August IS, 2007
EPA-HSRB-07-02
George Gray, Ph.D.
Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: April 18-20,2007 EPA Human Studies Review Board Meeting Report
Dear Dr. Gray:
The United States Environmental Protection Agency (EPA or Agency) requested
the Human Studies Review Board (HSRB) to review scientific and ethical issues addressing: (1)
completed repellent efficacy studies: IR3535 (aerosol); (2) mosquito repellent efficacy protocol
WPC-001; (3) completed patch test studies (48-hour dermal irritation patch test and repeated
insult patch test; (4) EPA's framework for developing best practices for subject recruitment for
handler exposure research and; (5) follow-up on Agricultural Handler Exposure Task Force
(AHETF) and Antimicrobial Exposure Assessment Task Force (AEATF) protocols. The Board
also commented on the meaning of "Substantial Compliance" with 40 CFR Part 26 in relation to
research conducted after April 7,2006.
Finally, as you know, this was the first opportunity for the Board to review confidential
business information (CBI) redacted submission. The Board appreciated the opportunity to
develop a framework cooperatively by the Board and EPA. This enabled the Board to obtain
adequate information required for a sound scientific and ethics review to be conducted at an open
meeting, using documents provided by the sponsor with CBI material redacted, in addition to
utilizing supplementary materials provided by EPA. The Board is also aware that there may be
future submissions to the Board with CBI claims and understands that modifications to the
framework may need to be made in order for the Board to provide its advice to the Agency,
striving to provide such advice in an open meeting.
The enclosed HSRB report addresses the Board's response to EPA charge questions at its
April 18-20, 2007 meeting.
A summary of the Board's conclusions is provided below.
Completed Repellent Efficacy Studies: IR3535 Aerosol (EMD-003.3 and EMD-004.3)
EMD-003.3: Tick Repellency with Aerosol Spray Formulations
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Scientific Considerations
• The Board concluded that the reported study on the efficacy of an aerosol formulation
of 1R353 S for repelling ticks (EMD-003 .3) was sufficiently sound, from a scientific
perspective, to be used to assess the repellent efficacy of this formulation against
ticks. However, the use of data following participant withdrawal from the study and
corresponding statistical considerations were questionable. Based on this factor, only
a minimum CPT could be calculated.
Ethical Considerations
• The Board concurred with the initial assessment of the Agency that the completed
study submitted for review meets the applicable requirements of §40CFR26, subparts
KandL.
EMD-004: Mosquito Repellency with Aerosol Spray Formulations
Scientific Considerations
• The Board concluded that the reported study on the efficacy of an aerosol formulation
of 1R3535 on repelling mosquitoes (EMD 004.3) was sufficiently sound, from a
scientific perspective, to be used to assess the repellent efficacy of this formulation
against mosquitoes.
Ethical Considerations
• The Board concurred with the initial assessment of the Agency that the completed
study submitted for review by the Board meets the applicable requirements of
§40CFR26, subparts K and L.
Mosquito Repellent Efficacy Protocol WPC-OO1
Scientific Considerations
• The Board raised several concerns about sample size, sample size considerations for
dropouts, statistical analysis and dose for WPC-00 1 that should be addressed. If the
recommendations provided by EPA and those suggested by the Board are followed,
protocol WPC-00 1 appears likely to generate scientifically valid data to assess the
efficacy of the test products against mosquitoes. In addition, the protocol would
satisfy the scientific criteria recommended by the HSRB, namely, producing
important infbrmation that cannot be obtained except by research with human
subjects, and having a clear scientific objective and study design that should produce
adequate data to test the hypothesis.
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Ethical Considerations
• The Board concurred with the initial assessment of the agency that, with minor revisions,
the protocol wpc-OOl submitted for review would meet the applicable requirements of
§40CFR26, subparts K and L.
Completed Patch Test Studies
48-Hour Dermal Irritation Patch Test
Scientific Considerations
• The Board concluded that the study was sufficiently sound, from a scientific
perspective, to be used as part of a weight-of-evidence assessment to evaluate the
potential of the formulations tested to irritate human skin.
Ethical Considerations
• The Board concluded that there was no clear and convincing evidence that the
conduct of the research was fundamentally unethical (e.g., the research was intended
to seriously harm participants or failed to obtain informed consent). There was no
clear and convincing evidence that the conduct of the study was significantly
deficient relative to the ethical standards prevailing when the study was conducted.
Thus,
• The Board concluded that this study, based on the evidence presented, deviated from,
but was not significantly deficient relative to, the ethical standards prevailing when
the study was conducted.
Repeated Insult Patch Test
Scientific Considerations
• The HSRB concluded that the repeated insult patch test studies provided an inadequate
description of methods, and a limited analysis of results. The choice of sample size was
not explained, the representativeness of the sample was questionable and studies overall
appeared to be of poor quality based on the material provided for review. The Board
concluded that these studies provided little, if any, useful knowledge for the agency to
include in a weight-of-evidence assessment to evaluate the potential of the fonnulations
tested to cause sensitization of human skin.
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Ethical Considerations
• The Board concluded that there was not clear and convincing evidence that the conduct
of the research was fUndamentally unethical (e.g., the research was intended to seriously
harm participants or failed to obtain informed consent).
• The Board concluded that, there was insufficient IRB review of all products to which
subjects were asked to agree to be exposed. in addition information concerning research
procedures within the consent form itself was inadequate, and the limited if any scientific
validity of the study did not produce an a apriori positive risk-benefit ratio. For these
reasons the Board concluded there was clear and convincing evidence that the conduct of
the study was significantly deficient relative to the ethical standards prevailing when the
study was conducted.
EPA ’s Framework For Developing Best Practices For Subject Recruitment For Handler
Exposure Research
• The Board was very supportive of the EPA’s initiative in producing this document.
Furthermore, the Board found this document to be of very high quality, and a very
valuable step in assuring that this type of research is conducted in an ethical manner.
Follow-up on Agricultural Handler Exposure Task Force (AHETF) and Antimicrobial
Exposure Assessment Task Force (AEATF) Protocols
• The HSRB concluded that the materials provided by EPA regarding the quality of the
scientific data currently available for assessing exposures for handlers provide a sound
justification for the societal value of proposed new handler exposure research. In
addition, the review and recommendations of the EPA FIFRA Scientific Advisory Panel
provided an excellent starting point for some methodological decisions and for the
identification of issues still to be addressed. The challenge as the Agency moves forward
with the AHETF study is to ensure that the study is designed and conducted in a way that
produces high quality exposure data suitable for use in Agency risk assessments.
• The Board recommended development of a “governing document” that would frame the
entire plan for the collection and statistical analysis of the data, and a clear narrative
regarding the uses to which the data would be put. The Board also recommended that
studies be conducted as a part of this project to determine the accuracy of dermal
exposure measurements. The Board further recommended that the agency consider
broadening participation in its discussions of the agricultural handler exposure database,
including additional members of the scientific community, as well as parties with a direct
interest in the database project, such as the labor community. Finally, the Board
recommended that the Agency draw upon its experience with the agricultural reentry task
force database to clari1 ’ how such data are used in its risk assessments, to capture the key
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“lessons learned” from this experience, and to avoid possible pitfalls in the use of such
databases.
In conclusion, the EPA HSRB appreciated the opportunity to advise the Agency on the
scientific and ethical aspects of human studies research and looks forward to future opportunities
to continue advising the Agency in this endeavor.
Sincerely,
Celia B. Fisher, Ph.D. Chair
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NOTICE
This report has been written as part of the activities of the EPA Human Studies Review
Board, a Federal advisory committee providing advice, information and recommendations on
issues related to scientific and ethical aspects of human subjects research. This report has not
been reviewed for approval by the Agency and, hence, the contents of this report do not
necessarily represent the view and policies of the Environmental Protection Agency, nor of other
agencies in the Executive Branch of the Federal government, nor does the mention of trade
names or commercial products constitute a recommendation for use. Further information about
the EPA Human Studies Review Board can be obtained from its website at
http://www.epa.gov/osa/hsrb/. Interested persons are invited to contact Paul Lewis, Designated
Federal Officer, via e-mait at lewis.paul epa.gov.
In preparing this document, the Board carefully considered all information provided and
presented by the Agency presenters, as well as information presented by public commenters.
This document addresses the information provided and presented within the structure of the
charge by the Agency.
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United States Environmental Protection Agency Human Studies Review Board
Chair
Celia B. Fisher, Ph.D., Marie Ward Doty Professor of Psychology, Director, Center for Ethics
Education, Fordliam University, Department of Psychology, Bronx, NY
Vice Chair
William S. Brimijoin, Ph.D., Chair and Professor, Molecular Pharmacology and Experimental
Therapeutics, Mayo Foundation, Rochester, MN
Members
David C. Bellinger, Ph.D., Professor of Neurology, Harvard Medical School
Professor in the Department of Environmental Health, Harvard School of Public Health
Children’s Hospital, Boston, MA *
Alicia Carriquiry, Ph.D., Professor, Department of Statistics, Iowa State University
Snedecor Hall, Ames, IA
Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office for Human Subjects
Protection, University of Rochester, Rochester, NY
Janice Chambers, Ph.D., D.A.B.T., William L. Giles Distinguished Professor, Director, Center
for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State
University, Mississippi State, MS
Richard Fenske, Ph.D., MPH, Professor, Department of Environmental and Occupational Health
Sciences, University of Washington, Seattle WA
Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology, Boston University
School of Public Health, Co-Director, MA in Clinical Investigation, Boston University School of
Medicine, Boston, MA
Suzanne C. Fitzpatrick, Ph.D., DART, Senior Science Policy Analyst, Office of the
Commissioner, Office of Science and Health Coordination, U.S. Food and Drug Administration,
Rockville, MD
Kannan Krishnan, Ph.D., Professor, Département de sante environnementale et sante au travail,
Faculté de medicine, Universitd de Montréal, Montréal, Canada
KyungMann Kim, Ph.D., CCRP, Professor & Associate Chair, Department of Biostatistics &
Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison,
Madison, WI
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Michael D. Lebowitz, Ph.D., FCCP, Professor of Public Health & Medicine. University of
Arizona, Tucson, AZ
Lois D. Lehman-Mckeeman, Ph.D., Distinguished Research Fellow, Discovery Toxicology,
Bristol-Myers Squibb Company, Princeton, NJ
Jerry A. Meaikoff, MD., Associate Professor of Law, Ethics & Medicine, Director of the
Institute for Bioethics, Law and Public Policy, University of Kansas Medical Center,
Kansas City, KS
Sean Philpott, PhD., MS Bioethics, Policy and Ethics Officer, PATH, Washington, DC
Richard Sharp, Ph.D., Assistant Professor of Medicine, Center for Medical Ethics and Health
Policy, Baylor College of Medicine, Houston, TX
Consultants to the Board
David Hoe!, Ph.D., Distinguished University Professor, Medical University of South Carolina
Charleston, SC and Clinical Professor, Department of Radiology, University of South Carolina
School of Medicine, Charleston, SC
Yiliang Thu, Ph.D., Professor, Director of Center for Collaborative Research, Director,
Biostatistics PhD Program, Department of Epidemiology and Biostatistics, College of Public
Health, University of South Florida, Tampa, FL
Human Studies Review Board Staff
Paul I. Lewis, Ph.D., Designated Federal Officer, United States Environmental Protection
Agency, Washington, DC
* Not in attendance at April 18-20, 2007 Public Meeting; resigned from Board.
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INTRODUCTION
From April 18-20, 2007, the United States Environmental Protection Agency’s (EPA or
Agency) Human Studies Review Board (HSRB) met to address scientific and ethical issues
concerning
(1) Completed 1R3535 Insect Repellent Efficacy Studies
In two previous meetings the HSRB reviewed and commented on materials relating to
two insect repellent efficacy protocols from Carroll-Loye Biological Research, submitted by Dr.
Scott Carroll. These two protocols described proposed research to evaluate the efficacy of three
new formulations of repellent products containing the active ingredient IR-3 535. The protocol,
identified as EMD-003, described a laboratory study of efficacy of the test formulations against
ticks. The protocol, identified as EMD-004, described a field study of efficacy of the test
formulations against mosquitoes.
The HSRB offered extensive comments on the two protocols at its June 2006 meeting.
Following that meeting, Dr. Carroll revised the protocols to address comments from the HSRB.
EPA reviewed Dr. Carroll’s revised protocols and concluded that they appeared likely to
generate scientifically sound, useful information and to meet the applicable provisions of the
EPA regulations in 40 CFR part 26, subparts K and L. When the HSRB reconsidered the revised
protocols at its October 2006 meeting, it concurred with EPA’s assessment and suggested some
minor additional refinements. Dr. Carroll proceeded to conduct the research and submitted the
results to EPA for review.
The Board reviewed the results of the research on two of the formulations, a lotion and a
pump spray, at its January 2007 meeting. The report on the study with the third formulation, an
aerosol, arrived too late to permit its review at the January meeting. Thus, EPA presented the
results of the aerosol testing at the April 2007 meeting.
The Agency’s regulation, 40 CFR §26.1602, requires EPA to seek HSRB review of an
EPA decision to rely on the results of these studies. The sponsor has not yet submitted an
application to register these products, but with Agency concurrence submitted the completed
studies ahead of the applications so that HSRB review would not compromise EPA’s ability to
review the application within the time allowed by statute. The Agency expects to receive such
an application in the near future. In order to facilitate timely review of the application, EPA has
reviewed the studies, applying the standard in 40 CFR §26.1705. That provision states:
§ 26.1705 Prohibition on reliance on unethical research with non-pregnant, non-
nursing adults conducted after April 7, 2006
Except as provided in §26.1706, in actions within the scope of 26.l701, EPA shall not
rely on data from any research initiated after April 7, 2006, unless EPA has adequate
information to determine that the research was conducted in substantial compliance
with subparts A through L of this part. . . This prohibition is in addition to the
prohibition in §26.1703.
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The Agency’s reviews concluded that the data are scientifically sound and that the
research was conducted in a maimer that deviates at least technically from some of the
requirements of subparts K and L of EPA’s final rule establishing Protections fbr Subjects in
Human Research—the only subparts of the rule which apply to third-party research. The
Agency seeks the Board’s advice on whether the available infbrmation supports a determination
of “substantial compliance” with the applicable rules. Assuming a potential determination of
substantial compliance, and because EPA would like to rely on these data to support an
application for registration of these fonnulations, EPA presented these studies for review at the
Board’s April 2007 meeting.
(2) Oil of Lemon Eucalyptus Insect Repellent Efficacy Protocol WPC-001
EPA requires data from efficacy studies using appropriate insect species to support
claims of greater efficacy than have previously been approved. An applicant for new or
amended registration typically conducts such research prior to submitting an application. In this
instance, however, EPA approved a conditional registration for the product with a label claim for
repellency lasting “up to 6 hours.” EPA required the company as a condition of continued
registration to conduct a field study to support the label efficacy claim.
EPA’s regulation, 40 CFR §26.1125, requires the sponsor or investigator to submit to
EPA, before conducting the study, materials describing the proposed human research in order to
allow EPA to conduct scientific and ethics reviews. In addition, EPA’s regulation, 40 CFR
§26.160 1, requires EPA to seek HSRB review of the research proposal.
Dr. Scott Carroll has submitted a description of proposed research to be perfonned by
Carroll-Loye Biological Research. The proposal, identified as WPC-001, describes a study to
evaluate the field efficacy against wild mosquitoes of a repellent product containing the active
ingredient Oil of Lemon Eucalyptus. The proposal bears many similarities to the protocols
EMD-004 and SCI-O01 that the HSRB had previously reviewed. EPA has reviewed Dr.
Carroll’s protocol and has concluded that, with some required refinements, it appears likely to
generate scientifically sound, useful information and to meet the applicable provisions of the
EPA regulations in 40 CFR part 26, subparts K and L.
EPA has identified some relatively easily corrected deficiencies in the protocol, which
must be corrected before execution. In the interest of providing a thorough and timely response
to the proposal, and since EPA finds the protocol generally meets applicable scientific and
ethical standards, EPA presented this protocol for review at the Board’s April 2007 meeting.
(3) Research Conducted After April 7, 2006: Meaning of “Substantial Compliance” with 40 CFR
Part 26
At the Board’s request, EPA discussed its approach to interpreting and applying the
standard in 40 CFR §26.1705: “. . . EPA shall not rely on data from any research initiated after
April 7, 2006, unless EPA has adequate information to determine that the research was
conducted in substantial compliance with [ EPA’s human studies rules].”
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(4) Completed Skin Irritation and Skin Sensitization Patch Test Studies
EPA requires applicants for registration of pesticide products that are intended for
extensive contact with human skin to provide scientific data evaluating the potential for such
products to cause irritation and sensitization. Although many products rely on the results of
studies conducted with laboratory animals, generally rats, mice, guinea pigs, or rabbits, EPA has
also accepted the results of such studies when conducted with humans.
EPA uses the results from dermal irritation and dermal sensitization studies to assign a
product to a hazard category and to require label statements appropriate to the category. EPA
can also use the data to determine whether potential exposure of people who handle a pesticide
poses a risk and whether those risks can be mitigated by labeling requirements, such as warning
statements or requirements for actions that could reduce exposure such as using protective
equipment.
The Agency has received an application for registration of a product that is intended to be
applied directly to human skin. The applicant / sponsor has submitted the results of two studies,
a 48 hour dermal irritation patch study and a repeated insult patch test sensitization study. Each
of these two studies was conducted with two different formulations containing the same active
ingredient. The studies were initiated before EPA’s Human Studies regulation took effect, and
therefore they are subject to review under § 26.1703 and 26.1704 of 40 CFR. Those sections
provide:
§26.1703 Prohibition on reliance on research involving intentional exposure of
human subjects who are pregnant women (and therefore their fetuses), nursing
women or children.
Except as provided in §26.1706, in actions within the scope of §26.1701, EPA shall not
rely on data from any research initiated after April 7, 2006, EPA shall not rely on data
from any research involving intentional exposure of any human subject who is a
pregnant woman (and therefore her fetus), a nursing woman, or child.
§26.1704 Prohibition on reliance on unethical research with non-pregnant, non-
nursing adults conducted before April 7, 2006
Except as provided in §26.1706, in actions within the scope of §26.1701, EPA shall not
rely on data from any research initiated before April 7, 2006, if there is clear and
convincing evidence that the conduct of the research was fundamentally unethical (e.g.,
the research was intended to seriously harm participants or failed to obtain infonned
consent), or was significantly deficient relative to the ethical standards prevailing at the
time the research was conducted. This prohibition is in addition to the prohibition in
§26.1703.
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The Agency has reviewed the studies in connection with the application and has concerns
regarding the design and conduct of the research. Because EPA has not previously received
HSRB views on these kinds of research, EPA will wait to make conclusions on the acceptability
of these studies pending the HSRB’s comments on the scientific and ethical merit of these
studies. Assuming that the studies are scientifically sound and ethically acceptable, EPA intends
to rely on them in reaching its decision on the pending application. The Agency believed these
studies are ready ibr review by the HSRB at its April meeting.
(5) Draft “Framework” Concerning Best Practices for Recruiting and Enrolling Subjects in
Studies of Occupational Exposure.
The Agency has been working with two industry task forces—the Agricultural Handlers
Exposure Task Force (AHETF) and the Antimicrobial Exposure Assessment Task Force
(AEATF)—planning to conduct research to measure exposure received by pesticide handlers
when mixing, loading, or applying agricultural or antimicrobial pesticides. In June 2006 the
Board reviewed 5 proposed protocols developed by the AHETF. The Board raised questions and
made numerous comments on both scientific and ethical aspects of the proposals.
Since June, EPA and the Task Forces have been addressing the issues identified by the
HSRB. Both the AHETF and AEATF are preparing extensively expanded justifications for their
proposed research, and expect to submit to EPA protocols and related materials for new research
that they plan to conduct in the winter of 2007—200 8 (AEATF) or during the pesticide use season
in 2008 (AHETF). Since EPA regards the proposed studies as “research involving intentional
exposure of human subjects,” EPA regulations require the Agency and the Board to review these
proposals before the investigators initiate the studies.
Although EPA and the Task Forces do not expect HSRB review of specific protocols to
occur until the Board’s October 2007 meeting, EPA believes that it would be useful for EPA and
the Board to provide guidance on selected, fundamental matters affecting all of the protocols
before they are submitted for review. In particular, EPA thinks it would be helpful to offer
guidance on best practices that investigators could employ to recruit and enroll subjects into this
kind of research. Since it is especially important that subjects participating in the research be
representative of the larger handler population, it is likely that some of the potential subjects will
have characteristics that require careful consideration and special procedures to ensure a
recruitment and enrollment process consistent with Subpart K. For example, potential subjects
may not speak English well, so the informed consent process may need to be conducted in a
language other than English. Potential subjects may also have limited education and will need
informed consent materials presented simply enough so they can understand them. Potential
subjects may be in the U.S. illegally, and investigators will need to address their legitimate
privacy concerns.
EPA has prepared a document that identifies the major elements of the recruitment and
enrollment processes that should be considered by investigators as they prepare protocols for
handler exposure research. In addition, the document discusses broad principles which should be
considered in the course of research design. In the future, through a participatory process
involving investigators, workers, and other stakeholders, EPA intends to add to the document
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specific best practices and identify publicly available resources that contain additional
discussion, information, and guidance relevant to the implementation of general ethical
principles in occupational exposure research. In order to ensure the Task Forces have timely
advice for use in drafting their protocols for subsequent review, the Agency is seeking HSRB
review of the draft framework for this effort at its April meeting.
(6) Assessing the Need for New Research on Pesticide Handler Exposure
As noted above, EPA has been working with two Task Forces that are planning to
conduct research to measure the exposure received by people who handle agricultural and
antimicrobial pesticides. In June 2006, EPA asked the HSRB to review 5 protocols developed
by one of these Task Forces, the Agricultural Handlers Exposure Task Force (AHETF). One of
the fundamental issues identified by the Board about these proposals was whether there was a
need for the new data that would result from the proposed research.
In response to scientific concerns raised by the HSRB, EPA analyzed the existing handler
exposure database, as well as relevant scientific literature. The Agency presented its analysis to
the FIFRA Scientific Advisory Panel (SAP) in January 2007. The Agency asked the SAP to
comment on, among other topics, the “limitations [ of existing data] and on EPA’s conclusion
that additional data could improve significantly EPA’s ability to estimate worker exposure.
This report transmits the HSRB’s comments and recommendations from its April 18-20,
2007 meeting.
REVIEW PROCESS
From April 18-20, 2007, the Board had a public face-to-face meeting in Arlington,
Virginia. Advance notice of the meeting was published in the Federal Register “Human Studies
Review Board: Notice of Public Meeting (72 Federal Register 57, 14101). At the public
meeting, following welcoming remarks from Agency officials, Celia B. Fisher, HRSB Chair,
summarized the Board’s process for its review. The Board then heard presentations from the
Agency on the following topics:
(1) Completed Repellent Efficacy Studies: 1R3535 Aerosol (EMD-003 .3 and EMD-004.3)
(2) Mosquito Repellent Efficacy Protocol WPC-001
(3) Research Conducted After April 7, 2006: Meaning of “Substantial Compliance” with 40 CFR
Part 26
(4) Completed Patch Test Studies
(5) Framework for Developing Best Practices for Subject Recruitment for Handler Exposure
Research
(6) Follow-up on AHETF and AEATF Protocols
Dr. Scott Carroll, on behalf of Carroll-Loye Biological Research, provided oral
comments addressing: (1) Completed Repellent Efficacy Studies: 1R3535 Aerosol (EMD-003.3
and EMD-004.3) and (2) Mosquito Repellent Efficacy Protocol WPC-001. James Mibauer MD
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and Ms. Milena Reckseit, on behalf of TKL Research, provided oral comments addressing
completed patch test studies.
For their deliberations, the Board considered the materials presented at the meeting,
written public comments and Agency background documents (e.g. pesticide human study,
Agency data evaluation record (DER) of the pesticide human study, weight of evidence review,
ethics review, pesticide human study protocols and Agency evaluation of the protocol).
CHARGE TO THE BOARD AND BOARD RESPONSE
Completed Repellent Efficacy Studies: 1R3535 Aerosol (EMD-003.3 and EMD-004.3)
Charge to the Board
EMD-003.3: Tick Repellency with Aerosol Spray Formulations
a. Is this study sufficiently sound, from a scientific perspective, to be used to assess the
repellent efficacy of the formulation tested against ticks?
Board Response
The active ingredient IR 3535 in an aerosol formulation was tested for its ability to repel
ticks on the forearms of volunteers by the protocol presented and modified by Carroll-Loye. The
protocol had been modified based on the suggestions and input of EPA and HSRB. The results
were reported in EMD-003.3, and was very similar to the previously reviewed studies EMD-
003.1 and EMD-003.2
The active ingredient was formulated into an aerosol product. The product was produced
using Good Manufacturing Practices. All experiments were conducted using Good Laboratory
Practices. A dosimetry experiment was done to determine the amount of product that would be
utilized by people using the product as directed. This dosimetry experiment was used to
determine a grand mean of the 12 individuals tested (3 subsamples each) per product that was
then used for all 10 individuals per product participating in the subsequent tick repellency tests
for each product (it should be noted that the dosimetry experiment was common for both this
study and the mosquito repellency study, EMD-004.3, since the same formulated product was
used for both studies). The dosimetry results allowed a 7% lower dosage to be tested than had
been the industry standard dosage.
The experiment was a laboratory study and was conducted according to the approved
protocol with only very minor deviations, and none of these deviations would have affected the
quality of the data or the safety of the subjects. Ten subjects, 4 female and 6 male, participated.
The number of 10 subjects was justified in the text as leading to sufficient statistical power while
exposing only a small number of people to the potential risks. Each subject had one limb treated.
Each of the subjects served as a negative control in that each tick was tested first on the untreated
limb to guarantee that the ticks demonstrated typical questing behavior (all did) prior to being
tested on the treated limb. All ticks were laboratory reared with no history of tick-borne
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pathogens. Each tick was used only once. Repellency was tested during a 3-mm interval each 15
minutes, starting 15 minutes after product application, using the criterion of First Confirmed
Crossing (FCC) for each individual (replicate) to calculate Complete Protection Time (CPT) for
the study. Stopping rules were employed. The study identified a range of 4.25 — 13.5 hrs, with a
mean CPT of 10.95 hr. The mean time to failure, adjusted for censoring was 11.3 hr. The CPT is
probably conservative as a number of the subjects reported no crossings at all, and the
experiment was terminated before a FCC.
Strengths
It appeared that the protocol was revised as per HSRB suggestions and generally was
adequate for the study to be sufficiently sound scientifically. The initial dosimetry study
appeared to have been appropriate and useful, though some questions remain (as discussed
below). The operation of the technicians throughout appears to have been very useful, and the
use of the Friedman 2-way ANOVA was acceptable (though not ideal since only 12 subjects
were utilized). It appeared that the routine study of each subject actually lasted about 12 hours,
so withdrawals were to be expected and Kaplan-Meier survival analysis was appropriate. The
stopping rule also was acceptable.
Weaknesses
The investigator’s defense of a sample size of 10 for the efficacy study (p.52 of EMD
2007) was weak and did not include a statistical power calculation. However, this issue of
sample size in this series of studies has been discussed within the HSRB before (in reviews of
EMD-003. 1-2 of the HSRB’s January 2007 meeting report), and sample size is not a fatal flaw if
the experiment and statistical analyses were performed properly, as discussed below.
The large intra- and inter- variation in self-dosing does not appear to be taken fully into
account in determining the actual grand mean of the dose used to determine application in the
efficacy study. Also, the application of withdrawal from the study and corresponding statistical
considerations were questionable. Based on this factor, only a minimum CPT can be calculated.
It is not clear what difference in outcome occurs by requiring a second crossing for failure, as
described (e.g., pp. 62 & 65), versus only requiring the first crossing (FCC). The document did
not indicate whether this is a customary and acceptable way of determining failure for insect
repellents, nor did it indicate that the 3 cm. traveling distance and the 15-minutes between
exposures were industry standards. Table 4 of EMD 2007 did not show if only one crossing
occurred and this was not considered adequate for defining failure (also see table on p.19 of
EMD 2007). However, these criteria were considered acceptable in the review of the prior
EMD-003 studies.
The Board recommended that the use of 7.5 minutes (half of the next expected observation
period) might have been better than an additional 15 minutes before censoring those who
withdrew from the study. However, the Board acknowledged that using either time would
probably not limit the utility of the study
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The problems with analyses of the efficacy data appear to be present still, especially after
viewing the results. Table p.19 of EMD 2007) indicated withdrawals by time for 4 subjects -
10 31, 54, and 57, and even though understood given the length of the experiment, it raised
significant issues about how conclusions concenung CPT can be determined.
The following is a summary of the points in the science criteria established earlier by the
HSRB fin completed studies, applied in reference to this study:
General HSRB Scientific Criteria
• The scientific question was stated (i.e., to test the efficacy of 1R3535 formulated as an
aerosol product in repelling ticks).
• Existing data were not adequate to answer the question of efficacy of this new product,
thus new studies involving human subjects were necessary.
• The potential benefits of the study were clear, i.e., that an effective repellent would be
available that would have either greater efficacy and/or fewer drawbacks than what was
currently approved.
• It is likely that the benefits would be realized because repellent efficacy was determined
in controlled experiments.
• The risks were minimal because the formulation products are of very low toxicity and
ticks were laboratory-reared with no evidence of vector-bone pathogens.
• The most likely relevant risk would have been irritation from tick bites, but participants
were instructed to remove ticks before they were bitten.
Study Design Criteria
• The purpose of the study was clearly defined (i.e., efficacy testing).
• There were specific objectives/hypotheses (i.e., that 1R3535 in the proposed formulation
is an effective repellent).
• The study as described tested this hypothesis.
• The sample size was 10 individuals per product with each individual serving as his/her
own negative control to test for tick questing behavior. A dosimetry experiment prior to
the field experiment quantified the amount of repellent being used.
• There was a plan allocating individuals to treatments.
• It is anticipated that the findings from this study can be generalized beyond the study
sample.
Participation Criteria :
• There was justification for the selection of the target population.
• The participants were representative of some of the population of concern; however,
them are others in the population unlike these participants who are likely to use these
products, but it would either be unethical to test them or would be less appropriate to test
them. The participating population is considered appropriate and reasonable.
• The inclusion/exclusion criteria were appropriate.
• The sample was not a vulnerable group.
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Measurement Criteria
• The measurements were accurate and reliable.
• The measurements were appropriate to the question being asked.
• Quality assurance was addressed.
Statistical Analysis Criteria
• The data can be analyzed to calculate CPT with a range of variability; however, other
methods of calculating efficacy might be better statistically, but would probably lead to
inconsistencies in comparison of this product with products already on the market.
• The statistical method was adequate; however, other statistical methods would probably
be better, but would probably lead to inconsistencies in comparison of this product with
products already on the market.
• Measures of uncertainty were addressed.
Laboratory and Field Conditions
• Laboratory experiments were appropriate.
• Field experiments were not conducted.
• The study included a stop rule plan, medical management plan, and a safety monitor.
HSRB Consensus and Rationale
The Board concluded that the reported study on the efficacy of an aerosol formulation of
1R3535 for repelling ticks (EMID-003.3) was sufficiently sound, from a scientific perspective, to
be used to assess the repellent efficacy of this formulation against ticks. However, the use of data
following participant withdrawal from the study and corresponding statistical considerations
were questionable. Based on this factor, only a minimum CPT could be calculated.
Charge to the Board
b. Does available information support a determination that this study was conducted in
substantial compliance with subparts K and L of EPA regulations at 40 CFR part 26?
Board Response
Brief Overview of the Study
The protocol for this study was initially reviewed at the June 2006 meeting of the Human
Studies Review Board, at which time the Board concluded that the study failed to meet the
requirements established in the Environmental Protection Agency’s final human studies rule (40
CFR Part 26). At that time, the protocol failed to comport with the applicable requirements of 40
CFR Part 26, subpart K. The Board also raised questions about: 1) equitable study participant
selection and recruitment; and 2) whether or not the documentation and process of study
volunteer enrollment was sufficient to meet prevailing standards of voluntary informed consent.
A revised Institutional Review Board (IRB)-approved protocol was submitted and reviewed at
the October 2006 meeting of the Human Studies Review Board, at which the Board concluded
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that revised research protocol, as submitted to the EPA, was compliant with the applicable
ethical requirements of 40 CFR Part 26, subparts K arid L.
Subsequent to the aforementioned October meeting of the HSRB, dosimetry and efficacy
studies for tick repellents containing 1R-3 535 in an aerosol spray formulation were conducted
from October 23 through November 18, 2006 (Carroll 2007a). Dosimetry and efficacy studies of
lotion- and pump spray-formulations of LR-3535-containing tick repellents were conducted at the
same time, using an overlapping set of study volunteers; these studies were reviewed at the
January 2007 meeting of the HSRB (EPA 115KB 2007a).
The dosimetry and efficacy studies of the aerosol formulations were performed in Davis,
California by researchers at Carroll-Loye Biological Research. The study was sponsored by
EMD Chemicals, Inc., Gibbstown, New Jersey (EMD Chemicals is the North American
subsidiary of Merck KGaA, Darmstadt, Germany). The documents provided by Carroll-Loye
specifically state that the study was conducted in compliance with the requirements of the U.S.
EPA Good Laboratory Practice Regulations for Pesticide Programs (40 CFR 160); 40 CFR 26
subparts K and L; FIFRA § I 2(a)(2)(P); and the California State EPA Department of Pesticide
Regulations for study monitoring (California Code of Regulations Title 3, Section 6710) (Carroll
2007a, 4, 42). The study was also reviewed and approved by a commercial human subjects
review committee, Independent Investigational Review Board (HRB), Inc., Plantation, FL.
Documentation provided to the EPA by IIRB indicated that it reviewed this study pursuant to the
standards of the Common Rule (45 C.F.R. Part 46, Subpart A) and determined it to be in
compliance with that Rule.
As submitted to the EPA, the completed study consisted of two interdependent analyses:
1) a dosimetry study designed to determine the amount of an insect-repelling compound, known
as IR-3535, that users would typically apply when provided with an aerosol spray formulation;
and 2) an efficacy study designed to measure the effectiveness of IR-3535 as a aerosol spray-
based tick repellent. Dosimetry was determined by passive dosimetry using self-adhesive roll-
gauze. The efficacy of IR-3535 as a tick repellent was determined by placing Western black-
legged ticks (Ixodespacj/icus) on IR-3535-treated and untreated forearms and measuring the
speed and distance that moving insects would penetrate into the treated area; each participant
served as their own control. The scientific strengths and weaknesses of each study design were
described above.
The dosimetry study enrolled a total of 12 individuals: seven women and five men. The
same 12 volunteers also participated in the dosimetry studies for the lotion and pump spray
formulations, described in the two previously reviewed studies (EPA HSRB 2007a). The efficacy
study enrolled 10 volunteers: four women and six men. None of the participants enrolled in the
dosimetry study participated in the efficacy study, giving a cumulative total of 22 individuals. In
addition, three alternate participants were enrolled: 1) to replace any individual who withdrew;
and 2) to protect the confidentiality of any volunteer excluded from the study as a result of
pregnancy or other potentially stigmatizing condition, as described below.
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Critique of Study
The Board concurred with the factual observations of the ethical strengths and
weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2007a). In general, the
research described in EMD-003.3 comports with the applicable requirements of 40 CFR Part 26,
subparts K and L. The risks to study participants were minimal and were justified by the likely
societal benefits, including data on the efficacy of LR-3535 as a tick repellent. As IR-3535 is
commercially available and has been used as a repellent in Europe for years with no evidence of
toxic effects, the participants enrolled in this study were unlikely to be at increased risk of
experiencing adverse side effects upon exposure. The ticks used for the study were bred and
raised in a laboratory environment and are considered to be pathogen-free, minimizing the risk of
vector-borne disease(s). Participants in the efficacy study worked in groups of three or four, to
facilitate monitoring and removal of ticks before biting. Clear stopping rules also were
developed, as were plans for the medical management of any side effects or adverse events; no
side effects or adverse events were reported. The study protocol also included several
mechanisms designed to minimize coercive recruitment and enrollment, compensation was not
considered to be so high as to unduly influence volunteers, and minors and pregnant or lactating
women were explicitly excluded from participation (pregnancy being confirmed by requiring all
female volunteers to undergo a self-administered over-the-counter pregnancy test on the day of
the study). The potential stigmatization resulting from study exclusion was minimized by the use
of so-called “alternate” participants, allowing for volunteers to withdraw or be excluded from
participating without unduly compromising their confidentiality.
Although the Board concluded that research described in EMD-003.3 corn ports with the
applicable requirements of 40 CFR Part 26, subparts K and L, and that there was no clear and
convincing evidence that the conduct of the research was fundamentally unethical, further
comments are warranted on certain events that took place during the conduct of the study. As
was also noted during the HSRB’s review of the companion lotion and pump spray studies (EPA
HSRB 2007a), the revised protocol and informed consent documents were reviewed and
approved by the IIRB, Inc., on November 1, 2006, nine days after study enrollment began, study
participants were enrolled using hand-corrected, unapproved consent forms in clear violation of
accepted practice.
Although it is unlikely that these changes knowingly and/or seriously impaired the
informed consent process, enrollment of study participants using unapproved protocols and
consent forms represents a significant and serious departure from accepted review and approval
practices. EPA regulations regarding review and approval of human subjects research require
LRBs to follow procedures that “ensure” investigators do not implement any protocol changes
without prior LR.B approval unless such changes are necessary to prevent immediate, serious
harm to study participants. The regulations also require investigators to only obtain consent using
IRB-approved forms. Furthermore, it is the policy of the IIRB, available online at httD://iirb.com .
that all “significant protocol deviations [ be] reported to the Independent Investigational Review
Board, Inc. in a timely manner.” Protocol violations or deviations occur when there is a variance
in a research study between what is described in the protocol approved by the LRB and the actual
activities performed by the research team. The failure of Carroll-Loye Biological Research to 1)
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obtain [ RB approval of the revised protocol and consent forms prior to enrollment of study
participants, and 2) report these deviations to IIRB, are serious regulatory breaches.
At the January 2007 meeting, the Board recommended that Carroll-Loye Biological
Research report these deviations to the fiRS as soon as possible and work with that organization
to develop and implement a corrective course of action (EPA HSRB 2007). From comments to
the Board by Dr. Carroll at the April 2007 meeting, it appeared that these deviations have since
been reported to the IIRB and appropriate corrective actions taken.
HSRB Consensus and Rationale
The Board concurred with the initial assessment of the Agency that the completed study
submitted for review meets the applicable requirements of §40CFR26, subparts K and L.
EMD-004.3: Mosquito Repellency with Aerosol Spray Formulations
Charge to the Board
a. Is this study sufficiently sound, from a scientific perspective, to be used to assess the
repellent efficacy of the formulation tested against mosquitoes?
Board Response
The active ingredient IR 3535 formulated as an aerosol was tested for its ability to repel
mosquitoes from the legs of volunteers by the protocol presented and modified by Carroll-Loye.
The protocol had been modified based on the suggestions and input of EPA and HSRB. The
results were reported in EMD-004 .3 .
The active ingredient was formulated into an aerosol. The product was produced using Good
Manufacturing Practices. All experiments were conducted using Good Laboratory Practices. A
passive dosimetry experiment was done, as suggested by the HSRB, to determine the amount of
product that would be utilized by people using the product as directed. This passive dosimetry
experiment was used to determine a grand mean of the 12 individuals tested (3 subsaniples each)
per product that was then used for all 10 individuals per product participating in the subsequent
mosquito repellency tests for each product (it should be noted that the dosimetry experiment was
in common for both this study and the tick repellency study, EMD-003, since the same
formulated product was used for both).
The experiment was a field study and was conducted according to the approved protocol with
only very minor deviations, and none of these deviations would have affected the quality of the
data or the safety of the subjects. Two locations in California were used, one a marshland (Mud
Slough, Merced County; Site 1) and the other a picnic area surrounded by forest and flooded
marshland (West Bear Creek, San Luis National Wildlife Refuge, Butte County; Site 2). The
two locations had differences in the composition and relative abundance of mosquito species. A
mixture of Culex, Anopheles, Aedes and Culiseta spp. were detected. For one of the field tests,
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the investigator selected an alternate site after insufficient biting pressure was noted in the site
originally selected.
Ten subjects participated in each location’s test. There were 2 females and 8 males in Site I
and 3 females and 7 males in Site 2. The number of 10 subjects per product was justified in the
text as leading to sufficient statistical power while exposing only a small number of people to the
potential risks. Only legs were tested in this study because of greater biting pressure on legs than
arms. Each subject had one leg treated, and the remainder of the body was covered with material
impervious to mosquitoes. There were two experienced persons serving as negative controls (i.e.,
without any repel lent product) to confirm mosquito biting pressure (and biting pressure was
maintained throughout the period of the study, defined as at least one Landing with Intent to
Bite, LIBe, per mm at Site 1 and the second site selected to be Site 2). Experimental subjects, in
pairs, monitored LIBe’s during a one minute interval each 15 minutes, until the First Confirmed
LIBe (FCLIBe) could be determined. Stopping rules were employed. Except for one subject, the
trials were terminated because of darkness without the remaining subjects experiencing a
FCLLBe. Because of this the results provide a minimum duration of performance and no
statistical treatment was possible. The Complete Protection Time (CPT) was determined to be
10.25 hr for the grassland site (i.e, the maximal length of time for the study plus 15 mm) and
calculated to be 9.75 hr for the wooded picnic area site, with a mean of 9.65 ± 0.32 hr. The CPT
was conservative as most of the subjects reported no LIBe’s at all, and the experiment was
terminated before a breakdown of efficacy.
The following is a summary of the points in the science criteria established earlier by the
HSRB for completed studies, applied in reference to this study:
General HSRB Scientific Criteria
• The scientific question was stated (i.e., to test the efficacy of 1R3535 formulated as an
aerosol in repelling mosquitoes).
• Existing data were not adequate to answer the question of efficacy of these new
formulations, thus new studies involving human subjects are necessary.
• The potential benefits of the study were clear, i.e., that an effective repellent would be
available that would have either greater efficacy and/or fewer drawbacks than what was
currently approved.
• It is likely that the benefits would be realized because repellent efficacy was determined
in carefully designed field experiments.
• The risks are minimal because the formulation product was of very low toxicity, the
mosquitoes were aspirated before they had an opportunity to bite, and the regions
selected did not have evidence of West Nile Virus.
• The most likely relevant risk would be irritation from mosquito bites, but participants
were instructed to remove mosquitoes before they were bitten, or the possibility of
infection with West Nile virus, but the regions selected had no evidence of the virus.
Study Desian Criteria
• The purpose of the study was clearly defined (i.e., efficacy testing).
• There were specific objectives/hypotheses (i.e., that 1R3535 as an aerosol formulation is
an effective repellent).
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• The study as described tested this hypothesis.
• The sample size was 10 individuals per product along with 2 experienced individuals to
confirm mosquito biting pressure. A dosimetry experiment prior to the field experiment
quantified the amount of repellent being used.
• There was a plan allocating individuals to treatments.
• It was anticipated that the findings from this study can be generalized beyond the study
sample.
Participation Criteria
• There was justification for the selection of the target population.
• The participants were representative of some of the population of concern; however,
there were others in the population unlike these participants who are likely to use these
products, but it would either be unethical to test them or would be less appropriate to test
them. The participating population is considered appropriate and reasonable.
• The inclusion/exclusion criteria were appropriate.
• The sample was not a vulnerable group.
Measurement Criteria
• The measurements were accurate, reliable and appropriate to the question being asked.
• Quality assurance was addressed.
Statistical Analysis Criteria
• The data were designed to be analyzed to calculate CPT with a range of variability;
however, since most of the participants had to stop before a FCLIBe because of darkness,
the CPT is conservative and no variability could be calculated.
• A statistical method could not be used because there was essentially no variability; 19 of
20 subjects yielded the maximum time possible in the study.
• Measures of uncertainty were addressed.
Laboratory and Field Conditions
• Laboratory experiments were not conducted.
• Field experiments were appropriate.
• The study included a stop rule plan, medical management plan, and a safety monitor.
HSRB Consensus and Rationale
The Board concluded that the reported study on the efficacy of an aerosol formulation of
1R3535 on repelling mosquitoes (EMD 004.3) was sufficiently sound, from a scientific
perspective, to be used to assess the repellent efficacy of this formulation against mosquitoes.
Charge to the Board
b. Does available information support a determination that this study was conducted in
substantial compliance with subparts K and L of EPA regulations at 40 CFR part 26?
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Brief Overview of the Study
This protocol for this study was initially reviewed at the June 2006 meeting of the HSRB,
at which time the Board concluded that the study failed to meet the requirements established in
the Environmental Protection Agency’s final human studies rule (40 CFR Part 26). At that time,
the study failed to comport with the applicable requirements of 40 CFR Part 26, subpart K The
Board also raised questions about: 1) equitable participant selection and recruitment; 2)
description and minimization of risks to volunteers; and 3) whether or not the documentation and
process of participant enrollment was sufficient to meet prevailing standards of voluntary
informed consent. A revised, Institutional Review Board (IRB)-approved protocol was submitted
and reviewed at the October 2006 meeting of the Human Studies Review Board, at which the
Board concluded that the revised research protocol, as submitted to the EPA, was compliant with
the applicable ethical requirements of 40 CFR Part 26, subparts K and L.
Subsequent to the aforementioned October meeting of the HSRB, dosimetry and efficacy
studies for mosquito repellents containing IR-3535 were conducted from October 23 through
November 19, 2006 (Carroll 2007b). Dosimetry and efficacy studies of lotion- and pump spray-
formulations of IR-3535-containing mosquito repellents were conducted at the same time, using
an overlapping set of study volunteers; these studies were reviewed at the January 2007 meeting
of the HSRB (EPA HSRB 2007b).
The dosimetry and efficacy studies of the aerosol formulations were performed at a
laboratory site in Davis, California, and at three field sites (one in Butte County and two in
Merced County, California), by researchers at Carroll-Loye Biological Research. The studies
were sponsored by EMD Chemicals, Inc., Gibbstown, New Jersey; EMD Chemicals is the North
American subsidiary of Merck KGaA, Darmstadt, Germany. The documents provided by
Carroll-Loye specifically stated that the study was conducted in compliance with the
requirements of the U.S. EPA Good Laboratory Practice Regulations for Pesticide Programs (40
CFR 160); 40 CFR 26 subparts K and L; FIFRA § 12(a)(2)(P); and the California State EPA
Department of Pesticide Regulations for study monitoring (California Code of Regulations Title
3, Section 6710) (Carroll 2007b, 5, 39). Each study was also reviewed and approved by a
commercial human subjects review committee, IIRB, Inc., Plantation, FL. Documentation
provided to the EPA by IIRB indicated that it reviewed these studies pursuant to the standards of
the Common Rule (45 C.F.R. Part 46, Subpart A) and determined them to be in compliance with
that Rule.
As submitted to the EPA, the completed study consisted of two interdependent analyses:
1) a dosimetry study designed to determine the amount of an insect-repelling compound, known
as LR-3535, that users would typically apply when provided with an aerosol spray formulation;
and 2) an efficacy study designed to measure the effectiveness of IR-3535 as a mosquito
repellent for each compound formulation. Dosimetry was determined by passive dosimetry using
self-adhesive roll-gauze. The efficacy of IR-3535 as a mosquito repellent was determined by
measuring the ability of the three formulations to prevent mosquito landings (defined as “Lite
with Intent to Bite”; LIBe) under field conditions. Mosquitoes were aspirated mechanically prior
to biting; prior to initiation of the efficacy study, all volunteers will be trained both to recognize a
mosquito landing with the intent to bite and to remove such mosquitoes with an aspirator using
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laboratory-raised, pathogen-free mosquitoes in a controlled laboratory setting. During the field
studies, participants worked in pairs to facilitate identification and aspiration of LIBing
mosquitoes during brief exposure periods. The scientific strengths and weaknesses of each study
design were described above.
The dosimetry study enrolled a total of 12 individuals: seven women and five men. The
same 12 volunteers also participated in the dosimetry studies for the lotion and pump spray
formulations, described in the two previously reviewed studies (EPA HSRB 2007a). The field-
based efficacy study for the aerosol spray formulation enrolled a total 14 volunteers: 10
participants (three women and seven men) tested the efficacy of the aerosol spray formulation at
a “forest” site in Butte County, and 10 volunteers (two women and eight men) the efficacy of the
aerosol spray formulation at two “marsh/grassland” sites in Merced County (low biting rates at
the first site, as measured by using ambient LIRe pressure with two untreated controls, lead the
Principal Investigator to move to a nearby alternative site). Two volunteers enrolled in the
dosimetry study also participated in the efficacy study: one at the “forest” site and one at the
“marsh/grassland” sites. Six additional individuals participated in both the “forest” and
“marsh/pasture” studies. All remaining volunteers participated in only one of the analytic phases
of EMD-004. 1 and EMD-004.2. Three controls, described as “experienced personnel” (Carroll
2007b) and who were untreated with repellent, also participated to determine ambient LIBe
pressure (one who participated at the Butte County site, one who participated at the Merced
County site, and one who participated at both sites), giving a cumulative total of 27 volunteers.
In addition, three alternate participants were enrolled to: I) replace any individual who withdrew;
and 2) protect the confidentiality of any participant excluded from the study as a result of
pregnancy or other potentially stigmatizing condition, as described below.
Critique of Study
The Board concurred with the factual observations of the ethical strengths and
weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2007b). In general, the
research described in EMD-004.3 comports with the applicable requirements of 40 CFR Part 26,
subparts K and L. The risks to study participants were minimal and were justified by the likely
societal benefits, including data on the efficacy of IR-3 535 as a mosquito repellent. IR-3535 is
commercially available and has been used as a repellent in Europe for years with no evidence of
toxic effects, so the individuals enrolled in this study were unlikely to be at increased risk of
experiencing adverse side effects upon exposure. Reactions to mosquito bites are usually mild
and easily treated with over-the-counter steroidal creams. The study also excluded individuals
who have a history of such severe skin reactions to further minimize the risk of a participant
experiencing a severe physical reaction to a mosquito bite. In addition, the study protocol was
designed specifically to minimize the likelihood that a mosquito would bite, through the use of
clear stopping rules, limited exposure periods, and paired observation; no side effects or adverse
events were reported. To minimize the risk that study participants would be exposed to illnesses
like West Nile Virus, the study protocol called for field tests of repellent efficacy to be
conducted only in areas where known vector-borne diseases have not been detected by county
and state health or vector/mosquito control agencies for at least one month. Although it would
have been ideal if the mosquitoes collected during the field studies were subjected to serologic or
molecular analyses to confirm that they were free of known pathogens, it is unlikely that failure
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to do so compromised participant safety in any significant way. Finally, the study protocol also
included several mechanisms designed to minimize coercive recruitment and enrollment,
compensation was not considered to be so high as to unduly influence participation, and minors
and pregnant or lactating women were explicitly excluded from volunteering (pregnancy being
confirmed by requiring all female volunteers to undergo a self-administered over-the-counter
pregnancy test on the day of the study). The potential stigmatization resulting from study
exclusion was minimized by the use of so-called “alternate” participants, allowing for volunteers
to withdraw or be excluded from participating without unduly compromising their
confidentiality.
Although the Board concluded that research described in EMD-004.3 comports with the
applicable requirements of 40 CFR Part 26, subparts K and L, and that there was no clear and
convincing evidence that the conduct of the research was fundamentally unethical, further
comments are warranted on certain events that took place during the conduct of the study. These
same deficiencies were also noted during the HSRB’s review of the companion lotion and pump
spray studies (EPA HSRB 2007).
First, as with the tick repellent study described above (EMD-003.3), the revised protocol
and informed consent documents used for this mosquito repellent study were reviewed and
approved by IIRB, several days after study enrollment began; some volunteers participating in
these studies were re-consented using IIRB-approved documents, but not all were. Although it is
unlikely that these changes knowingly and/or seriously impaired the informed consent process,
enrollment of participants using unapproved protocols and consent forms represents a significant
and serious departure from accepted review and approval practices. The failure of Carroll-Loye
Biological Research to 1) obtain IRB approval of the revised protocol and consent forms prior to
enrollment of study participants, and 2) report these deviations to IIRB, are serious regulatory
breaches.
Second, the ILRB-approved protocol and consent documents specifically stated that they
are to be conducted only in areas where known vector-borne diseases have not been detected by
county and state health or vector/mosquito control agencies for at least one month. One sentinel
poultry flock in Butte County, however, did test positive for West Nile Virus during the month
prior to conduct of the field studies (Carroll 2007b, 10). Sentinel flocks closer to the three study
sites did not test positive for arboviruses during this period, and a leading vector control
ecologist consulted by Carroll-Loye reported that “WNV activity in Northern California [ was]
effectively concluded for 2006” (Carroll 2007b, 10), so it is unlikely that participant safety was
compromised in any significant way. Nevertheless, initiation of field studies following the
detection of West Nile Virus in a sentinel chicken flock represents another deviation from the
approved protocol.
At the January 2007 meeting, the Board recommended that Carroll-Loye Biological
Research report these two deviations to the IIRB as soon as possible and work with that
organization to develop and implement a corrective course of action (EPA HSRB 2007). From
comments to the Board by Dr. Carroll at the April 2007 meeting, it appeared that these
deviations have since been reported to the IIRB and appropriate corrective actions taken.
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Finally, even though three IR-3535-untreated controls were enrolled in the study, the
IIRB-approved consent documents provided for review do not list the unique risks that these
volunteers faced. These participants were “experienced” personnel who were likely aware of
these risks, but nonetheless should have been consented using documents that listed these
dangers.
HSRB Consensus and Rationale
The Board concurred with the initial assessment of the Agency that the completed study
submitted for review by the Board meets the applicable requirements of §40CFR26, subparts K
and L.
Mosquito Repellent Efficacy Protocol WPC-OO1
Charge to the Board
a. If the proposed research described in Protocol WPC-OO 1 from Carroll-Loye Biological
Research is revised as suggested in EPA’s review, does the research appear likely to generate
scientifically reliable data, useful for assessing the efficacy of the test substances for repelling
mosquitoes?
Board Response to the Charge
This protocol intends to test the mosquito repellent efficacy of a new formulation containing
reduced concentration of an active ingredient oil of lemon eucalyptus. The issue then is not
really a concern for product safety since (1) EPA does seem to have relevant data for the product
with higher concentration and (ii) there is no indication of other ingredients being added or
altered in this newer formulation. In this regard, the protocol justifies the need for a human
study to reliably assess the efficacy of this newer formulation. The proposed studies are
essentially un-blinded, to be conducted in two sites.
The various essential elements of the protocol relating to study rationale, dose selection,
endpoint selection, and methods are described adequately, and appear appropriate.
Concerns/limitations regarding participant selection and statistical analysis remain, however.
• Sample size: From the standpoint of statistical power, ten treated and two untreated subject
as a sample size sufficient to demonstrate a significant treatment effect at P
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for the CPT and the one based on the first LIBE without the confirmation within 30 minutes
as a sensitivity analysis on the CPT definition.
• Statistical analysis: Using the standard that a distribution in which the mean is greater than
three standard deviations above zero may be regarded as effectively normal, it is sensible to
compute and report the normal 95% confidence interval in this study.
• Dose: The dosimetry computed should be compared with toxicology benchmarks to ensure
that the investigator is not proceeding with the efficacy testing (even though the Board does
not expect unusual results) — doing dosimetry and applying those in further studies without
knowing how the applied dose compares to the toxicology/safety benchmark doses.
HSRB Conclusion and Rationale
The Board raised several concerns about sample size, sample size considerations for
dropouts, statistical analysis and dose for WPC-O01 that should be addressed. If the
recommendations provided by EPA and those suggested by the Board are followed, protocol
WPC-001 appears likely to generate scientifically valid data to assess the efficacy of the test
products against mosquitoes. In addition, the protocol would satisfy the scientific criteria
recommended by the HSRB, namely, producing important information that cannot be obtained
except by research with human subjects, and having a clear scientific objective and study design
that should produce adequate data to test the hypothesis.
Charge to the Board
b. If the proposed research described in Protocol WPC-0O1 from Carroll-Loye Biological
Research is revised as suggested in EPA’s review, does the research appear to meet the
applicable requirements of 40 CFR part 26, subparts K and L?
Board Response to the Charge
The Board concurred with the factual observations of the ethical strengths and
weaknesses of the protocol, as described in the EPA’s Ethics Review. In general, the Board
concluded that the research proposed in WPC-00 1, with minor revisions, would meet the
applicable requirements of 40 CFR Part 26, subparts K and L.
The risks to study participants are minimal and have been minimized appropriately.
These risks are justified by the likely societal benefits of the study, including the generation of
data on the efficacy of a eucalyptus-based insect repellent that may be viewed by many as an
important alternative for individuals sensitive to the smell of other commercially available
mosquito repellents. Safety monitoring procedures are in place for the management of possible
side effects or adverse events
While the Board was generally supportive of the proposed research, it did raise several
concerns. First, as noted by the Board at its January 2007 meeting concerning similar research by
Dr. Carroll, the selection of field sites continues to be an issue.
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To minimize the risk that study participants would be exposed to arthropod-borne illness,
field tests ideally should be conducted only in areas where known vector-borne diseases have not
been detected by county and/or state health or vector-control agencies for at least one month. If
there is uncertainty as to whether vector-borne illness are present in the geographic region where
field studies are to be conducted (e.g., arthropod-borne illnesses have been detected previously at
a distant site but state or local vector-control authorities have determined that the seasonal
transmission of these diseases is effectively concluded), it is recommended that investigators trap
landing mosquitoes or other vectors for pooled serologic or nucleic acid-based testing. Such
testing would allow research participants to be warned of their potential exposure to vector-borne
pathogens, and allow them to seek appropriate testing and treatment if necessary.
Secondly, the Board expressed concerns about plans to recruit research subjects in
Florida, as these recruitment procedures were not described adequately in the protocol and
supporting materials. If the investigators do not plan to recruit research subjects in Florida, this
change should be made in the protocol and consent materials.
Finally, the Board raised questions about the informed consent procedures for control
subjects. Since control subjects would be presented with higher risks than treated subjects, the
informed consent procedures should modified to more clearly explain the risks to control
(untreated) research subjects.
HSRB Consensus and Rationale
The Board concurred with the initial assessment of the Agency that, with minor revision,
the protocol WPC-0O1 submitted for review would met the applicable requirements of
§40CFR26, subparts K and L.
Research Conducted After April 7, 2006: Meaning of “Substantial Compliance” with 40
CFR Part 26
Board Discussion
As requested by the Board, the Agency discussed its approach to interpreting and
applying the standard in 40 CFR §26.1705: “. . . EPA shall not rely on data from any research
initiated after April 7, 2006, unless EPA has adequate information to determine that the research
was conducted in substantial compliance with [ EPA’s human studies rules].” The Board
appreciated the Agency’s explanation of the term “substantial compliance” and raised several
points for consideration. In determining whether the research being reviewed by the Board was
conducted in substantial compliance with the Agency’s human studies rule, it is important to
differentiate between ethical and regulatory deficiencies. Substantial compliance is a term that
applies to the extent to which a study is in accord with EPA regulations. The likely or actual risk
of harm created by a lack of compliance is important in determining whether the study fails to
meet the “substantial compliance” criteria. In addressing this point, the Board also focused on the
issue of investigator intent. While considering the investigator’s intent may allow the Board to
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evaluate the nature and consequences of rule violations, it is difficult for the Board, or for that
matter the Agency, to realistically ascertain the actual intent of investigator. In addition, it
would be unrealistic for the Board to determine an investigator’s past conduct. Finally, the
Board acknowledged that many protocols will have minor errors (e.g. typographical errors) and
flexibility should be taken into account for such studies with minor deficiencies.
Completed Patch Test Studies
Part I. 48-Hour Dermal Irritation Patch Test
Charge to the Board
a. Is this study sufficiently sound, from a scientific perspective, to be used as part of a weight-
of-evidence assessment to evaluate the potential of the formulations tested to irritate human
skin?
Board Response
Critiaue of Study
Two spray insect repellent products were evaluated for skin irritation through 48-hour
patch testing. Product A contained 11 ingredients (including the active ingredient): previous
animal studies indicated that eight of these ingredients were mild or slight irritants (Category
IV), and three were moderate irritants (Category ifi). Product B contained 10 ingredients:
previous animal studies indicated that seven of these ingredients were mild or slight irritants
(Category IV), and three were moderate irritants (Category Ill). The Agency had indicated to the
sponsor that these products would be given a Category Ill classification. The sponsor believed
that the products should be classified as Category LV.
The primary concerns raised by the Agency regarding these studies focused on the
finding that I) the test product was applied to the patch and then air dried for 30 minutes, 2)
some subjects still showed reactions at 72-hours, and 3) the study did not include negative
control data to allow a more complete interpretation of these findings. The Agency Data
Evaluation Record concluded that these human patch studies were “incomplete and cannot be
used as part of the evidence in classif ’ing the irritancy of Products A and B.” However, in its
oral presentation to the Board at the April 2007 HSRB meeting, the Agency concluded that the
data were “sufficiently reliable to be used in conjunction with other information on the irritancy
potential of product ingredients to support the conclusion that these formulations do not cause
more than mild skin irritation.”
General Scientific Criteria
This study appeared to have been conducted in a professional manner. The performance
laboratory was TKL Research, Inc. (Paramus, NJ).
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Study Design Criteria
Purpose/objectives
The purpose of the study was clearly stated: to determine the ability of two experimental
insect repellent products to cause an immediate irritation by topical application to the skin of
humans under controlled patch study conditions. It appeared that the sponsor’s specific objective
was to determine whether these products should be assigned to Category III or Category IV in
regard to dermal irritation.
Design
The study involved simultaneous application of five products. The Agency received
results for only two of the five products. The sponsor indicated in a supplementary submission
that the “remaining three (3) test materials were R&D samples.” The Agency stated in its oral
remarks that the use of “multi-material, multi-sponsor patch studies” is common practice in
cosmetics and consumer products testing. The Agency concluded that the presence of the other
three test materials did not interfere with the results reported for Products A and B. The Board
concurred with the Agency in the case of dermal irritation studies such as this one.
The study extended over a 4-day period. On day 1, the patches were applied to the
infrascapular area of the back, either to the right or left of the midline. Material evaluated under
occlusive patch conditions was applied to a 2 cm x 2 cm Webril pad attached to a non-porous,
plastic film adhesive bandage, and the patch was secured with hypoallergenic tape as needed.
Forty-eight hours after application, the patches were removed. The sites were evaluated 48 and
72 hours after application for skin response.
The study was conducted without negative controls. That is, all of the skin sites evaluated
had been treated, so the evaluator was not blinded in this study. Also, the absence of negative
controls meant that the investigators were not able to determine whether or not observed minimal
or doubtful responses were artifacts associated with untreated patch occlusion. The absence of
negative controls deviated from the Cosmetic, Toiletry, and Fragrance Association Safety
Testing Guidelines.
Sample size
The sample size goal was 50. Fifty-four subjects were enrolled, and 53 completed the
study. No rationale was provided for the sample size. The investigators stated that this was a
“usual” number, with no further explanation. Considering that the Agency guidance for animal
studies requires only three animals, a sample size of 50 seemed adequate for the purposes of the
study.
Dose levels
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The tests involved a single dose level of approximately 50 mg/cm 2 . This level was 25%
higher than the level recommended by the Agency for animal studies. However, it was not clear
whether this loading level was representative of anticipated consumer use.
ParticiDation Criteria
No rationale was provided by the sponsor for the preponderance of female participants
(48 out of 54). Thus, the emphasis on female participants may make the results from the study
not generalizable to potential male users of the test materials.
The study excluded individuals considered to be sensitive to irritation; i.e., those who
were taking particular drugs or who had a known sensitivity to cosmetics, skin care products,
insect repellents, or “topical drugs as related to the material being evaluated.” The qualifier “as
related to the material being evaluated” was unclear. No information was provided regarding the
number of individuals who were excluded based on these criteria. Also, no information was
provided regarding the fraction of the general population who fall into these exclusion
categories. These exclusions raise questions as to the representative of the study population.
Should people in these categories not use these products? Will such cautions be on the label?
Measurement Criteria
The Agency provided test guidance for dermal irritation studies in animals (OPPTS
870.2500), but has not developed a guidance document for human studies. An occlusive patch
test method was used for these studies. This approach was similar to the Agency’s guidance for
animal studies. The products were applied to the patches, and the patches were then applied to
the backs of subjects for 48 hours. This approach was similar to the guidance that the Agency
provided for animal studies. However, the investigators provided no rationale for selection of
this method or for the specific procedures involved in the study, nor do they cite a reference for a
standard method.
Test materials were air-dried for 30 minutes before applying the patches to the designated
skin areas. Air-drying the patches before application to the skin is likely to diminish the irritancy
of the test materials substantially.
The investigators provided a detailed description of irritancy evaluation: evaluations
occurred at the time the patch was removed (48 hours) and again at 72 hours. They stated in their
protocol (p.35), “all responses will be graded by a trained dermatologic evaluator”. However, the
final report did not provide any information about the evaluator. The study was conducted
without negative controls. That is, all of the skin sites evaluated had been treated. Thus, the
evaluator was not blinded in this study.
At 48 hours three of 54 subjects for Product A and four of 54 subjects for Product B were
assigned a score of 1.0 (definite erythema, no edema). All of these subjects had reversed to a
score of 0.5 (minimal or doubtful response, slightly different from surrounding skin) at 72 hours.
At 72 hours 13 subjects for Product A and 18 subjects for Product B of 53 were assigned a score
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of 0.5, including those who had reversed from 1.0. Thus, all responses persisting at 72 hours
were graded “minimal” or “doubtful.”
Statistical Analysis Criteria
A weighted average of irritancy scores was calculated for each product. No other
statistical procedures were used.
The Primary Irritation Index should have been estimated with a notion of its variability
such as a 95% confidence interval. Perhaps better yet the maximum response score should be
used in determining the irritancy of the test materials as illustrated by the following example:
With 1000718-008, three out of 54 tested subjects experienced “definite erythema”
reaction. This gives a point estimate of 0.056 for the probability of “definite erythema” response
with a 95% one-sided upper confidence limit of 0.137, indicating that the probability of definite
erythema reaction can be as high as 0.137. With 1004006-005, four out of 54 tested subjects
experienced “definite erytifema” reaction. This gives a point estimate of 0.074 for the
probability of “definite erythema” response with a 95% one-sided upper confidence limit of
0.162, indicating that the probability of definite erythema reaction can be as high as 0.162.
Laboratory Conditions
Laboratory conditions appeared to be adequate. Statements regarding good clinical
practices and quality assurance were included in the protocol.
HSRB Consensus and Rationale
The Board concluded that the study was sufficiently sound, from a scientific perspective,
to be used as part of a weight-of-evidence assessment to evaluate the potential of the
formulations tested to irritate human skin.
The HSRB concluded that extension of the evaluation period beyond 72 hours would
have been desirable in this case, but the Board does not view the study as incomplete because
observation did not go beyond 72 hours. The European Commission’s Scientific Committee on
Consumer Products produced a memorandum in September 2005, after the studies under review
had been completed, indicating that observation at two days (48 hours) and at 3/4 days (72/96
hours) is an acceptable practice.
The presence of 0.5 scores at 72 hours raised some question as to whether irritant
reactions had fully reversed. However, the fact that all 1.0 scores at 48 hours reversed to 0.5 at
72 hours suggested to the Board that application of these products resulted in minimal response
in this population.
Charge to the Board
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b. Is there clear and convincing evidence that the conduct of this study was fundamentally
unethical or significantly deficient relative to the ethical standards prevailing at the time the
research was conducted?
Board Response
Brief Overview of the Study
Because of claims of confidential business information (CBI), the documents for this
study were provided to the HSRB in redacted form by the submitter, as product A in one
submission and product B in a separate submission. The two product submissions were
considered together, because they were conducted as a single study. While this study was
conducted in April 2005, 40 CFR 26.1303 applies because documentation was submitted in May
and November 2006. Because the study was initiated before April 7, 2006, pre-review of the
protocol was not required and applicable ethical standards are 40 CFR 26.1703 and 26.1704.
The purpose of this study was to determine the ability of products A and B insect
repellents to cause immediate irritation by topical application to the skin of humans under
controlled patch study conditions. The submitter requested a waiver of the usual animal testing
of dermal irritation because it has a submitter’s policy to avoid unnecessary use of animals in
testing, and because the ingredients are all well known to EPA and have extensive animal testing
literature. The study actually tested five products, but is only submitting results from two of the
products. Products A and B are both repellents containing the same EPA-registered active
ingredient at concentrations within a previously accepted range, and contain similar pesticide
inert ingredients. During public comment, representatives of TKL Laboratories indicated that the
three other products are R&D samples. According to documents submitted, this particular study
design is intended to identify strong irritants, and may not be able to identify weak irritants.
The study was performed at a laboratory site by TKL Research Inc in Paramus, New
Jersey on April 26-29, 2005. The documents provided specifically stated that the study was
conducted in compliance with the requirements of the EPA’s Good Laboratory Practice
regulations (40 CRF 160) and of the Food and Drug Administration (21 CFR 312, 50, and 56).
The study was also reviewed and approved by a commercial institutional review board (IRB),
Allendale IRB of Allendale, NJ. Documentation provided to the EPA by Allendale IRB indicated
that it reviewed these studies pursuant to the regulations of the US FDA (21 CFR 50 and 56), as
well as those of “HEW, NIH (LRB Registration #1RB00003787), CPSC and EPA regulations and
follows all relevant guidance available from these Agencies for the protection of human
subjects.”
As submitted to the EPA, the completed study consisted of a one-time exposure of
subjects to two insect-repellent products and three other R & D samples. At the first study visit,
the test articles were each placed on a separate designated site on the infrascapular area of the
back of study participants. Each test article (“approximately 0.2 mL or g of study material”) was
placed on a 2 cm x 2 cm Webril pad, allowed to air dry for 30 minutes, and then placed on the
skin using an occlusive dressing. Forty-eight hours after application, the patches were removed
and the area was examined for signs of dermal irritation. Any irritation was graded by a “trained
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dermatologic evaluator meeting TKL’s strict certification requirements to standardize the
assignment of response grades”. The standardized rating of response was described in the
protocol. At a third study visit at 72 hours after application, the exposed areas were again
examined for irritation.
While the protocol refers to a telephone recruitment scheme using a “Phone Screener
Questionnaire” provided in the submitted documents, clarification from representatives of TKL
revealed that study participants were recruited as they completed another study at TKL
Laboratories. Participants (healthy volunteers who were non-pregnant, non-nursing and at least
18 years of age.) were paid $30 upon completion of the study. There was a convenience sample
of 54 volunteers enrolled in the study, and one withdrew from participation, leaving 53
participants. Volunteers were predominately white, middle-aged and female.
The scientific strengths and weaknesses of the study design and implementation, as well
as those of the data analysis and interpretation, are described above. During the scientific review
of the protocol, concerns were raised about the ability of the study, as designed, to identify weak
irritants. Scientific validity is a requirement of ethical research; if this study is unable to identify
weak irritants and achieve its stated purpose, no amount of risk to subjects would have been
ethically justifiable.
Critique of Study
The Board concurred with the factual observations of the ethical strengths and
weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2007d). While the
documents submitted were sufficient to support adequate review of a study conducted prior to
promulgation of the EPA’s Final Human Studies Rule, the cursory discussions of risk, risk
minimization, benefits, and risk/benefit contained therein would not be acceptable for a study
begun after April 2006 and thus submitted for prospective review.
While the risks of this study appeared to be low and no participants were reportedly
harmed, the HSRB had several concerns about the review and conduct of the trial:
1. Recruitment and enrollment of subjects: recruitment and enrollment of subjects, as described,
was confusing and of considerable concern. Recruitment was of a convenience sample of
subjects who were completing another study at TKL Laboratories. The protocol included a
telephone screening script/questionnaire that offered a “referral fee” of $25 for “referring any
‘new’ participant that completes his/her ‘first’ patch study at TKL”. The Board was concerned
about the potentially coercive nature of this finder’s fee that might discourage voluntariness in
participation or withdrawal from the study by the ‘new’ participant.
Enrollment of subjects must occur after the subject had provided consent to participate.
This study used a screening interview to assess eligibility, after which the consent process
occurred. The Board was concerned about the collection of personally identifiable private
information prior to the consent process.
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2. Risks to subjects: The risks associated with participation were described to study participants
in generic terms; the risks for the 48 hour irritation study and RIPT study (see below) were
described identically, even though the RIFT study included many repeated applications
compared to the single application of the study discussed in this report. In addition, the same
risks are indicated for all five test articles used in the study. However, the Board had concerns
since only information regarding the risks of the two articles under consideration was submitted
to EPA for review. The Board could not determine nor confirm whether sufficient risk
information about the other three test articles used in the study but not submitted for EPA review
was provided to AIRB. Thus this raised concerns about research subjects protections.
The informed consent form stated that allergic reactions are possible, and that
“ [ w]henever possible, you will be informed as to the identity of the material in order that you
may avoid contact with it in the future.” The Board was concerned about any situation when it
might not be possible to inform the subject of the identity of a material to which he/she had an
allergic reaction.
The Board was concerned about inadequate justification for use of humans in this
research. While the active ingredients have undergone extensive animal testing, the combination
products apparently have not. The only rationale provided by the submitter for testing the
combination in humans is a policy of avoiding unnecessary experimentation with animals and
thus the sponsor chose not to do the usual studies in animals prior to testing it in humans. The
Board felt that with respect to federal regulations this argument alone provides insufficient
justification for exposure of human participants to potential risk.
3. Confidentiality: The informed consent form contained language that is required by the HIPAA
Privacy Rule. However, TKL is not a HIPAA-covered entity; this language is not required and
the rule does not apply. While any IRB may have requirements that are more stringent than the
regulations require, there was no documentation in the IRB’s SOPs that compliance with the
HIPAA Privacy Rule is required of all protocols. Furthermore, the inclusion of inapplicable,
I-IIPAA-speciflc language about retention and use of personal health information after
withdrawal from the study may lead some participants to believe erroneously that use of their
private medical information will continue, and might discourage requests from participants that
such data not be kept.
4. Subject remuneration: Subjects received $30 at the completion of their participation in the
study. This may unduly influence subjects not to withdraw from participation. Although
Allendale LRB stated in their SOPs that they comply with regulations and guidances from FDA
as well as other agencies, they did not follow FDA’s guidance for pro-rating payment should
subjects withdraw from participation prior to completion.
5. Allendale IRB: While the submitted documentation of IRB composition, procedures, and
review met regulatory requirements, the Board had several concerns about the independence of
the Allendale IRB and the nature of its review process. For example, many of the IRB members
seem to be related to each other, based on their last names; this brings into question the
independence of the members from each other. The IRB minutes that were submitted to EPA
were not readable, consisting of only a few illegible, handwritten remarks. The IRB approval
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letter dated 4/21/05 indicated that the study was approved, stating that “ [ w]ithout any substantive
changes, the Board agrees to the conduct of this protocol”, yet the approval letter also asks for
clarifications. While the Allendale IRB SOPs stated that “AIRB requests for minor changes or
documents that are judged to have no or minimal impact on safety to the subjects will be
requested of the sponsor without delaying study initiation,” this may be a regulatory violation.
This is certainly inconsistent with regulations and guidances that the Allendale IRB stated that it
follows; IRB approval requires that all criteria (45 CRF 46.111 and 21 CFR 56.111) be met, not
just those criteria relating to subject safety. Finally, the completeness of IRB review is in
question. If, in fact, this study design is unable to identify weak irritants, then the research
purpose cannot be achieved, and thus no risk to subjects would have been justifiable. It does not
appear that the IRB considered this issue in its deliberations.
6. Research-related injuries were described in the informed consent form as “any significant
reactions that may occur as a direct result of your participation in this study,” for which
“appropriate and reasonable medical treatment will be provided by TKL Research, Inc at no cost
to you to relieve the immediate problem.” The Board questioned the appropriateness of such
indemnifying language, raising concerns about who would determine what constituted a
significant reaction, what was considered appropriate and reasonable medical treatment, why
TKL Research (rather than a hospital or independent physician) would provide the treatment, and
why the treatment was limited solely to relief of the immediate problem rather than include
treatment for the entire problem.
HSRB Consensus and Rationale
The Board concluded that there was no clear and convincing evidence that the conduct of
the research was fundamentally unethical (e.g., the research was intended to seriously harm
participants or f iled to obtain informed consent). There was no clear and convincing evidence
that the conduct of the study was significantly deficient relative to the ethical standards
prevailing when the study was conducted.
The Board concluded that this study, based on the evidence presented, deviated from, but
was not significantly deficient relative to, the ethical standards prevailing when the study was
conducted.
Part II. Repeated Insult Patch Test
Charge to the Board
a. Is this study sufficiently sound, from a scientific perspective, to be used to be used as part of
a weight-of-evidence assessment to evaluate the potential of the formulations tested to cause
sensitization of human skin?
Board Response
Critique of Study
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Two insect repellent products were evaluated for skin sensitization in humans using a
repeat insult patch test (RIPT) method. Product A contained ii ingredients (including the active
ingredient) which are found in one or more of 16 previously registered products, and Product B
contained 10 ingredients used in the same previously registered products. These studies included
three phases: induction, rest, and challenge.
The Agency expressed several concerns regarding the scientific aspects of these RIPT
studies in its Data Evaluation Record.
First, there is extensive human experience with many of the components of the two insect
repellent products either in cosmetics or in foods, so the subjects participating in the patch
studies may already have been exposed to the product components.
Second, the test items were not applied directly to the subjects’ skin. Instead, the products
were applied to patches, and volatile components were allowed to evaporate before the patches
were placed on the subjects’ skin. This procedure was viewed as inconsistent with typical use of
the products. The Agency noted that these repellent products are supposed to form a water-
resistant coating on the skin. It was therefore unclear how the experimental procedures might
have altered absorption of the active ingredient or any of the other components of the products.
Third, although the scoring system used in the RIPT study was generally similar to that
used in the guinea pig maximization test (GPMT), the results at challenge in the GPMT are
compared to both responses of sham-treated control animals and responses seen during the initial
induction phase of the study. This approach was viewed by the Agency as probably more
effective for distinguishing irritation from sensitization responses than the method used in the
RITP study.
Fourth, the animal data on the components suggested that any sensitization that might
occur with dermal exposure to the two products would probably be weak. The RIPT method was
viewed as less likely than a GPMT or a local lymph node assay (LLNA) to detect such low-grade
responses. In fact, only one of the 210 subjects showed a definite response (rated as definite
erythema without edema) after the second exposure to both products, and this response did not
appear at any other observation time. The Agency acknowledged that the RIPT study data could
be viewed as supportive of the investigators’ conclusion that neither product is a sensitizer, but
the Agency concluded that there was uncertainty regarding the adequacy of the RIPT method.
General Scientific Criteria
The performing laboratory was TKL Research, Inc.
Study Desian Criteria
Purpose/objectives
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The purpose of the study was clearly stated: to confirm the inference of non-sensitization
from the animal evidence for each of the components.
Sample size
The sample size goal stated in the report was 200. The study enrolled 246 subjects, and
210 subjects completed the study. No rationale was provided for the sample size. No sampling
frame was presented, and the representativeness of the sample was not addressed. No control
subjects were included in these studies. Also, the subjects were divided into two cohorts, and two
separate but apparently identical studies were then conducted. No rationale was provided for this
aspect of the study design.
Dose levels
A volume of 0.2 ml of the test material was applied to a 2 x 2 cm. gauze pad attached to a
non-porous plastic film adhesive bandage (occlusive patch). Volatile components of each
product were allowed to evaporate from treated patches for 30 minutes prior to application to the
subject’s skin. Patches were secured with hypoallergenic tape to marked test sites on the
infrascapular area of the back, to the right or left of the midline, or to the upper arm. The
application rate on the patch was 0.05 mI/cm 2 (approximately 50 mg/cm 2 ).
No rationale was provided for the loading level selected. It was not clear how the selected
level compared with loading levels that would be typical among consumers using these products.
Participation Criteria
Male and female volunteers selected to participate in the study were at least 18 years old
and in generally good health. They were free of any systemic or dermatologic disorder that
would interfere with the results of the study or increase the risk of adverse events. Participants
were of any skin type or race, so long as the skin pigmentation allowed discernment of erythema.
Those volunteers selected for the study also completed a medical screening procedure and signed
an informed consent document. Volunteers were excluded from participation if they had any
visible skin disease that would interfere with the evaluation, if they were receiving systemic or
topical medication that would interfere with the study results, or if they had psoriasis or active
atopic dermatitis or eczema. Those who were pregnant, planned to become pregnant during the
study, or were breast-feeding were excluded as well. Finally, volunteers were excluded if they
had a known sensitivity to cosmetics, skin care products, insect repellents, or topical drugs as
related to the material being evaluated, or if they were participating in another study at the same
time.
The resulting sample seemed to be unbalanced in several ways that might have been
relevant for the response variable. Both cohorts had an excess of females, and the second cohort
included over 30% Hispanics. If gender and/or ethnicity happen to be associated with the
probability of a response to the product, then conclusions from these studies may not be
applicable to the general population.
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Measurement Criteria
The induction phase lasted three weeks, followed by a 10-15 day resting phase, followed
by a challenge phase. The induction phase consisted of 9 consecutive applications (every 48 to
72 hours) at the same test site. Skin reactions at test sites were evaluated 48 hours after the
preceding application. The next patch was applied immediately after reactions were noted.
Patches applied on Fridays were removed by the subject 24 hours afterward, and the test site was
not evaluated until the following Monday (72 hours post-application). Following the 9th
application the subjects were dismissed for the 10-15 day rest period. In the challenge phase,
patches were applied to previously unexposed test sites. Skin reactions were evaluated 48 and 72
hours after application. If evidence of a sensitization response was noted, the subject was re-
challenged to confirm the reaction. For both the induction and challenge phase, similar to the
Agency, the Board could not determine whether patches were removed 24 hours after application
by the subject or were removed 48-72 hours after application by the investigator (except on
Friday when patches were removed 24 hours after application by the subject).
Sensitization is characterized by an acute allergic contact dermatitis. Typical sensitization
reactions begin with an immunologic response in the dermis resulting in erythema, edema
formation, and secondary epidermal damage (vesiculation), sometimes extending beyond the
patch site and often accompanied by itching. Sensitization reactions tend to be delayed. The
reaction typically becomes evident between 24 and 48 hours, peaks at 48-72 hours and
subsequently subsides. The reaction is often greater at 72 hours than at 48 hours. The severity
of the reaction is generally greater during the challenge phase of a RIFT study than that seen
during induction.
The two cohorts were studied at different times and different locations. Since factors
external to the material of interest (e.g., weather conditions, pollution levels) may have a general
effect on subjects’ propensity to respond to any number of “insulting” agents, it would have been
important to have determined whether conditions under which both cohorts were studied were
comparable.
The study procedure called for application of the products to patches rather than directly
to the skin. Volatile components were allowed to evaporate before the patches were placed on
the subjects’ skin. It was not clear if this procedure resulted in an exposure representative of the
typical use of the products. The extent to which the experimental procedures might have altered
absorption of the active ingredient or any of the other components of the products was not
documented.
It appeared that the number of categories used in the scoring scale greatly exceeded those
used typically in animal studies. There is some question as to whether a scorer, even if trained,
could make meaningflul distinctions among all of the possible levels of erythema, edema, and
vesiculation described in these studies. The relationship between technicians and subjects was
not described clearly, and was not known whether any attempt was made to randomize subjects
across technicians.
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Statistical Analysis Criteria
Results reported were exclusively from a descriptive point of view. No mention is made
of any statistical analysis whatsoever. Given the type of data obtained and the fact that the
quantity of interest was the probability of a reaction to the product, one possible approach for the
analysis could have been the following:
> Let be the number of subjects at time t, I = 1 , 9 who react to the product
out of n, subjects exposed. Since y, can take on the values 0 (no reaction) or 1 (some
reaction), we can model it as a binomial random variable
B(p,, n,)
Where p, is the probability of a reaction in the tth induction phase application.
> We can then let the logit of the probability of the reaction depend on time T in a
linear fashion:
1ogit(p ) = b 0 + b, T
> The simple model described here provides a means to test, for example, whether the
probability of a reaction increases with the number of applications.
Laboratory Conditions
Laboratory conditions appeared to be adequate. Statements regarding good clinical
practices and quality assurance were included in the protocol.
HSRB Consensus and Rationale
The HSRB concluded that the RIPT studies provided an inadequate description of
methods, and a limited analysis of results. The choice of sample size was not explained, the
representativeness of the sample was questionable and studies overall appeared to be of poor
quality based on the material provided for review. The Board concluded that these studies
provided little, if any, useful knowledge for the Agency to include in a weight-of-evidence
assessment to evaluate the potential of the formulations tested to cause sensitization of human
skin.
Charge to the Board
b. Is there clear and convincing evidence that the conduct of this study was fundamentally
unethical or significantly deficient relative to the ethical standards prevailing at the time the
research was conducted?
Board Response
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Brief Overview of the Study
While this study was conducted in May-July 2005, 40 CFR 26.1303 applies because
documentation was submitted in May and November 2006. Because the study was initiated
before April 7, 2006, pre-review of the protocol was not required and applicable .ethical
standards are 40 CFR26.1703 and 26.1704.
The purpose of this study was to determine the ability of insect repellent products A and
B to cause sensitization by repeated applications to the skin of healthy human volunteers under
controlled patch study conditions. The submitter requested a waiver of the usual animal testing
of dermal sensitization because it has a submitter’s policy to avoid unnecessary use of animals in
testing, and because the ingredients are all well known to EPA and have extensive animal testing
literature. The study actually tested multiple products, but the results from only two of the
products were submitted to the EPA for review. Products A and B were both repellents
containing the same EPA-registered active ingredient at concentrations within a previously
accepted range, and contain similar pesticide inert ingredients. During public comment,
representatives of TKL Laboratories indicated that the other products are currently marketed
cosmetic products.
The study was performed at a laboratory site by TKL Research Inc in Parainus and
Lyndhurst, New Jersey from May 16-July 14, 2005. The documents provided specifically stated
that the study was conducted in compliance the requirements of the Food and Drug
Administration regulations (21 CFR 312, 50, and 56). The study was also reviewed and approved
by a commercial human subjects review committee, Allendale LRB of Allendale, NJ.
Documentation provided to the EPA by Allendale IRB indicated that it reviewed these studies
pursuant to the regulations of the US FDA (21 CFR 50 and 56), as well as those of “HEW, NIH
(IRE Registration #1RB00003787), CPSC and EPA regulations and follows all relevant guidance
available from these Agencies for the protection of human subjects.”
As submitted to the EPA, the completed study tested the same products (products A and
B) as those described for the 48-hour Primary Dermal Irritation Study. Sodium lauryl sulfate
was included as a positive control. Products A and B were both repellents and contained the
same EPA-registered active ingredient(s) and similar pesticidal inert ingredients. The two
submitted study reports each described results for one of 15 or 16 substances tested in two
parallel executions of the protocol using two sub-panels of subjects. The sponsor’s three patches
are reported to have remained in place for 24-72 hours (there is inconsistency within and
throughout the documents); all other patches were removed by subjects after 24 hours. Both
protocols used a single patch containing sodium lauryl sulfate as a “compliance check;” this
reflects use of a known concentration of a weak irritant to ensure that patches were not removed
early. There were 13 scheduled study visits for this protocol. Target enrollment was 200 to
complete the study.
The test encompassed three phases. The induction phase involved nine consecutive
applications of patches and readings of patch sites, occurring on Monday, Wednesday, and
Friday over the course of 3 weeks. This was followed by a rest period of 10 to 15 days, and then
by a challenge phase, in which identical patccies were applied to naïve sites and read after 48 and
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72 hours. During weeks 4 through 6 of the protocol, the subjects could miss application of one
patch and receive a “make-up” patch.
At the first study visit, the test articles were each placed on a separate designated site on
the infrascapular area of the back or on the arm of study participants. Each test article
(“approximately 0.2 mL or g of study material”) was placed on a 2 cm x 2 cm Webril pad,
allowed to air dry for 30 minutes, and then placed on the skin using an occlusive dressing. At a
subsequent study, the patches for the two products of interest were removed and the area was
examined for signs of dermal irritation. Any irritation was graded by a “trained dermatologic
evaluator meeting TKL’s strict certification requirements to standardize the assignment of
response grades”. The standardized rating of response was described in the protocol. A new set
of patches was then applied.
The protocol described a telephone recruitment scheme using a “Phone Screener
Questionnaire” provided in the submitted documents. Participants (healthy volunteers who were
non-pregnant, non-nursing and at least 18 years of age.) were paid $110 upon completion of the
study. There was a convenience sample of 246 research volunteers enrolled in the study; 210
participants completed the study. Study participants were predominately white, middle-aged and
female.
The scientific strengths and weaknesses of the study design and implementation, as well
as those of the data analysis and interpretation, are described above. If this human study design is
less able to identify weak reactions than are animal studies, then there may have been no
justifiable reason to perform this human study.
Critique of Study
Having no information concerning the other test articles used in the study but not
submitted for EPA review, the Board had limited confidence in the adequacy of informed
consent information. In fact, it appears that the IRB did not have specific information concerning
any of the other test materials used in the study, only that they were generally cosmetic products.
Thus it would have been impossible for the IRB to thoroughly and adequately review the study.
The Board concurred with the factual observations of the ethical strengths and
weaknesses of the study, as detailed in the EPA’s Ethics Review (Carley 2007c). While the
documents submitted were sufficient to allow the Board to adequately review this study
conducted prior to promulgation of the EPA’s Final Human Studies Rule, the cursory discussions
of risk, risk minimization, benefits, and risk/benefit contained therein would not be acceptable
for a study begun after April 2006 and thus submitted for prospective review.
While the risks of this study appeared to be low and no participants were reportedly
harmed, the HSRB had several concerns about the review and conduct of the trial:
I. Recruitment and enrollment of participants: recruitment and enrollment of participants, as
described, was confusing and of considerable concern.
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Enrollment of participants must occur after the volunteer has provided consent to
participate. This study used a screening interview/questionnaire to assess eligibility, after which
the consent process occurred. The Board was concerned about the collection of personal
identifiable private information prior to the consent process.
There were two telephone recruitment questionnaires submitted; the telephone
recruitment questionnaire for one of the cohorts referred to “testing fragrances”, which was
deceptive, since the purpose of the study was to test insect repellent products for sensitizing
properties.
2. Risks to participants: The risks associated with participation were described to study
participants in generic terms; the risks for the RIPT study and the 48 hour irritation study were
described identically, even though the RIPT study included many repeated applications
compared to the single application of the 48-hour irritation study. The risks of the many other
products tested were not described to participants in the consent form, nor were they described in
the protocol available for IRB review. The risks of irritation were not adequately differentiated
from the risks of sensitization, the endpoint of this study.
The informed consent form stated that allergic reactions are possible, and that
“ [ w]henever possible, you will be informed as to the identity of the material inorder that you
may avoid contact with it in the future.” The Board was concerned about any situation when it
might not be possible to inform the participant of the identity of a material to which he/she had
an allergic reaction. There was no plan evident to determine when the identity of the material
would be possible, indicating a lack of specificity in the protocol and the consent form, which
could negatively impact participant health and welfare
The Board was concerned about inadequate justification for use of humans in this
research. While the active ingredients have undergone extensive animal testing, the combination
products apparently have not. The only rationale provided by the submitter for performing this
testing in humans is a policy of avoiding unnecessary testing in animals. In addition,
sensitization studies in animals may provide stronger evidence than these sensitization studies in
humans. For this reason, the Board was concerned about the ability of this study to provide
useful information to EPA.
The risksto subjects were only described in the consent form, and not in the protocol that
was submitted to the IRB for its review. The IRB requires a complete description of potential
risks and their magnitude and duration for its deliberations.
The phrase in the consent document that states, “SLS which is a soap solution used as a
control for comparison” is inappropriately assuring and gives an inaccurate description of
procedures and risks. SLS is sodium lauryl sulfate, a strong irritant that is routinely used as a
skin irritant in skin testing. Misleading information in the consent process/form violates the
regulations. The name, nature and purpose of SLS should have been included in the consent
document.
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It appears that for this study the IRE used a “generic” or “one size fits all” type of
consent document rather than a form/process individualized to the particular study and
procedures that a potential subject would encounter. This practice violates regulatory standards
and guidelines. The Board was concerned about inadequate justification for use of humans in this
research. While the active ingredients have undergone extensive animal testing, the combination
products apparently have not. The only rationale provided by the submitter for testing the
combination in humans is a policy of avoiding unnecessary experimentation with animals and
thus the sponsor chose not to do the usual studies in animals prior to testing it in humans. The
Board felt that with respect to federal regulations this argument alone provides insufficient
justification for exposure of human participants to potential risk.
3. Description of research procedures: The consent document does not accurately describe the
procedures used in the research regarding the placement of patches (arms and back). The
consent document does not describe the procedures used in the research regarding patch removal
and reading of the skin reaction. This is a violation of the regulations. According to the report,
patches were placed on Monday, Wednesday and Friday and removed, respectively, on Tuesday,
Thursday and Saturday, i.e., 24 hours later. The readings were taken on Wednesday, Friday and
Monday, i.e., 24 hours after patch removal, or 48 hours for the Monday readings. Different
documents submitted to EPA reported the schedule of events in contradictory ways. A clear and
consistent description of the planned schedule should have been included in the consent
document.
4. Confidentiality: The informed consent form contains language that is required by the HLPAA
Privacy Rule. However, TKL. is not a FLIPAA-covered entity; thus this language is not required
and the rule does not apply. While any [ RB may have requirements that are more stringent than
the regulations require, there is no documentation in the IRB’s SOPs that compliance with the
I-LLPAA Privacy Rule is required of all protocols. Furthermore, the inclusion of inapplicable
HIPAA-speciflc language about retention and use of personal health information after
withdrawal from the study may lead some participants to believe erroneously that use of their
private medical information would continue, and might discourage some volunteers from
requesting that their data not be used if they withdraw from participation.
5. Participant remuneration: Participants received $110 at the completion of their 13 study visits.
This may have unduly influenced volunteers not to withdraw from participation. Although
Allendale [ RB states in their SOPs that they comply with regulation and guidances from FDA as
well as other agencies, they did not follow FDA’s guidance for pro-rating payment should
participants withdraw from participation prior to completion. While public comment from
representatives of TKL stated that participants were given partial payment for partial
participation, the informed consent document that subjects received stated otherwise. The
Board was also concerned that research participants received prorated payment only if they
withdrew for “reasons beyond their personal control,” with TKL being the arbiter of was or was
not an acceptable reason for withdrawal.
6. Allendale [ RB: While the submitted documentation of IRB composition, procedures, and
review meets regulatory requirement, the Board had substantial concerns. Many of the IRE
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members seem to be related to each other, based on their last names. This brings into question
the independence of the members from each other. The procedures of the independent IRB are
not fully compliant with EPA, FDA orHHS regulations (e.g., unanticipated problem reporting).
The IRB minutes that were submitted to EPA were not readable; they consisted of only a few
illegible, handwritten remarks. The IRB approval letter dated 5/12/05 indicated that the study
was approved, stating “ [ w]ithout any substantive changes, the Board agrees to the conduct of this
protocol”, yet asks for clarifications. The Allendale IRB SOPs stated that “AIRB requests for
minor changes or documents that are judged to have no or minimal impact on safety to the
subjects will be requested of the sponsor without delaying study initiation.” This is not
consistent with regulations and guidances that the IRB states in its SOPs that it follows; IRB
approval requires that all criteria (45 CFR 46.111 and 21 CFR 56.111) be met, not just those
criteria relating to subject safety.
Based on information available to the HSRB, the Allendale IRB did not have available to
it any information regarding the test articles other than products A and B. Thus, they could not
have been able to adequately review the risks or discomforts to the participants who were to be
exposed to all of the test articles. In addition, the IRB-approved consent form was deficient in its
discussion of risks and discomforts. For this reason, the HSRB determined that consent was
inadequate as concluded later.
7 Research-related injuries: research related injuries were described in the informed consent
form as “any significant reactions that may occur as a direct result of your participation in this
study,” for which “appropriate and reasonable medical treatment will be provided by TKL
Research, Inc at no cost to you to relieve the immediate problem.” The Board questioned the
appropriateness of such indemnifying language, raising concerns about who would determine
what constituted a significant reaction, what was considered appropriate and reasonable medical
treatment, why TKL Research (rather than a hospital or independent physician) would provide
the treatment, and why the treatment was limited solely to relief of the immediate problem rather
than include treatment for the entire problem. These concerns were unrelated to any information
that was missing due to redaction because of CBI claims.
HSRB Consensus and Rationale
The Board concluded that there was not clear and convincing evidence that the conduct
of the research was fundamentally unethical (e.g., the research was intended to seriously harm
participants or failed to obtain informed consent.
The Board concluded that, because (1) there was insufficient LRB review of all products
to which subjects were asked to agree to be exposed, (2) information concerning research
procedures within the consent form itself was inadequate, and (3) the limited scientific validity
of the study did not produce a positive risk-benefit ratio, there was clear and convincing evidence
that the conduct of the study was significantly deficient relative to the ethical standards
prevailing when the study was conducted.
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Framework for Developing Best Practices for Subject Recruitment for Handler Exposure
Research
Charge to the Board
a. What additional elements of the process of recruiting and enrolling subjects in handler
exposure research should be addressed in a “Best Practices Framework”?
b. For each of the elements in the “Best Practices Framework,” please identify any additional
sources of guidance that could be useful for an investigator who is designing a process for
recruiting and enrolling subjects in handler exposure research.
Board Response to the Charge
The Board addressed both of these questions together.
Brief Overview of the Issue.
As EPA stated, “ [ t]wo industry task forces—the Agricultural Handlers Exposure Task
Force (AHETF) and the Antimicrobial Exposure Assessment Task Force (AEATF)—are
preparing to conduct research to measure exposure received by professional pesticide handlers
who mix, load or apply pesticides in representative agricultural or antimicrobial use scenarios...
To help ensure that people who consider participating in these studies are treated ethically, EPA
plans to compile guidance on best practices that that investigators could employ to recruit and
enrol subjects in this kind of research.” In furtherance of that goal, the EPA has produced a draft
document describing a framework for such best practices. It is that document regarding which
the Board has been asked to comment.
The Board is very supportive of the EPA’s initiative in producing this document.
Furthermore, the Board finds this document to be of very high quality, and a very valuable step
in assuring that this type of research is conducted in an ethical manner.
The Board has attached a mark-up of the document with assorted suggested word
changes (Appendix A). In addition, the Board makes the following comments:
1. It would be helpful if, somewhere near the beginning of the document, there was a paragraph
making it clear that the topics discussed in the document are only a part of the rules that must be
followed to assure that research is conducted in an ethical manner, and that those other rules
(including local and state level regulations) are not being discussed in this document. The
paragraph could briefly list some of those other rules, e.g., the need for appropriate study design,
the relationship of risks and benefits, the need to minimize risks to subjects. It might also be
appropriate to similarly mention the various scientific issues that are not addressed in this report
(e.g., exposure and data collection methods and statistical issues), which issues may often have a
fundamental impact on whether or not a study is ethical.
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2. Somewhere near the beginning of the document, it would also be helpful to clarif ’ that this
guidance is specifically designed for studies that fall under the definition of “intentional
exposure” studies as defined in the relevant sections of the federal regulations.
3. Also at the beginning of the document, there could be a clarification of the extent to which this
document is intended to apply to studies conducted outside of the United States.
4. In the discussion of equitable subject selection (page 2), it would be appropriate to note that
some of the rules intended to protect vulnerable subjects might in some cases lead to under-
representation of such subjects. The document should mention that to assure adequate inclusion
of subjects from all appropriate groups, random sampling may be required. Convenience
sampling may not be appropriate. Further, lack of representativeness should not only be required
to be justified, but should be treated in the analyses in such a way as a) to determine the biases so
associated and their effects on the analysis and conclusions, and b) adjusted or considered in
analyses in such a way as to determine what the conclusions might have been if the sample was
not biased and not representative.
5. In the discussion of recruiting subjects who do not speak English (page 3), the document
should highlight the need for recruiting such subjects, given the fact that the agricultural work
force includes a high proportion of such individuals. The default should be that such subjects are
included.
6. An important element that should be added to the document is a more extended discussion of
the need for input, in the design and conduct of the study, from the community representing the
group of subjects being recruited (e.g., agricultural workers), and especially the vulnerable
members of that group. The document should discuss specific ways in which that input might be
obtained and used. There is a substantial literature on the topic of community participation in
research, some of which is discussed in the EPA National Exposure Research Laboratory’s
Report on the Workshop to Discuss State-of-the-Science Approaches for Observational Exposure
Measurement Studies.
7. If there is a possibility that genetic information will be collected in these studies, the special
issues relating to informing subjects about the consequences to them from such collection should
be mentioned in the discussion of informed consent. There may also be state regulations,
applicable to such studies, and those regulations vary widely.
8. Under the heading Essential Elements of a Consent Document (page 6), where it refers to the
qualifications of an investigator, you might consider being somewhat more specific about what
details regarding those qualifications should be included in the consent form.
9. In the discussion of Capacity to Make Decisions (page 6), it can be noted that some state laws
do not allow, under certain conditions, enrollment of subjects who lack the capacity to make
decisions.
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10. In the last paragraph under Language of Informed Consent (page 7), it would be helpful to
include an example, or some discussion, of what it means to include exculpatory language.
12. Under the heading Circumstances and Process (page 8), where the second paragraph
mentions the process of obtaining consent, it might be helpful to give some details of what
makes a good consent process, or perhaps provide a brief case study highlighting key principles.
13. With regard to the first sentence under the heading Confirming Understanding (page 9), the
Board notes that the regulations do not actually require that there be an investigator’s signature
on a consent form attesting to the subject’s understanding. However, this is an excellent practice
and it is welcome that the EPA wishes to adopt it. It would be helpful if the line under the
signature clearly states what the signature means (e.g., “Signature of Investigator Confirming
that the Subject Appeared to Appropriately Understand the Information Provided”).
14. On page 10, under the discussion of dependent relationships, the standard that an employer
should have “no” interest in the research is a strict one. The Board merely points this out to the
EPA.
15. In the discussion of Real Alternatives to Participation in Research (page 11), the document
asks a number of important questions, without providing answers to most of them. It would be
helpful, to the extent possible, to state some ethical principles that might enable answers to be
provided in this document to many of these questions, and to provide those answers if possible.
For example, it might be noted that in general, it would be inappropriate (and wrongly coercive)
if, as a result of the conduct of a study, a worker who chose not to participate in the study would
end up being worse off in any non-trivial manner (e.g., he earns less money during the day the
study is conducted than he would have if the study had not been conducted).
16. It might be helpful to provide a conclusion or summary at the end of the document.
In addition, with regard to possible sources of guidance that might be useful to an
investigator who is designing a process for recruiting and enrolling subjects in handler exposure
research (the second charge question), here are some suggested web sites, listed by topic. In
addition, note that the web site for the Office of Human Subjects Research, at
http://www.hhs.gov/ohrp, contains information on all of the topics listed below, in addition to the
Institutional Review Board Guidebook, at htto://www.hhs.aov/ohm/irb/irb auidebook.htm.
Ethical Principles
The Belmont Report, available at
http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm
Archival Documents relating to the Belmont Report, available at
httr ://www.hhs.gov/ohrpfbelmontArchive.html
Informed Consent Process
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A Brief Introduction to Informed Consent, available at
http://poynter.indiana.edu/sas/res/ic.ndf
An Informed Consent Bibliography, prepared by the Department of Veterans Affairs,
available at http://www.research.va.gov/resources/pubs/informed consent/
Capacity to Make Decisions
A volume from a report by the National Bioethics Advisory Commission containing
papers relating to Research involving Persons with Mental Disorders That May Affect Decision-
Making Capacity, available at
http://www.aeoraetown.edu/research/nrcbl/nbac/canaCit v/VOlumeilPdf
Lan uaae of Informed Consent
Guidelines for writing informed consent documents prepared by the Office of Human
Subjects Research, National Institutes of Health, available at
http://ohsr.od.nih.gov/info/sheet6.html
Complexity of Consent Materials
Simplification of Informed Consent Documents, prepared by the National Cancer
Institute, available at htw://www.cancer.aov/clinicaltrials/understandinalsimolification-of-
informed-consent-docs/yage2
With regard to textbooks on some of these topics, the following books are suggested:
Ethical Principles
Principles of Biomedical Ethics ( 5 th edition) Tom L. Beauchamp and James F. Childress.
Oxford University Press 2001
Informed Consent
A History and Theory of Informed Consent. Ruth R. Faden and Tom L. Beauchamp.
Oxford University Press 1986
Informed Consent: Legal Theory and Clinical Practice (2IH Edition). Jessica W. Berg,
Paul S. Appelbaum, Charles W. Lidz and Lisa S. Parker. Oxford University Press 2001.
Capacity to Make Decisions
Assessing Competence to Consent to Treatment. Thomas Grisso and Paul S. Appelbaum.
Oxford University Press 1998.
Follow-up on Agricultural Handler Exposure Task Force and Antimicrobial Exposure
Assessment Task Force Protocols
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Charge to the Board
Recognizing that protocol-specific science and ethics issues will be addressed in later
HSRB meetings, EPA has attempted to explain the basis for its conclusion that additional
information on exposure for people who mix, load, and apply pesticides (handlers) would be
useful in EPA ’s regulatory decision-making and therefore new research would be valuable. Do
the materials provided by EPA regarding the quality of the scientific data currently available for
assessing exposures for handlers contain useful information to establish the societal value of
proposed new handler exposure research, assuming individual protocols would generate
scientifically valid information?
Board Response to the Charge
The Board found that the joint U.S. EPA — California EPA — Health Canada background
document provided an excellent review of existing handler data, and identified important
limitations of these data. The report from the January 2007 meeting of the EPA FIFRA Scientific
Advisory Panel (SAP) extended this analysis, and provided an excellent rationale for the
collection of new occupational handler exposure data for use by EPA and other regulatory
agencies. In summary, the materials provided by EPA regarding the quality of the scientific data
currently available for assessing exposures for handlers provide a sound justification for the
societal value of proposed new handler exposure research. The challenge as the Agency moves
forward with the AHETF study is to ensure that the study is designed and conducted in a way
that produces high quality exposure data suitable for use in Agency risk assessments.
Charge to the Board
What additional information, if any, would the Board want with respect either to handler
research in general or to individual protocols?
Board Response to the Charge
The Agency brought the AHETF study to the Board’s attention because it considered this
study to fall within the boundaries of “intentional exposure” as defined in the EPA’s Human
Studies Rule. Substantial discussion occurred at the June 2006 meeting and again at this meeting
regarding the Agency’s decision process for classifying human studies as intentional or
observational. The Board would appreciate the opportunity to learn more about the Agency’s
approach to this issue, and contribute to this discussion at a Ibture HSRB meeting, particularly in
regard to occupational exposure studies.
The Board praised EPA’s decision to obtain a review and report of worker exposure
methods from the EPA FIFRA SAP. The Board found the meeting presentations by Drs.
Heeringa and Popendorfofthe EPA SAP particularly helpful in providing guidance on the
AHETF task force study.
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The Board commended EPA’s response to its questions regarding use of diazinon in the
A11E37 protocol. The Board understands that the Agency will require A1-LETF to identif ’ a
pesticide other than diazinon to use in this protocol to assess exposures associated with open
pour activities, and that EPA will ensure that future protocols comply with the most current risk
mitigation measures.
Overarchina Concerns
At its June 2006 meeting, the Board recommended development of a “governing
document” that would frame the entire study in regard to its purpose, general methodological
approach, and general analytical plan. Agency and SAP presentations at the April 2007 meeting
indicated that substantial progress had been made in this regard, both within the Agency and
within the Task Force. The Agency indicated that additional information to address this concern
would be presented at the June 2007 HSRB meeting.
More specifically, the Board recommended development of a clear and appropriate plan
for the collection and handling of the data being collected, including sample size and statistical
analysis. The Board recognized that this is a complex and iterative task. It would be most helpful
to have a timeline for development of the analytical and statistical plan.
At the April 2007 meeting, the Board indicated that there will be two tiers to its
evaluation of submitted protocols: (1) whether the model and general plan are scientifically and
ethically valid, and (2) how the protocol will be implemented at each site, i.e., how issues such as
compliance with data collection and entry will be managed, subject safety, and monitoring of
recruitment.
The Board recommended that the Agency and AHETF develop a clear narrative
regarding the uses to which the data would be applied. The Agency and SAP reports submitted to
the Board for this meeting provided substantial additional information regarding the use of data.
Articulation of these plans in a short draft document would likely move this process forward.
The Board also recommended that the Agency consider development of protocols for
repeated measures to appropriately estimate exposures within individuals. Such studies on at
least a small subset of the study population would allow adjustment for this source of variability
in statistical analysis. The SAP report addressed this issue in some detail, and has provided the
Agency with very useful guidance on this issue.
The Board discussed the potential value of examining the ways in which the agency has
used the Agricultural Reentry Task Force (ARTF) database in its risk assessments. This database
has a similar scenario-based structure as the databases under review, and used similar methods to
measure dermal exposure. The Board suggested that the agency share with the board its
experience with the ARTF database to identify “lessons learned” and possible pitfalls in the use
of such databases.
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Methodological Concerns Issues
The Board reaffirmed its interest in two recommendations from the June 2006 HSRB
meeting:
The Board recommended additional validation studies to determine the extent to which
dermal exposure measurements may underestimate true exposure. The Board would appreciate
an update on plans, if any, to address this recommendation.
The Board recommended that the Agency consider broadening participation in its
discussions of the Agricultural Handler Exposure Database, including additional members of the
scientific community, as well as parties with a direct interest in the database project, such as the
labor community. The Board would appreciate an update on plans, if any, to address this
recommendation.
At the April 2007 meeting, the Board also recommended that the following
methodological issues be considered in the development of documents and protocols:
A description of how EPA will evaluate its linear model assumption (exposure vs.
amount of active ingredient handled), given the SAP’s recommendations;
Information on sampling frame and where to focus data collection, based on usage
patterns for products; how sample size would be determined; strategies for replacement of
missing or partial data;
A statistical analysis plan including identification of covariates to be collected and a
rationale for emphasis on some covariates versus others;
Whether the Agency plans to include biomonitoring data in the task force activities as a
means of evaluating the validity of passive dosimetry measurements;
How the protocols represent, as closely as possible, the conditions of a true work day
including documented reasons for and proposed duration of the study.
Plans to meet the requirements established in 40 CFR part 26, subparts K and L.
HSRB Consensus and Rationale
The HSRB concluded that the materials provided by EPA regarding the quality of the
scientific data currently available for assessing exposures for handlers provide a sound
justification for the societal value of proposed new handler exposure research. In addition, the
review and recommendations of the EPA FIFRA SAP provide an excellent starting point for
some methodological decisions and for the identification of issues still to be addressed. The
challenge as the Agency moves forward with the AHETF study is to ensure that the study is
designed and conducted in a way that produces high quality exposure data suitable for use in
Agency risk assessments.
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The Board recommended development of a “governing document” that would frame the
entire plan for the collection and statistical analysis of the data, and a clear narrative
regarding the uses to which the data would be put. The Board also recommended that studies
be conducted as a part of this project to determine the accuracy of dennal exposure
measurements. The Board further recommended that the agency consider broadening
participation in its discussions of the agricultural handler exposure database, including
additional members of the scientific community, as well as parties with a direct interest in the
database project, such as the labor community. Finally, the Board recommended that the
Agency draw upon its experience with the Agricultural Reentry Task Force database to
clarify how such data are used in its risk assessments, to capture the key “lessons learned”
from this experience, and to avoid possible pitfalls in the use of such databases.
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REFERENCES
Carley, J.M. 2007a. Ethics Review of EMD-003.3 Report of Completed Efficacy Study for
Aerosol Tick Repellent Containing IR-3535. Dated March 14, 2007. Unpublished document
prepared by Office of Pesticide Programs, United States Environmental Protection Agency.
Carley, J.M. 2007b. Ethics Review of EMD-004.3 Report of Completed Efficacy Study for
Aerosol Mosquito Repellent Containing IR-3535. Dated March 14, 2007. Unpublished
document prepared by Office of Pesticide Programs, United States Environmental Protection
Agency.
Carroll, S. 2007a. Test of Personal Insect Repellents: Study EMD-003.3 (Aerosol) — Revised.
Dated February 5, 2007. Unpublished document prepared by Carroll-Loye Biological Research.
Carroll, S. 2007b. Test of Personal Insect Repellents: Study EMD-004.3 (Aerosol) — Revised.
Dated February 5, 2007. Unpublished document prepared by Carroll-Loye Biological Research.
Carley, J.M. 2007c . Ethics Review a Completed Human Study of Dermal Irritation of Two
Repellent Products. Dated March 15, 2007. Unpublished document prepared by Office of
Pesticide Programs, United States Environmental Protection Agency.
Carley, J.M. 2007d . Ethics Review a Completed Human Repeated Insult Patch Test (RIPT) of
Two Repellent Products. Dated March 15, 2007. Unpublished document prepared by Office of
Pesticide Programs, United States Environmental Protection Agency.
EMD 003.3 (Aerosol). 2007. EMD Chemicals.
EPA HSRB. 2007. January 24,2007 EPA Human Studies Review Board Meeting Report.
Washington, DC: Environmental Protection Agency. April 16,2007. EPA-HSRB-07-01
Georgeian K and Dosik JS. 2007a. Primary Irritation Patch Study [ redacted] Supplemented with
Additional Supporting Materials Satisf ’ing 40 CFR 26.1303 for [ redacted] [ Repellent Code]
1000718-008, concentrate of 1000718-009. Volumes I and 2. Unpublished document prepared
by toXcel, LLC. February 1, 2007.
Georgeian K and Dosik JS. 2007b. Primary Irritation Patch Study [ redacted] Supplemented with
Additional Supporting Materials Satisf ’ing 40 CFR 26.1303 for [ redacted] [ Repellent Code]
1004006-005. Volumes 1 and 2. Unpublished document prepared by toXcel, LLC. February 1,
2007.
Georgeian K and Dosik JS. 2007c. Repeated Insult Patch Study [ redacted] Supplemented with
Additional Supporting Materials Satisf ’ing 40 CFR 26.1303 for [ redacted] [ Repellent Code]
10007 18-008, concentrate of 10007 18-009. Volumes I and 2. Unpublished document prepared
by toXcel, LLC. February 1, 2007.
Page 54 of 67
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Georgeian K and Dosik JS. 2007d. Repeated Insult Patch Study [ redacted] Supplemented with
Additional Supporting Materials SatisI ’ing 40 CFR 26.1303 for [ redacted] [ Repellent Code]
1004006-005. Volumes 1 and 2. Unpublished document prepared by toXcel, LLC. February 1,
2007.
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APPENDIX A
Draft Framework for Developing Best Practices ___________
for Recruiting, Screening, and Obtaining Consent from Human Subjects for . - - -( Deleted: informing
Occupational Exposure Studies with Pesticides Deleted ,andConsentmg
1 Deleted:
,‘ Human Subjects
March 15, 2007
Deleted: of
Introduction
Deleted: an
One of the fundamental protections for people who participate as subjects in human
research is embodied in the requirement that their choice to participate be both fully informed
and fully voluntary. EPA’s regulation governing the conduct of third-party research involving
intentional exposure of human subjects for pesticides contains provisions that require that all
subjects provide written informed consent before participating in a covered study. See 40 CFR
§ 26. 1116, 26.1117. These sections, which closely parallel provisions in the Common Rule,
also require that informed consent documents contain certain basic information ( 26. 1116(a) and
(b)) and that investigators document each subject’s consent to participate ( 26. 1117). These
provisions, however, contain broad directions which must be interpreted and applied in the
context of specific research proposals to achieve their intent.
Two industry task forces—the Agricultural Handlers Exposure Task Force (AHETF) and
the Antimicrobial Exposure Assessment Task Force (AEATF)—are preparing to conduct research
to measure exposure received by professional pesticide handlers who mix, load, or apply
pesticides in representative agricultural or antimicrobial use scenarios. The Agency believes that
investigators undertaking this kind of research need to interpret the general requirements of the
regulations and apply them to the specific circumstances associated with this kind of research.
To help ensure that people who consider participating in these studies are treated ethically, EPA
plans to compile guidance on best practices that investigators could employ to recruit and enroll
subjects into this kind of research.
This paper addresses the major elements of ethical recruitment and enrollment and the
issues that typically arise during these processes. For each element, EPA discusses broad
principles which should be considered in the course of research design. In future, through a
participatory process involving investigators, workers, and other stakeholders, EPA intends to
add to the document specific best practices, and to identify publicly available resources that
contain additional discussion and guidance relevant to the application of general ethical
principles in occupational exposure research.
Overarching Concerns
J rernainderofthispaper presents a conceptual framework for considering an - - - { eleted: This
organizing best practices in occupational exposure studies for pesticides under four broad
headings:
Equitable Subject Selection
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• Fully Informed Choice to Participate
• Fully Voluntary Choice to Participate
• Respect for Prospective and Enrolled Subjects
Equitable subject selection
As a condition for approval of proposed research, the IRB must determine that subject
selection is equitable. (40 CFR §26.111 1(a)(3)). This passage continues:
In making this assessment the IRB should take into account the purposes of the
research and the setting in which the research will be conducted and should be
particularly cognizant of the special problems of research involving vulnerable
populations, such as prisoners, mentally disabled persons, or economically or
educationally disadvantaged persons.
Much of the available guidance on the interpretation and application of this requirement
focuses on the potential for inequitable exclusion from research of subjects who might
benefit from participation in it. This concern is clearly important in the context of medical
research which may offer therapeutic benefit to subjects. But in pesticide research with
human subjects, participation in the research typically offers the subjects no prospect of
direct benefit, so exclusion of potential beneficiaries is unlikely to weigh heavily. In
pesticide research the greater concern is usually for the potential for inequitable reliance on
subjects from vulnerable populations—especially those who are economically disadvantaged
or in a dependent or subordinate relationship to the investigators or others involved with the
research.
The essence of equity in selection of research subjects is that the burden of bearing the risks
of research be fairly distributed. There are several aspects of fair distribution.
Representativeness of sample
The Common Rule defines “research” as “a systematic investigation . . . designed to
develop or contribute to generalizable knowledge.” (40 CFR 26.1102(d)). Research
which is more broadly generalizable is of greater societal value than other research The
representativeness of the sample is thus directly related to the justification for the
research.
Ideally, the population selected for research participation would be randomly sampled
from the target population to which the study results will be generalized. This ideal
cannot often be attained, but it should guide the design of recruitment and selection
processes in three ways.
First, the target population should be identified and characterized demographically.
Second, a sampling frame should be defined, and its relation to the target population
should be characterized. Differences between the characteristics of the population in the
sampling frame and those of the target population—i.e , the extent to which the sampling
frame is unrepresentative of the target population to which the study results will be
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generalized—should be justified. Third, the sample should be selected from the sampling
frame in a way that preserves its representativeness of the target population. To be
equitably selected, the sample must be selected to serve the scientific purposes of the
research, and not for the convenience of the investigators or for other arbitrary reasons.
Appropriate use of inclusion/exclusion factors
S election of potential subjects from a sampling frame entails application of appropriate
inclusion and exclusion factors to screen candidates. These can serve both to preserve
the representativeness of the selected sample and to provide extra protections for
potentially vulnerable subjects. In the re ulatorv sense. “vulnerability” means that some
or all of the subjects may be overly susceptible to coercion or undue influence when
being enrolled into the research .
For example, in a study of agricultural worker exposure to pesticide residues in
previously treated orchards, it might make the research easier to conduct if candidates
who could not read and understand English fluently were excluded. But since a
significant proportion of orchard workers are of limited English language proficiency,
such an exclusion would diminish the representativeness of the sample, thereby reducing
the generalizability—and the societal value—of the resulting data.
As another example, EPA’s regulations (40 CFR §26.1203) prohibit the use of human
subjects in research involving intentional exposure to pesticides, if those subjects are
pregnant or nursing women, or children under age 18. Compliance with these
prohibitions and protection for potentially vulnerable subjects can both be ensured with
appropriate exclusion factors.
Special considerations for vulnerable populations
Special consideration is needed to ensure protection of vulnerable subjects. Many
potentially vulnerable populations should simply be excluded from research involving
pesticides. The absence of any potential direct benefit and the possibility of potentially ________________________
harmful dosing greater than that of normal occupational exposure to hem makcs it - - - - [ Deleted: potential hann to
fundamentally unethical to consider using prisoners, children, pregnant or nursing
women, or mentally disabled people as subjects in research with pesticides. Some other
examples of appropriate exclusions are discussed above.
Others, however, who may ethically be included as subjects in pesticide research may
also be vulnerable and require special considerations. For example, individuals with
limited English language proficiency may appropriately participate in some research, but
require translations of recruiting and informed consent materials into language they can
understand, and assistance in communicating with investigators in the consent process
and during the conduct of the research. Here the “vulnerability” is due to the possibility
that notential harms, or the directions to avoid them would not be correctly understood .
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In studies of occupational exposure to pesticides, subjects are quite appropriately drawn
from among those who are occupationally exposed to pesticides. But great care must be
taken in recruiting them to ensure that their decisions to participate in the research are
made freely, without any coercion or undue influence from their employers or
supervisors or the investigators. One prerequisite to a free choice to participate in
occupational exposure studies is a clear understanding of a real alternative to
participation.
In some past pesticide studies, subjects have been drawn from among the employees f
the sponsor or ç.students of the investigatorspf the research. It is very difficult to - --I Deleted: orsponsors
ensure either that such subjects are representative of the target population or that their
choice to participate is made freely and without any undue influence (intended or -
unintended) ; thus as a practical matter, the best course is not to involve 4hern as research - - - - - - [ Deleted: use
subjects.
Appropriate recruiting strategy
To ensure that a selected sample is as representative and equitable as possible, the
recruiting strategy must be appropriate to the design of the research. Fliers or
advertisements or other recruiting efforts may or may not reach the intended audience,
depending on where and when they appear. In order that no individual or group bears an
undue burden of research, it is important to use a recruiting strategy that will extend the
opportunity to participate to.a wide population consistent with ! ! rc!! design. - - - [ Deleted: the widest possible
Because of the potential for privacy infringement, recruiting procedures that involve one
person providing information about another person ,g g.potential subject without his/her - - - - - - [ Deleted: or
permission are discouraged. Information about the study should be provided to potential
subjects through flyers, advertisements or other means initiated by the investigators.
Potential subjects may then actively express interest in study participation by contacting
the investigator directly.
Prospective subjects may be recruited via advertisements, announcements, flyers or other
means. All recruitment materials—advertisements, flyers, postcards, brochures, press
releases, telephone scripts, or postings on the intemet—.peed to be reviewed by the IRB - - - -I Deleted: should
for accuracy in presentation of information.thg the prospective subject needs to
determine his/her eligibility and interest. The [ RB review onsider content, language, - - - - - -f Deleted: should
and design.
Fully infonned choice to participate.
The second over-arching concern is to ensure that subjects’ choices to participate in research
are filly informed. The Office for Human Research Protections (OHRP) states that
“informed consent is one of the primary requirements underpinning research with human
subjects; it reflects the basic principle of respect for persons.”
-
-
:
—
]
:
J
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Informed consent is the knowing consent of an individual or his/her legally authorized
representative, obtained without undue inducement or any element of force or coercion.
Obtaining informed consent doesn’t end with a signature on a piece of paper. It is a process
in which the subject receives enough information about a study to make an informed decision
about initial entry and continuing participation in the research. The process involves reading,
understanding and signing an informed consent document as well as discussing the details of
study participation with a knowledgeable member of the research team.
By signing the consent form, the project representative—the principal investigator or study
coordinator—who obtains consent is documenting that the consent process is complete. The
project representative is responsible for ensuring that everything is done to enhance
prospective subjects’ comprehension of the information and their ability to make free and
voluntary choices. The project representative must be knowledgeable about the study, able
to present information clearly in plain language, fluent in the preferred language of the
prospective subjects, and able to understand and resolve questions.
The subject who signs the consent form acknowledges having read the information in the _______________________
consent document and having had a chance to discuss itj sk questions about I e 4y _ - - - - [ Deleted: and
to have those questions answered . The subjects’ signatures also indicate agreement to
participate in the study, and understanding that they are free to change their minds at any
time and withdraw their consent to participate.
The primary purposq,pf the info edconsentprocess tocornrnunicateto prospective - - - -
subjects deguate information. expressed clearly in olain and understandable language. to - - -
make an informed decision about participating in the ro osed study. This information is
outlined in the required elements of consent (40 CFR 26. 111 6’ inctudin :
• ,Fhepurpose,risks,andbenefitsoftheresearch.
• The procedures involved and what would be expected of participants.
• That he/she retains the right to decline to participate or to withdraw from the study at
any time without penalty.
In addition, the informed consent process should:
• Confirm the prospective subject’s understanding of the information provided.
• Answer any questions the prospective subject may have about the study.
• Provide the subject with a copy of the completed consent form(s).
Essential Elements of a Consent Document
Basic and additional elements of an acceptable informed consent document are specified
in regulations at 40 CFR §26.1116(a), (b), and (e). The list below is based on these
regulations, but is rearranged for clarity. In case of any perceived conflict between this
list and the regulations, the regulations are authoritative.
A consent document for occupational exposure studies for pesticides should include:
(Deleted:
(Deleted:
(Deleted:
Deleted: Adequate information.
expressed clearly in plain and
understandable language, to make an
informed decision about participating
the proposed study
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• A statement that the subject is being asked to participate in research on a
pesticide, and the identity and pesticidal function of the pesticide(s) to which he
or she will be exposed. _________________________
• Identification of Jnvestigators involved in the study b name, qualifications, - - - - - - [ á ieted: all
and affiliation, and disclosure of any conflicts of interest.
• A plain-language, jargon-free explanation of the purposes of the research
• An explanation of the eligibility criteria used to identify prospective participants,
and the number of subjects being recruited.
• A description of where the research will be conducted and the expected duration
of the subject’s participation.
• A description of all the procedures that the subject will be asked to follow,
identifying any procedures that are experimental.
• A description of the nature and likelihood of any risks or discomforts the subjects
might encounter as a result of participation, and of the actions taken to minimize
these risks or discomforts. __________________________
• A,statement about compensation for iniui ’. if any. and whethe medicaI treatment - - - Deleted: a
or other arrangements are available . - - [ Deleted: if
• A statement that participation in the research will offer no direct benefit to the
subjects.
• A. tatement about potential benefits to society from the knowledge tmay - - - ( Deleted: discussion of
result from this research. This should realistically identify both the nature and fó ete i: of
magnitude of expected benefits and how they will be distributed—that is, who
will receive them. This should not be exa erated because it would then become
a source of undue influence .
• A description of the extent, if any, to which records identifying the subject will be
held confidential, explaining the procedures for using and storing data and who
will have access to it.
• Information about any payment or other incentive offered to participants,
describing what it is and what the subject must do to obtain it. If there is a
payment, a statement of the amount, the formula for proration should the subject
or investigator chose to discontinue participation, and when and how payment
will occur. If no payment or other incentive is offered, a statement that the
participant will not be paid to participate in this study. (Note: navments for ________________________
participation should not be described as individual “benefits” frq j.particioating in _ - - - f Dele : are not
the study.) fDe eted: of
• Contact information for study personnel and the responsible IRB, in case subjects ‘ fó tei: the research
have questions or concerns about the research, about their participation in it, or
about their rights as subjects.
• A statement that the subject’s participation is voluntary, and that if the subject
decides to participate, they can change their mind and stop their participation at
any time without penalty.
• A clear statement of alternatives to participation, specific to the context of the __________________________
research, should subjects decide not to participate or to withdraw. - { Coniment ( gIci]: 1116 E
• The identity of the Desticide and the nature of its pesticidal flinctiod . -,
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jDeleted:Compeaace
Cavacitv to Make Decisions
Like the Common Rule that governs research with human subjects conducted or
supported by the federal government, EPA’s regulations governing third-party research
involving intentional exposure of human subjects to pesticides provide that “ [ n]o
investigator may involve a human being as a subject in research. . . unless the
investigator has obtained the legally effective informed consent of the subject or the
subject’s legally authorized representative.” (40 CFR §26.1116)
But because research involving intentional exposure to pesticides is unlikely to be of
direct benefit to subjects, it is equally unlikely that it would ever be ethically appropriate
to obtain consent from a representative of a subject rather than from the subject him- or
herself. - -
In short, for these types of studies, it is essential to filly informed consent that the _______________
consenting subject J ave the capacity to understand te info tiot provided, ando - - - {Deieted: be competent
make a free choice to participate or not to participate. If there is any question about the
decisional papacitv of a p’p!Pc !Y J !ct that person should not be enrolled - - -- [ competence
research.
Language of Informed Consent
Thexegulatorv requirement for consent d c i -dfoz the - - - -I Deleted: first
entire infonned consent process—is that “ [ t]he information.. . given to the subject...
shall be in language understandable to the subject.” (40 CFR §26.1116)
That means, first, that the language used in the consent documents and throughout the
consent process should be selected for the benefit of the potential subjects, not for the
convenience of the investigators. If subjects with limited English proficiency are
expected to be enrolled, all consent materials should be translated into the language(s) in
which prospective subjects are comfortable, and the accuracy of the translation should be
confirmed, through back-translation or other means. Translated consent materials must
also be approved by an IRB before use. An interpreter fluent in the languages of both the
investigators and the prospective subjects may be needed to ensure that the information
provided in the consent process is fully understandable to the subjects.
Understandability also requires that consent materials be written in plain language,
avoiding technical jargon. Most authorities recommend writing consent materials at a 6 th
to 8 th grade reading level, using the second person (i.e., addressing the subject as “you.”)
Understandability of consent materials should be verified before they are used. A helpful
web site is: http://www.plainlanguage.gov/howto/index.cfm .
Finally, regulations forbid inclusion in consent materials of “any exculpatory language
through which the subject. . . is made to waive or appear to waive any of the subject’s
legal rights, or releases or appears to release the investigator, the sponsor, the institution
or its agents from liability for negligence.” (40 CFR §26.1116)
1
]
:
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Complexity of Consent Materials
It is easy to overwhelm subjects with too much information. The quality of consent
materials is not measured by their bulk, but by the accuracy and clarity with which they
present what subjects need to know to make a decision to participate. Many details
contained in the protocol itself are unnecessary in good consent materials, and careful
editing should exclude them.
One important element, however, that should be described in detail is the procedures
involved in the research, from the point of view of the subjects. The goal in developing
consent materials should be to discuss all the procedural elements in the research in one
place, as much as possible in the sequence they will occur, and in clear, plain language.
Circumstances and Process
The entire consent process and the circumstances in which it takes place are critical
components of fully informed and fully voluntary decisions. Most authorities consider
the consent process to begin with the potential subject’s initial contact with the
research—whether through advertisements, flyers, phone calls, or other means. The
regulations require investigators to seek consent “only under circumstances that provide
the prospective subject.. . sufficient opportunity to consider whether or not to participate
and that minimize the possibility of coercion or undue influence.” (40 CFR §26.1116)
The process should be designed to enhance the prospective subject’s comprehension of
the information and his or her ability to make a choice. It should take place in
circumstances designed to minimize the possibility of coercion or undue influence, and j - - - - fó Ieted: toan
an area and in a manner that protect the privacy and integrity of both prospective and
selected subjects.
Particular care is needed to ensure that the process is free from any element of coercion
or undue pressure wh n 1 third parties other than the investigators and subjectspI y a role - - - - -t Deleted: When
in the recruiting, informing, and consent processes, 1f for example, pesticide handlers - - - -
are recruited through their employers, care must be taken to ensure they have a ,fi
choice not to participate, and that their employers do not influence their decisions 2
intentionally or unintentionally .
nmunicating
Unless prospective subjects understand the risks associated with participation in research,
they cannot make a rational decision to participate. Risk should be addressed in consent
materials from the point of view of the subjects, rather than from the point of view of the
investigators. If the discussion of risk in the informed consent document is the same as
the discussion in the protocol, it almost certainly needs revision.
Three aspects of risk need to be addressed in consent materials:
Risks
-
-
Deleted: particular cain is needed to
ensure that the pmccsscs sin free from
any element of coeicion or undue
pressure
I
Deleted: legitimate
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Deleted: it
- - 4 Ieted: Page Break
Occupational exposure studies for pesticides do not offer any direct benefit to
participants. This must be clearly stated in consent materials.
Because of the absence of direct benefits, there are likely to be significant asymmetries in
the distribution of risks and benefits. The subjects are likely to bear all or nearly all risks, _________
whereas the benefits of the research are likely to accrue to others. jexplicit cssio
of the nature and distribution of benefits is essential to a fully informed decision by a
subject to participate in the research.
Potential societal benefits from the information expected to !e! !t from the research
should be described to potential subjects. If, for example, a study of pesticide handler
exposure is expected to provide information which EPA will use to define the minimum
personal protective equipment required for safe handling of pesticides in the relevant
exposure scenario, this could affect a potential subject’s decision to participate. If the 1 _________
beneficiaries of the research are likely to be pesticide registrants, this, too, should be
stated clearly. Care should be taken to not over-state Dotential benefits .
Compensation must not be described as a benefit to subjects.
Confirming Understanding
It is the responsibility of the research team to confirm subject understanding, and the
investigator’s signature on a consent form attests to this confirmation. It is not sufficient
to obtain signatures on forms worded so as to put the responsibility on the subjects. __________
Statements such as “I understand. . .“ in informed consent docwnents represent, n - - - { Deleted: such
unacceptable transfer of responsibility. As with consent itself, subject understanding is
an on oin urocess, which needs to be confirmed and enhanced if the proiect occurs over
time .
J s qualitative nature. Risks may be physic Irs of harm or discomfort; they may - - - Deleted: The first aspect of nsk is J
also be psychological, social, economic, or legal. For example, a prospective female ‘ ‘ fiiormatte : Bullets and Number
subject who learns she is pregnant as a result of a pregnancy test associated with ‘ f i 1
eligibility screening may experience psychological harm. If the news of her pregnancy is
not communicated to her with care and discretion, she may experience economic or social
harm as well. Risks and harms may also involve others such as family members and
future children . _____________________
J s likelihood. An informed choice toparticipate in research depends on a clear - - - -f Deleted: The second aspect of risk that
understanding of the distinction between likely and unlikely risks. Each risk identified in dd iSed nade a talY
an informed consent document should also be characterized in terms of its likelihood of i
occurrence. _________________________
Jeps taken by the investigators to minimize This should include telling potential - - Deleted: The third and final aspect of
subjects how injuries or other adverse effects resulting from participation in the research -‘ 1 that must be discussed is the
will be managed, what treatment will be available, and who will pay for it. Deleted :
f. ’ommunicaangBenefits
Comment (glc2]: Impact on
EPA/IRBis not relevant to the discussion
on subject consent
Deleted: Unless both the nature and the
distribution of anticipated benefits are
made explicit, neither the investigators,
the 11W, EPA, nor the HSRB can
conclude that the anticipated benefits
sufficiently outweigh the risks to subjer’
to justify proposed researeh By the
token, an
Deleted: of
J
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Fully voluntary choice to participate
Recruitment must be conducted without any element of coercion or undue influence to
participate. . ‘otentiaI sources of undue influence are from dependent relationships and from - - {Deleted: Principal potential
social pressure from peers. Is the consent process adequate to ensure that the subject’s
agreement to participate is informed, rational and voluntary? What safeguards could be
implemented to improve the consent process? Do candidates have a,ft ç..and real Iternative to - - - - - Deleted: legitimate
participating? Deleted: option
ManaffinRDependentRdationshflps -L D ele t ed:Corn Jw !efor
In many occupational exposure studies for pesticides 1 the subjects—whether they are
pesticide handlers or re-entrant workers—are recruited for the research through their
employers. In such cases 1 great care is needed to ensure this does not compromise the
voluntariness of the subjects’ choices to participate. The employer must have no
comøellin interest in the research, or in whether an individual chooses to participate in
it, and this must be clearly communicated to potential subjects. . ubjects must understand - - - - - [ Deleted: They
that their decision either to participate in research or not to participate will have no
impact on their job, their pay, or any other aspect of their relationship to their employer.
In some past studies for pesticides, the employers of the subjects have had a direct
interest in the research. klso. some cornpanies,Ø sponsoror conduct exposure studies - - - - - -t Deleted: Some
have recruited subjects from among their own employees. This practice is inconsistent - [ Deleted: who
with ensuring that subject choices to participate are entirely voluntary. -
In some exposure studies, subjects have been recruited as a crew, through a crew leader
or labor contractor. This introduces a clear potential for undue influence, especially
ecause some members of agricultural work crews may be in the U.S. ille aIly, and thus - - -
particularly vulnerable.
Minimizing Peer Pressure
- - -I Deleted: since
It may be essential to fWly voluntary choice to design the circumstances and process for
discussing the research, addressing questions about it, and seeking consent of potential
subjects so that each candidate has the privacy to act without any pressure from a peer
group. . Becauseit is often obvious whether someone is participating in research—as, for - - - - - [ Deleted: Since
example, when participants are all wearing whole-body dosimeters—it is important to
ensure privacy for individual choices and discretion concerning reasons for
nonparticipation. If each candidate is interviewed and makes a participation decision in
private, for example, non-participation could result from application of the exclusion
factors by the investigators or from personal choice by the candidate. A well-designed
process would leave it entirely up to the individual subject whether to disclose the;eason - - - - -1 Deleted: ue
for non-participation.
Real Alternatives to Participation in Research
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It is common practice to include in the consent materials for non-therapeutic research
such as that conducted with pesticides a statement to the effect that “this study is not
associated with any therapeutic treatment, so your only alternative to participation is not
to participate.” This simple statement is a carryover of habits associated with biomedical ________________________
research, where, lternativç treatments may not be available to potential subjects of - - - -f Deleted: consent materials are required7
research. But , uch an unexplained statement is inappropriate foroccupational exposure
studies for pesticides. Potential subjects in occupational studies must be told in some - 1 P!!!t it
detail what they would do if they decide not to participate in the research, or if they
decide later to withdraw from the research. This must be thought through in the course of
study design and spelled out in the consent materials, so subjects can understand their
options more fully.
For the following example, assume mixer/loaders and aerial applicators are recruited
from among the employees of a commercial pesticide application service to participate in
a study of agricultural handler exposure. The study coordinators have identified a
particular farmer who is a client of the application service, and arranged with him to
make his fields available for pesticide treatment in the course of the research. What does
it mean to tell an aerial applicator employed by the service that his only alternative to
participating in the research is not to participate? What would he do that day if he did not
participate in the research? Would he apply the same pesticide to the same field, but with
no measurement of his exposure? Would he be reassigned to service another client?
Would he get an unscheduled day off? Would he get paid?
To extend the example, what does it mean to tell an aerial applicator that he is free to
withdraw from the research at any time? If he decides to withdraw in the middle of the ________________________
study, will someone else,fly theplane? What would he do for the rest of the day? How - - - - - { Deleted: step up and
will the cooperating farmer’s field get treated? Would anyone’s income—his own, his
employer’s, perhaps the farmer’s—be affected by the pilot’s decision to withdraw from
the research?
For another example, consider a study of re-entrant agricultural worker exposure, for
which subjects were recruited through a crew boss. If one member of the crew chose not
to participate in the research, what would that individual do that day?
Respect for potential and enrolled subjects
Fully informed, fully voluntary participation in research is required by the principle of respect
for persons. But research subjects are sometimes treated in ways that undermine this principle.
Incentive Payments for..Subjects - - - [ Deleted: Compensation of
To assist in subject recruitment, an incentive may be offered. Any incentive should be
reasonable 5 taking into account the burden or inconvenience incurred by study
participants. The amount and type of incentive should not unduly influence prospective
subjects to participate. Subjects should understand what incentives will be offered before
they agree to participate in the study. The terms of the incentive should be described in
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the consent form. Incentives may also be described in general terms in recruitment
materials, but should not be emphasized. All incentives and methods of communication
( e.g.. fliers) to prospective subjects need to be approved by the IRB before use .
It is particularly important in research on occupational exposures to explain clearly to _________________________
potential subjects how any incentive avrnents_for their partic ipation in earcr sto - - - - coinpensanon
their normal compensation for doing theirjob. Will they be paid above and beyond their
usual pay? How will their pay be affected if they decide to withdraw from the research?
Privacy and Confidentiality
The protection of a prospective or enrolled subject’s privacy must be considered in the
design and conduct of research. A breach of confidentiality or a perceived invasion of
privacy may result in harm to the individual.
To maintain confidentiality of research data, the investigator should protect information
obtained from the subject to avoid unintentional access by others. Subjects should
understand the procedures used to protect confidentiality.
Guidelines for developing procedures to address confidentiality include:
• Limit the personal information recorded to that which is essential to the research;
• Store personally identifiable data securely and limit access to the principal
investigator and authorized staff;
• Code data as early in the research as possible and dispose of the code linking the
data to individual subjects when data have been processed;
• Do not disclose personally identifiable data to anyone other than the research
team without the written consent of the subjects. (Exceptions may be made in case
of emergency need for intervention or as required by regulatory agencies).
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