010b. Efficacy Test of KBR3023 (Picaridin; Icaridin)-Based Personal

639 Insect Repellents (20% Cream and 20% Spray) with Ticks Under Laboratory Conditions. Dated 

640 April 5, 2010. Unpublished document prepared by Carroll-Loye Biological Research. MRID 

641 48053801.

642

643 Carroll, S. 2010c. Supplemental Submission to EPA MRID 40853802. Dated April 19, 2009. 

644 Unpublished document amendment prepared by Carroll-Loye Biological Research. MRID 

645 48071301.

646

647 EPA Human Studies Review Board. 2006. June 27-30, 2006 Human Studies Review Board 

648 Meeting Report.

649

650 EPA Human Studies Review Board. 2008. October 21-22, 2008 Human Studies Review Board 

651 Meeting Report.

652

653 EPA Human Studies Review Board. 2009a. June 24-25, 2009 Human Studies Review Board 

654 Meeting Report.

655

656 EPA Human Studies Review Board. 2009b. October 20-21, 2009 Human Studies Review Board 

657 Meeting Report.
Final Draft Dated September 2, 2010

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658

659 Independent Institutional Review Board, Inc. (IIRB, Inc.). 2010. Roster and Procedures. 

660 Unpublished materials prepared by IIRB.

661

662 Office of Chemical Safety and Pollution Prevention. 2010. Product Performance Test Guidelines. 

663 OPPTS 810.3700: Insect Repellents to be Applied to Human Skin. Draft document prepared by

664 the Office of Chemical Safety and Pollution Prevention, United States Environmental Protection 

665 Agency.

666

667 Sweeney, K.J. 2010a. Science Review of Human Study of Black Fly Repellent Performance. 

668 Dated May 24, 2010. Unpublished document prepared by the Office of Chemical Safety and 

669 Pollution Prevention, United States Environmental Protection Agency.

670

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

672 May 24, 2010. Unpublished document prepared by the Office of Chemical Safety and Pollution 

673 Prevention, United States Environmental Protection Agency.