1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 June 25, 2008

EPA-HSRB-08-02

George Gray, Ph.D. Science Advisor Office of the Science Advisor 1200 Pennsylvania Avenue, NW Washington, DC 20460

Subject: April 9-10, 2008 EPA Human St udies Review Board Meeting Report

Dear Dr. Gray:

The United States Environmental Protecti on Agency (EPA or Agency) requested the Human Studies Review Boar d (HSRB) to review scientific an d ethical issues addressing: (1) EPA Review of Antimicrobial Exposure Asse ssment Task Force Mop and Wipe scenario protocols; (2) ICR Protocol: A382 and (3) Carroll-Loye Biol ogical Research Completed Studies: SCI 001.4 and SCI 001.5. The enclosed HSRB report provides the Board’s response to EPA charge questions presented at th e April 9-10, 2008 meeting. The Board also appreciates the Agency providing an update of the EPA/ORD document “Scientific and Ethical Approaches for Observational Exposure Studies.” The Board agrees with the Agency that the document will serve as a valuable resource for EP A and other researchers to rely on as they develop and conduct observational human e xposure studies. In addition to the recommendations for specific protocols and co mpleted studies summarized below, the Board provided comments on review and format of AEATF and AHETF protocols.

A summary of the Board’s conclu sions is provided below.

EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of the mop and wipe scenarios, both exposure scenarios were reviewed together) 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Science

The Board considered the AEATF-II study protocols to successfully address many design challenges. The Board apprec iated particularly the clarity of the protocols, the attention to detail, and the thorough description of quality assurance and quality control procedures. The Board concurred with the Agency that existing data on handler exposures to antimicrobials are inadequate and that the developm ent of more accurate information is an appropriate goal. The Board also concurred with the Agency that th ere are only minimal risks associated with the application of a dilute solution of didecyl dimethyl ammonium chloride as described in the study protocols.

While the Board concluded that the research could produce scientifically reliable data, the Board identified several contextual factors that may limit the generalizability of the findings. The Board therefore recommended that the Agency reconsider the design of the

Page 1 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 study, or develop an explicit statement of the limitations on the use of data that will be collected under the proposed de sign. Specifically the Board note d that any generalizations to moppers and wipers in other parts of the count ry and in other kinds of buildings would be based on expert opinion, and that such generalizations would not be statistical generalizations. The Board cautioned the Agency regarding the 3 x6 design in the protocols, suggesting future scenario designs for the AEATF- II program wo uld likely have three cl usters and six time durations, with the justification being the Bo ard’s recommendation of these protocols. The Board also concluded that the task duration tim e frame was not adequate to characterize daily exposure. The Board recommended that the work time frame be expanded to exceed the 95 th percentile of the Intern ational Sanitary Supply Associati on survey findings. The Board noted that if, instead of time, the number of Ai units handled were the measure that defined each person’s participation, the data would more likely lend themselves to a proper assessment of the assumption of proportionality.

Finally, the Board encourages modifications of future related protocols based on the lessons learned from this initial submission. Su ch adjustments are anticipated to improve the study design and subsequent results, leading to a more accurate charact erization of pesticide handler exposure.

20 21 22 23 24 25 26 Ethics

The Board concurred with the initial assessmen t of the Agency that if the proposed mop and wipe scenario design, prot ocol, and supporting documentation is revised as suggested in EPA’s review, the research w ould meet the applicable requi rements of 40 CFR part 26, subparts K and L.

27 28 ICR Protocol: A 382

29 30 31 32 33 34 35 36 Science

If amended in a manner consistent with the Board’s concerns and recommendations, and with particular modificati on to subject ethnicity, the Boar d concluded that the protocol ICR A382 studying the efficacy of two formulatio ns of picaridin for repelling stable flies would be sufficiently sound, from a scientific perspectiv e, to be used to assess the repellent efficacy of these formulations against stable flies.

37 38 39 40 41 42 Ethics

The Board concurred with the initial assessmen t of the Agency that, if the protocol is revised as suggested by EPA and the HSRB, the study submitted for review by the Board would meet the applicable requirements of 40 CFR 26, subparts K and L.

43 44 Carroll-Loye Biological Research Comp leted Studies: SCI 001.4 and SCI 001.5

45 Science

Page 2 of 371 2 3 4 5 6 The Board concluded that the study on th e efficacy of LipoDEET 320 and Coulson’s Duranon shows efficacy of both products in repelli ng mosquitoes, and agreed with the Agency that the study was sufficiently s ound, from a scientific perspective, to be used to accurately calculate the complete protection time for repelling mosquitoes.

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Ethics

The Board concurred with the initial assessmen t of the Agency that the study submitted for review by the Board meets the applicable re quirements of §40CFR26, subparts K and L. However, the Board expressed concern regardin g a pattern of deviations from IRB approved protocols apparent in this study and previous submissions by the investigator. Implications of this concern are noted below.

Over several meetings, including the April 2008 meeting, the Board has expressed concern with EPA submission for HSRB review of comp leted studies in which planned protocol deviations were conducted prior to IRB review and following HSRB review of the originally approved protocol. Such actions are in viol ation of 40 CFR 26, Subpart K Sec. §26.1108 IRB functions and operations.

Subpart K Sec. §26.1108 IRB functions and operations. “In order to fulfill the requirements of this subpart, each IRB shall: (a) Follow written procedures: (1) For conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (2) For determining which projects require review more often than annually and which projects need verification from sources other than the investi gator that no material changes have occurred since previous IRB review; (3) For ensuring prompt reporting to the IRB of proposed changes in research activity; and (4) For ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.”

The Board reached consensus regarding its futu re review procedures under such conditions:

1. Any study executed prior to IRB approval of the Informed Consent Form and the protocol, or changed in ways that were not approved by the IRB will be judged by the Board as failing to meet the applicable requirements of §40 CFR 26, subparts K. 2. If the EPA submits to the Board for review a completed protocol with scientific deviations from the original protocol reviewed by the Board, the EPA review of the completed protocol should provide the Bo ard with EPA's opinion regarding why the deviation did not meet the requirement for re-review and why the protocol still meets the applicable regulations.

Page 3 of 371 2 3 4 5 6 7 8 9 10 11 12 In conclusion, the EPA HSRB appreciated the opportunity to advise the Agency on the scientific and ethical aspect s of human studies research and looks forward to future opportunities to continue advising th e Agency in this endeavor.

Sincerely,

Celia Fisher, Ph.D., Chair EPA Human Studies Review Board

Page 4 of 37NOTICE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 This report has been written as part of th e activities of the EPA Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency a nd, hence, the contents of this report do not necessarily represent the view and policies of the Environmen tal Protection Agency, nor of other agencies in the Executive Branch of th e Federal government, nor does the mention of trade names or commercial products constitute a recommendation for use. Further information about the EPA Human Studies Review Boar d can be obtained from its website at http://www.epa.gov/osa/hsrb/. Interested persons are invited to contact Paul Lewis, Designated Federal Officer, via e-mail at lewis.paul@epa.gov.

In preparing this document, the Board car efully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the in formation provided and presented within the structure of the charge by the Agency.

Page 5 of 37U. S. ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD MEMBERS 1 2 3 4 5 6 7 8 Chair

Celia B. Fisher, Ph.D., Marie Ward Doty Professor of Psychology, Director, Center for Ethics Education, Fordham University, Department of Psychology, Bronx, NY

9 10 11 12 13 Vice Chair

William S. Brimijoin, Ph.D., Chair and Professo r, Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation, Rochester, MN *

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Members

Alicia Carriquiry, Ph.D., Professor, Departme nt of Statistics, Iowa State University Snedecor Hall, Ames, IA

Gary L. Chadwick, PharmD, MPH, CIP, A ssociate Provost, Direct or, Office for Human Subjects Protection, University of Rochester, Rochester, NY

Janice Chambers, Ph.D., D.A.B.T., William L. Gile s Distinguished Professor, Director, Center for Environmental Health Sciences, College of Veterinary Medici ne, Mississippi State University, Mississippi, MS

Richard Fenske, Ph.D., MPH, Professor, Depa rtment of Environmen tal and Occupational Health Sciences, University of Washington, Seattle, WA*

Susan S. Fish, PharmD, MPH, Professor, Bi ostatistics & Epidemiology, Boston University School of Public Health, Co-Director, MA in Cl inical Investigation, Bo ston University School of Medicine, Boston, MA

Suzanne C. Fitzpatrick, Ph.D., D.A.B.T, Seni or Science Policy Analyst, Office of the Commissioner, Office of Science and H ealth Coordination, U.S. Food and Drug Administration, Rockville, MD

Dallas E. Johnson, Ph.D., Professor Emeritus, Department of Statistics, Kansas State University, Manhattan, KS

Kannan Krishnan, Ph.D., Professor, Département de santé environnementale et santé au travail, Faculté de medicine, Université de Montréal, Mont réal, Canada

Michael D. Lebowitz, Ph.D., FCCP , Professor of Public Health & Medicine. University of Arizona, Tucson, AZ

Page 6 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Lois D. Lehman-Mckeeman, Ph.D., Distinguish ed Research Fellow, Discovery Toxicology, Bristol-Myers Squibb Co mpany, Princeton, NJ

Jerry A. Menikoff, M.D., Direct or, Office of Human Subjects Res earch, Office of the Director, National Institutes of Health, Bethesda, MD

Rebecca Parkin, Ph.D., MPH, Associate Dean for Research and Public Health Practice, School of Public Health and Human Services, The George Washington University, Washington, DC

Sean Philpott, Ph.D., MS Bioethics, Scien ce and Ethics Director, Global Campaign for Microbicides, Program for Appropriate Technology in Health, Washington, DC

Ernest D. Prentice, Ph.D., Associate Vice Chan cellor for Academic Affairs, University of Nebraska Medical Center, Omaha, NE*

Richard Sharp, Ph.D., Director of Bioethics Research, Department of Bioethics, Cleveland Clinic, Cleveland, OH

Linda J. Young, Ph.D., Professor, Department of Statistics, Institute of Food and Agricultural Sciences, University of Fl orida, Gainesville, FL

23 24 25 26 27 Consultants to the Board KyungMann Kim, Ph.D., CCRP, Professor and Associ ate Chair, Department of Biostatistics & Medical Informatics, School of Medicine a nd Public Health, University of WisconsinMadison, Madison, WI

28 29 30 31 32 33 34 35 Human Studies Revi ew Board Staff

Paul I. Lewis, Ph.D., Executive Director, Huma n Studies Review Board Staff, Office of the Science Advisor, United States Environm ental Protection Agency, Washington, DC

* Not in attendance at April 9-10, 2008 Public Meeting

Page 7 of 37Page 8 of 37INTRODUCTION 1 2 3 4 5 6 7 8 9 10 11 12 On April 9-10, 2008, the United States Environmental Protection Agency’s (EPA or Agency) Human Studies Review Board (HSRB) me t to address scientific and ethical issues concerning: Sampling strategi es in proposed pesticide handl er research, Antimicrobial Exposure Assessment Task Force (AEATF) Gove rning Document, EPA Review of AEATF-II Mop and Wipe Scenarios, ICR Protocol: A382, and Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI 001.5 Each of these topics is discussed more fully below. In addition, EPA’s Office of Pestic ide Programs provided a follow-up on pesticide specific HSRB recommendations. Finally, EPA’s Office of Research and Development provided an update on revisions to its document “Scientific and Ethical Approaches for Observational Exposure Studies.” Each of th ese topics is discussed more fully below.

1. Proposed AEATF Research on Exposure of Subjects Using an Anti microbial Pesticide 13 in Mopping and Wiping Activities 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 The HSRB has previously considered issues related to the de sign and conduct of research to measure the levels of exposur e received by people when handling (i.e., mixing, loading, or applying) pesticides. Two industr y Task Forces, the Antimicrobials Exposure Assessment Task Force II (AEATF) and the Agricultural Handlers Exposure Task Force (AHETF), have previously submitted materials for HSRB review. Based on the issues raised by the Board at its meeting in June 2006, EPA asked its FIFRA Scientific Advisory Panel (SAP), an advisory committee of independent expert scientific p eer reviewers providing technical advice to EPA on pest icide and pesticide-related is sues, to address a number of scientific issues at its January 2007 meeting. Drawing on the advice of the SAP, the Office of Pesticide Programs (OPP) presented additional issues relating to the proposed handler research again at the April and June 2007 HSRB meetings. In response to those reviews the Task Forces have extensively reworked their research proposals.

One issue, the design of the sampling strategi es to be used by the Task Forces, has drawn particular atten tion. To resolve this question OPP has consulted with experts both within and outside EPA, and has carefully c onsidered information presented by the Task Forces. Based on these interactions, OPP has decided to accept data developed through “hybrid” sampling strategies, i.e ., strategies that use a basi c purposive diversity sampling design but which incorporate random elements whenever feasible. OPP provided background documents on these interactions on Decem ber 5, 2007 to the HSRB for subsequent consideration. Those same background documents are provided again in this transmittal for the Board’s convenience in preparing for the April 2008 HSRB meeting.

The AEATF has submitted two proposals. Each includes both a scenario-specific design document and the associated field study pr otocol, along with s upporting documentation, for EPA and HSRB review. One proposal would measure inhalation and dermal exposure of subjects applying an antimicrobial pesticide by mopping floors. The other would measure exposure of subjects who apply an antimicrobial pesticide by wiping vertical and horizontal hard surfaces in two distinct scenarios—one using a spray-and-wipe technique, and the other using ready-to-use impregnated wipes.

Page 9 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 EPA’s regulation, 40 CFR §26.1125, requires the s ponsor or investigator to submit to EPA, before conducting a study involving inten tional exposure of human subjects, materials describing the proposed human rese arch in order to allow EPA to conduct scientific and ethics reviews. In addition, EPA’s regulation, 40 CFR §26.1601, requires EPA to seek HSRB review of the research proposal. Because the rese arch proposed by the AEATF involves scripted exposure, it meets the regulator y definition of “research involv ing intentional exposure of a human subject”, and thus these cited provisions of regulat ion apply to it.

EPA has reviewed the AEATF proposals and has concluded that, with a number of required revisions, they appear lik ely to generate scientifically sound, useful information and to meet the applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L. EPA has also concluded that the proposed hybrid sampling designs for all three proposed exposure scenarios effectively in corporate elements of randomization, consistent with EPA’s guidance to the AEATF. Because the sponsor wi shes to initiate testing pursuant to these protocols as soon as possible to meet regulatory requirements in other countries, and since EPA finds the protocols can meet applicable scientif ic and ethical standards, EPA presented this protocol for review at the Board’s April 2008 meeting.

EPA provided the following materials conc erning the AEATF Exposure Monitoring Program to the HSRB:

3. AEATF Exposure Monitoring Program

a. General Documents

(1) Volume 5 AEATF Governing Document (Revised 2/13/08)

(2) AEATF Governing Document (R evised 2/13/08; track changes)

(3) Summary of Changes to Governing Document of 2/13/08

(4) Volume 6 AEATF SOPs (Revised 2/25/08)

b. Documents specific to the Mop Scenario

(1) Volume 1 AEATF Mop Scenario De sign/Protocol: Primary Documentation (Revised 2/25/08)

(2) Volume 2 AEATF Mop Scenar io Design/Protocol: Secondary Documentation (Revised 2/25/08)

(3) EPA Science and Ethics Review: AEATF Mop Scenario (3/10/08)

c. Documents specific to the Wipe Scenarios

Page 10 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 (1) Volume 3 AEATF Wipe Scenario Design/Protocol: Primary Documentation (Revised 2/25/08)

(2) Volume 4 AEATF Wipe Scen ario Design/Protocol: Secondary Documentation (Revised 2/25/08)

(3) EPA Science and Ethics Revi ew: AEATF Wipe Scenarios (3/10/08)

d. Background documents on the Sampling Stra tegy Issue distributed to the HSRB on December 5, 2007

(1) Memorandum from William Jordan to Dr. Celia Fisher Re: “Design of Sampling Strategies in Proposed Handler Research”

(2) AHETF Study Design, Logistics, and Conduct (10-17-07) Power Point presentation by David Barnekow and Victor Cañez

(3) AEATF Introduction and Background (10-17-07) Power Point presentation by Hasmukh Shah

(4) AHETF Membership Benefits a nd Incentives (10-17-07) Power Point presentation by Victor Cañez and David Barnekow

(5) AHETF and AEATF Concepts, Objec tives, and Sampling Issues (10-17- 07) Power Point presentation by Larry Holden

(6) Report of Dr. Tapabrata Maiti, Asso ciate Professor of Statistics at Iowa State University, to EPA concerning sampling design issues in proposed handler exposure research (11-30-07)

(7) Letter from Debra Edwards, OPP director, to Hasmukh Shah, manager of the American Chemistry Council’s Biocides Panel, concerning issues involving the AEATF’s proposed handler research. (11-28-07)

(8) Summary of EPA/OPP Telec onferences with AHETF (11-28-07)

2. Proposed ICR Stable Fly Repellent Efficacy Study (A 382) 37 38 39 40 41 42 43 44 45 EPA requires submission of data from effi cacy studies when a pesticide product is directed against organisms classified as publ ic health pests. EPA’s regulation, 40 CFR §26.1125, requires a sponsor or investigator to submit to EPA, before conducting a study involving intentional exposure of human subjects, materials describing the proposed human research in order to allow EPA to conduct scie nce and ethics reviews. In addition, EPA’s regulation, 40 CFR §26.1601, requires EPA to seek HSRB review of the research proposal.

Page 11 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Insect Control & Research, Inc. (ICR) has submitted a proposal for new research to evaluate the efficacy of two conditionally registered products containing picaridin, to be conducted by Dr. William Gaynor. I CR protocol number G4330108001A382 (A382) describes a laboratory study of the efficacy of the test formulations against stable flies, a species classified as a public health pest.

EPA has reviewed ICR’s protocol and has concluded that, with several required revisions, it appears likely to ge nerate scientifically sound, useful information and to meet the applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L. The sponsor wishes to submit the data to EPA later th is year in support of an application to amend the registration of these picaridin products in or der to claim specifically that the products are effective at repelling stable f lies. In the interest of provi ding a thorough and timely decision on such applications, and since EPA finds the protoc ol can meet applicable scientific and ethical standards, EPA is presenting this protocol fo r review at the Board’ s April 2008 meeting.

EPA provided the following materials on the IC R repellent efficacy protocol A382 to the HSRB:

2. ICR Repellent Efficacy Protocol A382

a. ICR Stable Fly Prot ocol A382 (Rvsd 2/1/08)

b. EPA Science & Ethics Review (3/7/08)

3. Completed Insect Repellent Efficacy Studies (SCI-001.4 and SCI-001.5) of DEET 26 Formulations 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 In its January 2007 meeting the HSRB review ed protocol SCI-001 from Carroll-Loye Biological Research, submitted by Dr. Scott Carroll, to test mosquito repellent efficacy of three controlled-release formulations of DEET in th e field. The study was designed to measure the efficacy of the three test formulations and one “comparison article”—the US military standard repellent. The HSRB offered comments on th e protocol at its Ja nuary 2007 meeting.

Following that meeting, Dr. Carroll amended th e protocol to addr ess a comment from the HSRB and to substitute a new, unregistered repellent formulation for one of those proposed in the protocol. Dr. Carroll then proceeded to conduct the research ac cording to the amended protocol in July 2007, and submitted the results to EPA for review. At its October 2007 meeting, the HSRB reviewed the results of the research, determined that there were both scientific and ethical issues w ith the conduct of the research, and advised EPA not to rely on the data. Dr. Carroll further amended the prot ocol, obtained IRB approva l for both the original and subsequent amendments, and re-executed th e research in November 2007, testing only two of the originally proposed test repellent s and omitting the comparison positive control formulation. Reports of this testing have been submitted to EPA by the study sponsor, Scientific Coordination, Inc., under st udy numbers SCI-001.4 and SCI-001.5. EPA is

Page 12 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 presenting the results of the re-execution of prot ocol SCI-001 to the HSRB for review at this meeting.

The Agency’s regulation, 40 CFR §26.1602, requ ires EPA to seek HSRB review of an EPA decision to rely on the results of these studies. The sponsor has submitted data in support of applications for amended registration for the two test materials. In order to facilitate review of these applications within the time allowe d by statute, EPA has reviewed the research, applying the standa rd in 40 CFR §26.1705

. That provision states:

§26.1705 Prohibition on reliance on unethical research with non-pregnant, non-nursing adults conducted after April 7, 2006

Except as provided in §26.1706, in acti ons within the scope of §26.1701, EPA shall not rely on data from any research initiated after Ap ril 7, 2006, unless EPA has adequate information to determin e that the research was conducted in substantial compliance with subparts A through L of this part . . . This prohibition is in addition to the prohibition in §26.1703.

OPP has determined that the data are scie ntifically sound and that the research meets the standard in §26.1705. Therefore OPP proposes to rely on the result s in considering the pending applications.

EPA provided the following materi als on the completed insect repellent efficacy studies SCI001.4 and SCI-001.5 to the HSRB:

1. Insect Repellent Efficacy Studies SCI-001.4 and SCI-001.5

a. MRID 47322501 SCI-001.4: Test of DermAegis LipoDEET 302

b. MRID 47322401 SCI-001.5: Test of Coulston’s Duranon

c. Supplemental correspondence IIRB ↔ CLBR 3/5/08

d. EPA Science and Ethics Review (Protocol) SCI-001 (12/20/06)

e. Changes in consent form version of 11-6-07

f. EPA Ethics Review: SCI-001.4 and SCI-001.5 (3/7/08)

g. EPA Science Review: SCI-001.4 and SCI-001.5 (3/7/08)

This report transmits the HSRB’s commen ts and recommendations from its April 9- 10, 2008 meeting.

Page 13 of 371

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 REVIEW PROCESS

On April 9-10, 2008, the Board had a public face-to-face meeting in Arlington, Virginia. Advance notice of the meeting wa s published in the Federal Register “Human Studies Review Board: Notice of Public Me eting (73 Federal Regi ster 46, 12413). At the public meeting, following welcoming remarks from Agency officials the Board then heard presentations from the Agency on the following topics:

• Update On Revisions To The EPA Document “Scientific And Ethical Approaches For Observational Exposure Studies

• EPA Follow-up on Pesticide Spec ific HSRB Recommendations

• Overview of EPA’s Assessment of Proposed Pesticide Handler Research Sampling Strategies in Propos ed Pesticide Handler Research Antimicrobial Exposure Assessment Task Force (AEATF) Governing Document EPA Review of AEATF-II Mop and Wipe Scenarios

• ICR Protocol: A382

• Carroll-Loye Biological Research Comp leted Studies: SCI 001.4 and SCI 001.5

Oral comments The following oral comments were presented at the meeting:

25 26 27 28 AEATF-II Mop and Wipe Scenarios Jeff Driver, Ph.D. of infoscientif ic.com on behalf of the AEATF-II Larry Holden of Sielken and Associat es, Inc. on behalf of the AEATF-II

29 30 31 32 33 ICR Protocol: A382 William Gaynor, Ph.D. on behalf of ICR, Inc. Robin Todd, Ph.D. on beha lf of ICR, Inc. Ralph Piedmont, Ph.D. of Loyola Co llege on behalf of ICR, Inc.

34 35 36 37 38 39 Carroll-Loye Biological Research Comp leted Studies: SCI 001.4 and SCI 001.5 Scott Carroll, Ph.D. and Mr. Shawn King on behalf of Carroll-Loye Biological Research

Written comments Written comments were received by:

40 41 42 General Stephen A. McFadden, Independent Scientific Research Advocates

43 44 45 AEATF-II Mop and Wipe Scenarios American Chemistry Council on behalf of the AEATF-II

Page 14 of 37For their deliberations, the Board consider ed the materials presented at the meeting, written public comments and Agency background documents (e.g., the published literature, Agency data evaluation record, weight of ev idence review, ethics review, pesticide human study protocols and Agency evaluation of the protoc ol or study). For a comprehensive list of background documents visit the 1 2 3 4 www.regulations.gov , Docket ID No. EPA-HQ-ORD-2007- 0942, or EPA’s HSRB website at 5 http://www.epa.gov/osa/hsrb/oct-24-26-2007-public6 7 8

9

10 meeting.htm

.

CHARGE TO THE BOARD AND BOARD RESPONSE

Update On Revisions To The EPA Document “Scientific And Ethical Approaches For 11 Observational Exposure Studies 12 13 14 15 No Charge to the Board

EPA Follow-up on Pesticide Specific HSRB Recommendations 16 17 18 19 No Charge to the Board

Overview of EPA’s Assessment of Pr oposed Pesticide Handler Research 20 21 Sampling Strategies in Proposed Pesticide Handler Research 22 23 24 No Charge to the Board

Antimicrobial Exposure Assessment Ta sk Force (AEATF-II) Governing 25 Document 26 27 28 29 30 No Charge to the Board

Board Recommendations on Review and Fo rmat of AEATF and AHETF Protocols

31 32 33 34 35 36 37 38 39 Overall recommendations 1. Random sampling designs are preferred. 2. When random sampling is not possible, a purposive diversity sampling (PDS) protocol must nonetheless have a well-developed sampli ng frame based on knowledge of the range of active ingredient concentra tions and distribution of me thods used in the field. 3. Each protocol should be individually a ssessed for the feasibility of random assignment. When random sampling is not possible, each prot ocol should be individually assessed for the adequacy of the PDS sampling frame.

40 41 42 43 44 45 Format of protocols for subsequent HSRB review

1. A detailed description of the methods a nd rationale for data colle ction (e.g., neck wipes). 2. If random sampling is not used, a detaile d description of effort s made to incorporate random elements in each scenario-specific design and why it was not f easible (in terms of availability of information, costs, and time) to obtain a random sample.

Page 15 of 371 2 3 4 5 6 7 3. For both random and PDS designs, a detailed description, rationale a nd justification for the scenario, selection of clusters, and what wi ll be done within each cluster and why. 4. For all protocols, a detail ed explanation of how data will be analyzed and interpreted by AHETF & AEATF. 5. For all protocols, a detail ed explanation of how the data is anticipated to be analyzed by EPA and how it will be useful for EPA risk assessments.

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Format of Agency presentations, specif ically OPP presentations to the Board

1. OPP should develop a written glossary of terms (e.g., cluster, scenario) for HSRB and public reference. This glossary should be distributed but not summarized during OPP presentations. 2. For each protocol OPP should provide a br ief (1 page if possible) abstract in terms appropriate for a lay audience describing the nature and purpose of the study and how EPA intends to use the data. 3. OPP’s oral presentation should not focus on deta ils. The Board believes that such detailed presentations distract from focusing attention on those aspects of the protocol for which OPP is eliciting Board feedback. 4. OPP’s oral presentation on the science s hould not be a summary of the protocol, but a focused discussion of OPP’s evaluation of why they think the study has sufficient scientific validity; the presentation should in clude questions regarding scientif ic validity that OPP wishes the Board to address. 5. OPP’s oral presentation should also incl ude a description of how the Agency plans to analyze and use the data. 6. Similarly, OPP’s oral presentation should not focus on the details regarding the protection of human subjects as such detail s are described in the written ma terials. Rather, a brief oral presentation should identify thos e aspects of the design that O PP believes raise human subjects

concerns.

AHETF and AEATF Comment s at HSRB meetings:

1. Since the HSRB makes its recommendations to EPA and not directly to sponsors, it is the responsibility of the Agency to present the pr otocol to HSRB, along w ith EPA’s critique and conclusions. 2. Sponsors have the opportunity to express their perspectives and clarify information during the public comment periods. 3. During Board discussion of protocols, sponsors should be available for additional clarifications that may be needed. 4. In addition, if sponsors believe that a specif ic point has not been adequately addressed they should have the opportunity to alert OPP to th eir concerns during the time allotted to the protocol; OPP in consultation with the Chair and DFO may recommend to the Board that the sponsor provide additional clar ification on the issue(s).

EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of the mop and wipe scenarios, both exposure scenarios were reviewed together) 44 45 46

Page 16 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Science

Charge to the Board If the proposed research described in AEATF’s proposed mop scenario design, protocol, and supporting documentation is revise d as suggested in EPA’s review, does the research appear likely to gene rate scientifically re liable data, useful for assessing the exposure of handlers who apply an antimic robial pesticide by mopping?

If the proposed research described in AEATF’s proposed wipe scenario designs, protocol, and supporting documentation is revise d as suggested in EPA’s review, does the research appear likely to gene rate scientifically re liable data, useful for assessing the exposure of handlers who apply an antimic robial pesticide by wiping?

Board Response to the Charge

The two proposed human studies focus on handlers during floor mopping or surface wiping with a liquid antimicrobial pesticide product to determine potential dermal and inhalation exposures. The studies are (1) AE A03, “A Study for Measurement of Potential Dermal and Inhalation Exposure During Applic ation of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop Equipment for Cl eaning Indoor Surfaces,” and (2) AEA02, “A Study for Measurement of Potential Dermal a nd Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product using Tr igger Spray and Wipe or Ready to Use Wipes for Cleaning Indoor Surfaces.” The protocols associated with these studies have many similarities. The Board’s comments were ther efore very similar for the two studies. All comments below can be applied to bo th studies, unless otherwise noted.



### Study Objective 26

27 28 29 30 31 AEATF II stated that the primary purpose of the handler studies is to develop more accurate information on worker exposures to antimicrobials. AEATF II also presented information to indicate that ex isting human exposure data are in adequate. The Board concurred that existing data are inadequate and that the development of more accurate information is an appropriate goal.



### Benefits and Risks 32

33 34 35 36 37 38 39 The Board concurred with the Agency that the generation of new data for mop and wipe activities would be of value in the asse ssment of risks for antimicrobial products. The Board concurred with the Agency that there are only minimal risks associated with the application of a dilute soluti on of didecyl dimethyl ammonium chloride (DDAC) as described in the study protocols.

40 41 42 43 44 Study Design Criteria

The Board was pleased by the amount of ra ndomization included in the design of these studies. The investigators and the Agency have indicated that they are interested in knowing the statistical distribu tion of the exposure level, with an acceptable bound for the relative

Page 17 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 accuracy of the estimated mean and 95 percen tile. In both AEA03 (mop) and AES02 (wipe) studies, the same set of three si tes will be used as clusters, each representing a random sample of one for three different types of buildings. In order to understand th e spectrum of exposure, six volunteers will be randomly selected to fill each of six consecutive time durations. This configuration of three clusters of six handlers for each cluste r is based on a simulation study under two-stage cluster sampling with an intr a-class correlation coefficient of 0.3 and a geometric standard deviation (GSD) of 2.86. The sample size justification depends on these design parameters.

In an earlier mop study, conducted by th e Chemical Manufacturers’ Association (CMA), the estimated GSD was 3.53 . It therefore appeared to the Board that the proposed AEA03 study design would not ensure three-fold re lative accuracy ( K =3) for the resulting estimated mean and the 95 percentil e of the exposure distribution. Furthermore, in an earlier CMA wipe study the estimated GSD was 5.00, much larger than 2.86 assumed in the simulation study that was used to derive the sample size justifica tion. Again, it appeared unlikely to the Board that the AEA02 study design would produce a three-fold relative accuracy for the resulting estimated mean and th e 95 percentile of the exposure distribution.

The Board also noted that the stratified nature of selecting a cluster from each of three types of sites makes it impossible to assess the variabil ity of exposure distribution from site to site. Likewise, because of the stratified nature of selecting one handler for each of six mopping/wiping durations, one cannot estimate th e exposure distribution. The experimental design can be viewed as consisting of 18 desi gn points with 18 data poi nts, resulting in no degrees of freedom for estimation of variability as there are no replications at any design point.

In light of these concerns, the Board reco mmended that the Agency reconsider the design of the study, or develop an explicit statement of the limitations on the use of data that will be collected under the proposed design.

29

30 31 32 33 34 35 36 37 38 39 40 41 Site selection

The studies will take place in Fresno, Califor nia, in three buildings: an office building, a retail building, and a building with large meetin g spaces. The way in which the clusters have been defined suggests that they re present a fixed effect factor (i .e., building type) rather than a random effect factor. The proposed study design will not replicate this fixed effect by having more of than one building of each type. The Board acknowledged the prac tical considerations that led to the decision to ha ve both studies in the same c ity, using the same buildings. However, it must be realized that any generalizat ions to moppers and wipers in other parts of the country and in other kinds of buildings would be based on expert opinion, and that such generalizations would not be statistical generali zations. Nevertheless, th e Board concurred with the Agency that some generalizations from these data would seem to be reasonable at this point in time.

42

43 Sample size

Page 18 of 371 2 3 4 5 6 7 8 9 10 11 The proposed sample size of 18 observations for each scenario did not appear to have a statistical justification, as i ndicated above. The Board was concerned about recommending this sample size and the 3x6 design (three sites, si x workers per site) on which it is based. The concern is that all that all future scenario de signs for the AEATF- II program are likely to have three clusters and six time durations, with the justification being the Board’s recommending these protocols. The Board has s een this happen with insect repe llency studies repeatedly. That is, a new protocol has justified its sample size by reference to a previously submitted protocol. The adequacy of the proposed sample size for future studies will be informed by the data collection and analysis of this first set of studies . In general, the Board will not consider a new protocol that has justified its sample size by reference to a previously submitted protocol.

12

13 14 15 16 17 18 19 20

21 22

23

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Task duration

AEATF-II’s protocol for mopping proposed that handlers mop for a maximum of 90 minutes. This value was derived from a survey conducted by the Internat ional Sanitary Supply Association (ISSA). AEATF-II cal culated an average mopping duration to 83 minutes from the ISSA study data. The Board understood that this va lue was calculated in the following manner:

• ISSA data indicated that handlers spend, on average, 12 minutes to mop 1000 square feet.

• It was assumed that a hospital room consis ts of a 240 square feet (12x20) main room and a 36 square foot (6x6) bathroom for a total floor area of 276 sq ft.

• It was assumed that a worker would mop 25 such rooms for a total of 6,900 sq feet.

• Thus, 6900 square feet x 12 minutes per 1000 square feet = 82.8 minutes

A similar calculation was made for the wipe sc enarios, resulting in an estimated average wiping time of 212.75 minutes.

The Board concluded that the task duration tim e frame was not adequate to characterize daily exposure. The Board recommended that th e work time frame be expanded to exceed the 95 th percentile of the ISSA survey findings.

The Board also noted that the lengths of mopping (or wiping) would be consistently tested from the longest time period to the shorte st time period for each si te. For this to be a valid approach, one must be willing to assume th at there is no “carry-over” effect from one testing period to another. One factor that coul d lead to a carry-over e ffect would be whether residues from earlier mopping (or wiping) coul d affect the measurements on later study participants, especially respiratory effects. The Board recommended that these concerns be reflected in the protocols.

The Board found the explanation of potential analyses that the Agency would conduct based on these studies to be very helpful. A basic assumption for these analyses is that the distribution of exposure/unit hand led is the same regardless of the number of active ingredient (Ai) units handled or the tim e spent mopping (or wiping). However, the mean exposure/Ai

Page 19 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 unit and/or variance of the exposur e/unit is likely to increase w ith the number of units due to fatigue. This assumption could be at least part ially checked by plotting exposure/Ai unit by Ai unit, though such an analysis might conflict with the second analysis identified: the assessment of the assumption of proportionality. A regression would likely be conducted for this second analysis. If the distribution of exposure/unit handled were constant or increased with the number of units handled and proportionality wa s demonstrated, then both the mean and the variance would be expected to increase with th e number of units handled. In simple linear regression, the variance is assumed to be cons tant for all values of x. Thus, a weighted regression, not a simple linear regression woul d be needed. Because the protocol does not ensure that there will be repl ication of exposures for the sa me number of units, whether a simple or weighted regression would be more appropriate could not be fully evaluated. If, instead of time, the number of Ai units hand led were the measure that defined each person’s participation, the data would more likely le nd themselves to a proper assessment of the assumption of proportionality.

16 17 18 19 20 21 22 23 24 Participation Criteria

AEATF plans to recruit subjects from among identifiable and willing professional janitors. A rationale for this decision wa s provided. AEATF also assumes that these professionals would have higher exposures than consumers. One Board member expressed the view that professionals have substantial experience and perhap s training in how to minimize exposure, and that consumers might have hi gher exposures per Ai unit handled. AEATF-II plans to recruit subjects through service providers. The Board s uggested that unions also be considered in the development of the recruitment procedures.

25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Measurement Criteria

The Board noted that inhalation exposure from vapors would likely be low in these studies due to the relatively low volatility of the active ingredient used in the scenarios. However, the extent to which liquid aerosols gene rated in the mop protocol would contribute to aggregate exposure is not known. It was not clear what particle size range was expected to be generated in these studies, nor was it clear what particle size range w ould be captured by the sampling method. The Board suggested that a la boratory study that measured aerosol size under varying environmental cond itions would be helpful in clarifying these uncertainties.

The following are key variables that will ha ve an effect on inhalation exposure:

• Ventilation

• Temperature

• Total area treated

• Duration

• Volume of the enclosed space

The protocols state as follows: “light level, air temperature, and re lative humidity of the work area for the duration of exposure mon itoring will be documented with automated instrumentation logging and record ing at intervals appropriate for the duration of the work period. Monitoring equipment will be calibrated or standardized according to the cooperating

Page 20 of 371 2 3 4 5 6

7 8 9 10 11 12 13 contractors’ SOPs. HVAC will be described in detail and the air turnover rate will be measured or estimated.” The Board recommen ded that the equipment and pro cedures used to characterize these environmental factors be de scribed in greater detail, either in the protocols or in the SOPs. The Board also asked investigators to explain how the effects of such factors as ventilation, temperature and the volume of the en closed space would be used to modify or interpret study results.

AEATF-II proposed to use dermal exposure assessment methods similar to those used by the Agricultural Handler Exposure Task Force studies; i.e., cotton garm ents on most of the body, handwashing, and face/neck wiping. As in its previous reports, the Board noted that these methods have the potential to underestim ate exposure. The Board supported the use of a double layer of socks to capture potential exposure from spills or splashes.

14 15 16 17 18

19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Laboratory and Field Conditions

The Board considered the quality assuran ce and quality control procedures that accompanied these protocols to be of high quality. The Board appreciated the attention to detail provided by the investigators.

The Board raised several concer ns regarding field conditions.

These studies will use DDAC, contained in the product Sani-Care Lemon QuatTM as the chemical of interest. The Board agreed that th e choice of DDAC as the antimicrobial material for these studies was appropriate, given its wide us e, availability, and the existence of a reliable and sensitive analytical method.

The Board encouraged the Agency and the inve stigators to ensure that work activities be as realistic as possible. For example, a worker should use a bucke t of the disinfectant solution until it becomes dirty; the worker shou ld then empty the bucket and pick up a fresh bucket. All of this could be done without the in volvement of study staff. In general, the Board viewed the activities of the study staff described in the current pr otocols to be too disruptive of “usual practices”. The Board recommended that the protocols be revised to provide a more detailed description of what the workers will actually do, and that the presence of staff during the exposure period be kept to a minimum.

The Board was also concerned with what is sometimes called the “Hawthorne Effect”. That is, workers will change behavior consciou sly or unconsciously when they are aware that they are being observed. The current protocols indi cate that there will be constant surveillance of workers, including video recording. The Boar d urged the Agency and the investigators to minimize these observations and to train st aff to be as unobtrusive as possible.

Finally, the Board requested th at the protocol provide more specificity as to where study subjects will be located while waiting to participate in the study. There was a concern that observation of some study subjects by other study subjects c ould alter behavior.

46 HSRB Consensus and Rationale

Page 21 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 The Board considered the AEATF-II study protocols to successfully address many design challenges. The Board apprec iated particularly the clarity of the protocols, the attention to detail, and the thorough description of quality assurance and quality control procedures. The Board concurred with the Agency that existing data on handler exposures to antimicrobials are inadequate and that the developm ent of more accurate information is an appropriate goal. The Board also concurred with the Agency that th ere are only minimal risks associated with the application of a dilute solution of didecyl dimethyl ammonium chloride as described in the study protocols.

While the Board concluded that the research co uld produce scientifically reliable data, the Board identified several contextual factors that may limit the generalizability of the findings. The Board recommended that the Agency recons ider the design of the study, or develop an explicit statement of the limitations on the use of data that will be collected under the proposed design. The Board noted that any generalizations to moppers and wipers in other parts of the country and in other kinds of buildings would be based on ex pert opinion, and that such generalizations would not be statistical ge neralizations. The Board cautioned the Agency regarding the 3x6 design in the protocols, suggest ing future scenario designs for the AEATF- II program would likely have three cl usters and six time durations, w ith the justification being the Board’s recommendation of these protocols. Th e Board concluded that the task duration time frame was not adequate to characterize daily exposure. The Board recommended that the work time frame be expanded to exceed the 95 th percentile of the Intern ational Sanitary Supply Association survey findings. The Bo ard noted that if, instead of time, the number of Ai units handled were the measure that defined each person’s participation, the data would more likely lend themselves to a proper assessmen t of the assumption of proportionality.

In regard to inhalation e xposure assessment, the Board suggested that a laboratory study that measured aerosol si ze under varying environmenta l conditions would helpful in clarifying uncertainties regardi ng particle size and sampling methods. The Board raised several concerns regarding the field conditions for these studies: ensure that a ny carry-over effect in buildings is avoided; ensure that work activities be as realistic as possible; revise protocols to provide a more detailed descrip tion of what the workers will act ually do; keep the presence of staff and intrusive observation of workers dur ing the exposure period to a minimum; and, provide more specificity as to where study subjects will be located while waiting to participate in the study..

Finally, the Board encourages modifications of future related protocols based on the lessons learned from these initial submissions. Such adjustments are anticipated to improve the study design and subsequent results, leadi ng to a more accurate characterization of pesticide handler exposure.

42 43 44 45 Ethics

Charge to the Board

Page 22 of 371 2 3 4 5 6 7 8 9 10 If the proposed research described in AEATF’s proposed mop scenario design, protocol, and supporting documentation is revise d as suggested in EPA’s review, does the research appear to meet the applicable re quirements of 40 CFR part 26, subparts K and L?

If the proposed research described in AEATF’s proposed wipe scenario designs, protocol, and supporting documentation is revise d as suggested in EPA’s review, does the research appear to meet the applicable requi rements of 40 CFR part 26, subparts K and L?

Board Response to the Charge

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Brief Overview of the Studies

Each of these scenarios (mop and wipe) ha s been designed to develop data for a database of exposure monitoring information which will be used by the EPA for making regulatory decisions about future exposures to a variety of antimicrobial products and their active ingredients. The sponsor of both scenarios is the Antimi crobial Exposure Assessment Task Force II (AEATF-II) of the American Chemistry Council. The scenarios will be conducted on behalf of that entity by Golden Pacific Laboratories, LLC, of Fresno, California. For each of the scenarios, there will be three field sites in Fresno, California.

According to the protocols, these studies are intended to comply with the ethical standards contained in 40 CFR Part 26, subparts K and L, in addition to the requirements of FIFRA § 12(a)(2)(P), and Title 3, § 6710 of the Ca lifornia Code of Regulations. Both scenarios were reviewed and approved by a commercial IR B, the Independent Investigational Review Board, Inc. (IIRB, Inc.) of Plantation, Florida.

For each scenario, the protocols include detailed explanations of how the buildings in which the scenarios take place will be chosen, how the subjects will be recruited, how the informed consent of those subjects will be obtained, and what will take place during the conduct of the scenarios.

Each of the protocols requires that the subjec ts be at least 18 years of age, and they exclude female subjects who ar e pregnant or lactating.

The test substance that will be used in bot h scenarios is diluted Sani-Care Lemon Quat. Its two active ingredie nts are didecyl dimethyl ammoni um chloride (DDAC) and n-Alkyl dimethyl benzyl ammonium chlorides (ADBAC).

39 40 41 42 43 44 45 46 Critique of Studies

The Board concurred with the factual obs ervations of the ethical strengths and weaknesses of the studies, as detailed in the EPA’s Science and Ethics Reviews (Carley 2008a and 2008b).

In general, the research described in thes e two protocols appears to comport with the applicable requirements of 40 CF R Part 26, subparts K and L. Th e risks to study participants,

Page 23 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 in general, will be minimal and would appear to be justified by the likely societal benefits, specifically the production of data that could be used by the EP A in determining acceptable exposures to antimicrobial products used in certain mopping and wiping activities.

The test compound contains two active ingr edients, DDAC and ADBAC, both of which have been extensively tested in animals. The su bjects will only be exposed to concentrations of the test compound at the label d ilution rates. At thos e dilutions, animal te sting has shown the compound to have low acute toxicity and a lo w chronic hazard profile. Both of the active ingredients have already been approved by the EPA for use in many formulations, and in many janitorial products. In addition, the test co mpound itself, Sani-Care Lemon Quat, has been approved by the EPA, and will only be used in the scenarios in conformity with its approved labeling. All of the subjects will be professional janitors with extensive experience in using these products, and thus unlikely to misuse them in a way that might increase their likelihood of being harmed.

Although the risks to subjects fr om exposure to the test compound appear very low, it should be noted that in terms of the purposes of th ese scenarios, it is not actually necessary that subjects be exposed to an antimicrobial produc t. The scenarios are intended to measure only the amount of skin, clothing and inhalation expo sure when someone is engaged in certain activities relating to applying an antimicrobicide. They are not measuring the actual effects to the test subject from that exposure. Thus, it might be possible to design scenarios in which instead of an antimicrobicide, some less toxic tracer substance might be used. It would be appropriate for protocols to discu ss this possibility for further mi nimizing risks, and to indicate why (if it is true) such an option would not a llow the needed information to be collected.

Another possible risk is that of heat-relate d illness, given that the subjects will be required to wear two layers of clothing during the scenario ac tivities. That risk is being minimized by the fact that those activities will take place indoors in temperature-controlled environments. In addition, subjects will be give n appropriate breaks. The breaks will not only minimize the likelihood of heat-related illness, but also reduce the likelihood of cardiovascular harms.

With regard to subject selection, EPA observe d that “[n]o potential subjects are from a vulnerable population” (Carley 2008a and 2008b). In this regard, it should be noted that 45 CFR § 46.111(b) states that “economically or educationally disadvantaged persons” may constitute a vulnerable population. Accordingly, given that this study is recruiting from a population of individuals who may not have s ubstantial education, who may be relatively disadvantaged from an economic viewpoint, and many of whom may not speak or read English, it would be appropriate not to dismiss the possibility that the subjects in this study might be vulnerable to coercion and undue influence, but rather to instead recognize that there are sufficient safeguards in the de sign of the study to protect the subjects, even if they are vulnerable.

The study protocols included several mechan isms designed to minimize coercive recruitment and enrollment, including the fact th at subjects were not re cruited directly from their employers, but instead would themselves respond to flyers that have been posted.

Page 24 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Compensation was not considered to be so high as to unduly influence participation, and minors and pregnant or lactating women were explicitly excluded from volunteering (pregnancy being confirmed by re quiring all female volunteers under the age of 50 to undergo a urine pregnancy test). The potential stig matization resulting from study exclusion was minimized by the use of so-called ‘alternate’ pa rticipants, allowing for volunteers to withdraw or be excluded from participating wit hout unduly compromising their confidentiality.

With regard to the eligibility criteria, the Board believes that the requirement for females under the age of 50 to take a pregnancy test co uld be refined. It w ould be possible to design criteria that created a be tter fit between which female subjects might be able to get pregnant, and which of them are being asked to take that test. By doing this, the researchers would be showing greater respect for this group of subjects.

The protocol might provide a greater justif ication for why subjects older than 65 are excluded.

Most of the issues raised by the Board relate to informed consent and recruitment. With regard to the consent forms, as a general matte r, given the population from which subjects are being recruited, it would be appropriate to ma ke sure that the consent forms are at an appropriate level of readability. In at least so me places, there appears to be room for further simplification.

The consent forms do not appear to describe adequately the procedures discussed in the protocol relating to (a) still phot ography of the subjects, (b) videotaping of the subjects, and (c) observation of the subjects by members of th e study team. All of these procedures pose possible risks to the privacy and confidentiality of the subjects. The fact that each of these procedures will be part of the protocols should be adequately explained in the consent forms. That explanation should include the details re lating to who will be observing and who will be taking the photographs (e.g., member s of the study team, outside contractors, other subjects). In addition, both the protocol and the consent fo rms should explain what procedures will be in place to make sure that the photographs and vide os will be stored in a way that adequately protects both the confidentiality and the privacy of the subjects, and explains what harms to subjects might result if those prot ections are not adequate. If subj ects will be accorded the right to opt out of being photographed, that s hould be explained in the consent form.

In the Purpose section of the consent form , it should be explained that the underlying purpose of the study will be to collect informati on that will be provided to the EPA, and that the EPA would use that information to determ ine the appropriate standards for allowable exposures to products such as the test compound.

The consent form in one instance (the pa ragraph numbered 4 under Study Procedures) uses the term “same-sex person.” That confusing term should be replaced with the descriptions used elsewhere in the form, such as “a researcher of your own sex.”

Page 25 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 In the description of risks to subjects from exposure to the test compound, it is merely stated that the risks are low. If there is a known risk from getting the compound in a person’s eyes, for example, that risk should be explained.

The approved version of the consent form, under the Pregnancy Risks heading, begins with “We don’t know the risks to the unbor n from exposure to SANI-CARE LEMON QUAT and may be hazardous . . .” There is a word or words missi ng in this sentence, and it therefore needs to be revised. More significantly, the “a nd may be hazardous” language differs from the language that appears in the versions of the consent forms submitted to the IRB by the researchers. The Board was not able to determine how this change in language took place. There is not documentation that the IRB asked for the change, or that th e change was initiated by the researchers themselves, a nd that they submitted a copy of the consent form with this change to the IRB. This circumstance raises some concerns regarding whether the EPA was provided with the full documentation of what went on during the IRB approval process. The Board believes it would be appropriate for the EPA to determine how this change occurred. In addition, some members were conc erned that this lack of docum entation might relate to the operation of IIRB, Inc., which might reinforce pr ior Board concerns about the operation of that IRB.

With regard to the recruitment brochure, it would appear appropriate for that document to mention that the product which will be used in the study is Sani-Care Lemon Quat. At the beginning of that document, it fails to mention that the study will look not only at how much of the product “gets on” the workers, but also how much of it they inhale. Under the eligibility criteria, it states that subjects must be “Mal e or non pregnant, non or nursing female.” This language needs to be corrected. A nd in the last sentence, the broc hure incorrectly states that the EPA will use this information to reduce risks to workers. The statement should be revised to more accurately state the EPA will use the info rmation to determine how much of the product workers will be exposed to; it is not true that it will necessarily lead to a reduction in risks to workers.

The phone texts that are used for calls to employers, and for calls to workers making inquiries, fail to mention that the study will be looking at inhalation risk s in addition to risks relating to getting the compound on the worker’s skin and clothing.

With regard to recruiting and obtaining the informed consent of Spanish-speaking persons, the Board agrees w ith the changes recommended by the EPA (Carley 2008a and 2008b). It would also be appropria te for the protocol to includ e a more detailed discussion of how the researchers will obtain appropriate co mmunity involvement (such as, for example, discussions with unions repres enting janitorial workers).

With regard to the translations into Sp anish of the various documents, the Board believes that it is important to make sure that th e appropriate dialect of Sp anish is being used in he translations. The translati on of the consent form, for ex ample, was provided by someone from Miami, Florida, yet the study will be ta king place in California. The Spanish-speaking communities in Miami and California might well use significantly different dialects of Spanish.

Page 26 of 371 2 3 It was also not clear from the documents w ho was producing the Spanish-language version of some of the materials, such as the recruitment brochure.

4 5 6 7 8 9 10 HSRB Consensus and Rationale

The Board concurred with the initial assessmen t of the Agency that if the proposed mop and wipe scenario design, prot ocol, and supporting documentation is revised as suggested in EPA’s review, the research does appear to meet the applicable requirements of 40 CFR part 26, subparts K and L.

ICR Protocol: A382 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Science

Charge to the Board

If the proposed research desc ribed in ICR’s proposed picaridin protocol is revised as suggested in EPA’s review, does the research app ear likely to generate scientifically reliable data, useful for assessing the efficacy of the te st substances for repe lling stable flies?

Board Response

Protocol A382 outlined a laboratory test to evaluate the efficacy of picaridin against stableflies when applied dermally as a 20% cr eam or spray product. The purpose of the study was clearly defined (i.e., effi cacy testing), and the use of hu man subjects was adequately justified. Briefly, the proposed study will involve a total of 13 subjects, 12 of whom are designated for treatment with the picaridin spray and cream, with one additional subject designated as the negative control. The negative control will be selected at random and serves to establish the aggressiveness of each cage of stable flies to be used in the test. The first phase of the planned study will determine the averag e dose applied under normal use conditions, but will not exceed 4 mg/cm 2 . The second phase of the study is the repellency test in which subjects’ arms will be treated with measured amounts of bo th products (one product on each forearm), after which they will expose their treated forearms to stableflies for a 5 minute period every half hour for up to 10 hours. The submitted protocol proposed to use the time to first confirmed bite on both arms (both products) as the quantitative measure of repellent efficacy. The Sponsor provided a thorough stat istical justificati on for the protocol design, including the determination that a minimum of 7 subjects w ould be required to achieve a 95% confidence interval for assessing prot ection up to 8 hours with a ± 2-hour confidence limit.

There was general consensus that the protoc ol was well written and a sound scientific rationale was provided. There were several minor issues that were identified during the course of the HSRB discussion, representi ng issues that can easily be a ddressed in a revised protocol. These included: (1) clarifying the protocol to sp ecify that there are 13 subjects, representing 1 negative control and 12 treated individuals; (2 ) providing some information as to what activities are permitted during the 25 minute interv als when subjects are not actively on test and specifying what activities are precluded by be ing involved in the test; (3) ensuring the

Page 27 of 37accuracy of the margin of exposure (MOE) assu ming a maximum application rate of 4 mg/cm 2 ; and (4) recommending that the Sponsor design the test to randomize the treatment modalities (spray or cream) on the left and right arms and to ensure that the professional staff involved in the conduct of the study are blinded to the tr eatments. The HSRB recommends that these modifications should be made to the protocol and study conduct. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 There were however, three additional matters concerning the protocol design for which there was additional board discussion and more significant changes recommended to the proposed study. These issues were as follows:

1. It was noted during the Board’s discussion th at the Sponsor specified that the subject pool was exclusively Caucasian. There was co ncern as to whether the results obtained from such a constrained population could be generalized to other races, and there was a minority, but strongly voiced opinion that the protocol was not scientifically sound given this limitation. The HSRB recommended that the subjects used in this study should not be homogeneous, but rather, that th ere should be diversity across the subjects used for the test. The Board did not provide a specific recommendation on how diverse the test population should be, but suggested that, at a minimum, it should reflect the diversity of the region from which the possible subjects are drawn. The Board agreed that the Sponsor must address th is scientific issue prior to executing the study. 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 2. OPP staff recommended that a positive control be used in this study, suggesting that it would improve the overall scientific validity of the test. In its discussion, the HSRB concluded that the inclusion of a positive cont rol was not essential to the protocol, and the Board recommended against requiri ng a positive contro l in the study.

3. The protocol was designed to evaluate repellent efficacy using the accepted paradigm of time to first confirmed bite for each tr eatment (cream or spray product). As such, this design would result in a total of 4 bite s per subject upon loss of repellency (first bite to be followed by a confirming bite fo r each treatment). In consideration of the biology of stable flies, there was gene ral consensus among the HSRB that the study would be scientifically valid if the time to first bite, requiring only one bite per treatment, was used as the endpoint for evaluating the efficacy of the repellent.

36 37 38 39 40 41 42 43 HSRB Consensus and Rationale

If amended in a manner consistent with the Board’s concerns and recommendations, and with particular modification to subject ethnicity, the protoc ol ICR A382 studying the efficacy of two formulations of picaridin for repelling stable flies would be sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of these formulations against stable flies.

44 45 46 Ethics

Charge to the Board

Page 28 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 If the proposed research desc ribed in ICR’s proposed picaridin protocol is revised as suggested in EPA’s review, does the research app ear to meet the applicable requirements of 40 CFR part 26, subparts K and L?

Board Response

The Board concurred with the factual obs ervations of the ethical strengths and weaknesses of the proposed study, as detailed in the EPA’s Science and Ethics Review (Carley and Sweeney 2008).

Overall, this is a well written protocol, consent document, and a pplication, answering many of the questions that HSRB has asked when reviewing in other stud ies. The risks to study participants were minimal and were justified by the likely societal bene fits, including data on the efficacy of these new formulations as repellents against stable flies.

The 20% concentration of picarid in in the products to be used in this study is “higher than the marketed and EPA-registered formul ation.” Based on toxicological data currently available, however, picaridin has low acute toxicity. The poten tial risks include irritation or allergic response to the product. Individuals known to be sensitive to insect repellents or skin care products are excluded from the study. In add ition, subjects will be monitored for signs of reaction to the products during the dosimetr y portion of the study as well as during the repellent phase of the study.

While stable fly bites are acutely painful, the flies are not known to transmit any diseases to humans. Individuals known to be sensitive to stable fly bites are excluded from the study. Topical lotions and rubbing alcohol will be available to s ubjects to help relieve the itching from the bites.

The study protocol also included several mechanisms designed to minimize coercive recruitment and enrollment, compensation ( $11/hour, time-and-a-half over 9 hours) was not considered to be so high as to unduly influence participation, and minors and pregnant or lactating women were explicitly excluded fr om enrolling (pregnancy being confirmed by requiring all female volunteers to undergo a self-administered over-the-counter pregnancy test “shortly before any treatment with a test article”). The potential stigmatization resulting from study exclusion was minimized by the use of ‘alte rnate’ participants, al lowing for volunteers to withdraw or be excluded from participating without unduly compromising their confidentiality.

Several ethical issues were raised, and can be categorized as they relate to the Belmont Principles of Respect for Persons, Beneficence and Justice. The Board conc luded that all of the issues could be addressed with additional e xplanations or minor pr otocol modifications. Concerns were raised relating to the Justice prin ciple. Subjects greater than 70 years of age are excluded without adequate justification. S ubjects who cannot “read, speak, and understand English” are also excluded, wit hout a description of how that w ill be assessed or a justification of why reading English is required for this st udy. The recruitment pool of potential subjects is overwhelmingly Caucasian. While ICR will “look for recruits from the Afro-American

Page 29 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 community,” there are no plans presented to assure racial/ethnic di versity of the study population, which would be more appropriate give n that these products, if marketed, will be marketed to the genera l diverse population.

Issues related to the Respect for Persons pr inciple include the requirement that women not of child-bearing potential, such as wome n who have had a hysterectomy or who are postmenopausal, are nevertheless required to unde rgo a pregnancy test . Some HSRB members found this disrespectful, but a mi nority of other members did not.

While most issues related to the Beneficen ce principle were addr essed, the question of whether or not the stable flies to be used in this study would be give n bovine blood at any time prior to the study remained unanswered. Because bovi ne blood carries with it a potential risk to humans of Creutzfeld-Jacob disease or e xposure to bovine leukemia virus, the Board recommended that this question of whether or not the stable flies would receive bovine blood prior to their opportunity to bi te human volunteers and the atte ndant risks be addressed. In addition, the scientific issue of using unblinde d ICR staff to measure the outcome variable (stable fly bites) may jeopardize the scientific validity of the study, a nd thus alter the riskbenefit assessment. The HSRB recommended randomizing which pr oduct is applied to which arm, and using a blinded evaluator to measure the outcome variable.

21 22 23 24 25 26 HSRB Consensus and Rationale

The Board concurred with the initial assessmen t of the Agency that, if the protocol is revised as suggested by EPA and the HSRB, the study submitted for review by the Board meets the applicable requirements of 40 CFR 26, subparts K and L.

Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI 001.5 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Science

Charge to the Board

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

Board Response

The active ingredient DEET in two lotion formul ations was tested for its ability to repel mosquitoes from the arms of volunteers by the protocol presented and modified by CarrollLoye in two separately described studies wh ich were conducted simultaneously using common sites and negative controls. This was a repeat of two products previously tested but not accepted for ethical reasons at the October, 2007, HSRB meeting. The protocol had been modified based on the suggestions and input of EPA and HSRB. The results were reported in SCI.001.4, DermaAegis LipoDEET 302, and SCI .001.5 Coulston’s Duranon. The results on these two products were not compared to a pos itive control substance nor to one another. Because of the common elements between the two studies, they are discussed together in this

Page 30 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 report. All experiments were conducted using Good Laboratory Practices . Margins of exposure were high.

The dosimetry for the two products was done in the laboratory on November 7-9, 2007. The field tests were conducted on November 10, 2007, at Site 1 in Glenn County, a forest habitat, and on November 11, 2007, at Site 2 in Butte County, a grassland habitat, both in California. Slightly different mosquito spec ies composition occurred at the two sites, but overall the species composition of the two sites was similar. Ten subjects were used for the dosimetry tests. Ten subjects were used fo r each of the two products. The subjects were required to be above 18 years of age and no more than 55 years of age, and active in rural outdoor settings. Only arms were tested in th is study. There were two experienced persons serving as negative controls (i.e., without any repellent product) to confirm mosquito landing pressure (and landing pressure was maintained throughout the period of the study, defined as at least one Landing with Intent to Bite, LIBe, per min during th e period of exposure). LIBe’s were monitored in experimental subjects during a one min interval each 15 min, until the First Confirmed LIBe (FCLIBe) could be determin ed. Stopping rules were employed. No evidence of West Nile Virus was present in either test site from sentinels prio r to conduct of the study. Mosquitoes landing were taken to the laboratory for later identification, and for screening for West Nile, Western Equine Encephalitis, and St. Louis Encephalitis viruse s, and all mosquitoes were negative. All subjects wore Tyvek coverall, head nets and surgical gloves. Observation was initiated 150-180 minutes post applicati on. Complete protection time (CPT) was measured, defined as the time to the FCLIBe. The data were presented as mean ± standard deviations. Because of the low number of repellency failures observed, a Kaplan-Meier analysis (suggested at previous HSRB meetings) was not conducted.

LipoDEET 302 is 30% DEET on lipid spheres de signed to improve the durability and to improve the cosmetic properties. It yielde d a CPT of 11.25 ± 0.0 hr in Site 1 (no repellency failures) and 11.28 ± 0.79 hr in Site 2.

Coulson’s Duranon is 20% DEET in microsc opic protein spheres to reduced skin absorption of DEET, improve cosmetic properties and inhibit evaporation. It yielded a CPT of 11.25 ± 0.0 (no failures) in Site 1 and 10.78 ± 1.3 hr in Site 2.

The report was clearly written. The study wa s justified in that additional insect repellents that are more efficacious and/or more acceptable cosmetically to the public would be an advantage from both the standpoint of hea lth (to reduce the chan ces of contracting a mosquito-borne disease) and of comfort. The in formation should be generalizable to the public, although the exclusions, which we re highly appropriat e, excluded some subpopulations that would likely use insect repellents. The experiment was necessary to determine the field efficacy of these test formulations, and the expe riments were set up to meet the study objective. Measurements taken were appropriate for the ob jective and quality assu rance considerations were in place.

The experiment was conducted according to the approved protocol with some deviations, none of which negatively impacted th e scientific validity. Discussion was related to a lack of positive control (this was not considered a flaw and did not impact the usefulness of

Page 31 of 371 2 3 4 5 6 7 8 the data); the deviation of a la g time between application of the repellants and the initiation of monitoring (this was probably related to the shor t day length available for testing in November and the necessity of applying the repellant earl y to assure a sufficien tly long observation period before dark); and the allowance of an applica tion of repellant on the day before the study (it was clarified in the previous HSRB meeting that the repellant was washed off after dosimetry or testing, and the target skin was washed ag ain prior to a new study, thereby insuring that there was no carry-over to compromise data).

9 10 11 12 13 14 15 HSRB Consensus and Rationale

The Board concluded that the study on th e efficacy of LipoDEET 320 and Coulson’s Duranon shows efficacy of both products in repelli ng mosquitoes, and agreed with the Agency that the study was sufficiently s ound, from a scientific perspective, to be used to accurately calculate the CPT for repelling mosquitoes.

Ethics 16 17 18 19 20 21 22 23 24 Charge to the Board

Does available information support a determinati on that this study was conducted in substantial compliance with subparts K and L of EP A regulations at 40 CFR part 26?

Board Response

Brief Overview of the Study 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 The basic protocol for these studies (SCI- 001) was initially reviewed at the January 2007 HSRB meeting, at which time the Board co ncluded that the study would meet the requirements established in the Environmental Protection Agency’s final human studies rule (40 CFR Part 26) pending minor revision. Most, although not all, of these suggestions were incorporated into a revised protocol, submitted to the IRB of record (Institutional Review Board, Inc., [IIRB, Inc.] of Plantation, FL) for re-review, and approved (Carley 2008; Carroll 2008).

Using the revised protocol and consent documents for SCI-001, Carroll-Loye Biological Research conducted dosimetry and fi eld trials of three compounds in July 2007: DermAegis LipoDEET 302, DermAegis LipoDE ET 3434, and Coulston’s Duranon Personal Insect Repellent. At the Oct ober 2007 meeting of the HSRB, the Board recommended that the data obtained in July under protocol SCI- 001 not be accepted for regulatory decision-making purposes (EPA HSRB 2007). The Board conclude d that the use of a previously unapproved pesticide formulation (DermAegis LipoDEET 3434) violated the applicab le requirements of 40 CFR Part 26.

The data presented to the Board in April 2008 represents the results of new dosimetry and field trials of two compounds in November 2007: DermAegis LipoDEET 302 and Coulston’s Duranon Personal In sect Repellent. The documen ts provided by Carroll-Loye

Page 32 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 (Carroll 2007a; Carroll 2007b) specifically stat e that each study was conducted in compliance the requirements of the U.S. EPA Good La boratory Practice Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26 subparts K and L; FIFRA § 12(a)(2)(P); and the California State EPA Department of Pesticid e Regulations for study monitoring (California Code of Regulations Title 3, Section 6710). E ach study was also reviewed and approved by a commercial human subjects revi ew committee, IIRB, Inc. Docu mentation provided to the EPA by IIRB, Inc. indicates that it reviewed these studies pursuant to the standards of the Common Rule (45 C.F.R. Part 46, Subpart A) and determin ed them to be in compliance with that Rule.

As submitted to the EPA, each completed study consists of two interdependent analyses: 1) a dosimetry study designed to de termine the amount of an insect-repelling compound (30% DEET in liposomal capsules or 20% DEET in protein capsules) that typical users would typically apply when provided with a lotion formulations; and 2) an efficacy study designed to measure the effec tiveness of each compound as a mosquito repellent. The two studies, SCI-001.4 and SCI-001.5, were performed simu ltaneously at a laborat ory site in Davis, California, and at field sites in Butte and Glenn Counties, Califo rnia, by researchers at CarrollLoye Biological Research. The st udy sponsor was Scientific Coor dination, Inc., of Rockville, Maryland. The studies were conducted using products from two manufacturers: LipoDEET 302 was manufactured and supplied by DermAegis, Inc. of Rockford, Illinois; Duranon was manufactured and supplied by Sawyer Pr oducts of Safety Harbor, Florida.

Dosimetry was determined by direct measurement of compound application. The efficacy of each as a mosquito repellent was determined by measuri ng the ability of the formulations to prevent mosquito landings (defined as “Lite with Intent to Bite”; LIBe) under field conditions. Mosquitoes were aspirated mechanically prior to biting; prior to initiation of the efficacy study, all volunteers will be trained both to recognize a mosquito landing with the intent to bite and to remove such mosquitoes with an aspirator us ing laboratory-raised, pathogen-free mosquitoes in a controlled laboratory setting. During the field studies, participants worked in pairs to facilitate id entification and aspirati on of LIBing mosquitoes during brief exposure periods. The strengths and weaknesses of each study design are described above.

The dosimetry study enrolled a total of 10 individuals, ea ch of whom tested both formulations. Each efficacy study enrolled 10 subj ects for each formulation at each of the two field sites. Many volunteers participated in multiple analytic phases, both dosimetric and effective. In total, 29 volunteers participated in at least one analyt ic phase of SCI-001.4 and SCI-001.5. In addition, three alternate participants were enrolled to: 1) replace any individual who withdrew; and 2) protect th e confidentiality of any particip ant excluded from the study as a result of pregnancy or other potentially stigmatizing condition, as described below.

Critique of Study 41 42 43 44 45 The Board concurred with the factual obs ervations of the ethical strengths and weaknesses of the study, as deta iled in the EPA’s Science and Et hics Review (Carley 2008).

Page 33 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 In general, the research described in SCI-001.4 and SCI-001.5 comported with the applicable requirements of 40 CF R Part 26, subparts K and L. Th e risks to study participants, in general, were minimal and were justified by the likely societal bene fits, including data on the efficacy of these new formulations (30% DEET in liposomal capsules and 20% DEET in protein capsules) as pers onal insect repellents.

Based on toxicological data currently available for DermAegis LipoDEET 302 and Coulston’s Duranon Personal Ins ect Repellent, compounds regist ered with the EPA, the subjects enrolled in this study were unlikely to be at increased risk of experiencing adverse side effects upon exposure. Higher concentrations of DEET are commercially available and have been used as repellents for years.

Reactions to mosquito bites are usually mild and easily treated with over-the-counter steroidal creams. The study also excluded individuals who have a history of severe skin reactions to further minimize the risk of a par ticipant experiencing a seve re physical reaction to a mosquito bite. In addition, the study protoc ol was designed specifically to minimize the likelihood that a mosquito will bite, through the use of clear stopping rules, limited exposure periods, and paired observation; no side e ffects or adverse even ts were reported.

To minimize the risk that study participants will be exposed to illnesses like West Nile Virus, the study protocol called for field tests of repellent efficacy to be conducted only in areas where known vector-borne diseases have not been detected by county and state health or vector/mosquito control agencies for at least one month. Mosquitoes co llected during the field studies also were subjected to se rologic or molecular analyses to confirm that they were free of known pathogens.

The study protocol also included several mechanisms designed to minimize coercive recruitment and enrollment, compensation was no t considered to be so high as to unduly influence participation, and minor s and pregnant or la ctating women were explicitly excluded from volunteering (pregnancy being confirmed by requiring all female volunteers to undergo a self-administered over-the-counter pregnancy te st on the “day of the study”). The potential stigmatization resulting from study exclusion was minimized by the use of so-called ‘alternate’ participants, allowing for volunteer s to withdraw or be excluded from participating without compromising their confidentiality. There was so me question as to the appropriate timing of such testing (Carley 2008), but no female par ticipant was exposed to product without first undergoing pregnancy testing. Futu re trials conducted by Carrol l-Loye Biological Research, however, should use protocols and informed c onsent documents that explicitly outline the nature and timing of pregnancy te sting for female participants.

Several Board members raised ethical and procedural concerns about the numerous protocol changes present in the documents submitted to the EPA (Carroll 2007a, 2007b) but which were not presented to the Board prior to the conduct of the study. For example, in its initial review of Protocol SCI-001 in Janua ry 2007, the HSRB approved a protocol that involved the experimental administration of four compounds (three sponsor-submitted test compounds and one comparator [3M Ultrathon; 34.34% polymerized DEET]). The study, as completed, used only two test compounds and no comparator. Many HSRB members

Page 34 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 considered this to be a major change in study design, a change to which the Board was unaware until the study was completed and the data submitted for review. In light of these concerns, the Board recommended that the EPA re view existing regulations and establish clear guidelines as to when modified protocols s hould be submitted to the Board for re-review.

Finally, several Board members also voiced c oncerns about the type and nature of the protocol deviations reported by Dr. Carroll to IIRB, Inc. Many of these same deviations have occurred in completed studies previously submitted to the Ag ency and the Board for review, raising questions about the unanticip ated nature of these protocol ch anges. It is clearly stated in Federal regulations for research involving human subjects that the only protocol changes that can be made without prior IRB approval are those that are unantic ipated and which are necessary to protect the safety of trial particip ants. No protocol change s, reported or not, are allowed for reasons of expedience, as appeared to be the case here.

HSRB Consensus and Rationale 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 The Board concurred with the initial assessmen t of the Agency that the study submitted for review by the Board meets the applicable re quirements of §40CFR26, subparts K and L.

Board Decision Regarding Future Review of Protocols with Planned Deviations from Prior IRB Review

Over several meetings, including the April 2008 meeting, the Board has expressed concern with EPA submission for HSRB review of comp leted studies in which planned protocol deviations were conducted prior to IRB review and following HSRB review of the originally approved protocol. Such actions are in viol ation of 40 CFR 26, Subpart K Sec. §26.1108 IRB functions and operations.

Subpart K Sec. §26.1108 IRB functions and operations. “In order to fulfill the requirements of this subpart, each IRB shall: (a) Follow written procedures: (1) For conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (2) For determining which projects require review more often than annually and which projects need verification from sources other than the investi gator that no material changes have occurred since previous IRB review; (3) For ensuring prompt reporting to the IRB of proposed changes in research activity; and (4) For ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.”

The Board reached consensus regarding its futu re review procedures under such conditions:

1. Any study executed prior to IRB approval of the Informed Consent Form and the protocol, or changed in ways that were not approved by the IRB will be judged by the

Page 35 of 371 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

44 45 Board as failing to meet the applicable requirements of §40 CFR 26, subparts K.

2. If the EPA submits to the Board for revi ew a completed protocol with scientific deviations from the original protocol reviewed by the Board, the EPA review of the completed protocol should provide the Bo ard with EPA's opinion regarding why the deviation did not meet the requirement for re -review and why the protocol still meets the applicable regulations.

REFERENCES

Carley, J.M., Leighton T., Walls C. 2008a. Sc ience and Ethics Review of AEATF Mop Scenario Design and Protocol for Exposur e Monitoring. Dated March 10, 2008. Unpublished document prepared by Office of Pesticide Progr ams, United States Environmental Protection Agency.

Carley, J.M., Leighton T., Walls C. 2008b. Scien ce and Ethics Review of AEATF Scenario Design and Protocol for Expos ure Monitoring in Wipe Scenarios. Dated March 10, 2008. Unpublished document prepared by Office of Pes ticide Programs, United States Environmental Protection Agency.

Carley, J.M. 2008. Ethics Review of Reports of Completed Carroll-Loye Field Mosquito Repellent Efficacy Studies SCI-001.4 and SCI-001.5. Dated March 7, 2008. Unpublished document prepared by Office of Pesticide Progr ams, United States Environmental Protection Agency.

Carley, JM and Sweeney K. 2008. Science and Ethi cs Review of Protocol for Human Study of Stable Fly Repellent Performance. Unpublishe d document prepared by Office of Pesticide Programs, United States Envi ronmental Protection Agency.

Carroll, S. 2007a. SCI-001.4: Test of DermAe gis LipoDEET 302 Personal Insect Repellent (EPA Reg. #82810-1). MRID 47322501. Dated Nove mber 27, 2007. Unpublished study report prepared by Carroll-Loye Biological Research.

Carroll, S. 2007b. SCI-001.5: Test of Coulston’s Duranon Personal Insect Repellent (EPA Reg. #50404-8). MRID 47322401.Dated November 27, 2007. Unpublished study report prepared by Carroll-Loye Biological Research.

Carroll, S. 2008. Letter to John M. Carley tr ansmitting supplemental correspondence between Carroll-Loye Biological Research and Indepe ndent Investigations Review Board, Inc., concerning SCI-001, with enclosures. Dated March 5, 2008. Unpublished letter prepared by Carroll-Loye Biological Research.

EPA HSRB. 2007. October 24-26, 2 007 EPA Human Studies Revi ew Board Meeting Report.

National Commission for the Protection of Huma n Subjects of Biomedical and Behavioral Research. The Belmont Report:

Page 36 of 37Page 37 of 37 1 2 Ethical Principles and Guidelines for the Protection of Human Subjects of Research. 1979. http://www.hhs .gov/ohrp/humansubjects/guidance/belmont.htm