1 June 25, 2008
2
3 EPA-HSRB-08-02
4
5 George Gray, Ph.D.
6 Science Advisor
7 Office of the Science Advisor
8 1200 Pennsylvania Avenue, NW
9 Washington, DC 20460
10
11 Subj ect: April 9-10, 2008 EPA Human Studies Review Board Meeting Report
12
13 Dear Dr. Gray:
14
15 The United States Environmental Protection Agency (EPA or Agency) requested the
16 Human Studies Review Board (HSRB) to review scientific and ethical issues addressing: (1)
17 EPA Review of Antimicrobial Exposure Assessment Task Force Mop and Wipe scenario
18 protocols; (2) ICR Protocol: A382 and (3) Carroll-Loye Biological Research Completed
19 Studies: SCI 001.4 and SCI 001.5. The enclosed HSRB report provides the Board's response
20 to EPA charge questions presented at the April 9-10, 2008 meeting. The Board also
21 appreciates the Agency providing an update of the EPA/ORD document "Scientific and Ethical
22 Approaches for Observational Exposure Studies." The Board agrees with the Agency that the
23 document will serve as a valuable resource for EPA and other researchers to rely on as they
24 develop and conduct observational human exposure studies. In addition to the
25 recommendations for specific protocols and completed studies summarized below, the Board
26 provided comments on review and format of AEATF and AHETF protocols.
27
28 A summary of the Board's conclusions is provided below.
29
30 EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of the mop and wipe
31 scenarios, both exposure scenarios were reviewed together)
32
33 Science
34
35 The Board considered the AEATF-II study protocols to successfully address many
36 design challenges. The Board appreciated particularly the clarity of the protocols, the attention
37 to detail, and the thorough description of quality assurance and quality control procedures. The
38 Board concurred with the Agency that existing data on handler exposures to antimicrobials are
39 inadequate and that the development of more accurate information is an appropriate goal. The
40 Board also concurred with the Agency that there are only minimal risks associated with the
41 application of a dilute solution of didecyl dimethyl ammonium chloride as described in the
42 study protocols.
43
44 While the Board concluded that the research could produce scientifically reliable data,
45 the Board identified several contextual factors that may limit the generalizability of the
46 findings. The Board therefore recommended that the Agency reconsider the design of the
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1 study, or develop an explicit statement of the limitations on the use of data that will be
2 collected under the proposed design. Specifically the Board noted that any generalizations to
3 moppers and wipers in other parts of the country and in other kinds of buildings would be
4 based on expert opinion, and that such generalizations would not be statistical generalizations.
5 The Board cautioned the Agency regarding the 3x6 design in the protocols, suggesting future
6 scenario designs for the AEATF- II program would likely have three clusters and six time
7 durations, with the justification being the Board's recommendation of these protocols. The
8 Board also concluded that the task duration time frame was not adequate to characterize daily
9 exposure. The Board recommended that the work time frame be expanded to exceed the 95th
10 percentile of the International Sanitary Supply Association survey findings. The Board noted
11 that if, instead of time, the number of Ai units handled were the measure that defined each
12 person's participation, the data would more likely lend themselves to a proper assessment of
13 the assumption of proportionality.
14
15 Finally, the Board encourages modifications of future related protocols based on the
16 lessons learned from this initial submission. Such adjustments are anticipated to improve the
17 study design and subsequent results, leading to a more accurate characterization of pesticide
18 handler exposure.
19
20 Ethics
21
22 The Board concurred with the initial assessment of the Agency that if the proposed mop
23 and wipe scenario design, protocol, and supporting documentation is revised as suggested in
24 EPA's review, the research would meet the applicable requirements of 40 CFR part 26,
25 subparts K and L.
26
27 ICR Protocol: A 382
28
29 Science
30
31 If amended in a manner consistent with the Board's concerns and recommendations,
32 and with particular modification to subject ethnicity, the Board concluded that the protocol
33 ICR A3 82 studying the efficacy of two formulations of picaridin for repelling stable flies
34 would be sufficiently sound, from a scientific perspective, to be used to assess the repellent
35 efficacy of these formulations against stable flies.
36
37 Ethics
38
39 The Board concurred with the initial assessment of the Agency that, if the protocol is
40 revised as suggested by EPA and the HSRB, the study submitted for review by the Board
41 would meet the applicable requirements of 40 CFR 26, subparts K and L.
42
43 Carroll-Love Biological Research Completed Studies: SCI 001.4 and SCI 001.5
44
45 Science
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1 The Board concluded that the study on the efficacy of LipoDEET 320 and Coulson's
2 Duranon shows efficacy of both products in repelling mosquitoes, and agreed with the Agency
3 that the study was sufficiently sound, from a scientific perspective, to be used to accurately
4 calculate the complete protection time for repelling mosquitoes.
5
6
7 Ethics
8
9 The Board concurred with the initial assessment of the Agency that the study submitted for
10 review by the Board meets the applicable requirements of §40CFR26, subparts K and L.
11 However, the Board expressed concern regarding a pattern of deviations from IRB approved
12 protocols apparent in this study and previous submissions by the investigator. Implications of
13 this concern are noted below.
14
15 Over several meetings, including the April 2008 meeting, the Board has expressed concern
16 with EPA submission for HSRB review of completed studies in which planned protocol
17 deviations were conducted prior to IRB review and following HSRB review of the originally
18 approved protocol. Such actions are in violation of 40 CFR 26, Subpart K Sec. §26.1108 IRB
19 functions and operations.
20
21 Subpart K Sec. §26.1108 IRB functions and operations.
22 "In order to fulfill the requirements of this subpart, each IRB shall:
23 (a) Follow written procedures:
24 (1) For conducting its initial and continuing review of research and for reporting its
25 findings and actions to the investigator and the institution;
26 (2) For determining which projects require review more often than annually and which
27 projects need verification from sources other than the investigator that no material changes
28 have occurred since previous IRB review;
29 (3) For ensuring prompt reporting to the IRB of proposed changes in research activity;
30 and
31 (4) For ensuring that changes in approved research, during the period for which IRB
32 approval has already been given, may not be initiated without IRB review and approval except
33 where necessary to eliminate apparent immediate hazards to the human subjects. "
34
35 The Board reached consensus regarding its future review procedures under such conditions:
36
37 1. Any study executed prior to IRB approval of the Informed Consent Form and the
38 protocol, or changed in ways that were not approved by the IRB will be judged by the
39 Board as failing to meet the applicable requirements of §40 CFR 26, subparts K.
40 2. If the EPA submits to the Board for review a completed protocol with scientific
41 deviations from the original protocol reviewed by the Board, the EPA review of the
42 completed protocol should provide the Board with EPA's opinion regarding why the
43 deviation did not meet the requirement for re-review and why the protocol still meets
44 the applicable regulations.
45
46
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1 In conclusion, the EPA HSRB appreciated the opportunity to advise the Agency on the
2 scientific and ethical aspects of human studies research and looks forward to future
3 opportunities to continue advising the Agency in this endeavor.
4
5
6
7 Sincerely,
8
9
10
11 Celia Fisher, Ph.D., Chair
12 EPA Human Studies Review Board
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1 NOTICE
2
3 This report has been written as part of the activities of the EPA Human Studies Review
4 Board, a Federal advisory committee providing advice, information and recommendations on
5 issues related to scientific and ethical aspects of human subjects research. This report has not
6 been reviewed for approval by the Agency and, hence, the contents of this report do not
7 necessarily represent the view and policies of the Environmental Protection Agency, nor of
8 other agencies in the Executive Branch of the Federal government, nor does the mention of
9 trade names or commercial products constitute a recommendation for use. Further information
10 about the EPA Human Studies Review Board can be obtained from its website at
11 http://www.epa.gov/osa/hsrb/. Interested persons are invited to contact Paul Lewis, Designated
12 Federal Officer, via e-mail at lewis.paul@epa.gov.
13
14 In preparing this document, the Board carefully considered all information provided
15 and presented by the Agency presenters, as well as information presented by public
16 commenters. This document addresses the information provided and presented within the
17 structure of the charge by the Agency.
18
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1 U. S. ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW
2 BOARD MEMBERS
O
4 Chair
5
6 Celia B. Fisher, Ph.D., Marie Ward Doty Professor of Psychology, Director, Center for Ethics
7 Education, Fordham University, Department of Psychology, Bronx, NY
8
9 Vice Chair
10
11 William S. Brimijoin, Ph.D., Chair and Professor, Molecular Pharmacology and Experimental
12 Therapeutics, Mayo Foundation, Rochester, MN *
13
14 Members
15
16 Alicia Carriquiry, Ph.D., Professor, Department of Statistics, Iowa State University
17 Snedecor Hall, Ames, IA
18
19 Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office for Human
20 Subjects Protection, University of Rochester, Rochester, NY
21
22 Janice Chambers, Ph.D., D.A.B.T., William L. Giles Distinguished Professor, Director, Center
23 for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State
24 University, Mississippi, MS
25
26 Richard Fenske, Ph.D., MPH, Professor, Department of Environmental and Occupational
27 Health Sciences, University of Washington, Seattle, WA*
28
29 Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology, Boston University
30 School of Public Health, Co-Director, MA in Clinical Investigation, Boston University School
31 of Medicine, Boston, MA
32
33 Suzanne C. Fitzpatrick, Ph.D., D.A.B.T, Senior Science Policy Analyst, Office of the
34 Commissioner, Office of Science and Health Coordination, U.S. Food and Drug
35 Administration, Rockville, MD
36
37 Dallas E. Johnson, Ph.D., Professor Emeritus, Department of Statistics, Kansas State
38 University, Manhattan, KS
39
40 Kannan Krishnan, Ph.D., Professor, Departement de sante environnementale et sante au travail,
41 Faculte de medicine, Universite de Montreal, Montreal, Canada
42
43 Michael D. Lebowitz, Ph.D., FCCP, Professor of Public Health & Medicine. University of
44 Arizona, Tucson, AZ
45
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1 Lois D. Lehman-Mckeeman, Ph.D., Distinguished Research Fellow, Discovery Toxicology,
2 Bristol-Myers Squibb Company, Princeton, NJ
O
4 Jerry A. Menikoff, M.D., Director, Office of Human Subjects Research, Office of the Director,
5 National Institutes of Health, Bethesda, MD
6
7 Rebecca Parkin, Ph.D., MPH, Associate Dean for Research and Public Health Practice, School
8 of Public Health and Human Services, The George Washington University, Washington, DC
9
10 Sean Philpott, Ph.D., MS Bioethics, Science and Ethics Director, Global Campaign for
11 Microbicides, Program for Appropriate Technology in Health, Washington, DC
12
13 Ernest D. Prentice, Ph.D., Associate Vice Chancellor for Academic Affairs, University of
14 Nebraska Medical Center, Omaha, NE*
15
16 Richard Sharp, Ph.D., Director of Bioethics Research, Department of Bioethics, Cleveland
17 Clinic, Cleveland, OH
18
19 Linda J. Young, Ph.D., Professor, Department of Statistics, Institute of Food and Agricultural
20 Sciences, University of Florida, Gainesville, FL
21
22
23 Consultants to the Board
24 KyungMann Kim, Ph.D., CCRP, Professor and Associate Chair, Department of Biostatistics &
25 Medical Informatics, School of Medicine and Public Health, University of Wisconsin-
26 Madison, Madison, WI
27
28 Human Studies Review Board Staff
29
30 Paul I. Lewis, Ph.D., Executive Director, Human Studies Review Board Staff, Office of the
31 Science Advisor, United States Environmental Protection Agency, Washington, DC
32
33 * Not in attendance at April 9-10, 2008 Public Meeting
34
35
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Page 8 of 37
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1 INTRODUCTION
2 On April 9-10, 2008, the United States Environmental Protection Agency's (EPA or
3 Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues
4 concerning: Sampling strategies in proposed pesticide handler research, Antimicrobial
5 Exposure Assessment Task Force (AEATF) Governing Document, EPA Review of AEATF-II
6 Mop and Wipe Scenarios, ICR Protocol: A382, and Carroll-Loye Biological Research
7 Completed Studies: SCI 001.4 and SCI 001.5 Each of these topics is discussed more fully
8 below. In addition, EPA's Office of Pesticide Programs provided a follow-up on pesticide
9 specific HSRB recommendations. Finally, EPA's Office of Research and Development
10 provided an update on revisions to its document "Scientific and Ethical Approaches for
11 Observational Exposure Studies." Each of these topics is discussed more fully below.
12
13 1. Proposed AEATF Research on Exposure of Subjects Using an Antimicrobial Pesticide
14 in Mopping and Wiping Activities
15
16 The HSRB has previously considered issues related to the design and conduct of
17 research to measure the levels of exposure received by people when handling (i.e., mixing,
18 loading, or applying) pesticides. Two industry Task Forces, the Antimicrobials Exposure
19 Assessment Task Force II (AEATF) and the Agricultural Handlers Exposure Task Force
20 (AHETF), have previously submitted materials for HSRB review. Based on the issues raised
21 by the Board at its meeting in June 2006, EPA asked its FIFRA Scientific Advisory Panel
22 (SAP), an advisory committee of independent expert scientific peer reviewers providing
23 technical advice to EPA on pesticide and pesticide-related issues, to address a number of
24 scientific issues at its January 2007 meeting. Drawing on the advice of the SAP, the Office of
25 Pesticide Programs (OPP) presented additional issues relating to the proposed handler research
26 again at the April and June 2007 HSRB meetings. In response to those reviews the Task
27 Forces have extensively reworked their research proposals.
28
29 One issue, the design of the sampling strategies to be used by the Task Forces, has
30 drawn particular attention. To resolve this question OPP has consulted with experts both
31 within and outside EPA, and has carefully considered information presented by the Task
32 Forces. Based on these interactions, OPP has decided to accept data developed through
33 "hybrid" sampling strategies, i.e., strategies that use a basic purposive diversity sampling
34 design but which incorporate random elements whenever feasible. OPP provided background
35 documents on these interactions on December 5, 2007 to the HSRB for subsequent
36 consideration. Those same background documents are provided again in this transmittal for
37 the Board's convenience in preparing for the April 2008 HSRB meeting.
38
39 The AEATF has submitted two proposals. Each includes both a scenario-specific
40 design document and the associated field study protocol, along with supporting documentation,
41 for EPA and HSRB review. One proposal would measure inhalation and dermal exposure of
42 subjects applying an antimicrobial pesticide by mopping floors. The other would measure
43 exposure of subjects who apply an antimicrobial pesticide by wiping vertical and horizontal
44 hard surfaces in two distinct scenarios—one using a spray-and-wipe technique, and the other
45 using ready-to-use impregnated wipes.
46
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1 EPA's regulation, 40 CFR §26.1125, requires the sponsor or investigator to submit to
2 EPA, before conducting a study involving intentional exposure of human subjects, materials
3 describing the proposed human research in order to allow EPA to conduct scientific and ethics
4 reviews. In addition, EPA's regulation, 40 CFR §26.1601, requires EPA to seek HSRB review
5 of the research proposal. Because the research proposed by the AEATF involves scripted
6 exposure, it meets the regulatory definition of "research involving intentional exposure of a
7 human subject", and thus these cited provisions of regulation apply to it.
8
9 EPA has reviewed the AEATF proposals and has concluded that, with a number of
10 required revisions, they appear likely to generate scientifically sound, useful information and to
11 meet the applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L.
12 EPA has also concluded that the proposed hybrid sampling designs for all three proposed
13 exposure scenarios effectively incorporate elements of randomization, consistent with EPA's
14 guidance to the AEATF. Because the sponsor wishes to initiate testing pursuant to these
15 protocols as soon as possible to meet regulatory requirements in other countries, and since EPA
16 finds the protocols can meet applicable scientific and ethical standards, EPA presented this
17 protocol for review at the Board's April 2008 meeting.
18
19 EPA provided the following materials concerning the AEATF Exposure Monitoring
20 Program to the HSRB:
21
22 3. AEATF Exposure Monitoring Program
23
24 a. General Documents
25
26 (1) Volume 5 AEATF Governing Document (Revised 2/13/08)
27
28 (2) AEATF Governing Document (Revised 2/13/08; track changes)
29
30 (3) Summary of Changes to Governing Document of 2/13/08
31
32 (4) Volume 6 AEATF SOPs (Revised 2/25/08)
33
34 b. Documents specific to the Mop Scenario
35
36 (1) Volume 1 AEATF Mop Scenario Design/Protocol: Primary Documentation
37 (Revised 2/25/08)
38
39 (2) Volume 2 AEATF Mop Scenario Design/Protocol: Secondary
40 Documentation (Revised 2/25/08)
41
42 (3) EPA Science and Ethics Review: AEATF Mop Scenario (3/10/08)
43
44 c. Documents specific to the Wipe Scenarios
45
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1 (1) Volume 3 AEATF Wipe Scenario Design/Protocol: Primary Documentation
2 (Revised 2/25/08)
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4 (2) Volume 4 AEATF Wipe Scenario Design/Protocol: Secondary
5 Documentation (Revised 2/25/08)
6
7 (3) EPA Science and Ethics Review: AEATF Wipe Scenarios (3/10/08)
8
9 d. Background documents on the Sampling Strategy Issue distributed to the HSRB
10 on December 5, 2007
11
12 (1) Memorandum from William Jordan to Dr. Celia Fisher Re: "Design of
13 Sampling Strategies in Proposed Handler Research"
14
15 (2) AHETF Study Design, Logistics, and Conduct (10-17-07) Power Point
16 presentation by David Barnekow and Victor Cafiez
17
18 (3) AEATF Introduction and Background (10-17-07) Power Point presentation
19 by Hasmukh Shah
20
21 (4) AHETF Membership Benefits and Incentives (10-17-07) Power Point
22 presentation by Victor Cafiez and David Barnekow
23
24 (5) AHETF and AEATF Concepts, Objectives, and Sampling Issues (10-17-
25 07) Power Point presentation by Larry Holden
26
27 (6) Report of Dr. Tapabrata Maiti, Associate Professor of Statistics at Iowa
28 State University, to EPA concerning sampling design issues in proposed
29 handler exposure research (11-30-07)
30
31 (7) Letter from Debra Edwards, OPP director, to Hasmukh Shah, manager of
32 the American Chemistry Council's Biocides Panel, concerning issues
33 involving the AEATF's proposed handler research. (11-28-07)
34
35 (8) Summary of EPA/OPP Teleconferences with AHETF (11-28-07)
36
37 2. Proposed ICR Stable Fly Repellent Efficacy Study (A 382)
38
39 EPA requires submission of data from efficacy studies when a pesticide product is
40 directed against organisms classified as public health pests. EPA's regulation, 40 CFR
41 §26.1125, requires a sponsor or investigator to submit to EPA, before conducting a study
42 involving intentional exposure of human subjects, materials describing the proposed human
43 research in order to allow EPA to conduct science and ethics reviews. In addition, EPA's
44 regulation, 40 CFR §26.1601, requires EPA to seek HSRB review of the research proposal.
45
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1 Insect Control & Research, Inc. (ICR) has submitted a proposal for new research to
2 evaluate the efficacy of two conditionally registered products containing picaridin, to be
3 conducted by Dr. William Gaynor. ICR protocol number G4330108001 A382 (A382)
4 describes a laboratory study of the efficacy of the test formulations against stable flies, a
5 species classified as a public health pest.
6
7 EPA has reviewed ICR's protocol and has concluded that, with several required
8 revisions, it appears likely to generate scientifically sound, useful information and to meet the
9 applicable provisions of the EPA regulations in 40 CFR part 26, subparts K and L. The
10 sponsor wishes to submit the data to EPA later this year in support of an application to amend
11 the registration of these picaridin products in order to claim specifically that the products are
12 effective at repelling stable flies. In the interest of providing a thorough and timely decision on
13 such applications, and since EPA finds the protocol can meet applicable scientific and ethical
14 standards, EPA is presenting this protocol for review at the Board's April 2008 meeting.
15
16 EPA provided the following materials on the ICR repellent efficacy protocol A382 to
17 theHSRB:
18
19 2. ICR Repellent Efficacy Protocol A382
20
21 a. ICR Stable Fly Protocol A3 82 (Rvsd 2/1/08)
22
23 b. EPA Science & Ethics Review (3/7/08)
24
25
26 3. Completed Insect Repellent Efficacy Studies (SCI-001.4 and SCI-001.5) of DEET
27 Formulations
28
29 In its January 2007 meeting the HSRB reviewed protocol SCI-001 from Carroll-Loye
30 Biological Research, submitted by Dr. Scott Carroll, to test mosquito repellent efficacy of three
31 controlled-release formulations of DEET in the field. The study was designed to measure the
32 efficacy of the three test formulations and one "comparison article"—the US military standard
33 repellent. The HSRB offered comments on the protocol at its January 2007 meeting.
34
35 Following that meeting, Dr. Carroll amended the protocol to address a comment from
36 the HSRB and to substitute a new, unregistered repellent formulation for one of those proposed
37 in the protocol. Dr. Carroll then proceeded to conduct the research according to the amended
38 protocol in July 2007, and submitted the results to EPA for review. At its October 2007
39 meeting, the HSRB reviewed the results of the research, determined that there were both
40 scientific and ethical issues with the conduct of the research, and advised EPA not to rely on
41 the data. Dr. Carroll further amended the protocol, obtained IRB approval for both the original
42 and subsequent amendments, and re-executed the research in November 2007, testing only two
43 of the originally proposed test repellents and omitting the comparison positive control
44 formulation. Reports of this testing have been submitted to EPA by the study sponsor,
45 Scientific Coordination, Inc., under study numbers SCI-001.4 and SCI-001.5. EPA is
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1 presenting the results of the re-execution of protocol SCI-001 to the HSRB for review at this
2 meeting.
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4 The Agency's regulation, 40 CFR §26.1602, requires EPA to seek HSRB review of an
5 EPA decision to rely on the results of these studies. The sponsor has submitted data in support
6 of applications for amended registration for the two test materials. In order to facilitate review
7 of these applications within the time allowed by statute, EPA has reviewed the research,
8 applying the standard in 40 CFR §26.1705. That provision states:
9
10 §26.1705 Prohibition on reliance on unethical research with non-pregnant,
11 non-nursing adults conducted after April 7, 2006
12
13 Except as provided in §26.1706, in actions within the scope of §26.1701, EPA
14 shall not rely on data from any research initiated after April 7, 2006, unless EPA
15 has adequate information to determine that the research was conducted in
16 substantial compliance with subparts A through L of this part. . . This
17 prohibition is in addition to the prohibition in §26.1703.
18
19 OPP has determined that the data are scientifically sound and that the research meets
20 the standard in §26.1705. Therefore OPP proposes to rely on the results in considering the
21 pending applications.
22
23 EPA provided the following materials on the completed insect repellent efficacy studies SCI-
24 001.4 and SCI-001.5 to the HSRB:
25
26 1. Insect Repellent Efficacy Studies SCI-001.4 and SCI-001.5
27
28 a. MRID 47322501 SCI-001.4: Test of DermAegis LipoDEET 302
29
30 b. MRID 47322401 SCI-001.5: Test of Coulston's Duranon
31
32 c. Supplemental correspondence IIRB^CLBR 3/5/08
33
34 d. EPA Science and Ethics Review (Protocol) SCI-001 (12/20/06)
35
36 e. Changes in consent form version of 11-6-07
37
38 f. EPA Ethics Review: SCI-001.4 and SCI-001.5 (3/7/08)
39
40 g. EPA Science Review: SCI-001.4 and SCI-001.5 (3/7/08)
41
42 This report transmits the HSRB's comments and recommendations from its April 9-
43 10, 2008 meeting.
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2 REVIEW PROCESS
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4 On April 9-10, 2008, the Board had a public face-to-face meeting in Arlington,
5 Virginia. Advance notice of the meeting was published in the Federal Register "Human
6 Studies Review Board: Notice of Public Meeting (73 Federal Register 46, 12413). At the
7 public meeting, following welcoming remarks from Agency officials the Board then heard
8 presentations from the Agency on the following topics:
9
10 • Update On Revisions To The EPA Document "Scientific And Ethical Approaches For
11 Observational Exposure Studies
12 • EPA Follow-up on Pesticide Specific HSRB Recommendations
13 • Overview of EPA's Assessment of Proposed Pesticide Handler Research
14 Sampling Strategies in Proposed Pesticide Handler Research
15 Antimicrobial Exposure Assessment Task Force (AEATF) Governing
16 Document
17 EPA Review of AEATF-II Mop and Wipe Scenarios
18 • ICRProtocol: A382
19 • Carroll-Loye Biological Research Completed Studies: SCI 001.4 and SCI 001.5
20
21
22 Oral comments
23 The following oral comments were presented at the meeting:
24
25 AEATF-II Mop and Wipe Scenarios
26 Jeff Driver, Ph.D. ofinfoscientific.com on behalf of the AEATF-II
27 Larry Holden of Sielken and Associates, Inc. on behalf of the AEATF-II
28
29 ICR Protocol: A382
30 William Gaynor, Ph.D. on behalf of ICR, Inc.
31 Robin Todd, Ph.D. on behalf of ICR, Inc.
32 Ralph Piedmont, Ph.D. of Loyola College on behalf of ICR, Inc.
33
34 Carroll-Love Biological Research Completed Studies: SCI 001.4 and SCI 001.5
35 Scott Carroll, Ph.D. and Mr. Shawn King on behalf of Carroll-Loye Biological Research
36
37 Written comments
38 Written comments were received by:
39
40 General
41 Stephen A. McFadden, Independent Scientific Research Advocates
42
43 AEATF-II Mop and Wipe Scenarios
44 American Chemistry Council on behalf of the AEATF-II
45
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1 For their deliberations, the Board considered the materials presented at the meeting,
2 written public comments and Agency background documents (e.g., the published literature,
3 Agency data evaluation record, weight of evidence review, ethics review, pesticide human
4 study protocols and Agency evaluation of the protocol or study). For a comprehensive list of
5 background documents visit the www.regulations.gov. Docket ID No. EPA-HQ-ORD-2007-
6 0942, or EPA's HSRB website at http://www.epa.gov/osa/hsrb/oct-24-26-2007-public-
7 meeting.htm.
9 CHARGE TO THE BOARD AND BOARD RESPONSE
10
11 Update On Revisions To The EPA Document "Scientific And Ethical Approaches For
12 Observational Exposure Studies
13
14 No Charge to the Board
15
16 EPA Follow-up on Pesticide Specific HSRB Recommendations
17
18 No Charge to the Board
19
20 Overview of EPA's Assessment of Proposed Pesticide Handler Research
21
22 Sampling Strategies in Proposed Pesticide Handler Research
23 No Charge to the Board
24
25 Antimicrobial Exposure Assessment Task Force (AEATF-II) Governing
26 Document
27 No Charge to the Board
28
29 Board Recommendations on Review and Format of AEATF and AHETF Protocols
30
31 Overall recommendations
32 1. Random sampling designs are preferred.
33 2. When random sampling is not possible, a purposive diversity sampling (PDS) protocol
34 must nonetheless have a well-developed sampling frame based on knowledge of the range of
35 active ingredient concentrations and distribution of methods used in the field.
36 3. Each protocol should be individually assessed for the feasibility of random assignment.
37 When random sampling is not possible, each protocol should be individually assessed for the
38 adequacy of the PDS sampling frame.
39
40 Format of protocols for subsequent HSRB review
41
42 1. A detailed description of the methods and rationale for data collection (e.g., neck wipes).
43 2. If random sampling is not used, a detailed description of efforts made to incorporate
44 random elements in each scenario-specific design and why it was not feasible (in terms of
45 availability of information, costs, and time) to obtain a random sample.
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1 3. For both random and PDS designs, a detailed description, rationale and justification for the
2 scenario, selection of clusters, and what will be done within each cluster and why.
3 4. For all protocols, a detailed explanation of how data will be analyzed and interpreted by
4 AHETF & AEATF.
5 5. For all protocols, a detailed explanation of how the data is anticipated to be analyzed by
6 EPA and how it will be useful for EPA risk assessments.
7
8 Format of Agency presentations, specifically OPP presentations to the Board
9
10 1. OPP should develop a written glossary of terms (e.g., cluster, scenario) for HSRB and
11 public reference. This glossary should be distributed but not summarized during OPP
12 presentations.
13 2. For each protocol OPP should provide a brief (1 page if possible) abstract in terms
14 appropriate for a lay audience describing the nature and purpose of the study and how EPA
15 intends to use the data.
16 3. OPP's oral presentation should not focus on details. The Board believes that such detailed
17 presentations distract from focusing attention on those aspects of the protocol for which OPP is
18 eliciting Board feedback.
19 4. OPP's oral presentation on the science should not be a summary of the protocol, but a
20 focused discussion of OPP's evaluation of why they think the study has sufficient scientific
21 validity; the presentation should include questions regarding scientific validity that OPP wishes
22 the Board to address.
23 5. OPP's oral presentation should also include a description of how the Agency plans to
24 analyze and use the data.
25 6. Similarly, OPP's oral presentation should not focus on the details regarding the protection
26 of human subjects as such details are described in the written materials. Rather, a brief oral
27 presentation should identify those aspects of the design that OPP believes raise human subjects
28 concerns.
29
30 AHETF and AEATF Comments at HSRB meetings:
31
32 1. Since the HSRB makes its recommendations to EPA and not directly to sponsors, it is the
33 responsibility of the Agency to present the protocol to HSRB, along with EPA's critique and
34 conclusions.
35 2. Sponsors have the opportunity to express their perspectives and clarify information during
36 the public comment periods.
37 3. During Board discussion of protocols, sponsors should be available for additional
38 clarifications that may be needed.
39 4. In addition, if sponsors believe that a specific point has not been adequately addressed they
40 should have the opportunity to alert OPP to their concerns during the time allotted to the
41 protocol; OPP in consultation with the Chair and DFO may recommend to the Board that the
42 sponsor provide additional clarification on the issue(s).
43
44 EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of the mop
45 and wipe scenarios, both exposure scenarios were reviewed together)
46
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1 Science
2
3 Charge to the Board
4 If the proposed research described in AEATF's proposed mop scenario design,
5 protocol, and supporting documentation is revised as suggested in EPA's review, does the
6 research appear likely to generate scientifically reliable data, useful for assessing the exposure
7 of handlers who apply an antimicrobial pesticide by mopping?
8
9 If the proposed research described in AEATF's proposed wipe scenario designs,
10 protocol, and supporting documentation is revised as suggested in EPA's review, does the
11 research appear likely to generate scientifically reliable data, useful for assessing the exposure
12 of handlers who apply an antimicrobial pesticide by wiping?
13
14 Board Response to the Charge
15
16 The two proposed human studies focus on handlers during floor mopping or surface
17 wiping with a liquid antimicrobial pesticide product to determine potential dermal and
18 inhalation exposures. The studies are (1) AEA03, "A Study for Measurement of Potential
19 Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide
20 Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces," and (2) AEA02, "A
21 Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a
22 Liquid Antimicrobial Pesticide Product using Trigger Spray and Wipe or Ready to Use Wipes
23 for Cleaning Indoor Surfaces." The protocols associated with these studies have many
24 similarities. The Board's comments were therefore very similar for the two studies. All
25 comments below can be applied to both studies, unless otherwise noted.
26 Study Objective
27 AEATF II stated that the primary purpose of the handler studies is to develop more
28 accurate information on worker exposures to antimicrobials. AEATF II also presented
29 information to indicate that existing human exposure data are inadequate. The Board concurred
30 that existing data are inadequate and that the development of more accurate information is an
31 appropriate goal.
32 Benefits and Risks
33
34 The Board concurred with the Agency that the generation of new data for mop and
35 wipe activities would be of value in the assessment of risks for antimicrobial products. The
36 Board concurred with the Agency that there are only minimal risks associated with the
37 application of a dilute solution of didecyl dimethyl ammonium chloride (DDAC) as described
38 in the study protocols.
39
40 Study Design Criteria
41
42 The Board was pleased by the amount of randomization included in the design of these
43 studies. The investigators and the Agency have indicated that they are interested in knowing
44 the statistical distribution of the exposure level, with an acceptable bound for the relative
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1 accuracy of the estimated mean and 95 percentile. In both AEA03 (mop) and AES02 (wipe)
2 studies, the same set of three sites will be used as clusters, each representing a random sample
3 of one for three different types of buildings. In order to understand the spectrum of exposure,
4 six volunteers will be randomly selected to fill each of six consecutive time durations. This
5 configuration of three clusters of six handlers for each cluster is based on a simulation study
6 under two-stage cluster sampling with an intra-class correlation coefficient of 0.3 and a
7 geometric standard deviation (GSD) of 2.86. The sample size justification depends on these
8 design parameters.
9
10 In an earlier mop study, conducted by the Chemical Manufacturers' Association
11 (CMA), the estimated GSD was 3.53. It therefore appeared to the Board that the proposed
12 AEA03 study design would not ensure three-fold relative accuracy (K=3) for the resulting
13 estimated mean and the 95 percentile of the exposure distribution. Furthermore, in an earlier
14 CMA wipe study the estimated GSD was 5.00, much larger than 2.86 assumed in the
15 simulation study that was used to derive the sample size justification. Again, it appeared
16 unlikely to the Board that the AEA02 study design would produce a three-fold relative
17 accuracy for the resulting estimated mean and the 95 percentile of the exposure distribution.
18
19 The Board also noted that the stratified nature of selecting a cluster from each of three
20 types of sites makes it impossible to assess the variability of exposure distribution from site to
21 site. Likewise, because of the stratified nature of selecting one handler for each of six
22 mopping/wiping durations, one cannot estimate the exposure distribution. The experimental
23 design can be viewed as consisting of 18 design points with 18 data points, resulting in no
24 degrees of freedom for estimation of variability as there are no replications at any design point.
25
26 In light of these concerns, the Board recommended that the Agency reconsider the
27 design of the study, or develop an explicit statement of the limitations on the use of data that
28 will be collected under the proposed design.
29 Site selection
30
31 The studies will take place in Fresno, California, in three buildings: an office building,
32 a retail building, and a building with large meeting spaces. The way in which the clusters have
33 been defined suggests that they represent a fixed effect factor (i.e., building type) rather than a
34 random effect factor. The proposed study design will not replicate this fixed effect by having
35 more of than one building of each type. The Board acknowledged the practical considerations
36 that led to the decision to have both studies in the same city, using the same buildings.
37 However, it must be realized that any generalizations to moppers and wipers in other parts of
38 the country and in other kinds of buildings would be based on expert opinion, and that such
39 generalizations would not be statistical generalizations. Nevertheless, the Board concurred with
40 the Agency that some generalizations from these data would seem to be reasonable at this point
41 in time.
42 Sample size
43
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1 The proposed sample size of 18 observations for each scenario did not appear to have a
2 statistical justification, as indicated above. The Board was concerned about recommending this
3 sample size and the 3x6 design (three sites, six workers per site) on which it is based. The
4 concern is that all that all future scenario designs for the AEATF- II program are likely to have
5 three clusters and six time durations, with the justification being the Board's recommending
6 these protocols. The Board has seen this happen with insect repellency studies repeatedly. That
7 is, a new protocol has justified its sample size by reference to a previously submitted protocol.
8 The adequacy of the proposed sample size for future studies will be informed by the data
9 collection and analysis of this first set of studies. In general, the Board will not consider a new
10 protocol that has justified its sample size by reference to a previously submitted protocol.
11
12 Task duration
13
14 AEATF-IF s protocol for mopping proposed that handlers mop for a maximum of 90
15 minutes. This value was derived from a survey conducted by the International Sanitary Supply
16 Association (ISSA). AEATF-II calculated an average mopping duration to 83 minutes from the
17 ISSA study data. The Board understood that this value was calculated in the following manner:
18
19 • ISSA data indicated that handlers spend, on average, 12 minutes to mop 1000 square
20 feet.
21 • It was assumed that a hospital room consists of a 240 square feet (12x20) main room
22 and a 36 square foot (6x6) bathroom for a total floor area of 276 sq ft.
23 • It was assumed that a worker would mop 25 such rooms for a total of 6,900 sq feet.
24 • Thus, 6900 square feet x 12 minutes per 1000 square feet = 82.8 minutes
25
26 A similar calculation was made for the wipe scenarios, resulting in an estimated average
27 wiping time of 212.75 minutes.
28
29 The Board concluded that the task duration time frame was not adequate to characterize
30 daily exposure. The Board recommended that the work time frame be expanded to exceed the
31 95th percentile of the ISSA survey findings.
32
33 The Board also noted that the lengths of mopping (or wiping) would be consistently
34 tested from the longest time period to the shortest time period for each site. For this to be a
35 valid approach, one must be willing to assume that there is no "carry-over" effect from one
36 testing period to another. One factor that could lead to a carry-over effect would be whether
37 residues from earlier mopping (or wiping) could affect the measurements on later study
38 participants, especially respiratory effects. The Board recommended that these concerns be
39 reflected in the protocols.
40
41 The Board found the explanation of potential analyses that the Agency would conduct
42 based on these studies to be very helpful. A basic assumption for these analyses is that the
43 distribution of exposure/unit handled is the same regardless of the number of active ingredient
44 (Ai) units handled or the time spent mopping (or wiping). However, the mean exposure/Ai
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1 unit and/or variance of the exposure/unit is likely to increase with the number of units due to
2 fatigue. This assumption could be at least partially checked by plotting exposure/Ai unit by Ai
3 unit, though such an analysis might conflict with the second analysis identified: the assessment
4 of the assumption of proportionality. A regression would likely be conducted for this second
5 analysis. If the distribution of exposure/unit handled were constant or increased with the
6 number of units handled and proportionality was demonstrated, then both the mean and the
7 variance would be expected to increase with the number of units handled. In simple linear
8 regression, the variance is assumed to be constant for all values of x. Thus, a weighted
9 regression, not a simple linear regression would be needed. Because the protocol does not
10 ensure that there will be replication of exposures for the same number of units, whether a
11 simple or weighted regression would be more appropriate could not be fully evaluated. If,
12 instead of time, the number of Ai units handled were the measure that defined each person's
13 participation, the data would more likely lend themselves to a proper assessment of the
14 assumption of proportionality.
15
16 Participation Criteria
17
18 AEATF plans to recruit subjects from among identifiable and willing professional
19 janitors. A rationale for this decision was provided. AEATF also assumes that these
20 professionals would have higher exposures than consumers. One Board member expressed the
21 view that professionals have substantial experience and perhaps training in how to minimize
22 exposure, and that consumers might have higher exposures per Ai unit handled. AEATF-II
23 plans to recruit subjects through service providers. The Board suggested that unions also be
24 considered in the development of the recruitment procedures.
25 Measurement Criteria
26
27 The Board noted that inhalation exposure from vapors would likely be low in these
28 studies due to the relatively low volatility of the active ingredient used in the scenarios.
29 However, the extent to which liquid aerosols generated in the mop protocol would contribute to
30 aggregate exposure is not known. It was not clear what particle size range was expected to be
31 generated in these studies, nor was it clear what particle size range would be captured by the
32 sampling method. The Board suggested that a laboratory study that measured aerosol size
33 under varying environmental conditions would be helpful in clarifying these uncertainties.
34
35 The following are key variables that will have an effect on inhalation exposure:
36
37 • Ventilation
38 • Temperature
39 • Total area treated
40 • Duration
41 • Volume of the enclosed space
42
43 The protocols state as follows: "light level, air temperature, and relative humidity of the
44 work area for the duration of exposure monitoring will be documented with automated
45 instrumentation logging and recording at intervals appropriate for the duration of the work
46 period. Monitoring equipment will be calibrated or standardized according to the cooperating
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1 contractors' SOPs. HVAC will be described in detail and the air turnover rate will be measured
2 or estimated." The Board recommended that the equipment and procedures used to characterize
3 these environmental factors be described in greater detail, either in the protocols or in the
4 SOPs. The Board also asked investigators to explain how the effects of such factors as
5 ventilation, temperature and the volume of the enclosed space would be used to modify or
6 interpret study results.
7
8 AEATF-II proposed to use dermal exposure assessment methods similar to those used
9 by the Agricultural Handler Exposure Task Force studies; i.e., cotton garments on most of the
10 body, handwashing, and face/neck wiping. As in its previous reports, the Board noted that
11 these methods have the potential to underestimate exposure. The Board supported the use of a
12 double layer of socks to capture potential exposure from spills or splashes.
13
14 Laboratory and Field Conditions
15
16 The Board considered the quality assurance and quality control procedures that
17 accompanied these protocols to be of high quality. The Board appreciated the attention to detail
18 provided by the investigators.
19
20 The Board raised several concerns regarding field conditions.
21
22 These studies will use DDAC, contained in the product Sani-Care Lemon Quat™ as the
23 chemical of interest. The Board agreed that the choice of DDAC as the antimicrobial material
24 for these studies was appropriate, given its wide use, availability, and the existence of a reliable
25 and sensitive analytical method.
26
27 The Board encouraged the Agency and the investigators to ensure that work activities
28 be as realistic as possible. For example, a worker should use a bucket of the disinfectant
29 solution until it becomes dirty; the worker should then empty the bucket and pick up a fresh
30 bucket. All of this could be done without the involvement of study staff. In general, the Board
31 viewed the activities of the study staff described in the current protocols to be too disruptive of
32 "usual practices". The Board recommended that the protocols be revised to provide a more
33 detailed description of what the workers will actually do, and that the presence of staff during
34 the exposure period be kept to a minimum.
35
36 The Board was also concerned with what is sometimes called the "Hawthorne Effect".
37 That is, workers will change behavior consciously or unconsciously when they are aware that
38 they are being observed. The current protocols indicate that there will be constant surveillance
39 of workers, including video recording. The Board urged the Agency and the investigators to
40 minimize these observations and to train staff to be as unobtrusive as possible.
41
42 Finally, the Board requested that the protocol provide more specificity as to where
43 study subjects will be located while waiting to participate in the study. There was a concern
44 that observation of some study subjects by other study subjects could alter behavior.
45
46 HSRB Consensus and Rationale
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2 The Board considered the AEATF-II study protocols to successfully address many
3 design challenges. The Board appreciated particularly the clarity of the protocols, the attention
4 to detail, and the thorough description of quality assurance and quality control procedures. The
5 Board concurred with the Agency that existing data on handler exposures to antimicrobials are
6 inadequate and that the development of more accurate information is an appropriate goal. The
7 Board also concurred with the Agency that there are only minimal risks associated with the
8 application of a dilute solution of didecyl dimethyl ammonium chloride as described in the
9 study protocols.
10
11 While the Board concluded that the research could produce scientifically reliable data, the
12 Board identified several contextual factors that may limit the generalizability of the findings.
13 The Board recommended that the Agency reconsider the design of the study, or develop an
14 explicit statement of the limitations on the use of data that will be collected under the proposed
15 design. The Board noted that any generalizations to moppers and wipers in other parts of the
16 country and in other kinds of buildings would be based on expert opinion, and that such
17 generalizations would not be statistical generalizations. The Board cautioned the Agency
18 regarding the 3x6 design in the protocols, suggesting future scenario designs for the AEATF- II
19 program would likely have three clusters and six time durations, with the justification being the
20 Board's recommendation of these protocols. The Board concluded that the task duration time
21 frame was not adequate to characterize daily exposure. The Board recommended that the work
22 time frame be expanded to exceed the 95th percentile of the International Sanitary Supply
23 Association survey findings. The Board noted that if, instead of time, the number of Ai units
24 handled were the measure that defined each person's participation, the data would more likely
25 lend themselves to a proper assessment of the assumption of proportionality.
26
27 In regard to inhalation exposure assessment, the Board suggested that a laboratory
28 study that measured aerosol size under varying environmental conditions would helpful in
29 clarifying uncertainties regarding particle size and sampling methods. The Board raised several
30 concerns regarding the field conditions for these studies: ensure that any carry-over effect in
31 buildings is avoided; ensure that work activities be as realistic as possible; revise protocols to
32 provide a more detailed description of what the workers will actually do; keep the presence of
33 staff and intrusive observation of workers during the exposure period to a minimum; and,
34 provide more specificity as to where study subjects will be located while waiting to participate
35 in the study..
36
37 Finally, the Board encourages modifications of future related protocols based on the
38 lessons learned from these initial submissions. Such adjustments are anticipated to improve
39 the study design and subsequent results, leading to a more accurate characterization of
40 pesticide handler exposure.
41
42 Ethics
43
44 Charge to the Board
45
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1 If the proposed research described in AEATF's proposed mop scenario design,
2 protocol, and supporting documentation is revised as suggested in EPA's review, does the
3 research appear to meet the applicable requirements of 40 CFR part 26, subparts K and L?
4
5 If the proposed research described in AEATF's proposed wipe scenario designs,
6 protocol, and supporting documentation is revised as suggested in EPA's review, does the
7 research appear to meet the applicable requirements of 40 CFR part 26, subparts K and L?
8
9 Board Response to the Charge
10
11 Brief Overview of the Studies
12
13 Each of these scenarios (mop and wipe) has been designed to develop data for a
14 database of exposure monitoring information which will be used by the EPA for making
15 regulatory decisions about future exposures to a variety of antimicrobial products and their
16 active ingredients. The sponsor of both scenarios is the Antimicrobial Exposure Assessment
17 Task Force II (AEATF-II) of the American Chemistry Council. The scenarios will be
18 conducted on behalf of that entity by Golden Pacific Laboratories, LLC, of Fresno, California.
19 For each of the scenarios, there will be three field sites in Fresno, California.
20
21 According to the protocols, these studies are intended to comply with the ethical
22 standards contained in 40 CFR Part 26, subparts K and L, in addition to the requirements of
23 FIFRA § 12(a)(2)(P), and Title 3, § 6710 of the California Code of Regulations. Both scenarios
24 were reviewed and approved by a commercial IRB, the Independent Investigational Review
25 Board, Inc. (IIRB, Inc.) of Plantation, Florida.
26
27 For each scenario, the protocols include detailed explanations of how the buildings in
28 which the scenarios take place will be chosen, how the subjects will be recruited, how the
29 informed consent of those subjects will be obtained, and what will take place during the
30 conduct of the scenarios.
31
32 Each of the protocols requires that the subj ects be at least 18 years of age, and they
33 exclude female subjects who are pregnant or lactating.
34
35 The test substance that will be used in both scenarios is diluted Sani-Care Lemon Quat.
36 Its two active ingredients are didecyl dimethyl ammonium chloride (DDAC) and n-Alkyl
37 dimethyl benzyl ammonium chlorides (ADBAC).
38
39 Critique of Studies
40
41 The Board concurred with the factual observations of the ethical strengths and
42 weaknesses of the studies, as detailed in the EPA's Science and Ethics Reviews (Carley 2008a
43 and 2008b).
44
45 In general, the research described in these two protocols appears to comport with the
46 applicable requirements of 40 CFR Part 26, subparts K and L. The risks to study participants,
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1 in general, will be minimal and would appear to be justified by the likely societal benefits,
2 specifically the production of data that could be used by the EPA in determining acceptable
3 exposures to antimicrobial products used in certain mopping and wiping activities.
4
5 The test compound contains two active ingredients, DDAC and ADBAC, both of which
6 have been extensively tested in animals. The subjects will only be exposed to concentrations of
7 the test compound at the label dilution rates. At those dilutions, animal testing has shown the
8 compound to have low acute toxicity and a low chronic hazard profile. Both of the active
9 ingredients have already been approved by the EPA for use in many formulations, and in many
10 janitorial products. In addition, the test compound itself, Sani-Care Lemon Quat, has been
11 approved by the EPA, and will only be used in the scenarios in conformity with its approved
12 labeling. All of the subjects will be professional janitors with extensive experience in using
13 these products, and thus unlikely to misuse them in a way that might increase their likelihood
14 of being harmed.
15
16 Although the risks to subjects from exposure to the test compound appear very low, it
17 should be noted that in terms of the purposes of these scenarios, it is not actually necessary that
18 subjects be exposed to an antimicrobial product. The scenarios are intended to measure only
19 the amount of skin, clothing and inhalation exposure when someone is engaged in certain
20 activities relating to applying an antimicrobicide. They are not measuring the actual effects to
21 the test subject from that exposure. Thus, it might be possible to design scenarios in which
22 instead of an antimicrobicide, some less toxic tracer substance might be used. It would be
23 appropriate for protocols to discuss this possibility for further minimizing risks, and to indicate
24 why (if it is true) such an option would not allow the needed information to be collected.
25
26 Another possible risk is that of heat-related illness, given that the subjects will be
27 required to wear two layers of clothing during the scenario activities. That risk is being
28 minimized by the fact that those activities will take place indoors in temperature-controlled
29 environments. In addition, subjects will be given appropriate breaks. The breaks will not only
30 minimize the likelihood of heat-related illness, but also reduce the likelihood of cardiovascular
31 harms.
32
33 With regard to subject selection, EPA observed that "[n]o potential subjects are from a
34 vulnerable population" (Carley 2008a and 2008b). In this regard, it should be noted that 45
35 CFR § 46.11 l(b) states that "economically or educationally disadvantaged persons" may
36 constitute a vulnerable population. Accordingly, given that this study is recruiting from a
37 population of individuals who may not have substantial education, who may be relatively
38 disadvantaged from an economic viewpoint, and many of whom may not speak or read
39 English, it would be appropriate not to dismiss the possibility that the subjects in this study
40 might be vulnerable to coercion and undue influence, but rather to instead recognize that there
41 are sufficient safeguards in the design of the study to protect the subjects, even if they are
42 vulnerable.
43
44 The study protocols included several mechanisms designed to minimize coercive
45 recruitment and enrollment, including the fact that subjects were not recruited directly from
46 their employers, but instead would themselves respond to flyers that have been posted.
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1 Compensation was not considered to be so high as to unduly influence participation, and
2 minors and pregnant or lactating women were explicitly excluded from volunteering
3 (pregnancy being confirmed by requiring all female volunteers under the age of 50 to undergo
4 a urine pregnancy test). The potential stigmatization resulting from study exclusion was
5 minimized by the use of so-called 'alternate' participants, allowing for volunteers to withdraw
6 or be excluded from participating without unduly compromising their confidentiality.
7
8 With regard to the eligibility criteria, the Board believes that the requirement for
9 females under the age of 50 to take a pregnancy test could be refined. It would be possible to
10 design criteria that created a better fit between which female subjects might be able to get
11 pregnant, and which of them are being asked to take that test. By doing this, the researchers
12 would be showing greater respect for this group of subjects.
13
14 The protocol might provide a greater justification for why subjects older than 65 are
15 excluded.
16
17 Most of the issues raised by the Board relate to informed consent and recruitment. With
18 regard to the consent forms, as a general matter, given the population from which subjects are
19 being recruited, it would be appropriate to make sure that the consent forms are at an
20 appropriate level of readability. In at least some places, there appears to be room for further
21 simplification.
22
23 The consent forms do not appear to describe adequately the procedures discussed in the
24 protocol relating to (a) still photography of the subjects, (b) videotaping of the subjects, and (c)
25 observation of the subjects by members of the study team. All of these procedures pose
26 possible risks to the privacy and confidentiality of the subjects. The fact that each of these
27 procedures will be part of the protocols should be adequately explained in the consent forms.
28 That explanation should include the details relating to who will be observing and who will be
29 taking the photographs (e.g., members of the study team, outside contractors, other subjects).
30 In addition, both the protocol and the consent forms should explain what procedures will be in
31 place to make sure that the photographs and videos will be stored in a way that adequately
32 protects both the confidentiality and the privacy of the subjects, and explains what harms to
33 subjects might result if those protections are not adequate. If subjects will be accorded the right
34 to opt out of being photographed, that should be explained in the consent form.
35
36 In the Purpose section of the consent form, it should be explained that the underlying
37 purpose of the study will be to collect information that will be provided to the EPA, and that
38 the EPA would use that information to determine the appropriate standards for allowable
39 exposures to products such as the test compound.
40
41 The consent form in one instance (the paragraph numbered 4 under Study Procedures)
42 uses the term "same-sex person." That confusing term should be replaced with the descriptions
43 used elsewhere in the form, such as "a researcher of your own sex."
44
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1 In the description of risks to subjects from exposure to the test compound, it is merely
2 stated that the risks are low. If there is a known risk from getting the compound in a person's
3 eyes, for example, that risk should be explained.
4
5 The approved version of the consent form, under the Pregnancy Risks heading, begins
6 with "We don't know the risks to the unborn from exposure to SANI-CARE LEMON QUAT
7 and may be hazardous . . ." There is a word or words missing in this sentence, and it therefore
8 needs to be revised. More significantly, the "and may be hazardous" language differs from the
9 language that appears in the versions of the consent forms submitted to the 1KB by the
10 researchers. The Board was not able to determine how this change in language took place.
11 There is not documentation that the 1KB asked for the change, or that the change was initiated
12 by the researchers themselves, and that they submitted a copy of the consent form with this
13 change to the 1KB. This circumstance raises some concerns regarding whether the EPA was
14 provided with the full documentation of what went on during the 1KB approval process. The
15 Board believes it would be appropriate for the EPA to determine how this change occurred. In
16 addition, some members were concerned that this lack of documentation might relate to the
17 operation of IIKB, Inc., which might reinforce prior Board concerns about the operation of that
18 1KB.
19
20 With regard to the recruitment brochure, it would appear appropriate for that document
21 to mention that the product which will be used in the study is Sani-Care Lemon Quat. At the
22 beginning of that document, it fails to mention that the study will look not only at how much of
23 the product "gets on" the workers, but also how much of it they inhale. Under the eligibility
24 criteria, it states that subjects must be "Male or non pregnant, non or nursing female." This
25 language needs to be corrected. And in the last sentence, the brochure incorrectly states that the
26 EPA will use this information to reduce risks to workers. The statement should be revised to
27 more accurately state the EPA will use the information to determine how much of the product
28 workers will be exposed to; it is not true that it will necessarily lead to a reduction in risks to
29 workers.
30
31 The phone texts that are used for calls to employers, and for calls to workers making
32 inquiries, fail to mention that the study will be looking at inhalation risks in addition to risks
33 relating to getting the compound on the worker's skin and clothing.
34
35 With regard to recruiting and obtaining the informed consent of Spanish-speaking
36 persons, the Board agrees with the changes recommended by the EPA (Carley 2008a and
37 2008b). It would also be appropriate for the protocol to include a more detailed discussion of
38 how the researchers will obtain appropriate community involvement (such as, for example,
39 discussions with unions representing janitorial workers).
40
41 With regard to the translations into Spanish of the various documents, the Board
42 believes that it is important to make sure that the appropriate dialect of Spanish is being used in
43 he translations. The translation of the consent form, for example, was provided by someone
44 from Miami, Florida, yet the study will be taking place in California. The Spanish-speaking
45 communities in Miami and California might well use significantly different dialects of Spanish.
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1 It was also not clear from the documents who was producing the Spanish-language version of
2 some of the materials, such as the recruitment brochure.
O
4 HSRB Consensus and Rationale
5
6 The Board concurred with the initial assessment of the Agency that if the proposed mop
7 and wipe scenario design, protocol, and supporting documentation is revised as suggested in
8 EPA's review, the research does appear to meet the applicable requirements of 40 CFR part 26,
9 subparts K and L.
10
11 ICR Protocol: A382
12
13 Science
14
15 Charge to the Board
16
17 If the proposed research described in ICR's proposed picaridin protocol is revised as
18 suggested in EPA's review, does the research appear likely to generate scientifically reliable
19 data, useful for assessing the efficacy of the test substances for repelling stable flies?
20
21 Board Response
22
23 Protocol A3 82 outlined a laboratory test to evaluate the efficacy of picaridin against
24 stableflies when applied dermally as a 20% cream or spray product. The purpose of the study
25 was clearly defined (i.e., efficacy testing), and the use of human subjects was adequately
26 justified. Briefly, the proposed study will involve a total of 13 subjects, 12 of whom are
27 designated for treatment with the picaridin spray and cream, with one additional subject
28 designated as the negative control. The negative control will be selected at random and serves
29 to establish the aggressiveness of each cage of stable flies to be used in the test. The first phase
30 of the planned study will determine the average dose applied under normal use conditions, but
31 will not exceed 4 mg/cm2. The second phase of the study is the repellency test in which
32 subjects' arms will be treated with measured amounts of both products (one product on each
33 forearm), after which they will expose their treated forearms to stableflies for a 5 minute period
34 every half hour for up to 10 hours. The submitted protocol proposed to use the time to first
35 confirmed bite on both arms (both products) as the quantitative measure of repellent efficacy.
36 The Sponsor provided a thorough statistical justification for the protocol design, including the
37 determination that a minimum of 7 subjects would be required to achieve a 95% confidence
38 interval for assessing protection up to 8 hours with a + 2-hour confidence limit.
39
40 There was general consensus that the protocol was well written and a sound scientific
41 rationale was provided. There were several minor issues that were identified during the course
42 of the HSRB discussion, representing issues that can easily be addressed in a revised protocol.
43 These included: (1) clarifying the protocol to specify that there are 13 subjects, representing 1
44 negative control and 12 treated individuals; (2) providing some information as to what
45 activities are permitted during the 25 minute intervals when subjects are not actively on test
46 and specifying what activities are precluded by being involved in the test; (3) ensuring the
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1 accuracy of the margin of exposure (MOE) assuming a maximum application rate of 4 mg/cm2
2 ; and (4) recommending that the Sponsor design the test to randomize the treatment modalities
3 (spray or cream) on the left and right arms and to ensure that the professional staff involved in
4 the conduct of the study are blinded to the treatments. The HSRB recommends that these
5 modifications should be made to the protocol and study conduct.
6
7 There were however, three additional matters concerning the protocol design for which
8 there was additional board discussion and more significant changes recommended to the
9 proposed study. These issues were as follows:
10
11 1. It was noted during the Board's discussion that the Sponsor specified that the subject
12 pool was exclusively Caucasian. There was concern as to whether the results obtained
13 from such a constrained population could be generalized to other races, and there was a
14 minority, but strongly voiced opinion that the protocol was not scientifically sound
15 given this limitation. The HSRB recommended that the subjects used in this study
16 should not be homogeneous, but rather, that there should be diversity across the
17 subjects used for the test. The Board did not provide a specific recommendation on
18 how diverse the test population should be, but suggested that, at a minimum, it should
19 reflect the diversity of the region from which the possible subjects are drawn. The
20 Board agreed that the Sponsor must address this scientific issue prior to executing the
21 study.
22
23 2. OPP staff recommended that a positive control be used in this study, suggesting that it
24 would improve the overall scientific validity of the test. In its discussion, the HSRB
25 concluded that the inclusion of a positive control was not essential to the protocol, and
26 the Board recommended against requiring a positive control in the study.
27
28 3. The protocol was designed to evaluate repellent efficacy using the accepted paradigm
29 of time to first confirmed bite for each treatment (cream or spray product). As such,
30 this design would result in a total of 4 bites per subject upon loss of repellency (first
31 bite to be followed by a confirming bite for each treatment). In consideration of the
32 biology of stable flies, there was general consensus among the HSRB that the study
33 would be scientifically valid if the time to first bite, requiring only one bite per
34 treatment, was used as the endpoint for evaluating the efficacy of the repellent.
35
36 HSRB Consensus and Rationale
37
38 If amended in a manner consistent with the Board's concerns and recommendations,
39 and with particular modification to subject ethnicity, the protocol ICR A382 studying the
40 efficacy of two formulations of picaridin for repelling stable flies would be sufficiently sound,
41 from a scientific perspective, to be used to assess the repellent efficacy of these formulations
42 against stable flies.
43
44 Ethics
45
46 Charge to the Board
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1
2 If the proposed research described in ICR's proposed picaridin protocol is revised as
3 suggested in EPA's review, does the research appear to meet the applicable requirements of 40
4 CFR part 26, subparts K and L?
5
6 Board Response
7
8 The Board concurred with the factual observations of the ethical strengths and
9 weaknesses of the proposed study, as detailed in the EPA's Science and Ethics Review (Carley
10 and Sweeney 2008).
11
12 Overall, this is a well written protocol, consent document, and application, answering
13 many of the questions that HSRB has asked when reviewing in other studies. The risks to study
14 participants were minimal and were justified by the likely societal benefits, including data on
15 the efficacy of these new formulations as repellents against stable flies.
16
17 The 20% concentration of picaridin in the products to be used in this study is "higher
18 than the marketed and EPA-registered formulation." Based on toxicological data currently
19 available, however, picaridin has low acute toxicity. The potential risks include irritation or
20 allergic response to the product. Individuals known to be sensitive to insect repellents or skin
21 care products are excluded from the study. In addition, subjects will be monitored for signs of
22 reaction to the products during the dosimetry portion of the study as well as during the
23 repellent phase of the study.
24
25 While stable fly bites are acutely painful, the flies are not known to transmit any
26 diseases to humans. Individuals known to be sensitive to stable fly bites are excluded from the
27 study. Topical lotions and rubbing alcohol will be available to subjects to help relieve the
28 itching from the bites.
29
30 The study protocol also included several mechanisms designed to minimize coercive
31 recruitment and enrollment, compensation ($1 I/hour, time-and-a-half over 9 hours) was not
32 considered to be so high as to unduly influence participation, and minors and pregnant or
33 lactating women were explicitly excluded from enrolling (pregnancy being confirmed by
34 requiring all female volunteers to undergo a self-administered over-the-counter pregnancy test
35 "shortly before any treatment with a test article"). The potential stigmatization resulting from
36 study exclusion was minimized by the use of 'alternate' participants, allowing for volunteers to
37 withdraw or be excluded from participating without unduly compromising their confidentiality.
38
39 Several ethical issues were raised, and can be categorized as they relate to the Belmont
40 Principles of Respect for Persons, Beneficence and Justice. The Board concluded that all of the
41 issues could be addressed with additional explanations or minor protocol modifications.
42 Concerns were raised relating to the Justice principle. Subjects greater than 70 years of age are
43 excluded without adequate justification. Subjects who cannot "read, speak, and understand
44 English" are also excluded, without a description of how that will be assessed or a justification
45 of why reading English is required for this study. The recruitment pool of potential subjects is
46 overwhelmingly Caucasian. While ICR will "look for recruits from the Afro-American
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1 community," there are no plans presented to assure racial/ethnic diversity of the study
2 population, which would be more appropriate given that these products, if marketed, will be
3 marketed to the general diverse population.
4
5 Issues related to the Respect for Persons principle include the requirement that women
6 not of child-bearing potential, such as women who have had a hysterectomy or who are post-
7 menopausal, are nevertheless required to undergo a pregnancy test. Some HSRB members
8 found this disrespectful, but a minority of other members did not.
9
10 While most issues related to the Beneficence principle were addressed, the question of
11 whether or not the stable flies to be used in this study would be given bovine blood at any time
12 prior to the study remained unanswered. Because bovine blood carries with it a potential risk to
13 humans of Creutzfeld-Jacob disease or exposure to bovine leukemia virus, the Board
14 recommended that this question of whether or not the stable flies would receive bovine blood
15 prior to their opportunity to bite human volunteers and the attendant risks be addressed. In
16 addition, the scientific issue of using unblinded ICR staff to measure the outcome variable
17 (stable fly bites) may jeopardize the scientific validity of the study, and thus alter the risk-
18 benefit assessment. The HSRB recommended randomizing which product is applied to which
19 arm, and using a blinded evaluator to measure the outcome variable.
20
21 HSRB Consensus and Rationale
22
23 The Board concurred with the initial assessment of the Agency that, if the protocol is
24 revised as suggested by EPA and the HSRB, the study submitted for review by the Board
25 meets the applicable requirements of 40 CFR 26, subparts K and L.
26
27 Carroll-Love Biological Research Completed Studies: SCI 001.4 and SCI 001.5
28
29 Science
30
31 Charge to the Board
32
33 Are these studies sufficiently sound, from a scientific perspective, to be used to assess
34 the repellent efficacy of the formulations tested against mosquitoes?
35
36 Board Response
37
38 The active ingredient DEBT in two lotion formulations was tested for its ability to repel
39 mosquitoes from the arms of volunteers by the protocol presented and modified by Carroll-
40 Loye in two separately described studies which were conducted simultaneously using common
41 sites and negative controls. This was a repeat of two products previously tested but not
42 accepted for ethical reasons at the October, 2007, HSRB meeting. The protocol had been
43 modified based on the suggestions and input of EPA and HSRB. The results were reported in
44 SCI.001.4, DermaAegis LipoDEET 302, and SCI.001.5 Coulston's Duranon. The results on
45 these two products were not compared to a positive control substance nor to one another.
46 Because of the common elements between the two studies, they are discussed together in this
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1 report. All experiments were conducted using Good Laboratory Practices. Margins of exposure
2 were high.
O
4 The dosimetry for the two products was done in the laboratory on November 7-9, 2007.
5 The field tests were conducted on November 10, 2007, at Site 1 in Glenn County, a forest
6 habitat, and on November 11, 2007, at Site 2 in Butte County, a grassland habitat, both in
7 California. Slightly different mosquito species composition occurred at the two sites, but
8 overall the species composition of the two sites was similar. Ten subjects were used for the
9 dosimetry tests. Ten subjects were used for each of the two products. The subjects were
10 required to be above 18 years of age and no more than 55 years of age, and active in rural
11 outdoor settings. Only arms were tested in this study. There were two experienced persons
12 serving as negative controls (i.e., without any repellent product) to confirm mosquito landing
13 pressure (and landing pressure was maintained throughout the period of the study, defined as at
14 least one Landing with Intent to Bite, LIBe, per min during the period of exposure). LIBe's
15 were monitored in experimental subjects during a one min interval each 15 min, until the First
16 Confirmed LIBe (FCLIBe) could be determined. Stopping rules were employed. No evidence
17 of West Nile Virus was present in either test site from sentinels prior to conduct of the study.
18 Mosquitoes landing were taken to the laboratory for later identification, and for screening for
19 West Nile, Western Equine Encephalitis, and St. Louis Encephalitis viruses, and all mosquitoes
20 were negative. All subjects wore Tyvek coverall, head nets and surgical gloves. Observation
21 was initiated 150-180 minutes post application. Complete protection time (CPT) was
22 measured, defined as the time to the FCLIBe. The data were presented as mean ± standard
23 deviations. Because of the low number of repellency failures observed, a Kaplan-Meier
24 analysis (suggested at previous HSRB meetings) was not conducted.
25
26 LipoDEET 302 is 30% DEET on lipid spheres designed to improve the durability and
27 to improve the cosmetic properties. It yielded a CPT of 11.25 ± 0.0 hr in Site 1 (no repellency
28 failures) and 11.28 ± 0.79 hr in Site 2.
29
30 Coulson's Duranon is 20% DEET in microscopic protein spheres to reduced skin
31 absorption of DEET, improve cosmetic properties and inhibit evaporation. It yielded a CPT of
32 11.25 ±0.0 (no failures) in Site 1 and 10.78 ± 1.3 hr in Site 2.
33
34 The report was clearly written. The study was justified in that additional insect
35 repellents that are more efficacious and/or more acceptable cosmetically to the public would be
36 an advantage from both the standpoint of health (to reduce the chances of contracting a
37 mosquito-borne disease) and of comfort. The information should be generalizable to the public,
38 although the exclusions, which were highly appropriate, excluded some subpopulations that
39 would likely use insect repellents. The experiment was necessary to determine the field
40 efficacy of these test formulations, and the experiments were set up to meet the study objective.
41 Measurements taken were appropriate for the objective and quality assurance considerations
42 were in place.
43
44 The experiment was conducted according to the approved protocol with some
45 deviations, none of which negatively impacted the scientific validity. Discussion was related to
46 a lack of positive control (this was not considered a flaw and did not impact the usefulness of
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1 the data); the deviation of a lag time between application of the repellants and the initiation of
2 monitoring (this was probably related to the short day length available for testing in November
3 and the necessity of applying the repellant early to assure a sufficiently long observation period
4 before dark); and the allowance of an application of repellant on the day before the study (it
5 was clarified in the previous HSRB meeting that the repellant was washed off after dosimetry
6 or testing, and the target skin was washed again prior to a new study, thereby insuring that
7 there was no carry-over to compromise data).
8
9 HSRB Consensus and Rationale
10
11 The Board concluded that the study on the efficacy of LipoDEET 320 and Coulson's
12 Duranon shows efficacy of both products in repelling mosquitoes, and agreed with the Agency
13 that the study was sufficiently sound, from a scientific perspective, to be used to accurately
14 calculate the CPT for repelling mosquitoes.
15
16 Ethics
17
18 Charge to the Board
19
20 Does available information support a determination that this study was conducted in substantial
21 compliance with subparts K and L of EPA regulations at 40 CFR part 26?
22
23 Board Response
24
25 Brief Overview of the Study
26
27 The basic protocol for these studies (SCI-001) was initially reviewed at the January
28 2007 HSRB meeting, at which time the Board concluded that the study would meet the
29 requirements established in the Environmental Protection Agency's final human studies rule
30 (40 CFR Part 26) pending minor revision. Most, although not all, of these suggestions were
31 incorporated into a revised protocol, submitted to the IRB of record (Institutional Review
32 Board, Inc., [IIRB, Inc.] of Plantation, FL) for re-review, and approved (Carley 2008; Carroll
33 2008).
34
35 Using the revised protocol and consent documents for SCI-001, Carroll-Loye
36 Biological Research conducted dosimetry and field trials of three compounds in July 2007:
37 DermAegis LipoDEET 302, DermAegis LipoDEET 3434, and Coulston's Duranon Personal
38 Insect Repellent. At the October 2007 meeting of the HSRB, the Board recommended that the
39 data obtained in July under protocol SCI-001 not be accepted for regulatory decision-making
40 purposes (EPA HSRB 2007). The Board concluded that the use of a previously unapproved
41 pesticide formulation (DermAegis LipoDEET 3434) violated the applicable requirements of
42 40 CFR Part 26.
43
44 The data presented to the Board in April 2008 represents the results of new dosimetry
45 and field trials of two compounds in November 2007: DermAegis LipoDEET 302 and
46 Coulston's Duranon Personal Insect Repellent. The documents provided by Carroll-Loye
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1 (Carroll 2007a; Carroll 2007b) specifically state that each study was conducted in compliance
2 the requirements of the U.S. EPA Good Laboratory Practice Regulations for Pesticide
3 Programs (40 CFR 160); 40 CFR 26 subparts K and L; FIFRA § 12(a)(2)(P); and the
4 California State EPA Department of Pesticide Regulations for study monitoring (California
5 Code of Regulations Title 3, Section 6710). Each study was also reviewed and approved by a
6 commercial human subjects review committee, IIRB, Inc. Documentation provided to the EPA
7 by IIRB, Inc. indicates that it reviewed these studies pursuant to the standards of the Common
8 Rule (45 C.F.R. Part 46, Subpart A) and determined them to be in compliance with that Rule.
9
10 As submitted to the EPA, each completed study consists of two interdependent
11 analyses: 1) a dosimetry study designed to determine the amount of an insect-repelling
12 compound (30% DEET in liposomal capsules or 20% DEET in protein capsules) that typical
13 users would typically apply when provided with a lotion formulations; and 2) an efficacy study
14 designed to measure the effectiveness of each compound as a mosquito repellent. The two
15 studies, SCI-001.4 and SCI-001.5, were performed simultaneously at a laboratory site in Davis,
16 California, and at field sites in Butte and Glenn Counties, California, by researchers at Carroll-
17 Loye Biological Research. The study sponsor was Scientific Coordination, Inc., of Rockville,
18 Maryland. The studies were conducted using products from two manufacturers: LipoDEET
19 302 was manufactured and supplied by DermAegis, Inc. of Rockford, Illinois; Duranon was
20 manufactured and supplied by Sawyer Products of Safety Harbor, Florida.
21
22 Dosimetry was determined by direct measurement of compound application. The
23 efficacy of each as a mosquito repellent was determined by measuring the ability of the
24 formulations to prevent mosquito landings (defined as "Lite with Intent to Bite"; LIBe) under
25 field conditions. Mosquitoes were aspirated mechanically prior to biting; prior to initiation of
26 the efficacy study, all volunteers will be trained both to recognize a mosquito landing with the
27 intent to bite and to remove such mosquitoes with an aspirator using laboratory-raised,
28 pathogen-free mosquitoes in a controlled laboratory setting. During the field studies,
29 participants worked in pairs to facilitate identification and aspiration of LIBing mosquitoes
30 during brief exposure periods. The strengths and weaknesses of each study design are
31 described above.
32
33 The dosimetry study enrolled a total of 10 individuals, each of whom tested both
34 formulations. Each efficacy study enrolled 10 subjects for each formulation at each of the two
35 field sites. Many volunteers participated in multiple analytic phases, both dosimetric and
36 effective. In total, 29 volunteers participated in at least one analytic phase of SCI-001.4 and
37 SCI-001.5. In addition, three alternate participants were enrolled to: 1) replace any individual
38 who withdrew; and 2) protect the confidentiality of any participant excluded from the study as
39 a result of pregnancy or other potentially stigmatizing condition, as described below.
40
41 Critique of Study
42
43 The Board concurred with the factual observations of the ethical strengths and
44 weaknesses of the study, as detailed in the EPA's Science and Ethics Review (Carley 2008).
45
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1 In general, the research described in SCI-001.4 and SCI-001.5 comported with the
2 applicable requirements of 40 CFR Part 26, subparts K and L. The risks to study participants,
3 in general, were minimal and were justified by the likely societal benefits, including data on
4 the efficacy of these new formulations (30% DEBT in liposomal capsules and 20% DEBT in
5 protein capsules) as personal insect repellents.
6
7 Based on toxicological data currently available for DermAegis LipoDEET 302 and
8 Coulston's Duranon Personal Insect Repellent, compounds registered with the EPA, the
9 subjects enrolled in this study were unlikely to be at increased risk of experiencing adverse side
10 effects upon exposure. Higher concentrations of DEET are commercially available and have
11 been used as repellents for years.
12
13 Reactions to mosquito bites are usually mild and easily treated with over-the-counter
14 steroidal creams. The study also excluded individuals who have a history of severe skin
15 reactions to further minimize the risk of a participant experiencing a severe physical reaction to
16 a mosquito bite. In addition, the study protocol was designed specifically to minimize the
17 likelihood that a mosquito will bite, through the use of clear stopping rules, limited exposure
18 periods, and paired observation; no side effects or adverse events were reported.
19
20 To minimize the risk that study participants will be exposed to illnesses like West Nile
21 Virus, the study protocol called for field tests of repellent efficacy to be conducted only in
22 areas where known vector-borne diseases have not been detected by county and state health or
23 vector/mosquito control agencies for at least one month. Mosquitoes collected during the field
24 studies also were subjected to serologic or molecular analyses to confirm that they were free of
25 known pathogens.
26
27 The study protocol also included several mechanisms designed to minimize coercive
28 recruitment and enrollment, compensation was not considered to be so high as to unduly
29 influence participation, and minors and pregnant or lactating women were explicitly excluded
30 from volunteering (pregnancy being confirmed by requiring all female volunteers to undergo a
31 self-administered over-the-counter pregnancy test on the "day of the study"). The potential
32 stigmatization resulting from study exclusion was minimized by the use of so-called 'alternate'
33 participants, allowing for volunteers to withdraw or be excluded from participating without
34 compromising their confidentiality. There was some question as to the appropriate timing of
35 such testing (Carley 2008), but no female participant was exposed to product without first
36 undergoing pregnancy testing. Future trials conducted by Carroll-Loye Biological Research,
37 however, should use protocols and informed consent documents that explicitly outline the
38 nature and timing of pregnancy testing for female participants.
39
40 Several Board members raised ethical and procedural concerns about the numerous
41 protocol changes present in the documents submitted to the EPA (Carroll 2007a, 2007b) but
42 which were not presented to the Board prior to the conduct of the study. For example, in its
43 initial review of Protocol SCI-001 in January 2007, the HSRB approved a protocol that
44 involved the experimental administration of four compounds (three sponsor-submitted test
45 compounds and one comparator [3M Ultrathon; 34.34% polymerized DEET]). The study, as
46 completed, used only two test compounds and no comparator. Many HSRB members
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1 considered this to be a major change in study design, a change to which the Board was
2 unaware until the study was completed and the data submitted for review. In light of these
3 concerns, the Board recommended that the EPA review existing regulations and establish clear
4 guidelines as to when modified protocols should be submitted to the Board for re-review.
5
6 Finally, several Board members also voiced concerns about the type and nature of the
7 protocol deviations reported by Dr. Carroll to IIRB, Inc. Many of these same deviations have
8 occurred in completed studies previously submitted to the Agency and the Board for review,
9 raising questions about the unanticipated nature of these protocol changes. It is clearly stated in
10 Federal regulations for research involving human subjects that the only protocol changes that
11 can be made without prior IRB approval are those that are unanticipated and which are
12 necessary to protect the safety of trial participants. No protocol changes, reported or not, are
13 allowed for reasons of expedience, as appeared to be the case here.
14
15 HSRB Consensus and Rationale
16
17 The Board concurred with the initial assessment of the Agency that the study submitted for
18 review by the Board meets the applicable requirements of §40CFR26, subparts K and L.
19
20 Board Decision Regarding Future Review of Protocols with Planned Deviations from
21 Prior IRB Review
22
23 Over several meetings, including the April 2008 meeting, the Board has expressed concern
24 with EPA submission for HSRB review of completed studies in which planned protocol
25 deviations were conducted prior to IRB review and following HSRB review of the originally
26 approved protocol. Such actions are in violation of 40 CFR 26, Subpart K Sec. §26.1108 IRB
27 functions and operations.
28
29 Subpart K Sec. §26.1108 IRB functions and operations.
30 "In order to fulfill the requirements of this subpart, each IRB shall:
31 (a) Follow written procedures:
32 (1) For conducting its initial and continuing review of research and for reporting its
33 findings and actions to the investigator and the institution;
34 (2) For determining which projects require review more often than annually and which
35 projects need verification from sources other than the investigator that no material changes
3 6 have occurred since previous IRB review;
37 (3) For ensuring prompt reporting to the IRB of proposed changes in research activity;
38 and
3 9 (4) For ensuring that changes in approved research, during the period for which IRB
40 approval has already been given, may not be initiated without IRB review and approval except
41 where necessary to eliminate apparent immediate hazards to the human subjects. "
42
43 The Board reached consensus regarding its future review procedures under such conditions:
44
45 1. Any study executed prior to IRB approval of the Informed Consent Form and the
46 protocol, or changed in ways that were not approved by the IRB will be judged by the
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1 Board as failing to meet the applicable requirements of §40 CFR 26, subparts K.
2
3 2. If the EPA submits to the Board for review a completed protocol with scientific
4 deviations from the original protocol reviewed by the Board, the EPA review of the
5 completed protocol should provide the Board with EPA's opinion regarding why the
6 deviation did not meet the requirement for re-review and why the protocol still meets the
7 applicable regulations.
8
9 REFERENCES
10
11 Carley, J.M., Leighton T., Walls C. 2008a. Science and Ethics Review of AEATF Mop
12 Scenario Design and Protocol for Exposure Monitoring. Dated March 10, 2008. Unpublished
13 document prepared by Office of Pesticide Programs, United States Environmental Protection
14 Agency.
15
16 Carley, J.M., Leighton T., Walls C. 2008b. Science and Ethics Review of AEATF Scenario
17 Design and Protocol for Exposure Monitoring in Wipe Scenarios. Dated March 10, 2008.
18 Unpublished document prepared by Office of Pesticide Programs, United States Environmental
19 Protection Agency.
20
21 Carley, J.M. 2008. Ethics Review of Reports of Completed Carroll-Loye Field Mosquito
22 Repellent Efficacy Studies SCI-001.4 and SCI-001.5. Dated March 7, 2008. Unpublished
23 document prepared by Office of Pesticide Programs, United States Environmental Protection
24 Agency.
25
26 Carley, JM and Sweeney K. 2008. Science and Ethics Review of Protocol for Human Study of
27 Stable Fly Repellent Performance. Unpublished document prepared by Office of Pesticide
28 Programs, United States Environmental Protection Agency.
29
30 Carroll, S. 2007a. SCI-001.4: Test of DermAegis LipoDEET 302 Personal Insect Repellent
31 (EPAReg. #82810-1). MRID 47322501. Dated November 27, 2007. Unpublished study report
32 prepared by Carroll-Loye Biological Research.
33
34 Carroll, S. 2007b. SCI-001.5: Test of Coulston's Duranon Personal Insect Repellent (EPA Reg.
35 #50404-8). MRID 47322401 .Dated November 27, 2007. Unpublished study report prepared by
36 Carroll-Loye Biological Research.
37
38 Carroll, S. 2008. Letter to John M. Carley transmitting supplemental correspondence between
39 Carroll-Loye Biological Research and Independent Investigations Review Board, Inc.,
40 concerning SCI-001, with enclosures. Dated March 5, 2008. Unpublished letter prepared by
41 Carroll-Loye Biological Research.
42
43 EPA HSRB. 2007. October 24-26, 2007 EPA Human Studies Review Board Meeting Report.
44 National Commission for the Protection of Human Subjects of Biomedical and Behavioral
45 Research. The Belmont Report:
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1 Ethical Principles and Guidelines for the Protection of Human
2 Subjects of Research. 1979. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm
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