August 15, 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

Scientific Considerations

The Board concluded that the reported study on the efficacy of an
aerosol formulation of IR3535 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 K and L. 

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 IR3535 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-001

Scientific Considerations

The Board raised several concerns about sample size, sample size
considerations for dropouts, statistical analysis and dose for WPC-001
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.   

Ethical Considerations

The Board concurred with the initial assessment of the agency that, with
minor revisions, the protocol wpc-001 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 formulations tested to cause sensitization of human
skin.

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 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.

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



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-mail 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.

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, Fordham 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., DABT, 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 santé
environnementale et santé au travail, Faculté de medicine, Université
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  

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. Menikoff, M.D., 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 Hoel, 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 Zhu, 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.  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 IR3535 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-3535.  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
§26.1701, 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.

The Agency’s reviews concluded that the data are scientifically sound
and that the research was conducted in a manner that deviates at least
technically from some of the requirements of subparts K and L of EPA’s
final rule establishing Protections for 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 information
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 formulations, 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
§26.1601, requires EPA to seek HSRB review of the research proposal.  

Dr. Scott Carroll has submitted a description of proposed research to be
performed 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-001 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].”   

(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 informed
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.

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 for 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 2007–2008 (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 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: IR3535 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: IR3535 Aerosol (EMD-003.3 and EMD-004.3) and (2) Mosquito
Repellent Efficacy Protocol WPC-001.  James Mibauer MD 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: IR3535 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
pathogens.  Each tick was used only once. Repellency was tested during a
3-min 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

     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 concerning CPT can be
determined.

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 IR3535
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-borne 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 IR3535 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, there 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.

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 IR3535 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.  

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
that 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 tick repellents containing IR-3535 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 IR-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 HSRB 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 § 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 2007a, 4, 42). The study was also reviewed and approved by a
commercial human subjects review committee, Independent Investigational
Review Board (IIRB), 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 (Ixodes pacificus) 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.

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
IR-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
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. 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 IRBs to follow procedures that “ensure” investigators do not
implement any protocol changes without prior IRB 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   HYPERLINK "http://iirb.com"  http://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
IRB and the actual activities performed by the research team. 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. 

At the January 2007 meeting, the Board recommended that Carroll-Loye
Biological Research report these 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.

 

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 subsamples 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, 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 1 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 repellent 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 min 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 FCLIBe. 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 min) 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 IR3535
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 Design Criteria

The purpose of the study was clearly defined (i.e., efficacy testing).

There were specific objectives/hypotheses (i.e., that IR3535 as an
aerosol formulation is an effective repellent).

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 IR3535 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?

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 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 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 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 LIBe
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: 1) 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-3535 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 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 IIRB-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.

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-001

Charge to the Board

a. If the proposed research described in Protocol WPC-001 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 (i) 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<0.05 is questionable.  The
justification provided by the investigator is not convincing.  The Board
recommended reference to information in the results of completed studies
to determine adequate sample size.

Sample size considerations for dropouts. In previous studies, subjects
dropped out at different points potentially confounding the
quantification of the CPT. Considering the current practice, the sponsor
should present two different analyses, one using the current practice
based on the normality assumption and the other using the Kaplan-Meier
method.  Also the analysis should be presented in two different ways
based on the current definition 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-001
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-001 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-001, 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.  

 

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-001 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 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

Critique 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 III). 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 III). The Agency had indicated
to the sponsor that these products would be given a Category III
classification. The sponsor believed that the products should be
classified as Category IV.

The primary concerns raised by the Agency regarding these studies
focused on the finding that 1) 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
classifying 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).

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

The tests involved a single dose level of approximately 50 mg/cm2. 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.

Participation 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 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
erythema” 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

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 (IRB Registration #IRB00003787), 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 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. 

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 RIPT 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, HIPAA-specific 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 IRB 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 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 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.  

	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

Two insect repellent products were evaluated for skin sensitization in
humans using a repeat insult patch test (RIPT) method. Product A
contained 11 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 Design Criteria 

Purpose/objectives

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 ml/cm2 (approximately 50 mg/cm2).

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.

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 RIPT 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 meaningful
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.

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 yt be the number of subjects at time t, t = 1, . . . . . . . , 9 who
react to the product out of nt subjects exposed. Since yt can take on
the values 0 (no reaction) or 1 (some reaction), we can model it as a
binomial random variable

yt ~ B(pt , nt)

Where pt 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:

logit(pt) = b0 + b1 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

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 CFR
26.1703 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
Paramus 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 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 (IRB
Registration #IRB00003787), 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 patches were applied to naïve sites
and read after 48 and 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:

1. Recruitment and enrollment of participants: recruitment and
enrollment of participants, as described, was confusing and of
considerable concern.  

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 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 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 risks to 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.

It appears that for this study the IRB 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 HIPAA Privacy Rule. However, TKL is not a HIPAA-covered
entity; thus 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 is no documentation in the IRB’s SOPs that
compliance with the HIPAA Privacy Rule is required of all protocols.
Furthermore, the inclusion of inapplicable HIPAA-specific 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 IRB
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 IRB: While the submitted documentation of IRB composition,
procedures, and review meets regulatory requirement, the Board had
substantial concerns.  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 procedures of the
independent IRB are not fully compliant with EPA, FDA or HHS 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 IRB 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.  

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.

2. Somewhere near the beginning of the document, it would also be
helpful to clarify 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. 

 

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   HYPERLINK
"http://www.hhs.gov/ohrp/irb/irb_guidebook.htm" 
http://www.hhs.gov/ohrp/irb/irb_guidebook.htm .

Ethical Principles

	The Belmont Report, available at   HYPERLINK
"http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm" 
http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm 

	Archival Documents relating to the Belmont Report, available at  
HYPERLINK "http://www.hhs.gov/ohrp/belmontArchive.html" 
http://www.hhs.gov/ohrp/belmontArchive.html 

Informed Consent Process

	A Brief Introduction to Informed Consent, available at   HYPERLINK
"http://poynter.indiana.edu/sas/res/ic.pdf" 
http://poynter.indiana.edu/sas/res/ic.pdf 

	An Informed Consent Bibliography, prepared by the Department of
Veterans Affairs, available at   HYPERLINK
"http://www.research.va.gov/resources/pubs/informed_consent/" 
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  
HYPERLINK
"http://www.georgetown.edu/research/nrcbl/nbac/capacity/volumeii.pdf" 
http://www.georgetown.edu/research/nrcbl/nbac/capacity/volumeii.pdf 

Language of Informed Consent

	Guidelines for writing informed consent documents prepared by the
Office of Human Subjects Research, National Institutes of Health,
available at   HYPERLINK "http://ohsr.od.nih.gov/info/sheet6.html" 
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   HYPERLINK
"http://www.cancer.gov/clinicaltrials/understanding/simplification-of-in
formed-consent-docs/page2" 
http://www.cancer.gov/clinicaltrials/understanding/simplification-of-inf
ormed-consent-docs/page2 

With regard to textbooks on some of these topics, the following books
are suggested:

Ethical Principles

	Principles of Biomedical Ethics (5th 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 (2nd 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 

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 future 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 Popendorf of the EPA SAP
particularly helpful in providing guidance on the AHETF task force
study.

The Board commended EPA’s response to its questions regarding use of
diazinon in the AHE37 protocol.  The Board understands that the Agency
will require AHETF to identify 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.

Overarching 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.

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.

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 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.

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 Satisfying
40 CFR 26.1303 for [redacted] [Repellent Code] 1000718-008, concentrate
of 1000718-009. Volumes 1 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 Satisfying
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 Satisfying 40 CFR
26.1303 for [redacted] [Repellent Code] 1000718-008, concentrate of
1000718-009. Volumes 1 and 2. Unpublished document prepared by toXcel,
LLC. February 1, 2007. 

Georgeian K and Dosik JS. 2007d. Repeated Insult Patch Study [redacted]
Supplemented with Additional Supporting Materials Satisfying 40 CFR
26.1303 for [redacted] [Repellent Code] 1004006-005. Volumes 1 and 2.
Unpublished document prepared by toXcel, LLC. February 1, 2007. 

 

APPENDIX A

Draft Framework for Developing Best Practices

for Recruiting, Screening, and Informing, and Consenting

Human Subjects of an  Obtaining Consent from Human Subjects for
Occupational Exposure Studies with Pesticides

March 15, 2007

Introduction

	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 the 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

This The remainder of this paper presents a conceptual framework for
considering and organizing best practices in occupational exposure
studies for pesticides under four broad headings: 

Equitable Subject Selection

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 §26.1111(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 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

Selection 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 regulatory 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 potential
harm to them makes it 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 potential harms, or
the directions to avoid them would not be correctly understood.

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 of the sponsor or the students of the investigators or
sponsors of the research.  It is very difficult to 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 use them as research 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 the widest possible a wide population
consistent with research design.

Because of the potential for privacy infringement, recruiting procedures
that involve one person providing information about another person or as
a potential subject without his/her 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 internet—should need to be reviewed by the IRB for
accuracy in presentation of information that the prospective subject
needs to determine his/her eligibility and interest.  The IRB review
should considers content, language, and design.

Fully informed choice to participate.    

The second over-arching concern is to ensure that subjects’ choices to
participate in research are fully 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.”  

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
it, to and ask questions about the study, 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 purposes of the informed consent process are is to
communicate to prospective subjects :adequate information, expressed
clearly in plain and understandable language, to make an informed
decision about participating in the proposed study.  This information is
outlined in the required elements of consent (40 CFR §26.1116)
including:

Adequate information, expressed clearly in plain and understandable
language, to make an informed decision about participating in the
proposed study.

The purpose, risks, and benefits of the research.

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:

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 all the investigators involved in the study by name,
qualifications, 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.   

Aa statement about compensation for injury, if any, and whetherif
medical treatment or other arrangements are available.

A statement that participation in the research will offer no direct
benefit to the subjects.

A discussion of statement about potential benefits to society of from
the knowledge that may result from this research.  This should
realistically identify both the nature and magnitude of expected
benefits and how they will be distributed—that is, who will receive
them.  This should not be exaggerated 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: payments for participation are
not should not be described as individual “benefits” fromof the
researchparticipating in the study.)

Contact information for study personnel and the responsible IRB, in case
subjects 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.

.

CompetenceCapacity 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 fully informed
consent that the consenting subjects be competenthave the capacity to
understand the information provided, and to make a free choice to
participate or not to participate.  If there is any question about the
decisional competence capacity of a prospective subject, that person
should not be enrolled in research.

Language of Informed Consent

The first regulatory requirement for the language of informed consent
documents—and for the entire informed 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 6th to 8th 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)

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 toan in an area and in a
manner that protects 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 when When third parties other than
the investigators and subjects play a role in the recruiting, informing,
and consent processes particular care is needed to ensure that the
processes are free from any element of coercion or undue pressure.  If,
for example, pesticide handlers are recruited through their employers,
care must be taken to ensure they have a legitimate free choice not to
participate, and that their employers do not influence their decisions,
intentionally or unintentionally.

Communicating Risks

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:

  The first aspect of risk is Iits qualitative nature.  Risks may be
physical risks of harm or discomfort; they may also be psychological,
social, economic, or legal.  For example, a prospective female subject
who learns she is pregnant as a result of a pregnancy test associated
with 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.

  The second aspect of risk that must be addressed in an adequately
informative consent document is Iits likelihood.  An informed choice to
participate in research depends on a clear understanding of the
distinction between likely and unlikely risks.  Each risk identified in
an informed consent document should also be characterized in terms of
its likelihood of occurrence.

  The third and final aspect of risk that must be discussed is the
Ssteps taken by the investigators to minimize riskit.  This should
include telling potential subjects how injuries or other adverse effects
resulting from participation in the research will be managed, what
treatment will be available, and who will pay for it.  

Communicating Benefits

Occupational exposure studies for pesticides do not offer any direct
benefit to participants.  This must be clearly stated in consent
materials.  

 explicit discussion 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 of from the information expected to result
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 beneficiaries of the research are likely to be
pesticide registrants, this, too, should be stated clearly.  Care should
be taken to not over-state potential 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
documents represent such an unacceptable transfer of responsibility.  As
with consent itself, subject understanding is an ongoing process, which
needs to be confirmed and enhanced if the project occurs over time.

Fully voluntary choice to participate

Recruitment must be conducted without any element of coercion or undue
influence to participate.  Principal potentialPotential sources of undue
influence are from dependent relationships and from 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 legitimate free and real option alternative to
participating?

Compensating for Managing Dependent Relationships

In many occupational exposure studies for pesticides, the
subjects—whether they are pesticide handlers or re-entrant
workers—are recruited for the research through their employers.  In
such cases, great care is needed to ensure this does not compromise the
voluntariness of the subjects’ choices to participate.  The employer
must have no compelling interest in the research, or in whether an
individual chooses to participate in it, and this must be clearly
communicated to potential subjects.  They Subjects must understand 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.  Some Also, some companies who
that sponsor or conduct exposure studies have recruited subjects from
among their own employees.  This practice is inconsistent 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 since because some members of
agricultural work crews may be in the U.S. illegally, and thus
particularly vulnerable.

Minimizing Peer Pressure

It may be essential to fully 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.  Since Because it is often obvious whether someone is
participating in research—as, for 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
true reason for non-participation.

Real Alternatives to Participation in Research

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 consent materials are
required to discuss alternative treatments may not be available to
potential subjects of research.  But it such an unexplained statement is
inappropriate for occupational exposure studies for pesticides. 
Potential subjects in occupational studies must be told in some 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 step
up and fly the plane?  What would he do for the rest of the day?  How
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 forCompensation of Subjects

To assist in subject recruitment, an incentive may be offered.  Any
incentive should be reasonable, 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 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 compensation
payments for their participation in research relates to their normal
compensation for doing their job.  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).

Page   PAGE  1  of   NUMPAGES  67 

1116.E

Impact on EPA/IRB is not relevant to the discussion on subject consent.

